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1.  Platelet Integrin αIIbβ3 Inhibitor Rescues Progression of Apoptosis in Human Platelets 
Background
Apoptosis plays an important role in the physiology of platelet function. We aimed to detect the effect of the platelet integrin αIIbβ3 inhibitor, tirofiban, on apoptotic events, including mitochondrial inner-membrane potential (ΔΨm), phosphatidylserine (PS) exposure on platelet surface, and the generation of reactive oxygen species (ROS), when washed platelets were stimulated with thrombin.
Material/Methods
The study included washed platelets from healthy humans, divided into 4 groups: vehicle, and tirofiban (0.05 μg/ml, 0.25 μg/ml, and 0.5 μg/ml). Platelets were pretreated with vehicle or tirofiban and incubated at 37°C with agitation for 6 h and 24 h. Before thrombin addition, the vehicle group divided into 2 equal groups. Except one vehicle group, the other 4 groups were all stimulated with thrombin (1 U/ml) for 30 min at 37°C. Using flow cytometry, we studied the ΔΨm and PS exposure on platelet surfaces, and the generation of ROS in platelets.
Results
We observed that at the time of 6 h and 24 h, thrombin-stimulated vehicle platelets induced significant depolarization of ΔΨm, higher PS exposure, and increased ROS production compared with the vehicle group (P<0.01). However, the tirofiban group had significantly more recovery of ΔΨm, PS exposure, and ROS production compared with the thrombin group (P<0.01).
Conclusions
The platelet integrin αIIbβ3 inhibitor, tirofiban, inhibits the depolarization of ΔΨm, PS exposure on platelet surface, and ROS production when stimulated with thrombin. These results suggest that αIIbβ3 inhibitor inhibits the initiation of apoptosis in platelets, showing a potential clinical application of tirofiban as an apoptosis inhibitor.
doi:10.12659/MSM.900820
PMCID: PMC5108368  PMID: 27827357
Apoptosis; Flow Cytometry; Mitochondrial Membranes; Phosphatidylserines; Platelet Aggregation Inhibitors
2.  A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses 
Scientific Reports  2016;6:36631.
Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson’s disease and Huntington’s disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and other amyloidoses.
doi:10.1038/srep36631
PMCID: PMC5100551  PMID: 27824125
3.  Myocyte-specific enhancer factor 2C: a novel target gene of miR-214-3p in suppressing angiotensin II-induced cardiomyocyte hypertrophy 
Scientific Reports  2016;6:36146.
The role of microRNA-214-3p (miR-214-3p) in cardiac hypertrophy was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced mouse cardiac hypertrophy. In mice with either Ang-II infusion or transverse aortic constriction (TAC) model, miR-214-3p expression was markedly decreased in the hypertrophic myocardium. Down-regulation of miR-214-3p was observed in the myocardium of patients with cardiac hypertrophy. Expression of miR-214-3p was upregulated in Ang-II-induced hypertrophic neonatal mouse ventricular cardiomyocytes. Cardiac hypertrophy was attenuated in Ang-II-infused mice by tail vein injection of miR-214-3p. Moreover, miR-214-3p inhibited the expression of atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC) in Ang-II-treated mouse cardiomyocytes in vitro. Myocyte-specific enhancer factor 2C (MEF2C), which was increased in Ang-II-induced hypertrophic mouse myocardium and cardiomyocytes, was identified as a target gene of miR-214-3p. Functionally, miR-214-3p mimic, consistent with MEF2C siRNA, inhibited cell size increase and protein expression of ANP and β-MHC in Ang-II-treated mouse cardiomyocytes. The NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in cardiomyocytes. Taken together, our results revealed that MEF2C is a novel target of miR-214-3p, and attenuation of miR-214-3p expression may contribute to MEF2Cexpressionin cardiac hypertrophy.
doi:10.1038/srep36146
PMCID: PMC5087095  PMID: 27796324
4.  Role of regulatory b cells in neuroimmunologic disorders 
Journal of Neuroscience Research  2016;94(8):693-701.
B lymphocytes augment the immune response by producing antibodies and activating T cells by antigen presentation. Recent studies have highlighted a specific and functionally significant B‐cell subset that could downregulate excessive immune and inflammatory responses through a vast array of inhibitory cytokines, such as interleukin (IL)‐10 and transforming growth factor‐β (TGF‐β). This subset of B cells is generally referred to as regulatory B cells (Bregs). In addition, recent studies have shown that IL‐35‐producing Bregs also play a role in downregulation of immunity. Diverse phenotypes of Bregs have been proposed to underlie human disorders and their animal models. Most studies have focused on the role of different subsets of Bregs and Bregs‐associated molecules such as IL‐10, TGF‐β, and IL‐35 in the pathogenesis of neuroimmunologic disorders. Furthermore, Bregs exert regulatory function mainly through suppressing the differentiation of Th1/Th17 cells and promoting regulatory T‐cell expansion. Reduced presence of Bregs is reportedly associated with progression of several neuroimmunologic disorders. This Review summarizes the current knowledge on the role of Bregs in neuroimmunologic disorders, including multiple sclerosis, neuromyelitis optica, and myasthenia gravis. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
doi:10.1002/jnr.23749
PMCID: PMC5074285  PMID: 27112131
regulatory B cells; IL‐10; TGF‐β; IL‐35; neuroimmunologic disorders
5.  Characterization of a Highly Thermostable and Organic Solvent-Tolerant Copper-Containing Polyphenol Oxidase with Dye-Decolorizing Ability from Kurthia huakuii LAM0618T 
PLoS ONE  2016;11(10):e0164810.
Laccases are green biocatalysts that possess attractive advantages for the treatment of resistant environmental pollutants and dye effluents. A putative laccase-like gene, laclK, encoding a protein of 29.3 kDa and belonging to the Cu-oxidase_4 superfamily, was cloned and overexpressed in Escherichia coli. The purified recombinant protein LaclK (LaclK) was able to oxidize typical laccase substrates such as 2,6-dimethoxyphenol and l-dopamine. The characteristic adsorption maximums of typical laccases at 330 nm and 610 nm were not detected for LaclK. Cu2+ was essential for substrate oxidation, but the ratio of copper atoms/molecule of LaclK was determined to only be 1:1. Notably, the optimal temperature of LaclK was 85°C with 2,6-dimethoxyphenol as substrates, and the half-life approximately 3 days at 80°C. Furthermore, 10% (v/v) organic solvents (methanol, ethanol, isopropyl alcohol, butyl alcohol, Triton x-100 or dimethyl sulfoxide) could promote enzymatic activity. LaclK exhibited wide-spectrum decolorization ability towards triphenylmethane dyes, azo dyes and aromatic dyes, decolorizing 92% and 94% of Victoria Blue B (25 μM) and Ethyl Violet (25 μM), respectively, at a concentration of 60 U/L after 1 h of incubation at 60°C. Overall, we characterized a novel thermostable and organic solvent-tolerant copper-containing polyphenol oxidase possessing dye-decolorizing ability. These unusual properties make LaclK an alternative for industrial applications, particularly processes that require high-temperature conditions.
doi:10.1371/journal.pone.0164810
PMCID: PMC5065135  PMID: 27741324
6.  P16/INK4A up-regulation mediated by SIX6 defines retinal ganglion cell pathogenesis in glaucoma 
Molecular cell  2015;59(6):931-940.
SUMMARY
Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene P16/INK4A (cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in P16/INK4A expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing P16/INK4A expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.
Graphical abstract
doi:10.1016/j.molcel.2015.07.027
PMCID: PMC4648709  PMID: 26365380
7.  IL-35 improves Treg-mediated immune suppression in atherosclerotic mice 
Interleukin (IL)-35 is an anti-inflammatory cytokine that may have a protective role in atherosclerosis (AS). However, the exact role of IL-35 in the disease, and the etiology of AS, remain incompletely understood. The present study aimed to investigate whether exogenous IL-35 was able to attenuate the formation of atherosclerotic lesions in apoE−/− mice, and analyze alterations in the expression levels of forkhead box protein 3 (Foxp3) in peripheral blood and the lesions during the progression of AS. ApoE−/− mice were randomly divided into two groups that received either a basal diet (negative control group) or a high-fat diet (HFD) for 4 weeks. The HFD group was further subdivided into groups that received IL-35, atorvastatin or no treatment for 12 weeks. Diagnostic enzyme assay kits were applied for the detection of plasma lipids, and hematoxylin and eosin staining was used to analyze the severity of atherosclerotic lesions in apoE−/− mice. Immunohistochemistry and flow cytometry were performed to analyze the expression of Foxp3 in the plasma and atherosclerotic plaques. As compared with the negative control group, the plasma lipids were significantly increased, and the lesions were obviously formed, in the HFD groups. Furthermore, the area of the lesion was reduced in IL-35- and atorvastatin-treated groups, as compared with the AS control group. In addition, Foxp3 expression was upregulated in the plasma and lesions of the IL-35- and atorvastatin-treated groups, as compared with the AS control group. The present study demonstrated that IL-35 improved Treg-mediated immune suppression in atherosclerotic mice, thus suggesting that IL-35 may be a novel therapeutic target for AS.
doi:10.3892/etm.2016.3649
PMCID: PMC5038850  PMID: 27698748
interleukin-35; forkhead box protein 3; atherosclerosis; therapy
8.  Low Night Temperature Affects the Phloem Ultrastructure of Lateral Branches and Raffinose Family Oligosaccharide (RFO) Accumulation in RFO-Transporting Plant Melon (Cucumismelo L.) during Fruit Expansion 
PLoS ONE  2016;11(8):e0160909.
Due to the importance and complexity of photo assimilate transport in raffinose family oligosaccharide (RFO)-transporting plants such as melon, it is important to study the features of the transport structure (phloem) particularly of the lateral branches connecting the source leaves and the sink fruits, and its responses to environmental challenges. Currently, it is unclear to what extents the cold environmental temperature stress would alter the phloem ultrastructure and RFO accumulation in RFO-transporting plants. In this study, we firstly utilized electron microscopy to investigate the changes in the phloem ultrastructure of lateral branches and RFO accumulation in melons after being subjected to low night temperatures (12°C and 9°C). The results demonstrated that exposure to 9°C and 12°C altered the ultrastructure of the phloem, with the effect of 9°C being more obvious. The most obvious change was the appearance of plasma membrane invaginations in 99% companion cells and intermediary cells. In addition, phloem parenchyma cells contained chloroplasts with increased amounts of starch grains, sparse cytoplasm and reduced numbers of mitochondria. In the intermediary cells, the volume of cytoplasm was reduced by 50%, and the central vacuole was present. Moreover, the treatment at 9°C during the night led to RFO accumulation in the vascular bundles of the lateral branches and fruit carpopodiums. These ultrastructural changes of the transport structure (phloem) following the treatment at 9°C represented adaptive responses of melons to low temperature stresses. Future studies are required to examine whether these responses may affect phloem transport.
doi:10.1371/journal.pone.0160909
PMCID: PMC4976869  PMID: 27501301
9.  Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague–Dawley rats 
Respiratory Research  2016;17:85.
Background
The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague–Dawley (SD) rats.
Methods
We determined the effect of AgNPs generated from a spark generator (mass concentration: 600–800 μg/mm3; mean diameter: 13–16 nm; total lung doses: 8 [Low] and 26–28 [High] μg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function.
Results
In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains.
Conclusions
Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs.
doi:10.1186/s12931-016-0407-7
PMCID: PMC4950697  PMID: 27435725
Lungs; Silver nanospheres; Inhalation; Inflammation
10.  Assessment of Retinal and Choroidal Measurements in Chinese School-Age Children with Cirrus-HD Optical Coherence Tomography 
PLoS ONE  2016;11(7):e0158948.
Purpose
To evaluate retinal thickness (RT), retinal volume (RV) and choroidal thickness (ChT) in Chinese children using Cirrus-HD optical coherence tomography (OCT), and assess their associations with spherical equivalent (SE), age and gender.
Methods
This was a prospective study that recruited 193 healthy Chinese children (193 eyes) with no ophthalmic disease history between December 2012 and December 2013. RT and RV were acquired using OCT. Subfoveal ChT (SFCT) and ChT1-mm and 2-mm temporal, nasal, superior and inferior to the fovea were measured manually.
Results
RT in the inner temporal and nasal regionsdiffered significantly between refraction groups (both P<0.05). Significant differences were also found inSFCT andChT 1- and 2-mm inferior to the fovea (all P<0.05). RT differed significantly between males and females in the outer superior region in the emmetropia group (P<0.05). ChT differed significantly between males and females 2-mm temporal to the fovea in the emmetropia group (P<0.05), and 1-mm temporal to the fovea in the mild myopia group (P<0.05). SE correlated positively with RT in the inner temporal (r = 0.230),nasal (r = 0.252) and inferior (r = 0.149) regions (all P<0.05). Age correlated positively with foveolar (r = 0.169), total macular (r = 0.202), inner temporal (r = 0.237), inner nasal (r = 0.248), inner superior (r = 0.378) and inner inferior (r = 0.345) region thicknesses, and with RV (r = 0.207)(all P<0.05). SE correlated positively with SFCT (r = 0.195), and with ChT1-mm temporal (r = 0.167), 1- and 2-mm nasal (r = 0.144 and r = 0.162), 2-mm superior (r = 0.175), and 1- and 2-mm inferior (r = 0.207 and r = 0.238) to the fovea (all P<0.05). Age had no significant association with ChT.
Conclusions
SE, age and gender did not influence macular RT and ChT in most regions, and correlations of RT with age and ChT with SE were weak.
doi:10.1371/journal.pone.0158948
PMCID: PMC4938617  PMID: 27391015
11.  Treatment of a giant arteriovenous malformation associated with intracranial aneurysm rupture during pregnancy: A case report 
Arteriovenous malformations (AVMs) associated with aneurysm have rarely been reported in the literature. The present study reports the case of a 21-year-old pregnant female patient who presented with a subarachnoid hemorrhage and an intracranial hematoma located in the anterior end of the corpus callosum. Furthermore, an anterior cerebral aneurysm and an AVM were identified by digital subtraction angiography and magnetic resonance angiography. The aneurysm was clipped and the AVM was successfully removed by microsurgery. The diagnosis of AVM associated with an aneurysm was confirmed via intraoperative and postoperative pathological examinations. By performing a review of the current literature, issues and surgical considerations associated with AVM associated with aneurysm were analyzed.
doi:10.3892/etm.2016.3505
PMCID: PMC4997910  PMID: 27588055
arteriovenous malformation; aneurysm; treatment
12.  Equilibrium of sortase A dimerization on Staphylococcus aureus cell surface mediates its cell wall sorting activity 
Experimental Biology and Medicine  2015;241(1):90-100.
Staphylococcus aureus sortase A (SrtA) transpeptidase is a therapeutically important membrane-bound enzyme in Gram-positive bacteria, which organizes the covalently attached cell surface proteins on the peptidoglycan cell wall of the organism. Here, we report the direct observation of the highly selective homo-dimerization of SrtA on the cell membrane. To address the biological significance of the dimerization towards enzyme function, site-directed mutagenesis was performed to generate a SrtA mutant, which exists as monomer on the cell membrane. We observed that the cell surface display of adhesive proteins in S. aureus cells expressing monomeric SrtA mutant is more prominent than the cells expressing the wild-type enzyme. A cell-based invasion assay was also performed to evaluate the activities of wild-type SrtA and its monomeric mutant as well. Our data demonstrated that S. aureus cells expressing SrtA in monomeric form invade host mammalian cells more efficiently than those expressing wild-type SrtA in dimer-monomer equilibrium. The results suggested that the monomeric form of SrtA is more active than the dimeric form of the enzyme in terms of cell surface display of virulence factors for infection. This is the first study to present the oligomerization of SrtA and its related biological function on the cell membrane. Study of SrtA dimerization has implications for understanding its catalytic mechanism at the cellular level as well as the development of novel anti-infective agents.
doi:10.1177/1535370215592122
PMCID: PMC4935425  PMID: 26129884
Sortase A; dimerization; cell sorting activity; cell membrane
13.  Dissecting AI-2-mediated quorum sensing through C5-analogue synthesis and biochemical analysis 
Tetrahedron  2015;72(25):3593-3598.
Autoinducer-2 (AI-2)-mediated quorum sensing (QS) is utilised for both intra- and inter-species communication by a wide variety of bacteria. An understanding of the mechanism of this communication has the potential to elucidate new targets for antibacterial therapeutics. Herein, we report the synthesis of DPD analogues with modified dynamic equilibria and the evaluation of their behaviour in Gram-negative bacteria. None of the compounds showed modulation of QS in S. Typhimurium, and although no antagonism of V. harveyi was observed, chloro-analogue C5-Cl-DPD showed modest agonism in this marine bacterium. This raises the possibility that access to a cyclic form of DPD may not be required for AI-2-mediated QS in V. harveyi.
Graphical abstract
doi:10.1016/j.tet.2015.08.063
PMCID: PMC4915392  PMID: 27340303
14.  Characterization of virulent Newcastle disease viruses from vaccinated chicken flocks in Eastern China 
BMC Veterinary Research  2016;12:113.
Background
Newcastle disease (ND) is one of the most contagious and devastating diseases to poultry in the world. The causative agents are virulent strains of Newcastle disease virus (NDV), which belong to the genus Avulavirus, sub-family Paramyxoviridae, family Paramyxovirinae. Knowing the genomic and antigenic characteristics of virulent NDVs might contribute to ND control in China.
Results
The results showed that all of the virulent strains belonged sub-genotype VIId shared the same cleavage site 112RRQKR/F117 in the fusion protein. At least 69 % (38 of 55) of the NDV strains possessed E347K variation in the hemagglutinin-neuraminidase protein. The cross-neutralization tests confirmed that the strains harboring 347 K showed lower antigenic relatedness with LaSota. Furthermore, the immune-challenge experiment indicated that LaSota could not provide complete protection against infection with the E347K variant NDVs as the vaccinated birds were still able to be infected and shed virulent challenge viruses.
Conclusions
Currently, sub-genotype VIId NDVs are the prevalent virulent strains circulating among vaccinated chicken flocks in Eastern China. Our findings indicated that the E347K variation in HN gene would expand the antigenic difference with LaSota, which may be responsible for the increasing isolation rate of these strains from vaccinated chickens.
doi:10.1186/s12917-016-0732-6
PMCID: PMC4910237  PMID: 27305943
Virulent Newcastle disease virus; Sub-genotype VIId; E347K; Variation; Antigenic difference
15.  Association between maternal age at conception and risk of idiopathic clubfoot 
Acta Orthopaedica  2016;87(3):291-295.
Background and purpose
Results from case-control studies of maternal age at conception and risk of idiopathic clubfoot have been inconsistent. We conducted a meta-analysis to determine whether there is any association between maternal age at conception and the morbidity of idiopathic clubfoot.
Methods
We searched PubMed-MEDLINE, EMBASE, and the Cochrane Library up to June 2015 and supplemented the search with manual searches of the reference lists of the articles identified. 11 studies published between 1990 and 2015 were pooled. We investigated heterogeneity in maternal age and whether publication bias might have affected the results.
Results
Compared to a control group, maternal age at conception of between 20 and 24 years old was associated with an increased risk of occurrence of clubfoot (OR = 1.2, 95% CI: 1.1–1.4). No such association was found for the age groups of ≥ 35, 30–34, 25–29, and < 20 years. There was no heterogeneity in the age groups of ≥ 35, 30–34, and 20–24 years, moderate heterogeneity in the 25- to 29-year age group, and a large degree of heterogeneity in the group that was < 20 years of age. The prediction intervals for the age groups of 25–29 and < 20 years were 0.56 to 1.3 and −0.39 to 2.4, respectively. We found no evidence of significant publication bias.
Interpretation
From the results of this meta-analysis of 11 studies, maternal age at conception between 20 to 24 years of age appears to be associated with an increased risk of occurrence of clubfoot.
doi:10.3109/17453674.2016.1153359
PMCID: PMC4900088  PMID: 26901038
16.  Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat 
Frost tolerance is critical for wheat survival during cold winters. Natural variation for this trait is mainly associated with allelic differences at the VERNALIZATION 1 (VRN1) and FROST RESISTANCE 2 (FR2) loci. VRN1 regulates the transition between vegetative and reproductive stages and FR2, a locus including several tandemly duplicated C-REPEAT BINDING FACTOR (CBF) transcription factors, regulates the expression of Cold regulated genes. We identified sequence and copy number variation at these two loci among winter and spring wheat varieties and characterized their association with frost tolerance. We identified two FR-A2 haplotypes – ‘FR-A2-S’ and ‘FR-A2-T’ – distinguished by two insertion/deletions and ten single nucleotide polymorphisms within the CBF-A12 and CBF-A15 genes. Increased copy number of CBF-A14 was frequently associated with the FR-A2-T haplotypes and with higher CBF14 transcript levels in response to cold. Factorial ANOVAs revealed significant interactions between VRN1 and FR-A2 for frost tolerance in both winter and spring panels suggesting a crosstalk between vernalization and cold acclimation pathways. The model including these two loci and their interaction explained 32.0 and 20.7% of the variation in frost tolerance in the winter and spring panels, respectively. The interaction was validated in a winter wheat F4:5 population segregating for both genes. Increased VRN-A1 copy number was associated with improved frost tolerance among varieties carrying the FR-A2-T allele but not among those carrying the FR-A2-S allele. These results suggest that selection of varieties carrying the FR-A2-T allele and three copies of the recessive vrn-A1 allele would be a good strategy to improve frost tolerance in wheat.
doi:10.1007/s00122-014-2290-2
PMCID: PMC4876961  PMID: 24626953
VRN-A1; CBF; haplotype; copy number variation; frost tolerance; Triticum aestivum
17.  Implementation of dispersion-free slow acoustic wave propagation and phase engineering with helical-structured metamaterials 
Nature Communications  2016;7:11731.
The ability to slow down wave propagation in materials has attracted significant research interest. A successful solution will give rise to manageable enhanced wave–matter interaction, freewheeling phase engineering and spatial compression of wave signals. The existing methods are typically associated with constructing dispersive materials or structures with local resonators, thus resulting in unavoidable distortion of waveforms. Here we show that, with helical-structured acoustic metamaterials, it is now possible to implement dispersion-free sound deceleration. The helical-structured metamaterials present a non-dispersive high effective refractive index that is tunable through adjusting the helicity of structures, while the wavefront revolution plays a dominant role in reducing the group velocity. Finally, we numerically and experimentally demonstrate that the helical-structured metamaterials with designed inhomogeneous unit cells can turn a normally incident plane wave into a self-accelerating beam on the prescribed parabolic trajectory. The helical-structured metamaterials will have profound impact to applications in explorations of slow wave physics.
There is great interest in slow wave propagation for a variety of applications. Here, Zhu et al. present a dispersion-free helical-structured metamaterial that implements acoustic wave deceleration at broad bandwidth and demonstrates specially designed phase modulation to incident sound through helicity tuning.
doi:10.1038/ncomms11731
PMCID: PMC4876457  PMID: 27198887
18.  Nanoparticle biointerfacing via platelet membrane cloaking 
Nature  2015;526(7571):118-121.
Development of functional nanoparticles can be encumbered by unanticipated material properties and biological events, which can negatively impact nanoparticle effectiveness in complex, physiologically relevant systems1–3. Despite the advances in bottom-up nanoengineering and surface chemistry, reductionist functionalization approaches remain inadequate in replicating the complex interfaces present in nature and cannot avoid exposure of foreign materials. Here we report on the preparation of polymeric nanoparticles enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to a variety of disease-relevant substrates4–7. The resulting nanoparticles possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. As compared to uncoated particles, the platelet membrane-cloaked nanoparticles have reduced cellular uptake by macrophage-like cells and are absent of particle-induced complement activation in autologous human plasma. The cloaked nanoparticles also display platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures as well as enhanced binding to platelet-adhering pathogens. In an experimental rat model of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic nanoparticles. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach in developing functional nanoparticles for disease-targeted delivery.
doi:10.1038/nature15373
PMCID: PMC4871317  PMID: 26374997
19.  Serum expression levels of microRNA-382-3p, −598-3p, −1246 and −184 in breast cancer patients 
Oncology Letters  2016;12(1):269-274.
The purpose of the present study was to investigate the serum levels of microRNA (miRNA/miR)-382-3p, −598-3p, −1246 and −184 in breast cancer patients and to assess their feasibility as biomarkers for breast cancer screening. Serum samples were obtained from 100 breast cancer patients and 40 age-matched healthy control subjects in Taizhou Central Hospital (Taizhou, Zhejiang, China) between January 2013 and September 2014. The serum expression levels of miR-382-3p, −598-3p, −1246 and −184 were determined by stem-loop reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were drawn to evaluate the sensitivity and specificity of the serum miRNA expression levels for the screening of breast cancer. miR-382-3p and −1246 were significantly upregulated in the serum of the breast cancer patients, while miR-598-3p and −184 were significantly downregulated. The sensitivity and specificity to detect breast cancer were as follows: miR-382-3p, 52.0 and 92.5%; miR-598-3p, 95.0 and 85.0%; miR-1246, 93.0 and 75.0%; and miR-184, 87.5 and 71.0%, respectively. The expression levels of the four serum miRNAs were not correlated with the patients' clinical stage. In summary, miR-382-3p, −598-3p, −1246 and −184 are all involved in the development of breast cancer, and are promising biomarkers for breast cancer detection.
doi:10.3892/ol.2016.4582
PMCID: PMC4906595  PMID: 27347136
breast cancer; microRNAs; quantitative polymerase chain reaction; biomarker
20.  Protrusive waves guide 3D cell migration along nanofibers 
The Journal of Cell Biology  2015;211(3):683-701.
Reductionist approaches based on 3D fibers reveal that single-cell migration along fibers is driven by lateral actin-based waves for various cell types.
In vivo, cells migrate on complex three-dimensional (3D) fibrous matrices, which has made investigation of the key molecular and physical mechanisms that drive cell migration difficult. Using reductionist approaches based on 3D electrospun fibers, we report for various cell types that single-cell migration along fibronectin-coated nanofibers is associated with lateral actin-based waves. These cyclical waves have a fin-like shape and propagate up to several hundred micrometers from the cell body, extending the leading edge and promoting highly persistent directional movement. Cells generate these waves through balanced activation of the Rac1/N-WASP/Arp2/3 and Rho/formins pathways. The waves originate from one major adhesion site at leading end of the cell body, which is linked through actomyosin contractility to another site at the back of the cell, allowing force generation, matrix deformation and cell translocation. By combining experimental and modeling data, we demonstrate that cell migration in a fibrous environment requires the formation and propagation of dynamic, actin based fin-like protrusions.
doi:10.1083/jcb.201501106
PMCID: PMC4639865  PMID: 26553933
21.  Interleukin-1β-Targeted Vaccine Improves Glucose Control and β-Cell Function in a Diabetic KK-Ay Mouse Model 
PLoS ONE  2016;11(5):e0154298.
Interleukin-1β (IL-1β) has been implicated as a key proinflammatory cytokine involved in the pancreatic islet inflammation of type 2 diabetes mellitus (T2DM). Excess IL-1β impairs islet function by inducing insulin resistance and β-cell apoptosis. Therefore, specifically reducing IL-1β activity provides a therapeutic improvement for T2DM by sustaining the inhibition of IL-1β-mediated islet inflammation. In this study, we developed an IL-1β-targeted epitope peptide vaccine adjuvanted with polylactic acid microparticles (1βEPP) and applied it to a diabetic KK-Ay mouse model. Results showed that the 1βEPP elicited high antibody responses, which neutralized the biological activity of IL-1β, and induced barely detectable inflammatory activity. 1βEPP immunization reduced body weight gain, protected KK-Ay mice from hyperglycemia, improved glucose tolerance and insulin sensitivity, and decreased the serum levels of free fatty acids, total cholesterol and triglyceride. Moreover, 1βEPP restored β-cell mass; inhibited β-cell apoptosis; decreased the expression of IL-1β; and interrupted NF-κB activation by reducing IKKβ and pRelA levels. These studies indicated that the IL-1β-targeted vaccine may be a promising immunotherapeutic for T2DM treatment.
doi:10.1371/journal.pone.0154298
PMCID: PMC4859560  PMID: 27152706
22.  Development of an antibody that neutralizes soluble IgE and eliminates IgE expressing B cells 
Cellular and Molecular Immunology  2015;13(3):391-400.
Immunoglobulin E (IgE) plays a key role in allergic asthma and is a clinically validated target for monoclonal antibodies. Therapeutic anti-IgE antibodies block the interaction between IgE and the Fc epsilon (Fcε) receptor, which eliminates or minimizes the allergic phenotype but does not typically curtail the ongoing production of IgE by B cells. We generated high-affinity anti-IgE antibodies (MEDI4212) that have the potential to both neutralize soluble IgE and eliminate IgE-expressing B-cells through antibody-dependent cell-mediated cytotoxicity. MEDI4212 variants were generated that contain mutations in the Fc region of the antibody or alterations in fucosylation in order to enhance the antibody's affinity for FcγRIIIa. All MEDI4212 variants bound to human IgE with affinities comparable to the wild-type (WT) antibody. Each variant was shown to inhibit the interaction between IgE and FcεRI, which translated into potent inhibition of FcγRI-mediated function responses. Importantly, all variants bound similarly to IgE at the surface of membrane IgE expressing cells. However, MEDI4212 variants demonstrated enhanced affinity for FcγRIIIa including the polymorphic variants at position 158. The improvement in FcγRIIIa binding led to increased effector function in cell based assays using both engineered cell lines and class switched human IgE B cells. Through its superior suppression of IgE, we anticipate that effector function enhanced MEDI4212 may be able to neutralize high levels of soluble IgE and provide increased long-term benefit by eliminating the IgE expressing B cells before they differentiate and become IgE secreting plasma cells.
doi:10.1038/cmi.2015.19
PMCID: PMC4856805  PMID: 25942513
antibody therapeutic; anti-IgE; asthma; IgE; monoclonal antibody
23.  The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners 
Oncotarget  2016;7(17):23740-23756.
The DEK oncogene is overexpressed in various cancers and overexpression of DEK correlates with poor clinical outcome. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis, a process essential for tumor growth and metastasis. However, whether DEK enhances tumor angiogenesis remains unclear. Here, we show that DEK is a key regulator of VEGF expression and tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that DEK promoted VEGF transcription in breast cancer cells (MCF7, ZR75-1 and MDA-MB-231) by directly binding to putative DEK-responsive element (DRE) of the VEGF promoter and indirectly binding to hypoxia response element (HRE) upstream of the DRE through its interaction with the transcription factor hypoxia-inducible factor 1α (HIF-1α), a master regulator of tumor angiogenesis and growth. DEK is responsible for recruitment of HIF-1α and the histone acetyltransferase p300 to the VEGF promoter. DEK-enhanced VEGF increases vascular endothelial cell proliferation, migration and tube formation as well as angiogenesis in the chick chorioallantoic membrane. DEK promotes tumor angiogenesis and growth in nude mice in HIF-1α-dependent and -independent manners. Immunohistochemical staining showed that DEK expression positively correlates with the expression of VEGF and microvessel number in 58 breast cancer patients. Our data establish DEK as a sequence-specific binding transcription factor, a novel coactivator for HIF-1α in regulation of VEGF transcription and a novel promoter of angiogenesis.
doi:10.18632/oncotarget.8060
PMCID: PMC5029660  PMID: 26988756
angiogenesis; VEGF; DEK; HIF-1α; tumor growth
24.  Clinical investigation of speech signal features among patients with schizophrenia 
Shanghai Archives of Psychiatry  null;28(2):95-102.
Background
A new area of interest in the search for biomarkers for schizophrenia is the study of the acoustic parameters of speech called 'speech signal features'. Several of these features have been shown to be related to emotional responsiveness, a characteristic that is notably restricted in patients with schizophrenia, particularly those with prominent negative symptoms.
Aim
Assess the relationship of selected acoustic parameters of speech to the severity of clinical symptoms in patients with chronic schizophrenia and compare these characteristics between patients and matched healthy controls.
Methods
Ten speech signal features-six prosody features, formant bandwidth and amplitude, and two spectral features-were assessed using 15-minute speech samples obtained by smartphone from 26 inpatients with chronic schizophrenia (at enrollment and 1 week later) and from 30 healthy controls (at enrollment only). Clinical symptoms of the patients were also assessed at baseline and 1 week later using the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impression-Schizophrenia scale.
Results
In the patient group the symptoms were stable over the 1-week interval and the 1-week test-retest reliability of the 10 speech features was good (intraclass correlation coefficients [ICC] ranging from 0.55 to 0.88). Comparison of the speech features between patients and controls found no significant differences in the six prosody features or in the formant bandwidth and amplitude features, but the two spectral features were different: the Mel-frequency cepstral coefficient (MFCC) scores were significantly lower in the patient group than in the control group, and the linear prediction coding (LPC) scores were significantly higher in the patient group than in the control group. Within the patient group, 10 of the 170 associations between the 10 speech features considered and the 17 clinical parameters considered were statistically significant at the p<0.05 level.
Conclusions
This study provides some support for the potential value of speech signal features as indicators (i.e., biomarkers) of the severity of negative symptoms in schizophrenia, but more detailed studies using larger samples of more diverse patients that are followed over time will be needed before the potential utility of such acoustic parameters of speech can be fully assessed.
doi:10.11919/j.issn.1002-0829.216025
PMCID: PMC5004093  PMID: 27605865
schizophrenia; speech; speech signal features; biomarkers; negative symptoms; China
25.  BEDAM Binding Free Energy Predictions for the SAMPL4 Octa-Acid Host Challenge 
The Binding Energy Distribution Analysis Method (BEDAM) protocol has been employed as part of the SAMPL4 blind challenge to predict the binding free energies of a set of octa-acid host-guest complexes. The resulting predictions were consistently judged as some of the most accurate predictions in this category of the SAMPL4 challenge in terms of quantitative accuracy and statistical correlation relative to the experimental values, which were not known at the time the predictions were made. The work has been conducted as part of a hands-on graduate class laboratory session. Collectively the students, aided by automated setup and analysis tools, performed the bulk of the calculations and the numerical and structural analysis. The success of the experiment confirms the reliability of the BEDAM methodology and it shows that physics-based atomistic binding free energy estimation models, when properly streamlined and automated, can be successfully employed by non-specialists.
doi:10.1007/s10822-014-9795-2
PMCID: PMC4832917  PMID: 25726024

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