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1.  Long-Duration Muscle Dedifferentiation during Limb Regeneration in Axolotls 
PLoS ONE  2015;10(2):e0116068.
Although still debated, limb regeneration in salamanders is thought to depend on the dedifferentiation of remnant tissue occurring early after amputation and generating the progenitor cells that initiate regeneration. This dedifferentiation has been demonstrated previously by showing the fragmentation of muscle fibers into mononucleated cells and by revealing the contribution of mature muscle fibers to the regenerates by using lineage-tracing studies. Here, we provide additional evidence of dedifferentiation by showing that Pax7 (paired-box protein-7) transcripts are expressed at the ends of remnant muscle fibers in axolotls by using in situ hybridization and by demonstrating the presence of Pax7+ muscle-fiber nuclei in the early bud and mid-bud stages by means of immunohistochemical staining. During the course of regeneration, the remnant muscles did not progress; instead, muscle progenitors migrated out from the remnants and proliferated and differentiated in the new tissues at an early stage of differentiation. The regenerating muscles and remnant muscles were largely disconnected, and this left a gap between them until extremely late in the late stage of differentiation, at which point the new and old muscles connected together. Notably, Pax7 transcripts were detected in the regions of muscles that faced these gaps; thus, Pax7 expression might indicate dedifferentiation in the remnant-muscle ends and partial differentiation in the regenerating muscles. The roles of this long-duration dedifferentiation in the remnants remain unknown. However, the results presented here could support the hypothesis that long-duration muscle dedifferentiation facilitates the connection and fusion between the new and old muscles that are both in an immature state; this is because immature Pax7+ myoblasts readily fuse during developmental myogenesis.
doi:10.1371/journal.pone.0116068
PMCID: PMC4324932  PMID: 25671422
2.  SHP-2 Mediates Target-Regulated Axonal Termination and NGF-Dependent Neurite Growth in Sympathetic Neurons 
Developmental biology  2002;252(2):170-187.
The tyrosine phosphatase SHP-2 has been implicated in a variety of signaling pathways, including those mediated by neurotrophins in neurons. To examine the role of SHP-2 in the development of sympathetic neurons, we inhibited the function of SHP-2 in transgenic mice by overexpressing a catalytically inactive SHP-2 mutant under the control of the human dopamine β-hydroxylase promoter. Expression of mutant SHP-2 did not influence the survival, axon initiation, or pathfinding abilities of the sympathetic neurons. However, mutant SHP-2 expression resulted in an overproduction of sympathetic fibers in sympathetic target organs. This was due to interference with SHP-2 function, as overexpression of wild type SHP-2 had no such effect. In vitro, NGF-dependent neurite growth was inhibited in neurons expressing mutant SHP-2 but not in those expressing wild type SHP-2. Mutant (but not wt) SHP-2 expression also inhibited NGF-stimulated ERK activation. The NGF-dependent survival pathway was less affected than the neurite growth pathway. Our results suggest that NGF-regulated axon growth signals, and to a lesser degree survival signals, are mediated through a SHP-2-dependent pathway in sympathetic neurons. The increased sympathetic innervation in target tissues of neurons expressing mutant SHP-2 may result from interference with normal “stop” signals dependent on signaling by gradients of NGF.
PMCID: PMC4303248  PMID: 12482708
tyrosine phosphatases; neurotrophins; ERKs; transgenic mouse
3.  Coupling between endocytosis and sphingosine kinase I recruitment 
Nature cell biology  2014;16(7):652-662.
Genetic studies have suggested a functional link between cholesterol/sphingolipid metabolism and endocytic membrane traffic. Here we show that perturbing the cholesterol/sphingomyelin balance in the plasma membrane results in the massive formation of clusters of narrow endocytic tubular invaginations positive for N-BAR proteins. These tubules are intensely positive for sphingosine kinase 1 (SPHK1). SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals, cellular compartments specialized for exo-endocytosis. Membrane recruitment of SPHK1 involves a direct, curvature-sensitive interaction with the lipid bilayer mediated by a hydrophobic patch on the enzyme’s surface. The knockdown of SPHKs results in endocytic recycling defects, and a mutation that disrupts the hydrophobic patch of C. elegans SPHK fails to rescue the neurotransmission defects in loss-of-function mutants of this enzyme. Our studies support a role of sphingosine phosphorylation in endocytic membrane trafficking beyond the established function of sphingosine-1-phosphate in intercellular signaling.
doi:10.1038/ncb2987
PMCID: PMC4230894  PMID: 24929359
4.  Efficacy of Continuous Positive Airway Pressure on Testosterone in Men with Obstructive Sleep Apnea: A Meta-Analysis 
PLoS ONE  2014;9(12):e115033.
Objective
To evaluate the efficacy of continuous positive airway pressure (CPAP) on serum testosterone in men with obstructive sleep apnea (OSA).
Methods
Two reviewers independently searched PubMed, Cochrane library, Embase and Web of Science before June 2014. Information on characteristics of subjects, study design, pre- and post-CPAP treatment of serum total testosterone, free testosterone and sexual hormone blinding protein (SHBG) was extracted for analysis.
Results
A total of 7 studies with 9 cohorts that included 232 men were pooled into meta-analysis. There was no change of total testosterone levels before and after CPAP treatment in OSA men (standardized mean difference (SMD) = −0.14, 95%CI: −0.63 to 0.34, z = 0.59, p = 0.558), even subdivided by CPAP therapeutic duration (>3 months). Meanwhile, no significant differences in free testosterone and SHBG were detected after CPAP treatment (SMD =  0.16, 95%CI: −0.09 to 0.40, z = 1.25, p = 0.211 and SMD = −0.58, 95%CI: −1.30 to 0.14, z = 1.59, p = 0.112, respectively).
Conclusion
CPAP has no influence on testosterone levels in men with OSA, further large-scale, well-design interventional investigation is needed.
doi:10.1371/journal.pone.0115033
PMCID: PMC4263732  PMID: 25503098
5.  Biomechanical comparison of laminectomy, hemilaminectomy and a new minimally invasive approach in the surgical treatment of multilevel cervical intradural tumour: a finite element analysis 
European Spine Journal  2013;22(12):2719-2730.
Purpose
The objective of this study was to investigate the impact of the less invasive procedures of hemilaminectomy and unilateral multilevel interlaminar fenestration (UMIF) on the cervical spinal biomechanics.
Methods
A validated nonlinear finite element model of the intact cervical spine (C2–C7) was modified to study the biomechanical changes as a result of surgical alteration for treatment of intradural tumours at C3–6 using multilevel laminectomy (ML), multilevel hemilaminectomy (MHL) and UMIF with or without unilateral graded facetectomy.
Results
Under the load-controlled method, the greatest biomechanical changes occurred at the surgical segments. The largest increases occurred in flexion motions following ML approach with 70, 62 and 60 % increase at C3–4, C4–5 and C5–6, respectively. The increases were significantly reduced to no more than 14 % under MHL and UMIF. When combined with graded facetectomy, the changes in flexion under ML approach have a significantly further increase, up to 110 % at C3–4. The further increase was not significantly following MHL and UMIF, with no more than 31 % increase at C3–4, C4–5 and C5–6. The motion following UMIF was only slightly smaller in axial rotation than MHL. The maximum stresses in the annulus occurred during flexion in ML model, with 39, 34 and 38 % more stress than the intact at C3–4, C4–5 and C5–6, respectively. The increases of stress were significantly reduced to 5–7 % under MHL and UMIF.
Conclusions
The less invasive approaches of UMIF and MHL greatly preserved the flexion motion (more than 48 %) of the cervical spine compared with laminectomy, and the preserved motion mean the low-risk of postoperative spinal instability. UMIF and MHL also reduced the increased stress of annulus caused by ML, and the lesser stress will lower the risk of postoperative disc degeneration. The posterior bone elements play a slight role in spinal stability after removal of the attached ligaments.
doi:10.1007/s00586-013-2992-1
PMCID: PMC3843793  PMID: 24013720
Finite element; Cervical spine; Minimally invasive; Unilateral multilevel interlaminar fenestration; Laminectomy
6.  Size- and time-dependent alteration in metabolic activities of human hepatic cytochrome P450 isozymes by gold nanoparticles via microsomal coincubations 
Nanoscale Research Letters  2014;9(1):642.
Nano-sized particles are known to interfere with drug-metabolizing cytochrome P450 (CYP) enzymes, which can be anticipated to be a potential source of unintended adverse reactions, but the mechanisms underlying the inhibition are still not well understood. Herein we report a systematic investigation of the impacts of gold nanoparticles (AuNPs) on five major CYP isozymes under in vitro incubations of human liver microsomes (HLMs) with tannic acid (TA)-stabilized AuNPs in the size range of 5 to 100 nm. It is found that smaller AuNPs show more pronounced inhibitory effects on CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in a dose-dependent manner, while 1A2 is the least susceptible to the AuNP inhibition. The size- and dose-dependent CYP-specific inhibition and the nonspecific drug-nanogold binding in the coincubation media can be significantly reduced by increasing the concentration ratio of microsomal proteins to AuNPs, probably via a noncompetitive mode. Remarkably, AuNPs are also found to exhibit a slow time-dependent inactivation of 2D6 and 3A4 in a β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate (NADPH)-independent manner. During microsomal incubations, UV–vis spectroscopy, dynamic light scattering, and zeta-potential measurements were used to monitor the changes in particle properties under the miscellaneous AuNP/HLM/CYP dispersion system. An improved stability of AuNPs by mixing HLM with the gold nanocolloid reveals that the stabilization via AuNP-HLM interactions may occur on a faster time scale than the salt-induced nanoaggregation by incubation in phosphate buffer. The results suggest that the AuNP induced CYP inhibition can be partially attributed to its adhesion onto the enzymes to alter their structural conformations or onto the HLM membrane therefore impairing the integral membrane proteins. Additionally, AuNPs likely block the substrate pocket on the CYP surface, depending on both the particle characteristics and the structural diversity of the isozymes. These findings may represent additional mechanisms for the differential inhibitory effects arising from the coincubated AuNPs on the metabolic activities of the hepatic CYP isozymes.
doi:10.1186/1556-276X-9-642
PMCID: PMC4266508  PMID: 25520592
Gold nanoparticle; Cytochrome P450; Inhibition; Microsome; Incubation; Nanoprecipitation
7.  Serum Dickkopf-1 (DKK1) is significantly lower in patients with lung cancer but is rapidly normalized after treatment 
DKK1 is a secreted glycoprotein that inhibits Wnt/β-catenin signaling but may up-regulate the nonconanical Wnt signaling. Consistent with its inhibitory function in Wnt/β-catenin signaling, aberrant DKK1 expression has been observed in many types of human cancers, while contradicting findings have been reported in other studies. There are also several studies on serum DKK1 levels in various cancers with conflicting findings. In the present study, serum DKK1 was determined in 217 non- small cell lung cancer (NSCLC) patients, 35 small cell lung cancer (SCLC) patients and 286 matched healthy controls using a commercially available ELISA assay kit. Compared to healthy controls, serum DKK1 level was significantly lower in NSCLC (p < 10-28) and SCLC (p <10-4) patients. Interestingly, serum DKK1 level was higher in NSCLC patients in stage IV (p < 0.0005), with lymph node involvement (p < 0.0002) or with metastasis (p < 0.0001), suggesting that DKK1 may promote metastasis. After surgery and/or chemotherapy, serum DKK1 level is rapidly increased and reached levels observed in healthy controls in most patients. The degree of post therapeutic DKK1 increase varied in different treatment regimens. Our results thus provide strong evidence for the reduced levels of serum DKK1 in both types of lung cancer. However, in the context of all published studies, DKK1 appears to have a dichotomous role in cancer and its effect in a given cancer type or even a given cancer patient is likely to depend on the molecular context of the patient.
PMCID: PMC4297352  PMID: 25628795
DKK1; biomarker; lung cancer; wnt signaling
8.  Damage Identification of Piles Based on Vibration Characteristics 
The Scientific World Journal  2014;2014:150516.
A method of damage identification of piles was established by using vibration characteristics. The approach focused on the application of the element strain energy and sensitive modals. A damage identification equation of piles was deduced using the structural vibration equation. The equation contained three major factors: change rate of element modal strain energy, damage factor of pile, and sensitivity factor of modal damage. The sensitive modals of damage identification were selected by using sensitivity factor of modal damage firstly. Subsequently, the indexes for early-warning of pile damage were established by applying the change rate of strain energy. Then the technology of computational analysis of wavelet transform was used to damage identification for pile. The identification of small damage of pile was completely achieved, including the location of damage and the extent of damage. In the process of identifying the extent of damage of pile, the equation of damage identification was used in many times. Finally, a stadium project was used as an example to demonstrate the effectiveness of the proposed method of damage identification for piles. The correctness and practicability of the proposed method were verified by comparing the results of damage identification with that of low strain test. The research provided a new way for damage identification of piles.
doi:10.1155/2014/150516
PMCID: PMC4251653  PMID: 25506062
9.  Diallyl Disulfide Suppresses SRC/Ras/ERK Signaling-Mediated Proliferation and Metastasis in Human Breast Cancer by Up-Regulating miR-34a 
PLoS ONE  2014;9(11):e112720.
Diallyl disulfide (DADS) is one of the major volatile components of garlic oil. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human breast cancer have not been elucidated, particularly in vivo. In this study, we demonstrated that the expression of miR-34a was up-regulated in DADS-treated MDA-MB-231 cells. miR-34a not only inhibited breast cancer growth but also enhanced the antitumor effect of DADS, both in vitro and in vivo. Furthermore, Src was identified as a target of miR-34a, with miR-34a inhibiting SRC expression and consequently triggering the suppression of the SRC/Ras/ERK pathway. These results suggest that DADS could be a promising anticancer agent for breast cancer. miR-34a may also demonstrate a potential gene therapy agent that could enhance the antitumor effects of DADS.
doi:10.1371/journal.pone.0112720
PMCID: PMC4232521  PMID: 25396727
10.  A case of multiple macronodular hepatic tuberculosis difficult to differentiate from hepatocellular carcinoma with intrahepatic metastasis: CT-guided fine needle aspiration biopsy confirmed the diagnosis 
Multiple macronodular hepatic tuberculosis is difficult to be differentiated from hepatocellular carcinoma with intrahepatic metastasis in clinical practice, especially when hepatitis B with or without liver cirrhosis coexists with it. Herein, we report a 30-year-old man with a 10-year history of hepatitis B and a family medical history of hepatocellular carcinoma related with hepatitis B that was finally diagnosed as multiple macronodular hepatic tuberculosis. Abdominal B-mode ultrasonography (US) and plain computed tomography (CT) revealed multiple unequal-sized nodules in the liver. CT-guided fine needle aspiration biopsy (FNAB) of the liver demonstrated a caseating granuloma with lymphocytes, multinucleate giant cells and epithelioid cells compatible with the diagnosis of tuberculosis and no hepatoma cells were detected. Thus, the diagnosis of hepatic tuberculosis was confirmed and hepatocellular carcinoma with intrahepatic metastasis was excluded.
PMCID: PMC4270537  PMID: 25550879
Multiple macronodular hepatic tuberculosis; hepatocellular carcinoma; intrahepatic metastasis; FNAB
11.  Cocaine-Induced Membrane Adaptation in the Central Nucleus of Amygdala 
Neuropsychopharmacology  2013;38(11):2240-2248.
Exposure to drugs of abuse lead to both rewarding effects and the subsequent development of negative affects. The progressive dysregulation of both processes is thought to critically contribute to the addictive state. Whereas cocaine-induced maladaptations in reward circuitry have been extensively examined, the cellular substrates underlying negative affect remain poorly understood. This study focuses on the central nucleus of the amygdala (CeA), a brain region that has been implicated in negative affective states upon withdrawal from chronic cocaine use. We observed that the two major types of CeA neurons, low-threshold bursting (LTB) neurons and regular spiking (RS) neurons, exhibited different sensitivity to corticotrophin-releasing factor (CRF), a stress hormone that has been implicated in negative affect during drug withdrawal. Furthermore, LTB and RS neurons developed opposite membrane adaptations following short-term (5 day) cocaine self-administration; the membrane excitability was increased in LTB neurons but decreased in RS neurons. These short-term exposure-induced effects were transient as they were present on withdrawal day 1 but disappeared on withdrawal day 21. However, extended exposure (21 day) led to sustained increase in the membrane excitability of LTB neurons such that it lasted over 21 days into the withdrawal period. These results suggest that CeA neurons can be a cellular target for cocaine to reshape the circuitry mediating negative affects during withdrawal, and that the long-lasting cellular alterations in selective subpopulations of CeA neurons may lead to unbalanced CeA processing, thus contributing to the progressive aggravation of negative affective states during withdrawal from chronic cocaine exposure.
doi:10.1038/npp.2013.124
PMCID: PMC3773674  PMID: 23756609
addiction & substance abuse; amygdala; central nucleus; CRF; depression; unipolar / bipolar; low-threshold bursting; membrane excitability; neurophysiology; psychostimulants; regular spiking; amygdala; cocaine; addiction; membrane excitability; low-threshold bursting; regular spiking
12.  Electrical Stimulation Promotes Regeneration of Defective Peripheral Nerves after Delayed Repair Intervals Lasting under One Month 
PLoS ONE  2014;9(9):e105045.
Background
Electrical stimulation (ES) has been proven to be an effective means of enhancing the speed and accuracy of nerve regeneration. However, these results were recorded when the procedure was performed almost immediately after nerve injury. In clinical settings, most patients cannot be treated immediately. Some patients with serious trauma or contaminated wounds need to wait for nerve repair surgery. Delays in nerve repair have been shown to be associated with poorer results than immediate surgery. It is not clear whether electrical stimulation still has any effect on nerve regeneration after enough time has elapsed.
Methods
A delayed nerve repair model in which the rats received delayed nerve repair after 1 day, 1 week, 1 month, and 2 months was designed. At each point in time, the nerve stumps of half the rats were bridged with an absorbable conduit and the rats were given 1 h of weak electrical stimulation. The other half was not treated. In order to analyze the morphological and molecular differences among these groups, 6 ES rats and 6 sham ES rats per point in time were killed 5 days after surgery. The other rats in each group were allowed to recover for 6 weeks before the final functional test and tissue observation.
Results
The amounts of myelinated fibers in the distal nerve stumps decreased as the delay in repair increased for both ES rats and sham ES rats. In the 1-day-delay and 1-week-delay groups, there were more fibers in ES rats than in sham ES rats. And the compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) results were better for ES rats in these two groups. In order to analyze the mechanisms underlying these differences, Masson staining was performed on the distal nerves and quantitative PCR on the spinal cords. Results showed that, after delays in repair of 1 month and 2 months, there was more collagen tissue hyperplasia in the distal nerve in all rats. The brain-derived neurotrophic factor (BDNF) and trkB expression levels in the spinal cords of ES rats were higher than in sham ES rats. However, these differences decreased as the delay in repair increased.
Conclusions
Electrical stimulation does not continue to promote nerve regeneration after long delays in nerve repair. The effective interval for nerve regeneration after delayed repair was found to be less than 1 month. The mechanism seemed to be related to the expression of nerve growth factors and regeneration environment in the distal nerves.
doi:10.1371/journal.pone.0105045
PMCID: PMC4152131  PMID: 25181499
13.  ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma 
Oncotarget  2014;5(18):8569-8582.
ATF3 was a transcription factor involved in the progression of certain cancers. Here, we sought to explore the expression and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). The prognostic significance of ATF3 expression was evaluated in 150 ESCC samples and 21 normal squamous cell epithelium tissues. Results showed that ATF3 was down-regulated in ESCC lesions compared with paired non-cancerous tissues and low tumorous ATF3 expression significantly correlated with shorter overall survival (OS) and disease-free survival (DFS). Cox regression analysis confirmed that ATF3 expression was an independent prognostic factor. Experimentally, forced expression of ATF3 led to decreased growth and invasion properties of ESCC cells in vitro and in vivo, whereas knockdown of ATF3 did the opposite. Furthermore, ATF3 upregulated the expression of MDM2 by increasing the nuclear translocation of P53 and formed an ATF3/MDM2/MMP-2 complex that facilitated MMP-2 degradation, which subsequently led to inhibition of cell invasion. Finally, we showed that Cisplatin could restrain the invasion of ESCC cells by inducing the expression of ATF3 via P53 signaling. Combined, our findings highlight a suppressed role for ATF3 in ESCC and targeting ATF3 might be a potential therapeutic strategy.
PMCID: PMC4226705  PMID: 25149542
ATF3; independent prognostic factor; cell invasion and metastasis; MMP-2; esophageal squamous cell carcinoma
14.  EttA regulates translation by binding to the ribosomal E site and restricting ribosome-tRNA dynamics 
Cells express many ribosome-interacting factors whose functions and molecular mechanisms remain unknown. Here, we elucidate the mechanism of a newly characterized regulatory translation factor, Energy-dependent Translational Throttle A (EttA), which is an Escherichia coli representative of the ATP-binding cassette F (ABC-F) protein family. Using cryo-EM, we demonstrate that the ATP-bound form of EttA binds to the ribosomal tRNA exit (E) site, where it forms bridging interactions between the ribosomal L1 stalk and the tRNA bound in the peptidyl-tRNA binding (P) site. Using single-molecule fluorescence resonance energy transfer (smFRET), we show that the ATP-bound form of EttA restricts ribosome and tRNA dynamics required for protein synthesis. This work represents the first example, to our knowledge, where the detailed molecular mechanism of any ABC-F family protein has been determined and establishes a framework for elucidating the mechanisms of other regulatory translation factors.
doi:10.1038/nsmb.2741
PMCID: PMC4143144  PMID: 24389465
protein translation regulation; ABC-F protein family; ribosome; cryo-EM; single-molecule FRET; YjjK
15.  The N-terminal portion of autoinhibitory element modulates human endothelial nitric-oxide synthase activity through coordinated controls of phosphorylation at Thr495 and Ser1177 
Bioscience Reports  2014;34(4):e00129.
NO production catalysed by eNOS (endothelial nitric-oxide synthase) plays an important role in the cardiovascular system. A variety of agonists activate eNOS through the Ser1177 phosphorylation concomitant with Thr495 dephosphorylation, resulting in increased ·NO production with a basal level of calcium. To date, the underlying mechanism remains unclear. We have previously demonstrated that perturbation of the AIE (autoinhibitory element) in the FMN-binding subdomain can also lead to eNOS activation with a basal level of calcium, implying that the AIE might regulate eNOS activation through modulating phosphorylation at Thr495 and Ser1177. Here we generated stable clones in HEK-293 (human embryonic kidney 293) cells with a series of deletion mutants in both the AIE (Δ594–604, Δ605–612 and Δ626–634) and the C-terminal tail (Δ14; deletion of 1164–1177). The expression of Δ594–604 and Δ605–612 mutants in non-stimulated HEK-293 cells substantially increased nitrate/nitrite release into the culture medium; the other two mutants, Δ626–634 and Δ1164–1177, displayed no significant difference when compared with WTeNOS (wild-type eNOS). Intriguingly, mutant Δ594–604 showed close correlation between Ser1177 phosphorylation and Thr495 dephosphorylation, and NO production. Our results have indicated that N-terminal portion of AIE (residues 594–604) regulates eNOS activity through coordinated phosphorylation on Ser1177 and Thr495.
Our findings demonstrate for the first time that AIE insert exerts its regulatory function by coordinate phosphorylation on eNOS Ser1177 and Thr495, highlighting the importance of AIE in regulating agonist-induced eNOS activation.
doi:10.1042/BSR20140079
PMCID: PMC4122979  PMID: 24993645
autoinhibitory element; calcium/calmodulin; CaM-binding domain; endothelial nitric-oxide synthase; mobility shift gel; phosphorylation/dephosphorylation; AIE, autoinhibitory element; CaM, calmodulin; CBD, CaM-binding domain; DMEM, Dulbecco’s modified Eagle’s medium; EGFP, enhanced green fluorescent protein; eNOS, endothelial nitric-oxide synthase; H4B, (6R)-5,6,7,8-tetrahydro-L-biopterin; GS, goat serum; HEK-293, human embryonic kidney 293 cell; heNOS, human eNOS; iNOS, inducible NOS; Myr−eNOS, myristylation-deficient eNOS; nNOS, neuronal NOS; WTeNOS, wild-type eNOS
16.  Macromolecular Crowding Effect on Cartilaginous Matrix Production: A Comparison of Two-Dimensional and Three-Dimensional Models 
Macromolecular crowding (MMC) has been shown to have a beneficial effect on production and maturation of extracellular matrices in a monolayer cell culture model. To explore its potential in tissue engineering, a mixture of Ficoll 70 and Ficoll 400 is used to examine its MMC effect on cartilaginous matrix production of monolayer cultured porcine chondrocytes as well as on in vitro engineered cartilage formation using porcine chondrocytes and polyglycolic acid-unwoven fibers. The results showed that the production of total collagens and glycosaminoglycans production was enhanced by MMC in monolayer cultured cells (two-dimensional model), but the matrix production and tissue formation were significantly inhibited in the in vitro engineered cartilage (three-dimensional model) by the macromolecules. Further mechanism study on this phenomenon will be important for MMC applications in regenerative medicine.
doi:10.1089/ten.tec.2012.0408
PMCID: PMC3689930  PMID: 23421450
17.  The ABC-F protein EttA gates ribosome entry into the translation elongation cycle 
ABC-F proteins have evaded functional characterization even though they comprise one of the most widely distributed branches of the ATP-binding cassette (ABC) superfamily. Herein, we demonstrate that YjjK, the most prevalent eubacterial ABC-F protein, gates ribosome entry into the translation elongation cycle through a nucleotide-dependent interaction sensitive to ATP/ADP ratio. Accordingly, we rename this protein Energy-dependent Translational Throttle A (EttA). We determined the crystal structure of Escherichia coli EttA and used it to design mutants for biochemical studies, including enzymological assays of the initial steps of protein synthesis. These studies suggest that EttA may regulate protein synthesis in energy-depleted cells, which have a low ATP/ADP ratio. Consistent with this inference, ΔettA cells exhibit a severe fitness defect in long-term stationary phase. These studies demonstrate that an ABC-F protein regulates protein synthesis via a novel mechanism sensitive to cellular energy status.
doi:10.1038/nsmb.2740
PMCID: PMC4101993  PMID: 24389466
Protein synthesis; translational regulation; ABC-F protein family; YjjK; ATP/ADP ratio; stationary phase fitness; X-ray crystallography
18.  Oxygenated Eremophilane- and Neolemnane-Derived Sesquiterpenoids from the Soft Coral Lemnalia philippinensis 
Marine Drugs  2014;12(8):4495-4503.
Five sesquiterpene-related metabolites (1–5), including two new eremophilane-type compounds, philippinlins C and D (1 and 2) and a 4,5-seconeolemnane philippinlin E (3), were isolated from the organic extract of a Taiwanese soft coral Lemnalia philippinensis. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis and by comparison of NMR data with those of related metabolites. Compound 3 was suggested to be derived from the neolemnane skeleton.
doi:10.3390/md12084495
PMCID: PMC4145327  PMID: 25196835
Lemnalia philippinensis; eremophilane; neolemnane
19.  Marked improvement of anti-N-methyl-D-aspartate receptor encephalitis by large-dose methylprednisolone and plasmapheresis therapy combined with 18F-fluorodeoxyglucose positron emission tomography imaging: A case report 
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a recently defined and frequently misdiagnosed disease characterized by psychiatric symptoms, seizures, movement disorders and autonomic dysfunction, has been observed predominantly in young females with ovarian teratoma. Conventional imaging techniques, including computed tomography (CT) and magnetic resonance imaging (MRI), are often ineffective for diagnosis of the disease. If diagnosed early, the initiation of immunotherapy and removal of the tumor (if present) may result in recovery. The current study presents the case of a 38-year-old female with classic clinical symptoms of anti-NMDAR encephalitis. The MRI brain scan results were unremarkable, cerebral spinal fluid (CSF) biochemistry indicated non-specific lymphocytic pleocytosis and the CSF microbiology studies were negative. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging revealed significant generalized asymmetric hypometabolism. The patient demonstrated marked recovery following treatment with a high dose of corticosteroids and plasmapheresis. Accordingly, the follow-up 18F-FDG PET imaging revealed significant improvement.
doi:10.3892/etm.2014.1849
PMCID: PMC4151669  PMID: 25187817
anti-N-methyl-D-aspartate receptor encephalitis; plasmapheresis; 18F-fluorodeoxyglucose positron emission tomography
20.  Dynamic Responses and Vibration Control of the Transmission Tower-Line System: A State-of-the-Art Review 
The Scientific World Journal  2014;2014:538457.
This paper presented an overview on the dynamic analysis and control of the transmission tower-line system in the past forty years. The challenges and future developing trends in the dynamic analysis and mitigation of the transmission tower-line system under dynamic excitations are also put forward. It also reviews the analytical models and approaches of the transmission tower, transmission lines, and transmission tower-line systems, respectively, which contain the theoretical model, finite element (FE) model and the equivalent model; shows the advances in wind responses of the transmission tower-line system, which contains the dynamic effects under common wind loading, tornado, downburst, and typhoon; and discusses the dynamic responses under earthquake and ice loads, respectively. The vibration control of the transmission tower-line system is also reviewed, which includes the magnetorheological dampers, friction dampers, tuned mass dampers, and pounding tuned mass dampers.
doi:10.1155/2014/538457
PMCID: PMC4106223  PMID: 25105161
21.  miRNA-93 Inhibits GLUT4 and Is Overexpressed in Adipose Tissue of Polycystic Ovary Syndrome Patients and Women With Insulin Resistance 
Diabetes  2013;62(7):2278-2286.
Approximately 70% of women with polycystic ovary syndrome (PCOS) have intrinsic insulin resistance (IR) above and beyond that associated with body mass, including dysfunctional glucose metabolism in adipose tissue (AT). In AT, analysis of the IRS/PI3-K/AKT pathway signaling components identified only GLUT4 expression to be significantly lower in PCOS patients and in control subjects with IR. We examined the role of miRNAs, particularly in the regulation of GLUT4, the insulin-sensitive glucose transporter, in the AT of PCOS and matched control subjects. PCOS AT was determined to have a differentially expressed miRNA profile, including upregulated miR-93, -133, and -223. GLUT4 is a highly predicted target for miR-93, while miR-133 and miR-223 have been demonstrated to regulate GLUT4 expression in cardiomyocytes. Expression of miR-93 revealed a strong correlation between the homeostasis model assessment of IR in vivo values and GLUT4 and miR-93 but not miR-133 and -223 expression in human AT. Overexpression of miR-93 resulted in downregulation of GLUT4 gene expression in adipocytes through direct targeting of the GLUT4 3′UTR, while inhibition of miR-93 activity led to increased GLUT4 expression. These results point to a novel mechanism for regulating insulin-stimulated glucose uptake via miR-93 and demonstrate upregulated miR-93 expression in all PCOS, and in non-PCOS women with IR, possibly accounting for the IR of the syndrome. In contrast, miR-133 and miR-223 may have a different, although yet to be defined, role in the IR of PCOS.
doi:10.2337/db12-0963
PMCID: PMC3712080  PMID: 23493574
22.  Clinicopathological variables predicting HER-2 gene status in immunohistochemistry-equivocal (2+) invasive breast cancer 
Journal of Thoracic Disease  2014;6(7):896-904.
Background and objective
Human epidermal growth factor receptor-2 (HER-2) gene status is crucial to guide treatment decisions regarding the use of HER-2-targeted therapies in breast cancer. An invasive breast cancer with HER-2 2+ score is regarded as HER-2 status equivocal and should further determine by fluorescent in situ hybridization (FISH), which is considered the standard test for HER-2 status. Here, we aimed to establish a risk score to allow for prediction of the presence of HER-2 gene status.
Methods
A total of 182 HER-2 2+ by immunohistochemistry (IHC) invasive breast cancer cases were enrolled in this study. The association between clinicopathological variables like age, sex, tumor grade, hormone receptor (HR) status, P53 and proliferation index (Ki67), and FISH result using US Food and Drug Administration (FDA) criteria was evaluated. Also, we compared the HER-2 FISH results using FDA criteria and 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline.
Results
The study population had a median age of 48 years (range, 29-78 years). Estrogen receptor (ER) was expressed in 131 (72.0%) patients. 73.1% of patients (133/182) were progesterone receptor (PR) positive. The median Ki67 value was 20% (range, 3-90%). There was good agreement between the FDA and 2013 ASCO/CAP guideline. Sixty-three of all patients were HER-2 FISH amplified (positive) based on FDA criteria. Tumors with HER-2 amplified were more likely to harbor ER negative (58.8% vs. 25.2%, P<0.001) or PR negative (57.1% vs. 26.3%, P<0.001) or P53 negative (44.8% vs. 29.8%, P=0.048). A significant high level of Ki67 was detected in HER-2 amplified groups (P=0.006). We created a risk score that comprised HR, P53 and Ki67. A significant association between risk score and HER-2 FISH amplification was observed (χ2=30.41, P<0.001).
Conclusions
This novel immunohistochemical risk score could be highly useful to predict the presence of HER-2 gene status in invasive breast cancer.
doi:10.3978/j.issn.2072-1439.2014.07.27
PMCID: PMC4120177  PMID: 25093085
Invasive breast cancer; human epidermal growth factor receptor-2 (HER-2); immunohistochemistry (IHC); fluorescent in situ hybridization (FISH); prediction
23.  Noninvasive in-vehicle alcohol detection with wavelength-modulated differential photothermal radiometry 
Biomedical Optics Express  2014;5(7):2333-2340.
This study describes the potential of wavelength-modulated differential photothermal radiometry (WM-DPTR) for non-invasive in-vehicle alcohol detection which can be of great importance in reducing alcohol-impaired driving. Ethanol content in the range of concern, 0-100 blood alcohol concentration (BAC) in water phantoms and blood serum diffused in human skin in vitro were measured with high sensitivity. The results show that the WM-DPTR system can be optimized for alcohol detection with the combination of two sensitivity-tuning parameters, amplitude ratio R and phase shift ΔP. WM-DPTR has demonstrated the potential to be developed into a portable alcohol ignition interlock biosensor that could be fitted as a universal accessory in vehicles.
doi:10.1364/BOE.5.002333
PMCID: PMC4102367  PMID: 25071967
(280.1415) Biological sensing and sensors; (170.1470) Blood or tissue constituent monitoring; (300.6430) Spectroscopy, photothermal
24.  Metaplastic breast carcinoma development following surgical resection of an inflammatory myofibroblastic tumor in the right breast: A case report 
Oncology Letters  2014;8(3):1345-1347.
Inflammatory myofibroblastic tumors (IMTs) are uncommon, mesenchymal lesions, and malignant transformation is extremely rare. The current study presents the case of a 56-year-old female with a rapidly growing mass in the right breast, which was diagnosed as IMT. Immunohistochemically, the mass was positive for smooth muscle actin (SMA) and Ki-67 (positive staining in 30% of the cells), and negative for S-100, cluster of differentiation (CD)34, p63 and cytokeratin. Malignant transformation to metaplastic carcinoma of the spindle-cell type was observed following surgical resection. This metaplastic carcinoma demonstrated positive immunoreactivity for cytokeratin, vimentin, CD34, p63 and Ki-67 (>30%), and was negative for cytokeratin 7, SMA, desmin and S-100. The patient underwent total mastectomy of the right breast, followed by palliative chemotherapy with capecitabine; however, the patient succumbed to the disease after 12 weeks. The unusual case presented in the current study emphasizes the importance of pre-operative examinations to determine the benign or malignant nature of IMTs, which aids in the choice of appropriate surgical procedures.
doi:10.3892/ol.2014.2261
PMCID: PMC4114583  PMID: 25120721
benign disease; breast carcinoma; case report; malignant progression
25.  Damage Detection on Sudden Stiffness Reduction Based on Discrete Wavelet Transform 
The Scientific World Journal  2014;2014:807620.
The sudden stiffness reduction in a structure may cause the signal discontinuity in the acceleration responses close to the damage location at the damage time instant. To this end, the damage detection on sudden stiffness reduction of building structures has been actively investigated in this study. The signal discontinuity of the structural acceleration responses of an example building is extracted based on the discrete wavelet transform. It is proved that the variation of the first level detail coefficients of the wavelet transform at damage instant is linearly proportional to the magnitude of the stiffness reduction. A new damage index is proposed and implemented to detect the damage time instant, location, and severity of a structure due to a sudden change of structural stiffness. Numerical simulation using a five-story shear building under different types of excitation is carried out to assess the effectiveness and reliability of the proposed damage index for the building at different damage levels. The sensitivity of the damage index to the intensity and frequency range of measurement noise is also investigated. The made observations demonstrate that the proposed damage index can accurately identify the sudden damage events if the noise intensity is limited.
doi:10.1155/2014/807620
PMCID: PMC4058814  PMID: 24991647

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