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1.  Diagnostic Accuracy of Contrast-Enhanced Ultrasound Enhancement Patterns for Thyroid Nodules 
Background
The aim of this study was to investigate the accuracy of contrast-enhanced ultrasound (CEUS) enhancement patterns in the assessment of thyroid nodules.
Material/Methods
A total of 158 patients with suspected thyroid cancer underwent conventional ultrasound (US) and CEUS examinations. The contrast enhancement patterns of the lesions, including the peripheries of the lesions, were assessed by CEUS scans. The relationship between the size of the lesions and the degree of enhancement was also studied. US- and/or CEUS-guided biopsy was used to obtain specimens for histopathological diagnosis.
Results
The final data included 148 patients with 157 lesions. Seventy-five patients had 82 malignant lesions and 73 patients had 75 benign lesions. Peripheral ring enhancement was seen in 40 lesions. The differences of enhancement patterns and peripheral rings between benign and malignant nodules were significant (p=0.000, 0.000). The diagnostic sensitivity, specificity, and accuracy for malignant were 88%, 65.33%, and 88.32%, respectively, for CEUS, whereas they were 98.33%, 42.67%, and 71.97%, respectively, for TC by conventional US. The misdiagnosis rate by conventional US was 57.33% and 34.67% by CEUS (p=0.005). With regard to the size of lesions, a significant difference was found between low-enhancement, iso-enhancement, high-enhancement, iso-enhancement with no-enhancement area and no-enhancement (p=0.000).
Conclusions
In patients with suspicious US characteristics, CEUS had high specificity and contributed to establishing the diagnosis. Therefore, CEUS could avoid unnecessary biopsy.
doi:10.12659/MSM.899834
PMCID: PMC5154710  PMID: 27916971
Contrast Media; Thyroid Neoplasms; Ultrasonography, Doppler
2.  Be Strong Enough to Say No: Self-Affirmation Increases Rejection to Unfair Offers 
Frontiers in Psychology  2016;7:1824.
We propose that self-affirmation may endow people more psychological resources to buffer against the negative influence of rejecting unfair offers in the classic ultimatum game (UG) and further lead to a stronger tendency to reject those offers. We tested this possibility by conducting an event-related potential (ERP) study about the UG, with the ERP component P3 as an indirect indicator of psychological resources. Participants were randomly assigned to the affirmation or control condition and then completed the UG through electrophysiological recording. As expected, the behavioral data indicated that compared with unaffirmed ones, affirmed participants were more likely to reject unfair UG offers; the electrophysiological data indicated that compared to the unaffirmed, affirmed participants showed a greater P3 in response to the presentation of an offer. These findings suggest that psychological resources may play a role in rejecting others beyond the fairness concern, and additionally shed light on the neural mechanisms underlying self-affirmation.
doi:10.3389/fpsyg.2016.01824
PMCID: PMC5118568  PMID: 27920742
self-affirmation; social decision-making; ultimatum game; fairness; social rejection; event-related potential; P3
3.  Generalised monogamy relation of convex-roof extended negativity in multi-level systems 
Scientific Reports  2016;6:36700.
In this paper, we investigate the generalised monogamy inequalities of convex-roof extended negativity (CREN) in multi-level systems. The generalised monogamy inequalities provide the upper and lower bounds of bipartite entanglement, which are obtained by using CREN and the CREN of assistance (CRENOA). Furthermore, we show that the CREN of multi-qubit pure states satisfies some monogamy relations. Additionally, we test the generalised monogamy inequalities for qudits by considering the partially coherent superposition of a generalised W-class state in a vacuum and show that the generalised monogamy inequalities are satisfied in this case as well.
doi:10.1038/srep36700
PMCID: PMC5114565  PMID: 27857163
4.  Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation 
Scientific Reports  2016;6:35533.
The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells. AKI603 inhibited cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation. Surprisingly, inhibition of AurA by AKI603 induced leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells. Furthermore, the induction of senescence was associated with enhancing reactive oxygen species (ROS) level. Moreover, the anti-tumor effect of AKI603 was proved in the BALB/c nude mice KBM5-T315I xenograft model. Taken together, our data demonstrate that the small molecule AurA inhibitor AKI603 may be used to overcome drug resistance induced by BCR-ABL-T315I mutation in CML.
doi:10.1038/srep35533
PMCID: PMC5099696  PMID: 27824120
5.  Vitamin D deficiency may predict a poorer outcome of IgA nephropathy 
BMC Nephrology  2016;17:164.
Background
Experimental studies showed that 25-hydroxy-vitamin D [25(OH)D] deficiency (defined as 25-hydroxy-vitamin D < 15 ng/ml) has been associated with CKD progression. Patients with IgA nephropathy have an exceptionally high rate of severe 25(OH)D deficiency; however, it is not known whether this deficiency is a risk factor for progression of IgA nephropathy. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and certain clinical parameters and renal histologic lesions in the patients with IgA nephropathy, and to evaluate whether the 25(OH)D level could be a good prognostic marker for IgA nephropathy progression.
Methods
A total of 105 patients with biopsy-proven IgA nephropathy were enrolled between 2012 and 2015. The circulating concentration of 25(OH)D was determined using serum samples collected at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; a 30 % or more decline compared to the baseline).
Results
Mean eGFR decreased and proteinuria worsened proportionally as circulating 25(OH)D decreased (P < 0.05). The 25(OH)D deficiency was correlated with a higher tubulointerstitial score by the Oxford classification (P = 0.008). The risk for reaching the primary endpoint was significantly higher in the patients with a 25(OH)D deficiency compared to those with a higher level of 25(OH)D (P = 0.001). As evaluated using the Cox proportional hazards model, 25(OH)D deficiency was found to be an independent risk factor for renal progression [HR 5.99, 95 % confidence intervals (CIs) 1.59–22.54, P = 0.008].
Conclusion
A 25(OH)D deficiency at baseline is significantly correlated with poorer clinical outcomes and more sever renal pathological features, and low levels of 25(OH)D at baseline were strongly associated with increased risk of renal progression in IgAN.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-016-0378-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-016-0378-4
PMCID: PMC5094030  PMID: 27806690
Disease progression; IgA nephropathy; Prognosis; Risk factor; Vitamin D
6.  Chemerin Stimulates Vascular Smooth Muscle Cell Proliferation and Carotid Neointimal Hyperplasia by Activating Mitogen-Activated Protein Kinase Signaling 
PLoS ONE  2016;11(10):e0165305.
Vascular neointimal hyperplasia and remodeling arising from local inflammation are characteristic pathogeneses of proliferative cardiovascular diseases, such as atherosclerosis and post angioplasty restenosis. The molecular mechanisms behind these pathological processes have not been fully determined. The adipokine chemerin is associated with obesity, metabolism, and control of inflammation. Recently, chemerin has gained increased attention as it was found to play a critical role in the development of cardiovascular diseases. In this study, we investigated the effects of chemerin on the regulation of vascular smooth muscle cells and carotid neointimal formation after angioplasty. We found that circulating chemerin levels increased after carotid balloon injury, and that knockdown of chemerin significantly inhibited the proliferative aspects of vascular smooth muscle cells induced by platelet-derived growth factor-BB and pro-inflammatory chemokines in vitro as well as prohibited carotid neointimal hyperplasia and pro-inflammatory chemokines in vivo after angioplasty. Additionally, inhibition of chemerin down-regulated the expression of several proteins, including phosphorylated p38 mitogen-activated protein kinase, phosphorylated extracellular signal regulated kinase 1/2, nuclear factor-kappa B p65, and proliferation cell nuclear antigen. The novel finding of this study is that chemerin stimulated vascular smooth muscle cells proliferation and carotid intimal hyperplasia through activation of the mitogen-activated protein kinase signaling pathway, which may lead to vascular inflammation and remodeling, and is relevant to proliferative cardiovascular diseases.
doi:10.1371/journal.pone.0165305
PMCID: PMC5085037  PMID: 27792753
7.  Metastasis-associated long noncoding RNAs in gastrointestinal cancer: Implications for novel biomarkers and therapeutic targets 
World Journal of Gastroenterology  2016;22(39):8735-8749.
Long non-coding RNAs (lncRNAs), a newly discovered class of ncRNA molecules, have been widely accepted as crucial regulators of various diseases including cancer. Increasing numbers of studies have demonstrated that lncRNAs are involved in diverse physiological and pathophysiological processes, such as cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Aberrant expression of lncRNAs frequently occurs in gastrointestinal cancer and plays emerging roles in cancer metastasis. In this review, we focus on and outline the regulatory functions of recently identified metastasis-associated lncRNAs, and evaluate the potential roles of lncRNAs as novel diagnostic biomarkers and therapeutic targets in gastrointestinal cancer.
doi:10.3748/wjg.v22.i39.8735
PMCID: PMC5075548  PMID: 27818589
Gastrointestinal cancer; Tumor metastasis; Long noncoding RNAs; Epithelial-to-mesenchymal transition; MicroRNAs
8.  Normobaric oxygen treatment in acute ischemic stroke: a clinical perspective 
Medical Gas Research  2016;6(3):147-153.
Acute ischemic stroke is a common and serious neurological disease. Oxygen therapy has been shown to increase oxygen supply to ischemic tissues and improve outcomes after cerebral ischemia/reperfusion. Normobaric hyperoxia (NBO), an easily applicable and non-invasive method, shows protective effects on acute ischemic stroke animals and patients in pilot studies. However, many critical scientific questions are still unclear, such as the therapeutic time window of NBO, the long-term effects and the benefits of NBO in large clinic trials. In this article, we review the current literatures on NBO treatment of acute ischemic stroke in preclinical and clinical studies and try to analyze and identify the key gaps or unknowns in our understanding about NBO. Based on these analyses, we provide suggestions for future studies.
doi:10.4103/2045-9912.191360
PMCID: PMC5110139  PMID: 27867482
normobaric hyperoxia; oxygen therapy; stroke; ischemia; neuroprotection; oxidative stress; clinical studies; preclinical studies
9.  Hyaluronic acid-modified manganese-chelated dendrimer-entrapped gold nanoparticles for the targeted CT/MR dual-mode imaging of hepatocellular carcinoma 
Scientific Reports  2016;6:33844.
Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. The early and effective diagnosis has always been desired. Herein, we present the preparation and characterization of hyaluronic acid (HA)-modified, multifunctional nanoparticles (NPs) targeting CD44 receptor-expressing cancer cells for computed tomography (CT)/magnetic resonance (MR) dual-mode imaging. We first modified amine-terminated generation 5 poly(amidoamine) dendrimers (G5.NH2) with an Mn chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), fluorescein isothiocyanate (FI), and HA. Then, gold nanoparticles (AuNPs) were entrapped within the above raw product, denoted as G5.NH2-FI-DOTA-HA. The designed multifunctional NPs were formed after further Mn chelation and purification and were denoted as {(Au0)100G5.NH2-FI-DOTA(Mn)-HA}. These NPs were characterized via several different techniques. We found that the {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} NPs exhibited good water dispersibility, stability under different conditions, and cytocompatibility within a given concentration range. Because both AuNPs and Mn were present in the product, {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} displayed a high X-ray attenuation intensity and favorable r1 relaxivity, which are advantageous properties for targeted CT/MR dual-mode imaging. This approach was used to image HCC cells in vitro and orthotopically transplanted HCC tumors in a unique in vivo model through the CD44 receptor-mediated endocytosis pathway. This work introduces a novel strategy for preparing multifunctional NPs via dendrimer nanotechnology.
doi:10.1038/srep33844
PMCID: PMC5032118  PMID: 27653258
10.  Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP 
Scientific Reports  2016;6:32656.
Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson’s disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation.
doi:10.1038/srep32656
PMCID: PMC5020318  PMID: 27619562
12.  Hygrothermal environment may cause influenza pandemics through immune suppression 
Human Vaccines & Immunotherapeutics  2015;11(11):2641-2646.
Over the past few decades, climate warming has caused profound changes in our living environment, and human diseases, including infectious diseases, have also been influenced by these changes. However, it remains unclear if a warm-wet climate can influence the infectivity of influenza and result in influenza pandemics. This study focused on observations of how the hydrothermal environment influences the infectivity of the influenza virus and the resulting immunoreactions of the infected mice. We used a manual climatic box to establish the following 3 environments with different temperatures and humidity: normal environment (T: 24 ± 1°C, RH: 50% ± 4%), wet environment (T: 24 ± 1°C, RH: 95% ± 4%) and warm-wet environment (T: 33 ± 1 °C, RH: 95% ± 4%), and the mice were fed and maintained in these 3 different environments. After 14 days, half of the mice were infected with H1N1 (A/FM1/1/47, a lung adapted strain of the flu virus specific for the mouse lung) virus for 4 d After establishing the animal model, we observed the microstructure of the lung tissue, the Th1/Th2 T cell subsets, the Th17/Treg balance, the expression of cytokines in the peripheral blood serum and the expression of the immune recognition RLH signal pathway. The results showed that mice in different environments have different reaction. Results showed that after infection, the proportion of Th1/Th2 and Th17/Treg cells in the spleen was significantly increased, and these proportions were increased the most in the infected group kept in wet-hot conditions. After infection, the mRNA levels and protein expression of the RLH (RIG-1-like helicases) signal pathway components were up-regulated while the uninfected animals in the 3 diverse environments showed no significant change. The infected mice kept in the wet and warm-wet environments showed a slight elevation in the expression of RLH pathway components compared to infected mice maintained in the normal environment. Our study suggested that the warm-wet environment may have interfered with the immune response and balance. The mice kept in the warm-wet environment displayed immune tolerance when they were exposed to the influenza virus, and the body was not able to effectively clear the virus, leading to a persistent infection. A warm-wet climate may thus be a factor that contributes to influenza pandemics, people should focus on the warm-wet climate coming and advance prepare to vaccine manufacture.
doi:10.1080/21645515.2015.1084452
PMCID: PMC4685681  PMID: 26359946
immunity; influenza; FM1; RLH; warm-wet climate
13.  VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease 
Nature Communications  2016;7:12646.
Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.
Mitochondria defects caused by mutant huntingtin (mtHtt) have been implicated in Huntington's disease. Here authors show that VCP binds to mtHtt on the mitochondria, and that treatment with a peptide that disrupts this interaction reduces the cellular and behavioural deficits in mouse models of HD.
doi:10.1038/ncomms12646
PMCID: PMC5007466  PMID: 27561680
14.  Crystallization and X-ray diffraction of virus-like particles from a piscine betanodavirus 
This is the first report of the crystallization conditions for VLPs from a grouper fish nervous necrosis virus, and the VLP structure diffracted X-rays to 7.5 Å with high completeness.
Dragon grouper nervous necrosis virus (DGNNV), a member of the genus Betanodavirus, causes high mortality of larvae and juveniles of the grouper fish Epinephelus lanceolatus. Currently, there is no reported crystal structure of a fish nodavirus. The DGNNV virion capsid is derived from a single open reading frame that encodes a 338-amino-acid protein of approximately 37 kDa. The capsid protein of DGNNV was expressed to form virus-like particles (VLPs) in Escherichia coli. The VLP shape is T = 3 quasi-symmetric with a diameter of ∼38 nm in cryo-electron microscopy images and is highly similar to the native virion. In this report, crystals of DGNNV VLPs were grown to a size of 0.27 mm within two weeks by the hanging-drop vapour-diffusion method at 283 K and diffracted X-rays to ∼7.5 Å resolution. In-house X-ray diffraction data of the DGNNV VLP crystals showed that the crystals belonged to space group R32, with unit-cell parameters a = b = 353.00, c = 800.40 Å, α = β = 90, γ = 120°. 23 268 unique reflections were acquired with an overall R merge of 18.2% and a completeness of 93.2%. Self-rotation function maps confirmed the fivefold, threefold and twofold symmetries of the icosahedron of DGNNV VLPs.
doi:10.1107/S2053230X14013703
PMCID: PMC4118809  PMID: 25084387
Dragon grouper nervous necrosis virus (DGNNV); Betanodavirus; Epinephelus lanceolatus
15.  Reverse surface-polariton cherenkov radiation 
Scientific Reports  2016;6:30704.
The existence of reverse Cherenkov radiation for surface plasmons is demonstrated analytically. It is shown that in a metal-insulator-metal (MIM) waveguide, surface plasmon polaritons (SPPs) excited by an electron moving at a speed higher than the phase velocity of SPPs can generate Cherenkov radiation, which can be switched from forward to reverse direction by tuning the core thickness of the waveguide. Calculations are performed in both frequency and time domains, demonstrating that a radiation pattern with a backward-pointing radiation cone can be achieved at small waveguide core widths, with energy flow opposite to the wave vector of SPPs. Our study suggests the feasibility of generating and steering electron radiation in simple plasmonic systems, opening the gate for various applications such as velocity-selective particle detections.
doi:10.1038/srep30704
PMCID: PMC4967887  PMID: 27477061
16.  Forebrain neuronal specific ablation of p53 gene provide protection in a cortical ischemic stroke model 
Neuroscience  2015;295:1-10.
Cerebral ischemic injury involves death of multiple cell types at the ischemic sites. As a key regulator of cell death, the p53 gene has been implicated in the regulation of cell loss in stroke. Less focal damage is found in stroke animals pre-treated with a p53 inhibitor or in traditional p53 knockout (ko) mice. However, whether the p53 gene plays a direct role in regulating neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 ko mice, we utilized a neuronal specific conditional ko mouse line (CamcreTRP53 loxP/loxP) to achieve forebrain neuronal specific deletion of p53 and examined the role of the p53 gene in ischemia-induced cell death in neurons. Expression of p53 after stroke is examined using immunohistochemical method and outcome of stroke is examined by analysis of infarction size and behavioral deficits caused by stroke. Our data showed that p53 expression is upregulated in the ischemic region in neuronal cells in wildtype (wt) mice but not in CamcreTRP53 loxP/loxP ko mice. Deletion of the p53 gene in forebrain neurons results in a decreased infarction area in ko mice. Locomotor behavior, measured in automated activity chambers, showed that CamcreTRP53 loxP/loxP ko mice have less locomotor deficits compared to wt mice after MCAo. We conclude that manipulation of p53 expression in neurons may lead to unique therapeutic development in stroke.
doi:10.1016/j.neuroscience.2015.03.018
PMCID: PMC4966168  PMID: 25779964
conditional p53 knockout; stroke; neuroprotection
17.  On-chip sub-terahertz surface plasmon polariton transmission lines with mode converter in CMOS 
Scientific Reports  2016;6:30063.
An on-chip low-loss and high conversion efficiency plasmonic waveguide converter is demonstrated at sub-THz in CMOS. By introducing a subwavelength periodic corrugated structure onto the transmission line (T-line) implemented by a top-layer metal, surface plasmon polaritons (SPP) are established to propagate signals with strongly localized surface-wave. To match both impedance and momentum of other on-chip components with TEM-wave propagation, a mode converter structure featured by a smooth bridge between the Ground coplanar waveguide (GCPW) with 50 Ω impedance and SPP T-line is proposed. To further reduce area, the converter is ultimately simplified to a gradual increment of groove with smooth gradient. The proposed SPP T-lines with the converter is designed and fabricated in the standard 65 nm CMOS process. Both near-field simulation and measurement results show excellent conversion efficiency from quasi-TEM to SPP modes in a broadband frequency range. The converter achieves wideband impedance matching (<−9 dB) with excellent transmission efficiency (averagely −1.9 dB) from 110 GHz–325 GHz. The demonstrated compact and wideband SPP T-lines with mode converter have shown great potentials to replace existing waveguides as future on-chip THz interconnects. To the best of the author’s knowledge, this is the first time to demonstrate the (sub)-THz surface mode conversion on-chip in CMOS technology.
doi:10.1038/srep30063
PMCID: PMC4956764  PMID: 27444782
18.  An ultrahigh-accuracy Miniature Dew Point Sensor based on an Integrated Photonics Platform 
Scientific Reports  2016;6:29672.
The dew point is the temperature at which vapour begins to condense out of the gaseous phase. The deterministic relationship between the dew point and humidity is the basis for the industry-standard “chilled-mirror” dew point hygrometers used for highly accurate humidity measurements, which are essential for a broad range of industrial and metrological applications. However, these instruments have several limitations, such as high cost, large size and slow response. In this report, we demonstrate a compact, integrated photonic dew point sensor (DPS) that features high accuracy, a small footprint, and fast response. The fundamental component of this DPS is a partially exposed photonic micro-ring resonator, which serves two functions simultaneously: 1) sensing the condensed water droplets via evanescent fields and 2) functioning as a highly accurate, in situ temperature sensor based on the thermo-optic effect (TOE). This device virtually eliminates most of the temperature-related errors that affect conventional “chilled-mirror” hygrometers. Moreover, this DPS outperforms conventional “chilled-mirror” hygrometers with respect to size, cost and response time, paving the way for on-chip dew point detection and extension to applications for which the conventional technology is unsuitable because of size, cost, and other constraints.
doi:10.1038/srep29672
PMCID: PMC4945865  PMID: 27417734
19.  Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat 
Background
Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.
Methods
The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).
Results
Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.
Conclusions
Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.
doi:10.1186/s12974-016-0631-6
PMCID: PMC4924242  PMID: 27353053
Pomalidomide; Thalidomide; Traumatic brain injury; Controlled cortical impact; Tumor necrosis factor-α; Interleukin-1β; Interleukin-6; Glutamate excitotoxicity; Neuronal apoptosis; Neuroinflammation
20.  Multifunctional Fe3O4 @ Au core/shell nanostars: a unique platform for multimode imaging and photothermal therapy of tumors 
Scientific Reports  2016;6:28325.
We herein report the development of multifunctional folic acid (FA)-targeted Fe3O4 @ Au nanostars (NSs) for targeted multi-mode magnetic resonance (MR)/computed tomography (CT)/photoacoustic (PA) imaging and photothermal therapy (PTT) of tumors. In this present work, citric acid-stabilized Fe3O4/Ag composite nanoparticles prepared by a mild reduction route were utilized as seeds and exposed to the Au growth solution to induce the formation of Fe3O4 @ Au core/shell NSs. Followed by successive decoration of thiolated polyethyleneimine (PEI-SH), FA via a polyethylene glycol spacer, and acetylation of the residual PEI amines, multifunctional Fe3O4 @ Au NSs were formed. The designed multifunctional NSs possess excellent colloidal stability, good cytocompatibility in a given concentration range, and specific recognition to cancer cells overexpressing FA receptors. Due to co-existence of Fe3O4 core and star-shaped Au shell, the NSs can be used for MR and CT imaging of tumors, respectively. Likewise, the near infrared plasmonic absorption feature also enables the NSs to be used for PA imaging and PTT of tumors. Our study clearly demonstrates a unique theranostic nanoplatform that can be used for high performance multi-mode imaging-guided PTT of tumors, which may be extendable for theranostics of different diseases in translational medicine.
doi:10.1038/srep28325
PMCID: PMC4914846  PMID: 27325015
21.  V-ATPase-activity in the TGN/EE is required for exocytosis and recycling in Arabidopsis 
Nature plants  2015;1:15094.
In plants, vacuolar H+-ATPase (V-ATPase) activity acidifies both the trans-Golgi network/early endosome (TGN/EE) and the vacuole. This dual V-ATPase function has impeded our understanding in how the pH homeostasis within the plant TGN/EE controls exo- and endocytosis. Here, we show that the weak V-ATPase mutant deetiolated3 (det3) displayed a pH increase in the TGN/EE, but not in the vacuole, strongly impairing secretion and recycling of the brassinosteroid receptor and the cellulose synthase complexes to the plasma membrane, in contrast to mutants lacking tonoplast-localized V-ATPase activity only. The brassinosteroid insensitivity and the cellulose deficiency defects in det3 were tightly correlated with reduced Golgi and TGN/EE motility. Thus, our results provide strong evidence that acidification of the TGN/EE, but not of the vacuole, is indispensable for functional secretion and recycling in plants.
doi:10.1038/nplants.2015.94
PMCID: PMC4905525  PMID: 27250258
22.  Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms 
PLoS ONE  2016;11(6):e0156493.
Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the ‘Blalock Alzheimer’s Disease Up’ pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound’s ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI.
doi:10.1371/journal.pone.0156493
PMCID: PMC4890804  PMID: 27254111
23.  Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics 
Brain and Behavior  2016;6(8):e00491.
Abstract
Introduction
The dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drug‐dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology.
Methods
In this study, we produced DA neurons differentiated using iPSCs derived from opioid‐dependent and control subjects carrying different 3′ VNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSC‐derived human DA neurons are also examined.
Results
We present the first evidence suggesting that the 3′ VNTR polymorphism in the hDAT gene affects DAT expression level in iPSC‐derived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioid‐dependent iPSC cell lines.
Conclusions
Our data suggest that human iPSC‐derived DA neurons may be useful in in vitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development.
doi:10.1002/brb3.491
PMCID: PMC4884574  PMID: 27547496
3′ VNTR; hDAT gene; iPSCs; opioid dependent
24.  Efficiency of neural respiratory drive for the assessment of bronchodilator responsiveness in patients with chronic obstructive pulmonary disease: an exploratory study 
Journal of Thoracic Disease  2016;8(5):958-965.
Background
Conventional lung function parameters, such as forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC) are often used to assess the therapeutic outcomes of bronchodilators, but they lack sensitivity. A novel indicator, namely efficiency of neural respiratory drive (NRD), may objectively evaluate the physiological changes in patients with chronic obstructive pulmonary disease (COPD). We investigated whether this indicator could be used to more accurately assess the responsiveness to inhaled bronchodilators.
Methods
Thirty-six subjects with moderate-to-severe COPD were randomized into group A (n=18) and group B (n=18). Participants in group A inhaled 400 µg placebo, 400 µg salbutamol and 80 µg ipratropium in sequence whereas those in group B had the salbutamol and ipratropium reversed. At different time points after administration of placebo or bronchodilators, evaluated indices included FEV1, FVC, IC, root mean square (RMS) of diaphragm electromyogram (EMGdi), and efficiency of NRD [herein defined as the ratio of minute ventilation (VE) to RMS, or VE/RMS].
Results
FEV1, FVC, IC, RMS, and VE/RMS significantly improved after inhaled bronchodilators and VE/RMS had the largest improvement among five indices. The detection efficiency of VE/RMS was greater than FEV1, FVC, IC (all P<0.05), but not different from RMS. The accuracy and sensitivity of VE/RMS were significantly higher than FEV1, FVC, IC, and RMS (all P<0.05).
Conclusions
Efficiency of NRD may be a sensitive tool to evaluate the efficacy of inhaled bronchodilators in COPD.
doi:10.21037/jtd.2016.03.70
PMCID: PMC4842829  PMID: 27162672
Chronic obstructive pulmonary disease (COPD); bronchodilator; respiratory function tests; neural respiratory drive (NRD)
25.  Evaluation of Liver Ischemia-Reperfusion Injury in Rabbits Using a Nanoscale Ultrasound Contrast Agent Targeting ICAM-1 
PLoS ONE  2016;11(4):e0153805.
Objective
To assess the feasibility of ultrasound molecular imaging in the early diagnosis of liver ischemia-reperfusion injury (IRI) using a nanoscale contrast agent targeting anti-intracellular adhesion molecule-1 (anti-ICAM-1).
Methods
The targeted nanobubbles containing anti-ICAM-1 antibody were prepared using the avidin-biotin binding method. Human hepatic sinusoidal endothelial cells (HHSECs) were cultured at the circumstances of hypoxia/reoxygenation (H/R) and low temperature. The rabbit liver IRI model (I/R group) was established using the Pringle’s maneuver. The time-intensity curve of the liver contrast ultrasonographic images was plotted and the peak intensity, time to peak, and time of duration were calculated.
Results
The size of the targeted nanobubbles were 148.15 ± 39.75 nm and the concentration was 3.6–7.4 × 109/ml, and bound well with the H/R HHSECs. Animal contrast enhanced ultrasound images showed that the peak intensity and time of duration of the targeted nanobubbles were significantly higher than that of common nanobubbles in the I/R group, and the peak intensity and time of duration of the targeted nanobubbles in the I/R group were also significantly higher than that in the SO group.
Conclusion
The targeted nanobubbles have small particle size, stable characteristic, and good targeting ability, which can assess hepatic ischemia-reperfusion injury specifically, noninvasively, and quantitatively at the molecular level.
doi:10.1371/journal.pone.0153805
PMCID: PMC4847801  PMID: 27120181

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