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1.  In vivo imaging of C. elegans endocytosis 
Methods (San Diego, Calif.)  2014;68(3):518-528.
Over the past decade, the early C. elegans embryo has proven to be a useful animal model to study a variety of membrane trafficking events, at least in part due to its large size, optical transparency, and ease of manipulation. Importantly, the stereotypic nature of membrane remodeling that occurs during early embryogenesis has enabled quantitative measurement of endocytic flux. In the absence of exogenous stimulation, resumption of the cell cycle triggered by fertilization is coupled to a dramatic redistribution of plasma membrane content. Numerous proteins are rapidly internalized via clathrin-mediated endocytosis, and the fate of these cargoes can be followed precisely using live imaging in utero. Key to these studies is the maintenance of animal health and their immobilization, which can become technically challenging during extended imaging sessions. Here we highlight recent advances in live imaging techniques that have facilitated the interrogation of endocytic transport in live animals. We focus on the use of transgenic C. elegans strains that stably express fluorescently-tagged proteins, including components of the endosomal system and cargo molecules that traverse this network of membranes. Our findings demonstrate the utility of the C. elegans embryo in defining regulatory mechanisms that control the numerous steps of endocytic trafficking.
PMCID: PMC4112158  PMID: 24704355
2.  Long-term efficacy of subtotal splenectomy due to portal hypertension in cirrhotic patients 
BMC Surgery  2015;15:89.
Portal hypertension (PHT) requires invasive measures to prevent rupture and bleeding of esophagogastric varices; however, the long-term results of subtotal splenectomy plus fixation of the retrosternal omentum majus (SSFROM) have not been reported. Specifically, the advantages and disadvantages of surgery that preserves the spleen and the long-term hematologic effects have not been described.
Study design
Our studies relating to SSFROM commenced in February 1999. As of April 2014 we have performed 256 subtotal splenectomies The records of 65 patients with PHT who underwent SSFROM were reviewed retrospectively.
Four patients died within 4 years of surgery, with a 4-year survival rate of 94 %; the 11-year survival rate was 60 %. Eleven patients (17 %) had re-bleeding from esophagogastric varices. The white blood cell and platelet counts were higher 6 and 11 years post-operatively compared with pre-operative values (P < 0.01). Portal venous diameter, portal venous flow volume, splenic artery flow volume, as well as splenic length, thickness, and average cross-sectional areas were shown to be significantly constricted or decreased (P < 0.01). The proportion of serum CD3+ T cells, CD4+ T cells, and CD8+ T cells was increased (P < 0.01), while the serum levels of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor were significantly decreased (P < 0.01). There was no significant change in the serum levels of IgA, IgM, IgG, and Tuftsin (P > 0.05). DSA demonstrated that 15 cases formed collateral circulations between the portal vein and superior vena cava.
SSFROM provide long-term hemostasis for esophagogastric variceal bleeding in PHT and corrected hypersplenism. SSFROM is an effective treatment for patients with PHT in whom long-term survival is expected.
PMCID: PMC4511991  PMID: 26205377
Portal hypertension; Splenomegaly; Subtotal splenectomy; Shunt
3.  DNA Microarray Characterization of Pathogens Associated with Sexually Transmitted Diseases 
PLoS ONE  2015;10(7):e0133927.
This study established a multiplex PCR-based microarray to detect simultaneously a diverse panel of 17 sexually transmitted diseases (STDs)-associated pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma, Herpes simplex virus (HSV) types 1 and 2, and Human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 35, 39, 54 and 58. The target genes are 16S rRNA gene for N. gonorrhoeae, M. genitalium, M. hominism, and Ureaplasma, the major outer membrane protein gene (ompA) for C. trachomatis, the glycoprotein B gene (gB) for HSV; and the L1 gene for HPV. A total of 34 probes were selected for the microarray including 31 specific probes, one as positive control, one as negative control, and one as positional control probe for printing reference. The microarray is specific as the commensal and pathogenic microbes (and closely related organisms) in the genitourinary tract did not cross-react with the microarray probes. The microarray is 10 times more sensitive than that of the multiplex PCR. Among the 158 suspected HPV specimens examined, the microarray showed that 49 samples contained HPV, 21 samples contained Ureaplasma, 15 contained M. hominis, four contained C. trachomatis, and one contained N. gonorrhoeae. This work reports the development of the first high through-put detection system that identifies common pathogens associated with STDs from clinical samples, and paves the way for establishing a time-saving, accurate and high-throughput diagnostic tool for STDs.
PMCID: PMC4514671  PMID: 26208181
4.  Genetically Encoding an Electrophilic Amino Acid for Protein Stapling and Covalent Binding to Native Receptors 
ACS Chemical Biology  2014;9(9):1956-1961.
Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capable of reacting with histidine and lysine, thereby expanding the diversity of target proteins and the scope of the proximity-enabled protein cross-linking technology. In addition to efficient cross-linking of proteins inter- and intramolecularly, this Uaa permits direct stapling of a protein α-helix in a recombinant manner and covalent binding of native membrane receptors in live cells. The target diversity, recombinant stapling, and covalent targeting of endogenous proteins enabled by this versatile Uaa should prove valuable in developing novel research tools, biological diagnostics, and therapeutics by exploiting covalent protein linkages for specificity, irreversibility, and stability.
PMCID: PMC4168779  PMID: 25010185
5.  A statistical frame based TDMA protocol for human body communication 
Human body communication (HBC) using the human body as the transmission medium, which has been regarded as one of the most promising short-range communications in wireless body area networks (WBAN). Compared to the traditional wireless networks, two challenges are existed in HBC based WBAN. (1) Its sensor nodes should be energy saving since it is inconvenient to replace or recharge the battery on these sensor nodes; (2) the coordinator should be able to react dynamically and rapidly to the burst traffic triggered by sensing events. Those burst traffic conditions include vital physical signal (electrocardiogram, electroencephalogram etc.) monitoring, human motion detection (fall detection, activity monitoring, gesture recognition, motion sensing etc.) and so on. To cope with aforementioned challenges, a statistical frame based TDMA (S-TDMA) protocol with multi-constrained (energy, delay, transmission efficiency and emergency management) service is proposed in this paper.
The scenarios where burst traffic is often triggered rapidly with low power consumption and low delay is handled in our proposed S-TDMA. A beacon frame with the contained synchronous and poll information is designed to reduce the possibility of collisions of request frames. A statistical frame which broadcasts the unified scheduling information is adopted to avoid packet collisions, idle listening and overhearing. Dynamic time slot allocation mechanism is presented to manage the burst traffic and reduce the active period in each beacon period. An emergency mechanism is proposed for vital signals to be transmitted. The theory analysis is proceed and the result is evaluated in the hardware platform.
To verify its feasibility, S-TDMA was fully implemented on our independently-developed HBC platform where four sensor nodes and a coordinator are fastened on a human body. Experiment results show that S-TDMA costs 89.397 mJ every 20 s when the payload size is 122 bytes, 9.51% lower than Lightweight MAC (LMAC); the average data latency of S-TDMA is 6.3 ms, 7.02% lower than Preamble-based TDMA (PB-TDMA); the transmission efficiency of S-TDMA is 93.67%, 4.83% higher than IEEE 802.15.6 carrier sense multiple access/collision avoidance (CSMA/CA) protocol.
With respect to the challenges of HBC based WBANs, a novel S-TDMA protocol was proposed in this paper. Compared to the traditional protocols, the results demonstrate that S-TDMA successfully meets the delay and transmission efficiency requirements of HBC while keeping a low energy consumption. We also believe that our S-TDMA protocol will promote development of HBC in wearable applications.
PMCID: PMC4495947  PMID: 26155949
Human body communication; Wireless body area networks; Media access control; Time division multi access; Statistical frame
6.  HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα 
Molecular cell  2014;55(1):31-46.
MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.
PMCID: PMC4188514  PMID: 24882211
7.  Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma 
Neuro-Oncology  2014;16(7):960-970.
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target.
Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples.
Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG.
These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients.
PMCID: PMC4057138  PMID: 24470554
brain tumor; epiregulin; ERK/MAPK; GBM
8.  p62 Provides Dual Cytoprotection Against Oxidative Stress in the Retinal Pigment Epithelium 
Biochimica et biophysica acta  2014;1843(7):1248-1258.
As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.
PMCID: PMC4019388  PMID: 24667411
Autophagy; aging; Nrf2; Oxidative stress; p62
9.  The effects of spinal cord injury on bone healing in patients with femoral fractures 
Orthopedic literature states that fractures of long bones, when associated with traumatic brain injuries, frequently heal with excessive callus and faster than normal. Few studies, however, have reported these phenomena being induced by spinal cord injury (SCI). Our objective is to compare the extent of callus and the rate of healing of long-bone fractures in patients with or without SCI. Subgroup comparisons were performed among the patients with SCI in terms of different levels of SCI.
The final mean volume of callus formation and the rate of union of nailed fractures of the femur were determined radiologically in 22 femoral fracture patients with SCI (seven cervical, six thoracic, and nine lumbar spine injury) and compared with those in a group of 22 patients with similar types of fractures but without SCI.
The final mean callus volume in the fracture/SCI group was significantly higher than the fracture-only group (P < 0.001). The fractures in the fracture/SCI group united in an average time of 22.86 weeks compared with 25.04 weeks in the fracture-only group (P < 0.05). We observed 84.6% (11 of 13) of patients with cervical and thoracic SCI patients with accelerated fracture healing (cervical 6 of 7, thoracic 5 of 6), but only 44.4% (4 of 9) of patients with lumbar SCI appeared to show this phenomenon (P < 0.05).
These results confirm that SCI may be associated with accelerated fracture healing and enhanced callus formation. Furthermore, our study revealed a trend toward enhanced osteogenesis in cervical or thoracic SCI compared with lumbar SCI.
PMCID: PMC4116725  PMID: 24621032
Spinal cord injury; Femoral fracture; Bone healing; Callus
10.  Ionic mechanisms underlying tonic and phasic firing behaviors in retinal ganglion cells 
Channels  2014;8(4):298-307.
In the retina, the firing behaviors that ganglion cells exhibit when exposed to light stimuli are very important due to the significant roles they play in encoding the visual information. However, the detailed mechanisms, especially the intrinsic properties that generate and modulate these firing behaviors is not completely clear yet. In this study, 2 typical firing behaviors—i.e., tonic and phasic activities, which are widely observed in retinal ganglion cells (RGCs)—are investigated. A modified computational model was developed to explore the possible ionic mechanisms that underlie the generation of these 2 firing patterns. Computational results indicate that the generation of tonic and phasic activities may be attributed to the collective actions of 2 kinds of adaptation currents, i.e., an inactivating sodium current and a delayed-rectifier potassium current. The concentration of magnesium ions has crucial but differential effects in the modulation of tonic and phasic firings, when the model neuron is driven by N-methyl-D-aspartate (NMDA) -type synaptic input instead of constant current injections. The proposed model has robust features that account for the ionic mechanisms underlying the tonic and phasic firing behaviors, and it may also be used as a good candidate for modeling some other firing patterns in RGCs.
PMCID: PMC4203731  PMID: 24769919
computational model; tonic activity; phasic activity; retinal ganglion cell; adaptation
11.  Evaluation of hGM-CSF/hTNFα surface-modified prostate cancer therapeutic vaccine in the huPBL-SCID chimeric mouse model 
To validate its efficacy in the context of the human immune system, a novel therapeutic vaccine of hGM-CSF/hTNFα surface-modified PC-3 cells against human prostate cancer was evaluated in the human peripheral blood lymphocytes-severe combined immunodeficiency (huPBL-SCID) chimeric mouse model. The hGM-CSF or/and hTNFα modified vaccines inhibited prostate cancer growth effectively so as to prolong the mouse survival significantly. The splenocytes from the hGM-CSF/hTNFα vaccine-inoculated mice showed the strongest tumor-specific cytotoxicity against PC-3 cells and the highest production of IFNɤ. These features indicated that type 1 protective immune response was induced efficiently against human prostate cancer and further enhanced through synergetic adjuvant effects of hGM-CSF and hTNFα.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0175-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4490636  PMID: 26108270
Cancer immunotherapy; Adjuvant; Synergetic effect; Human immune system; PC-3 prostate cancer cell
12.  Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T-Cell Non-Hodgkin’s Lymphoma Patient 
Genome Announcements  2015;3(3):e00673-15.
An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin’s lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and β-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified.
PMCID: PMC4481284  PMID: 26112786
13.  Changes in Extremely Hot Summers over the Global Land Area under Various Warming Targets 
PLoS ONE  2015;10(6):e0130660.
Summer temperature extremes over the global land area were investigated by comparing 26 models of the fifth phase of the Coupled Model Intercomparison Project (CMIP5) with observations from the Goddard Institute for Space Studies (GISS) and the Climate Research Unit (CRU). Monthly data of the observations and models were averaged for each season, and statistics were calculated for individual models before averaging them to obtain ensemble means. The summers with temperature anomalies (relative to 1951–1980) exceeding 3σ (σ is based on the local internal variability) are defined as “extremely hot”. The models well reproduced the statistical characteristics evolution, and partly captured the spatial distributions of historical summer temperature extremes. If the global mean temperature increases 2°C relative to the pre-industrial level, “extremely hot” summers are projected to occur over nearly 40% of the land area (multi-model ensemble mean projection). Summers that exceed 5σ warming are projected to occur over approximately 10% of the global land area, which were rarely observed during the reference period. Scenarios reaching warming levels of 3°C to 5°C were also analyzed. After exceeding the 5°C warming target, “extremely hot” summers are projected to occur throughout the entire global land area, and summers that exceed 5σ warming would become common over 70% of the land area. In addition, the areas affected by “extremely hot” summers are expected to rapidly expand by more than 25%/°C as the global mean temperature increases by up to 3°C before slowing to less than 16%/°C as the temperature continues to increase by more than 3°C. The area that experiences summers with warming of 5σ or more above the warming target of 2°C is likely to maintain rapid expansion of greater than 17%/°C. To reduce the impacts and damage from severely hot summers, the global mean temperature increase should remain low.
PMCID: PMC4474600  PMID: 26090931
14.  Heterosexual risk of HIV-1 infection per sexual act: a systematic review and meta-analysis of observational studies 
The Lancet. Infectious diseases  2009;9(2):118-129.
We conducted a systematic review and meta-analysis of observational studies of the risk of HIV-1 transmission per heterosexual contact. The search to September 2008 identified 43 publications based on 25 different study populations. Pooled female-to-male (0·0004,95%CI=0·0001-0·0014) and male-to-female (0·0008,CI=0·0006-0·0011) transmission estimates in developed countries reflected a low risk of infection in the absence of antiretrovirals. Developing country female-to-male (0·0038,CI=0·0013-0·0110) and male-to-female (0·0030,CI=0·0014-0·0063) estimates in absence of commercial sex(CS) work were higher. In meta-regression analysis, the infectivity across estimates in absence of CS work was significantly associated with gender, setting, the interaction between setting and gender and HIV prevalence. The pooled receptive anal intercourse estimate was much higher (0·017,CI=0·003-0·089). Estimates for the early and late phase of HIV infection were 9·2(CI=4·5-18·8) and 7·3(CI=4·5-11·9)-fold larger than for the asymptomatic phase, respectively. After adjusting for CS exposure, presence or history of genital ulcers in either couple member increased per-act infectivity 5·3(CI=1·4-19·5)-fold compared to no sexually transmitted infection. Study estimates among non-circumcised men were at least twice those among circumcised men. Developing country estimates were more heterogeneous than developed country estimates, which indicates poorer study quality, greater heterogeneity in risk factors or under-reporting of high-risk behaviour. Efforts are needed to better understand these differences and quantify infectivity in developing countries.
PMCID: PMC4467783  PMID: 19179227
15.  Direct and Indirect Effects of Fetal Irradiation on Cortical Gray and White Matter Volume in the Macaque 
Biological psychiatry  2005;57(1):83-90.
Schizophrenia is associated with reductions in thalamic neuronal number and cortical gray matter volume. Exposure of nonhuman primates to x-irradiation in early gestation has previously been shown to decrease thalamic volume and neuronal number. Here we examine whether early gestational irradiation also results in cortical volume reduction.
High-resolution, T1-weighted magnetic resonance scans were collected in adult monkeys 1) exposed to irradiation during the early gestational period (E33-E42) corresponding to thalamic neurogenesis, 2) irradiated in midgestation (E70-81) during neocortical neurogenesis, and 3) not exposed to irradiation. Cortical gray matter and white matter volumes were derived via manual segmentation; frontal and nonfrontal volumes were distinguished via sulcal landmarks.
Monkeys irradiated in early gestation exhibited a trend reduction in nonfrontal gray matter volume (17%) and significant reductions in white matter volume in frontal (26%) and nonfrontal (36%) lobes. Monkeys irradiated in midgestation had smaller gray (frontal: 28%; nonfrontal: 22%) and white matter (frontal: 29%; nonfrontal: 38%) volumes.
The cortical deficits observed in midgestationally irradiated monkeys are consistent with a reduction in cortical neuronal number. Cortical volume reductions following early gestational irradiation may be secondary to reduced thalamic neuronal number and therefore model the thalamocortical pathology of schizophrenia.
PMCID: PMC4465560  PMID: 15607304
Frontal; magnetic resonance; neurogenesis; schizophrenia; thalamus
16.  Structural pathology underlying neuroendocrine dysfunction in schizophrenia 
Behavioural brain research  2010;218(1):106-113.
Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.
PMCID: PMC4465073  PMID: 21093493
hyponatremia; polydipsia; morphometry; 3rd ventricle; amygdala; stress diathesis; shape analysis; LDDMM
17.  Combining Anatomical Manifold Information via Diffeomorphic Metric Mappings for Studying Cortical Thinning of the Cingulate Gyrus in Schizophrenia 
NeuroImage  2007;37(3):821-833.
Spatial normalization is a crucial step in assessing patterns of neuroanatomical structure and function associated with health and disease. Errors that occur during spatial normalization can influence hypothesis testing due to the dimensionalities of mapping algorithms and anatomical manifolds (landmarks, curves, surfaces, volumes) used to drive the mapping algorithms. The primary aim of this paper is to improve statistical inference using multiple anatomical manifolds and Large Deformation Diffeomorphic Metric Mapping (LDDMM) algorithms. We propose that combining information generated by the various manifolds and algorithms improves the reliability of hypothesis testing. We used this unified approach to assess variation in the thickness of the cingulate gyrus in subjects with schizophrenia and healthy comparison subjects. Three different LDDMM algorithms for mapping landmarks, curves and triangulated meshes were used to transform thickness maps of the cingulate surfaces into an atlas coordinate system. We then tested for group differences by combining the information from the three types of anatomical manifolds and LDDMM mapping algorithms. The unified approach provided reliable statistical results and eliminated ambiguous results due to surface mismatches. Subjects with schizophrenia had non-uniform cortical thinning over the left and right cingulate gyri, especially in the anterior portion, as compared to healthy comparison subjects.
PMCID: PMC4465219  PMID: 17613251
Large Deformation Diffeomorphic Metric Mapping (LDDMM); the Laplace-Beltrami Operator; Gaussian Random Field; cingulate gyrus; cortical thickness; schizophrenia
18.  FoxO1-negative cells are cancer stem-like cells in pancreatic ductal adenocarcinoma 
Scientific Reports  2015;5:10081.
Flow cytometry assays using aldehyde dehydrogenase (ALDH) activity or CD133 positivity to isolate cancer stem cells (CSCs) are widely applied but have limitations. Thus, characterization of CSC makers for a specific cancer is potentially important. We have previously shown that miR-21 regulates cancer cell growth via FoxO1 in pancreatic ductal adenocarcinoma (PDAC). Here, we areported evidence of FoxO1-negative PDAC cells as CSCs in PDAC. Both ALDH-high and CD133-high cell fractions isolated from PDAC of the patients expressed high levels of miR-21 and null FoxO1. Cultured PDAC cells were virally transduced with GFP under FoxO1 promoter. GFP (FoxO1)-null PDAC cells expressed high levels of miR-21, and grew more quickly than FoxO1-positive PDAC cells. Moreover, the fold increases in growth of FoxO1-negative vs FoxO1-positive cells were greater than CD133-high vs CD133-low cells, or ALDH-high vs ALDH-low cells. Further, FoxO1-negative cells formed tumor spheres in culture and developed tumors after serial adoptive transplantation into NOD/SCID mice, while the FoxO1-positive cells did not. Finally, selective elimination of FoxO1-negative cells completely inhibited the growth of PDAC cells. Together, these data suggest that FoxO1-negative cells as CSCs in PDAC, and targeting FoxO1-negative cells in PDAC may provide better therapeutic outcome.
PMCID: PMC4464177  PMID: 26068418
19.  Identification of a critical determinant that enables efficient fatty acid synthesis in oleaginous fungi 
Scientific Reports  2015;5:11247.
Microorganisms are valuable resources for lipid production. What makes one microbe but not the other able to efficiently synthesize and accumulate lipids is poorly understood. In the present study, global gene expression prior to and after the onset of lipogenesis was determined by transcriptomics using the oleaginous fungus Mortierella alpina as a model system. A core of 23 lipogenesis associated genes was identified and their expression patterns shared a high similarity among oleaginous microbes Chlamydomonas reinhardtii, Mucor circinelloides and Rhizopus oryzae but was dissimilar to the non-oleaginous Aspergillus nidulans. Unexpectedly, Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD) in the pentose phosphate pathway (PPP) were found to be the NADPH producers responding to lipogenesis in the oleaginous microbes. Their role in lipogenesis was confirmed by a knockdown experiment. Our results demonstrate, for the first time, that the PPP plays a significant role during fungal lipogenesis. Up-regulation of NADPH production by the PPP, especially G6PD, may be one of the critical determinants that enables efficiently fatty acid synthesis in oleaginous microbes.
PMCID: PMC4462047  PMID: 26059272
20.  Dynamic Magnetic Responsive Wall Array with Droplet Shedding-off Properties 
Scientific Reports  2015;5:11209.
Directional control of droplets on a surface is an important issue for tasks of long-range liquid-transport, self-cleaning and water repellency. However, it is still challenging to control the structure motions in orientations so as to control the shedding-off of droplets. Herein, we report a novel dynamic magnetic responsive wall (DMRW) array on PDMS (polydimethylsiloxane) -based surface. The walls can easily tilt through the effect of the external magnet because of the magnetic material in the DMRW. The droplets can be shed off directionally on the surface. Particularly, with the shape recovery and flexible properties, it achieves simultaneous control of the tilt angles (0-60°) of DMRW for shedding-off of droplets with different volumes (1-15 μL) under magnetic action on DMRW. The mechanism of droplet shedding-off on DMRW is elucidated by theory of interfaces. It offers an insight into design of dynamic interface for water repellency. This strategy realizes the preparation of multifunctional, tunable and directional drive functions.
PMCID: PMC4462108  PMID: 26061176
21.  Morphometry of the hippocampus and amygdala in bipolar disorder and schizophrenia 
Bipolar disorders  2010;12(3):341-343.
PMCID: PMC4461218  PMID: 20565442
amygdala; bipolar disorder; hippocampus; schizophrenia
22.  Using the Fuzzy DEMATEL to Determine Environmental Performance: A Case of Printed Circuit Board Industry in Taiwan 
PLoS ONE  2015;10(6):e0129153.
The method by which high-technology product manufacturers balance profits and environmental performance is of crucial concern for governments and enterprises. To examine the environmental performance of manufacturers, the present study applied Fuzzy-DEMATEL model to examine environmental performance of the PCB industry in Taiwan. Fuzzy theory was employed to examine the environmental performance criteria of manufacturers and analyse fuzzy linguistics. The fuzzy-DEMATEL model was then employed to assess the direction and level of interaction between environmental performance criteria. The core environmental performance criteria which were critical for enhancing environmental performance of the PCB industry in Taiwan were identified and presented. The present study revealed that green design (a1), green material procurement (a2), and energy consumption (b3) constitute crucial reason criteria, the core criteria influencing other criteria, and the driving factors for resolving problems.
PMCID: PMC4459958  PMID: 26052710
23.  Clinical impact of circulating miR-26a, miR-191, and miR-208b in plasma of patients with acute myocardial infarction 
Aberrant expression of several types of miRNAs has been reported in acute myocardial infarction (AMI). The objective of our study was to compare miRNA expression in AMI patients and normal healthy people and determine whether miR-26a, miR-191, and miR-208b could be measured in plasma as indicators for AMI.
Detection of AMI patients and normal persons by using miRNA microarray chip analysis and miR-26a, miR-191, and miR-208b was screened out. Eighty-seven AMI patients and eighty-seven homogeneous healthy individuals were recruited. Total mRNA including miRNA was isolated and miR-26a, miR-191, and miR-208b expression were determined by qRT-PCR. Receiver operating characteristic curve analysis was performed to evaluate the instructive power of miR-26a, miR-191, and miR-208b for AMI. Dual-luciferase reporter assays indicated p21 is a direct target of miR-208b.
miR-26a and miR-191 were low expressed in AMI compared with normal healthy people, but miR-208b was expressed at a high level in AMI. miR-26a showed an area under the curve (AUC) of 0.745, with a sensitivity of 73.6 % and a specificity of 72.4 %.The AUC for miR-191 was 0.669, with a sensitivity of 62.1 % and a specificity of 69.0 %.The AUC for miR-208b was 0.674, with a sensitivity of 59.8 % and a specificity of 73.6 %.
miR-208b was significantly increased in the AMI compared with healthy people, while miR-26a and miR-191 were decreased. miR-26a, miR-191, and miR-208b were potential indices of AMI, and miR-208b was more effective in patients with non-ST-elevation myocardial infarction.
PMCID: PMC4459687  PMID: 26044724
Acute myocardial infarction; miR-26a; miR-191; miR-208b
24.  Acupuncture for psoriasis: protocol for a systematic review 
BMJ Open  2015;5(6):e007526.
The described systematic review aims to assess the effectiveness and safety of acupuncture for psoriasis.
Methods and analysis
We will electronically search for randomised controlled trials in the following databases from inception to 31 March 2015: OVID MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese Medical Current Content, Chinese Scientific Journal Database (VIP database), Wan-Fang Database and China National Knowledge Infrastructure. We will also try to obtain literature by manually searching reference lists, conference proceedings and registers of clinical trials (eg, the Meta Register of Controlled Trials and the Chinese Clinical Trial Registry). Changes in disease status as evaluated by clinical signs or any available tool will be measured as the primary outcome. Global changes as well as changes in participant status (as evaluated by quality of life), safety (as measured by the prevalence and severity of adverse effects or adverse events) and costs (if available) will be measured as secondary outcomes. Two researchers will independently undertake selection of studies, data extraction and assessment of the quality of included studies. Data synthesis and subgroup analyses will be performed using special software (Review Manager). Data will be combined with a random effect model. Results will be presented as risk ratios for dichotomous data and the standardised mean difference for continuous data.
Ethics and dissemination
Ethical approval will not be required as this is a protocol for a systematic review. The systematic review will evaluate the current evidence regarding acupuncture therapy for psoriasis. Findings will be disseminated through peer-reviewed publications and conference presentations.
Trial registration number
PROSPERO CRD 42014013695.
PMCID: PMC4458605  PMID: 26048208
25.  Detection of Serum Protein Biomarkers for the Diagnosis and Staging of Hepatoblastoma 
The present study aimed to identify serum biomarkers for the detection of hepatoblastoma (HB). Serum samples were collected from 71 HB patients (stage I, n = 19; stage II, n = 19, stage III, n = 19; and stage IV, n = 14) and 23 age- and sex-matched healthy children. Differential expression of serum protein markers were screened using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS), and the target proteins were isolated and purified using HPLC and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), SEQUEST, and bioinformatics analysis. Differential protein expression was confirmed by enzyme-linked immunosorbent analysis (ELISA). SELDI-TOF-MS screening identified a differentially expressed protein with an m/z of 9348 Da, which was subsequently identified as Apo A–I; its expression was significantly lower in the HB group as compared to the normal control group (1546.67 ± 757.81 vs. 3359.21 ± 999.36, respectively; p < 0.01). Although the expression level decreased with increasing disease stage, pair-wise comparison revealed significant differences in Apo A–I expression between the normal group and the HB subgroups (p < 0.01). ELISA verified the reduced expression of Apo A–I in the HB group. Taken together, these results suggest that Apo A–I may represent a serum protein biomarker of HB. Further studies will assess the value of using Apo A–I expression for HB diagnosis and staging.
PMCID: PMC4490467  PMID: 26053398
hepatoblastom; SELDI-TOF-MS; MALDI-TOF-MS; 2D-LC-LTQ-MS; apolipoprotein A–I; protein biomarker

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