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1.  Imaging Spatiotemporal Activities of ZAP-70 in Live T Cells Using a FRET-based Biosensor 
Annals of biomedical engineering  2016;44(12):3510-3521.
The zeta-chain-associated protein kinase 70 kDa (ZAP-70), a member of the spleen tyrosine kinase (Syk) family, plays an essential role in early T cell receptor (TCR) signaling. Defects in ZAP-70 lead to impaired thymocyte development and peripheral T cell activation. To better understand its activation dynamics and regulation, we visualized ZAP-70 activities in single live T cells with a Förster resonance energy transfer (FRET)-based biosensor, which was designed for probing kinase activities of the Syk family. We observed in Jurkat E6.1 T cells rapid and specific FRET changes following anti-CD3 stimulation and subsequent piceatannol inhibition. The initiation of ZAP-70 activation was prompt (within 10 sec) and correlates with the accompanied intracellular calcium elevation, as revealed by simultaneous imaging of the biosensor and calcium. Different from the previously reported ZAP-70 activation in the immunological synapse and the opposite pole (anti-synapse), we have observed rapid and sustained ZAP-70 activation only at the synapse with superantigen-pulsed Raji B cells. Furthermore, ZAP-70 signaling was impaired by cholesterol depletion, further supporting the importance of membrane organization in TCR signaling. Together our results provide a direct characterization of the spatiotemporal features of ZAP-70 activity in real time at subcellular levels.
doi:10.1007/s10439-016-1683-6
PMCID: PMC5114152  PMID: 27384937
TCR signaling; Syk family kinase; Immunological synapse; Membrane microdomains
2.  A Co3O4-CDots-C3N4 three component electrocatalyst design concept for efficient and tunable CO2 reduction to syngas 
Nature Communications  2017;8:1828.
Syngas, a CO and H2 mixture mostly generated from non-renewable fossil fuels, is an essential feedstock for production of liquid fuels. Electrochemical reduction of CO2 and H+/H2O is an alternative renewable route to produce syngas. Here we introduce the concept of coupling a hydrogen evolution reaction (HER) catalyst with a CDots/C3N4 composite (a CO2 reduction catalyst) to achieve a cheap, stable, selective and efficient route for tunable syngas production. Co3O4, MoS2, Au and Pt serve as the HER component. The Co3O4-CDots-C3N4 electrocatalyst is found to be the most efficient among the combinations studied. The H2/CO ratio of the produced syngas is tunable from 0.07:1 to 4:1 by controlling the potential. This catalyst is highly stable for syngas generation (over 100 h) with no other products besides CO and H2. Insight into the mechanisms balancing between CO2 reduction and H2 evolution when applying the HER-CDots-C3N4 catalyst concept is provided.
Simultaneous electrochemical reduction of CO2 and H+/H2O is an attractive renewable route to produce syngas mixtures. Here, the authors introduce a ternary Co3O4-CDots-C3N4 electrocatalyst that couples hydrogen evolution and CO2 reduction catalysts and achieves cheap, stable and tunable production of syngas.
doi:10.1038/s41467-017-01893-7
PMCID: PMC5705642  PMID: 29184053
3.  Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion 
Experimental cell research  2016;349(1):85-94.
Cell-matrix adhesion complexes are multi-protein structures linking the extracellular matrix (ECM) to the cytoskeleton. They are essential to both cell motility and function by bidirectionally sensing and transmitting mechanical and biochemical stimulations. Several types of cell-matrix adhesions have been identified and they share many key molecular components, such as integrins and actin-integrin linkers. Mechanochemical coupling between ECM molecules and the actin cytoskeleton has been observed from the single cell to the single molecule level and from immune cells to neuronal cells. However, the mechanisms underlying force regulation of integrin-mediated mechanotransduction still need to be elucidated. In this review article, we focus on integrin-mediated adhesions and discuss force regulation of cell-matrix adhesions and key adaptor molecules, three different force-dependent behaviors, and molecular mechanisms for mechanochemical coupling in force regulation.
doi:10.1016/j.yexcr.2016.10.001
PMCID: PMC5101173  PMID: 27720950
Mechanotransduction; Cell-matrix adhesion; Integrin; Talin; Vinculin; Actin; Force regulation
4.  Local cellular and cytokine cues in the spleen regulate in situ T cell receptor affinity as well as function and fate of CD8+ T cells 
Immunity  2016;45(5):988-998.
Summary
T cells rapidly undergo contraction upon viral clearance, but how T cell function and fate are determined during this phase is unclear. During the contraction phase of an acute infection with lymphocytic choriomeningitis virus, we found that virus-specific CD8+ T cells within the splenic red pulp (RP) had higher two-dimensional (2D) effective affinity than those within the white pulp (WP). This increased antigen recognition of RP-derived CD8+ T cells correlated with more efficient target cell killing and improved control of viremia. FoxP3+ regulatory T cells and cytokine TGF-β limited the 2D-affinity in the WP during the contraction phase. Anatomical location drove gene expression patterns in CD8+ T cells that led to preferential differentiation of memory precursor WP T cells into long-term memory cells. These results highlight that intricate regulation of T cell function and fate is determined by anatomic compartmentalization during the early immune contraction phase.
Graphical abstract
doi:10.1016/j.immuni.2016.10.024
PMCID: PMC5131716  PMID: 27851926
5.  Altered apoptosis/autophagy and epigenetic modifications cause the impaired postimplantation octaploid embryonic development in mice 
Cell Cycle  2016;16(1):82-90.
ABSTRACT
Polyploids are pervasive in plants and have large impacts on crop breeding, but natural polyploids are rare in animals. Mouse diploid embryos can be induced to become tetraploid by blastomere fusion at the 2-cell stage and tetraploid embryos can develop to the blastocyst stage in vitro. However, there is little information regarding mouse octaploid embryonic development and precise mechanisms contributing to octaploid embryonic developmental limitations are unknown. To investigate the genetic and epigenetic mechanisms underlying octaploid embryonic development, we generated mouse octaploid embryos and evaluated the in vitro/in vivo developmental potential. Here we show that octaploid embryos can develop to the blastocyst stage in vitro, but all fetus impaired immediately after implantation. Our results indicate that cell lineage specification of octaploid embryo was disorganized. Furthermore, these octaploid embryos showed increased apoptosis as well as alterations in epigenetic modifications when compared with diploid embryos. Thus, our cumulative data provide cues for why mouse octaploid embryonic development is limited and its failed postimplantation development.
doi:10.1080/15384101.2016.1252884
PMCID: PMC5270531  PMID: 27830977
apoptosis; embryo development; epigenetics; octaploid
6.  A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-associated Mutation 
Structure (London, England : 1993)  2016;24(11):1898-1906.
SUMMARY
The majority of amyotrophic lateral sclerosis (ALS)-related mutations in the enzyme Cu, Zn superoxide dismutase (SOD1), as well as a post-translational modification, glutathionylation, destabilize the protein and lead to a misfolded oligomer that is toxic to motor neurons. The biophysical role of another physiological SOD1 modification, T2-phosphorylation, has remained a mystery. Here, we find that a phosphomimetic mutation, T2D, thermodynamically stabilizes SOD1 even in the context of a strongly SOD1-destabilizing mutation, A4V, one of the most prevalent and aggressive ALS-associated mutations in North America. This stabilization protects against formation of toxic SOD oligomers and positively impacts motor neuron survival in cellular assays. We solve the crystal structure of T2D-SOD1 and explain its stabilization effect using DMD simulations. These findings imply that T2-phosphorylation may be a plausible innate cellular protection response against SOD1-induced cytotoxicity, and stabilizing the SOD1 native conformation might offer us viable pharmaceutical strategies against currently incurable ALS.
Graphical Abstract
doi:10.1016/j.str.2016.08.011
PMCID: PMC5093072  PMID: 27667694
7.  Dual Biomembrane Force Probe enables single-cell mechanical analysis of signal crosstalk between multiple molecular species 
Scientific Reports  2017;7:14185.
Conventional approaches for studying receptor-mediated cell signaling, such as the western blot and flow cytometry, are limited in three aspects: 1) The perturbing preparation procedures often alter the molecules from their native state on the cell; 2) Long processing time before the final readout makes it difficult to capture transient signaling events (<1 min); 3) The experimental environments are force-free, therefore unable to visualize mechanical signals in real time. In contrast to these methods in biochemistry and cell biology that are usually population-averaged and non-real-time, here we introduce a novel single-cell based nanotool termed dual biomembrane force probe (dBFP). The dBFP provides precise controls and quantitative readouts in both mechanical and chemical terms, which is particularly suited for juxtacrine signaling and mechanosensing studies. Specifically, the dBFP allows us to analyze dual receptor crosstalk by quantifying the spatiotemporal requirements and functional consequences of the up- and down-stream signaling events. In this work, the utility and power of the dBFP has been demonstrated in four important dual receptor systems that play key roles in immunological synapse formation, shear-dependent thrombus formation, and agonist-driven blood clotting.
doi:10.1038/s41598-017-13793-3
PMCID: PMC5660210  PMID: 29079742
8.  The cellular environment regulates in situ kinetics of T-cell receptor interaction with peptide major histocompatibility complex 
European journal of immunology  2015;45(7):2099-2110.
T cells recognize antigens at the two-dimensional (2D) interface with antigen-presenting cells (APCs), which trigger T-cell effector functions. T-cell functional outcomes correlate with 2D kinetics of membrane-embedded T-cell receptors (TCRs) binding to surface-tethered peptide-major histocompatibility complex molecules (pMHCs). However, most studies have measured TCR–pMHC kinetics for recombinant TCRs in 3D by surface plasmon resonance, which differs drastically from 2D measurements. Here, we compared pMHC dissociation from native TCR on the T-cell surface to recombinant TCR immobilized on glass surface or in solution. Force on TCR–pMHC bonds regulated their lifetimes differently for native than recombinant TCRs. Perturbing the cellular environment suppressed 2D on-rates but had no effect on 2D off-rate regardless of whether force was applied. In contrast, for the TCR interacting with its monoclonal antibody, the 2D on-rate was insensitive to cellular perturbations and the force-dependent off-rates were indistinguishable for native and recombinant TCRs. These data present novel features of TCR–pMHC kinetics that are regulated by the cellular environment, underscoring the limitations of 3D kinetics in predicting T-cell functions and calling for further elucidation of the underlying molecular and cellular mechanisms that regulate 2D kinetics in physiological settings.
doi:10.1002/eji.201445358
PMCID: PMC5642113  PMID: 25944482
Adhesion; Cellular immunology; Molecular immunology; TCRs; T cells
9.  Association between fibrinogen level and the severity of coronary stenosis in 418 male patients with myocardial infarction younger than 35 years old 
Oncotarget  2017;8(46):81361-81368.
Fibrinogen (Fib) is a useful marker for predicting the severity of coronary artery disease (CAD) in adult population. However, whether Fib can be a predictor for the presence and severity of CAD in very young MI patients (≤35 years old) remains to be determined. A total of 418 males from 61,863 patients with MI who were under 35 years old were sequentially recruited in our study. The patients were divided into two main groups and three subgroups according to coronary angiograph and Gensini score (GS) system: no coronary artery stenosis (group A), the results of the coronary artery stenosis (group B); low GS, intermediate GS and high GS. Data indicated that Fib, body mass index, current smoking, white blood cell count (WBCC) and GS were significantly higher in group B than those in group A (all P < 0.01). Moreover, there were significant differences in Fib, mean age, diabetes mellitus, family history of CAD, WBCC, left ventricular ejection fraction, and GS between high GS and low GS subgroups (all P < 0.01). A positive correlation between Fib levels and GS was found (r = 0.242, p < 0.001). Receiver operating characteristics curve analysis demonstrated that the best cut-off level of Fib predicting the severity of coronary stenosis was 3.475g/L (sensitivity 64%; specificity 70%) and the area under the curve was 0.656. Fib was also independently associated with high GS (OR=2.173, 95%CI 1.011–4.670, P = 0.047) after adjusting for potential confounders. In conclusion, Fib is significantly related to the presence and severity of coronary stenosis in male patients with MI under 35 years old.
doi:10.18632/oncotarget.18578
PMCID: PMC5655290
fibrinogen; myocardial infarction; coronary artery; very young patients; Gensini score
10.  Iron(II)-Catalyzed Intermolecular Aminofluorination of Unfunctionalized Olefins Using Fluoride Ion 
Journal of the American Chemical Society  2016;138(35):11360-11367.
We herein report a new catalytic method for intermolecular olefin aminofluorination using earth-abundant iron catalysts and nucleophilic fluoride ion. This method tolerates a broad range of unfunctionalized olefins, especially nonstyrenyl olefins that are incompatible with existing olefin aminofluorination methods. This new iron-catalyzed process directly converts readily available olefins to internal vicinal fluoro carbamates with high regioselectivity (N vs F), many of which are difficult to prepare using known methods. Preliminary mechanistic studies demonstrate that it is possible to exert asymmetric induction using chiral iron catalysts and that both an iron-nitrenoid and carbocation species may be reactive intermediates.
Graphical Abstract
doi:10.1021/jacs.6b07221
PMCID: PMC5050046  PMID: 27529196
11.  Practical Synthetic Procedures for the Iron-Catalyzed Intermolecular Olefin Aminohydroxylation Using Functionalized Hydroxylamines 
Synthesis  2016;48(18):3031-3041.
A set of practical synthetic procedures for the iron-catalyzed intermolecular olefin aminohydroxylation reactions in gram scale is reported. In these transformations, a bench-stable functionalized hydroxylamine is applied as the amination reagent. This method is compatible with a broad range of synthetically valuable olefins including those that are incompatible with the existing aminohydroxylation methods. It also provides valuable amino alcohol building blocks with regio- and stereo-chemical arrays that are complementary to known methods.
Graphical abstract
doi:10.1055/s-0035-1562515
PMCID: PMC5226647  PMID: 28090124
iron; alkenes; oxidation; amination; asymmetric catalysis
12.  Quantitative reproducibility analysis for identifying reproducible targets from high-throughput experiments 
BMC Systems Biology  2017;11:73.
Background
High-throughput assays are widely used in biological research to select potential targets. One single high-throughput experiment can efficiently study a large number of candidates simultaneously, but is subject to substantial variability. Therefore it is scientifically important to performance quantitative reproducibility analysis to identify reproducible targets with consistent and significant signals across replicate experiments. A few methods exist, but all have limitations.
Methods
In this paper, we propose a new method for identifying reproducible targets. Considering a Bayesian hierarchical model, we show that the test statistics from replicate experiments follow a mixture of multivariate Gaussian distributions, with the one component with zero-mean representing the irreproducible targets.
Results
A target is thus classified as reproducible or irreproducible based on its posterior probability belonging to the reproducible components. We study the performance of our proposed method using simulations and a real data example.
Conclusion
The proposed method is shown to have favorable performance in identifying reproducible targets compared to other methods.
doi:10.1186/s12918-017-0444-y
PMCID: PMC5553769  PMID: 28800759
Reproducibility; High-throughput experiment; Bayesian classification; Empirical Bayes; Gaussian mixture; EM algorithm
13.  Constitutive Lck activity drives sensitivity differences between CD8+ memory T cell subsets 
CD8+ T cells develop increased sensitivity following antigen experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that more than 50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with less than 20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM. Further, we observed superior cytotoxic effector function in TEM compared with TCM, and provide evidence that this results from a lower probability of TCM reaching threshold signaling due to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8+ TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase (Csk), and use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM. Together, this work demonstrates a role for constitutive Lck activity in controlling antigen sensitivity, and suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications.
doi:10.4049/jimmunol.1600178
PMCID: PMC4935560  PMID: 27271569
15.  Free fatty acids and cardiovascular outcome: a Chinese cohort study on stable coronary artery disease 
doi:10.1186/s12986-017-0195-1
PMCID: PMC5485743
Free fatty acids; Cardiovascular events; Stable coronary artery disease
16.  Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity 
Science (New York, N.Y.)  2017;355(6331):1320-1324.
Notch receptor activation initiates cell fate decisions, and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5 angstrom crystal structure of the extracellular interacting regions of Notch1 complexed with an engineered, high-affinity variant of Jagged1 (Jag1) reveals a binding interface that extends ∼120 angstroms along five consecutive domains of each protein. O-Linked fucose modifications on Notch1 EGF domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch domains are favored in binding to Jag1 compared to those that bind to the Delta-like 4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate amongst Notch ligands and potentiate Notch signaling.
doi:10.1126/science.aaf9739
PMCID: PMC5459593  PMID: 28254785
17.  Late Neolithic phytolith and charcoal records of human activities and vegetation change in Shijiahe culture, Tanjialing site, China 
PLoS ONE  2017;12(5):e0177287.
There is significant archaeological evidence marking the collapse of the Shijiahe culture in the middle reaches of the Yangtze River in China during the late Neolithic Period. However, the causes for this cultural collapse remain unclear. Our sedimentary records from a 3.3 m long profile and 76 phytolith and charcoal samples from the Tanjialing archaeological sites provide records of interactions between an ancient culture and vegetation change. During the early Shijiahe culture (c, 4850–4400 cal BP), the climate was warm and humid. Fire was intensively used to clear the vegetation. In the mid-period of the Shijiahe culture (c, 4400–4200 cal BP), the climate became slightly dry-cold and this was accompanied by decreasing water, leading to settlements. From c, 4200 cal BP, severe drought eroded the economic foundation of rice-cultivation. These conditions forced people to abandon the Shijiahe ancient city to find water in other regions, leading to the collapse of the Shijiahe culture.
doi:10.1371/journal.pone.0177287
PMCID: PMC5438134  PMID: 28542219
18.  L-selectin mechanochemistry restricts neutrophil priming in vivo 
Nature Communications  2017;8:15196.
Circulating neutrophils must avoid premature activation to prevent tissue injury. The leukocyte adhesion receptor L-selectin forms bonds with P-selectin glycoprotein ligand-1 (PSGL-1) on other leukocytes and with peripheral node addressin (PNAd) on high endothelial venules. Mechanical forces can strengthen (catch) or weaken (slip) bonds between biological molecules. How these mechanochemical processes influence function in vivo is unexplored. Here we show that mice expressing an L-selectin mutant (N138G) have altered catch bonds and prolonged bond lifetimes at low forces. Basal lymphocyte homing and neutrophil recruitment to inflamed sites are normal. However, circulating neutrophils form unstable aggregates and are unexpectedly primed to respond robustly to inflammatory mediators. Priming requires signals transduced through L-selectin N138G after it engages PSGL-1 or PNAd. Priming enhances bacterial clearance but increases inflammatory injury and enlarges venous thrombi. Thus, L-selectin mechanochemistry limits premature activation of neutrophils. Our results highlight the importance of probing how mechanochemistry functions in vivo.
Neutrophil adhesion is tightly regulated to enforce protective immunity, but it is unclear how mechanochemical processes such as catch bonds and slip bonds modulate neutrophils in vivo. Here the authors show that a point mutation in the adhesion molecule L-selectin alters mechanochemical regulation to affect neutrophil functions in mice.
doi:10.1038/ncomms15196
PMCID: PMC5437312  PMID: 28497779
19.  Therapeutic role of glutamine in management of radiation enteritis: a meta-analysis of 13 randomized controlled trials 
Oncotarget  2017;8(18):30595-30605.
Objective
To systematically evaluate the clinical efficacy of glutamine in treating radiation enteritis in cancer patients treated with radiotherapy.
Methods
Electronic databases including Pubmed, Embase, the Cochrane library, and CNKI were systematically searched, until April 2016. Randomized controlled trials (RCT) of glutamine in the treatment of radiation enteritis in cancer patients were searched, and RevMan 5.3 software was used for Meta-analysis.
Results
A total of 13 RCTs were included, involving 979 patients. The results of meta-analysis showed that the total efficacy of glutamine was higher for patients with radiation enteritis compared with that in control group, however, there was no statistically significant difference(OR = 3.07, 95%CI: 0.79-11.96; P > 0.05). The combined ORs for all 5 grades(from grade 0 to grade 4) of radiation enteritis in patients receiving glutamine were 2.06, 1.35, 0.55, 0.62 and 0.59, respectively(P > 0.05 for all). Glutamine also failed to significantly improve the symptoms of radiation enteritis in terms of tenesmus, abdominal cramping and blood in bowel movement(P > 0.05).
Conclusions
Implementation of glutamine fails to improve the severity and symptoms in patients with radiation enteritis.
doi:10.18632/oncotarget.15741
PMCID: PMC5444768  PMID: 28427169
radiation enteritis; glutamine; radiotherapy; meta-analysis; evidence based medicine
20.  An optimized transit peptide for effective targeting of diverse foreign proteins into chloroplasts in rice 
Scientific Reports  2017;7:46231.
Various chloroplast transit peptides (CTP) have been used to successfully target some foreign proteins into chloroplasts, but for other proteins these same CTPs have reduced localization efficiencies or fail completely. The underlying cause of the failures remains an open question, and more effective CTPs are needed. In this study, we initially observed that two E.coli enzymes, EcTSR and EcGCL, failed to be targeted into rice chloroplasts by the commonly-used rice rbcS transit peptide (rCTP) and were subsequently degraded. Further analyses revealed that the N-terminal unfolded region of cargo proteins is critical for their localization capability, and that a length of about 20 amino acids is required to attain the maximum localization efficiency. We considered that the unfolded region may alleviate the steric hindrance produced by the cargo protein, by functioning as a spacer to which cytosolic translocators can bind. Based on this inference, an optimized CTP, named RC2, was constructed. Analyses showed that RC2 can more effectively target diverse proteins, including EcTSR and EcGCL, into rice chloroplasts. Collectively, our results provide further insight into the mechanism of CTP-mediated chloroplastic localization, and more importantly, RC2 can be widely applied in future chloroplastic metabolic engineering, particularly for crop plants.
doi:10.1038/srep46231
PMCID: PMC5387683  PMID: 28397859
21.  Novel and traditional lipid-related biomarkers and their combinations in predicting coronary severity 
Scientific Reports  2017;7:360.
We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend <0.05). However, gender stratification analyses showed similar associations between lipids and GS in men but not in women. Secondly, multiple logistic regression analyses indicated that the 12 indices were predictive for high GS (≥24) but not for low GS (1–23) compared with normal coronary (GS = 0) except for TG (neither) and apoB (both). Finally, we found that interactions between two indices with mutually exclusive composition were positively associated with GS status except for couples of TC + apoC3, apoB/PCSK9/apoC3 + sdLDL-C. Concordant elevations in the two showed the highest predictive values for high GS (all p for trend <0.05). Therefore, lipid biomarkers were associated with coronary severity and their adverse changes in combination emerged greater risks in men but not in women.
doi:10.1038/s41598-017-00499-9
PMCID: PMC5428477  PMID: 28336922
22.  Effects of glucocorticoid on the expression and regulation of aquaporin 5 in the paranasal sinus of rats with chronic rhinosinusitis 
Aquaporins (AQPs) are water-specific membrane channel proteins that regulate water homeostasis for cells and organisms. AQP5 serves an important role in the maintenance of mucosal water homeostasis, and potentially contributes to mucosal edema and inflammation formation in chronic rhinosinusitis (CRS). The aim of the present study was to explore the expression pattern of AQP5 and the effect of glucocorticoids on AQP5 expression in rats with CRS. The rats were randomly divided into three equal groups, as follows: CRS, dexamethasone (dexa) treatment and control groups. A polyvinyl acetal material containing Staphylococcus aureus was inserted into the left nasal cavity of each rat from the CRS and dexa groups. On the 90th post-operative day, the dexa group received dexamethasone (2 mg/kg/day) via intraperitoneal injection for 7 days. The controls did not receive any treatment. The expression of AQP5 in the sinonasal mucosa was determined using immunohistochemistry and quantitative PCR. The immunoreactivities of AQP5 were primarily noted in the epithelial lining and glandular cells, the vascular endothelium and in the goblet cells in the sinonasal mucosa. The AQP5 mRNA expression level was significantly higher in the dexa group than in the control and CRS groups (P=0.006 and P=0.014, respectively). However, no significant difference was indicated between the CRS and control groups (P=0.760). In conclusion, the current study suggests that glucocorticoids induce AQP5 expression in the sinonasal mucosa of CRS rats, which highlights AQP5 as a potential target in the diagnosis and treatment of CRS.
doi:10.3892/etm.2017.4215
PMCID: PMC5443270
aquaporin 5; chronic rhinosinusitis; glucocorticoid
23.  3D-Printing of Meso-structurally Ordered Carbon Fiber/Polymer Composites with Unprecedented Orthotropic Physical Properties 
Scientific Reports  2017;7:43401.
Here we report the first example of a class of additively manufactured carbon fiber reinforced composite (AMCFRC) materials which have been achieved through the use of a latent thermal cured aromatic thermoset resin system, through an adaptation of direct ink writing (DIW) 3D-printing technology. We have developed a means of printing high performance thermoset carbon fiber composites, which allow the fiber component of a resin and carbon fiber fluid to be aligned in three dimensions via controlled micro-extrusion and subsequently cured into complex geometries. Characterization of our composite systems clearly show that we achieved a high order of fiber alignment within the composite microstructure, which in turn allows these materials to outperform equivalently filled randomly oriented carbon fiber and polymer composites. Furthermore, our AM carbon fiber composite systems exhibit highly orthotropic mechanical and electrical responses as a direct result of the alignment of carbon fiber bundles in the microscale which we predict will ultimately lead to the design of truly tailorable carbon fiber/polymer hybrid materials having locally programmable complex electrical, thermal and mechanical response.
doi:10.1038/srep43401
PMCID: PMC5338294  PMID: 28262669
24.  Effect of Prior Atorvastatin Treatment on the Frequency of Hospital Acquired Pneumonia and Evolution of Biomarkers in Patients with Acute Ischemic Stroke: A Multicenter Prospective Study 
BioMed Research International  2017;2017:5642704.
Objective. To investigate whether prior treatment of atorvastatin reduces the frequency of hospital acquired pneumonia (HAP). Methods. Totally, 492 patients with acute ischemic stroke and Glasgow Coma Scale ≤ 8 were enrolled in this study. Subjects were assigned to prior atorvastatin treatment group (n = 268, PG) and no prior treatment group (n = 224, NG). All the patients were given 20 mg atorvastatin every night during their hospital stay. HAP frequency and 28-day mortality were measured. Levels of inflammatory biomarkers [white blood cell (WBC), procalcitonin (PCT), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)] were tested. Results. There was no significant difference in the incidence of HAP between PG and NG (25.74% versus. 24.55%, p > 0.05) and 28-day mortality (50.72% versus 58.18%, p > 0.05). However, prior statin treatment did modify the mortality of ventilator associated pneumonia (VAP) (36.54% versus 58.14%, p = 0.041) and proved to be a protective factor (HR, 0.564; 95% CI, 0.310~0.825, p = 0.038). Concentrations of TNF-α and IL-6 in PG VAP cases were lower than those in NG VAP cases (p < 0.01). Conclusions. Prior atorvastatin treatment in patients with ischemic stroke was associated with a lower concentration of IL-6 and TNF-α and improved the outcome of VAP. This clinical study has been registered with ChiCTR-ROC-17010633 in Chinese Clinical Trial Registry.
doi:10.1155/2017/5642704
PMCID: PMC5357518
25.  miR-21 and KLF4 jointly augment epithelial-mesenchymal transition via the Akt/ERK1/2 pathway 
International Journal of Oncology  2017;50(4):1109-1115.
miR-21 induces epithelial-mesenchymal transition (EMT) of human cholangiocarcinoma (CCA) cells. However, the mechanism by which this occurs remains unclear. In the present study, high throughput platform was employed to detect the genes that are differential expressed in QBC939 cells transfected with a hsa-miR-21 antagomir or control vectors. The EMT-related Krüppel-like factor 4 (KLF4) gene was down-regulated after miR-21 was knocked down. Overexpression of miR-21 upregulated KLF4, Akt, ERK and mesenchymal cell markers (N-cadherin and vimentin), downregulated the expression of epithelial cell marker E-cadherin and reduced cell migration and invasion. Immunohistochemistry showed that KLF4, pAkt and pERK were upregulated in tumor xenografts transfected with miR-21 mimics. Inhibitors of the PI3K-Akt and ERK1/2 pathways, LY294002 and U0126, significantly suppressed the EMT phenotype. The present data demonstrated that overexpression of miR-21, accompanied with KLF4, augmented the EMT via inactivation of Akt and ERK1/2 pathways. In conclusion, we have identified a novel mechanism that may be targeted in an attempt to relieve the malignant biological behavior of CCA cells.
doi:10.3892/ijo.2017.3876
PMCID: PMC5363879  PMID: 28197636
cholangiocarcinoma; KLF4; miR-21; signal pathway; epithelial-mesenchymal transition

Results 1-25 (169)