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1.  Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2 
IL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM.
In the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants.
Myocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration.
Elevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.
PMCID: PMC4580368  PMID: 26394923
Diabetic cardiomyopathy; Endoplasmic reticulum stress; Apoptosis; IL-1; IRAK-2
2.  Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma 
OncoTargets and therapy  2015;8:2645-2650.
To evaluate whether the addition of two biological markers (MYC and BCL-2 protein overexpression) improves the stratification of high-risk patients with diffuse large B-cell lymphoma (DLBCL).
Seven risk factors were identified at diagnosis, and a maximum of 7 points were assigned to each patient. The patients were classified according to four risk groups: low (0–1), low-intermediate (2–3), high-intermediate (4), and high (5–7). Only high-risk patients with DLBCL were included in this analysis. We retrospectively examined 20 cases from 2008 to 2013 at the Nanjing Drum Tower Hospital.
The median expression of MYC protein was 60%, and 17 of 20 (65%) evaluable cases overexpressed MYC. The median expression of BCL-2 protein was also 60%. Eighteen of 20 (90%) evaluable cases showed BCL-2 overexpression. Additionally, 12 out of 20 cases (60%) demonstrated coexpression of MYC and BCL-2 proteins. The percentages of overall survival and progression-free survival at the median follow-up time (36 months) were 33.3%±16.1% and 16.9%±13.5%, respectively. By comparison, nine, four, and 20 patients were classified as high risk based on the International Prognostic Index (IPI), National Comprehensive Cancer Network(NCCN)-IPI, and revised IPI criteria, respectively. According to the IPI and NCCN-IPI stratification, the risk groups demonstrated closely overlapping survival curves. In addition, four out of 20 cases were identified as low-intermediate risk according to the NCCN-IPI criteria.
The addition of MYC and BCL-2 protein expression to the IPI could identify a subset of DLBCL patients with high-risk clinicopathological characteristics and poor clinical outcome.
PMCID: PMC4583112  PMID: 26425100
diffuse large B-cell lymphoma; MYC; BCL-2; International Prognostic Index
3.  Calycosin-7-O-β-D-glucoside promotes oxidative stress-induced cytoskeleton reorganization through integrin-linked kinase signaling pathway in vascular endothelial cells 
Dysfunction of vascular endothelium is implicated in many pathological situations. Cytoskeleton plays an importance role in vascular endothelial permeability barrier and inflammatory response. Many Chinese herbs have the endothelial protective effect, of which, “Astragalus membranaceus” is a highly valued herb for treatment of cardiovascular and renal diseases in traditional Chinese medicine, In this study, we tested whether calycosin-7-O-β-D-glucoside (Calycosin), a main effective monomer component of “Astragalus membranaceus”, could protect endothelial cells from bacterial endotoxin (LPS)-induced cell injury.
Endothelial cell injury was induced by exposing human umbilical vein endothelial cells (HUVECs) to LPS. The effects of calycosin on LPS-induced changes in cell viability, apoptosis rate, cell migration, nitric oxide synthase (NOS), generationof intracellular reactive oxygen species (ROS) and cytoskeleton organization were determined. Microarray assay was employed to screen the possible gene expression change. Based on the results of microarray assay, the expression profile of genes involved in Rho/ROCK pathway and AKT pathway were further evaluated with quantitative real-time RT-PCR or western blot methods.
Calycosin improved cell viability, suppressed apoptosis and protected the cells from LPS-induced reduction in cell migration and generation of ROS, protein level of NOS at a comparable magnitude to that of Y27632 and valsartan. Similar to Y27632 and valsartan, Calycosin, also neutralized LPS-induced actomyosin contraction and vinculin protein aggregation. Microarray assay, real-time PCR and western blot results revealed that LPS induced expression of FN, ITG A5, RhoA, PI3K (or PIP2 in western blotting), FAK, VEGF and VEGF R2, and inhibited expression of MLCP. We believed multiple pathways involved in the regulation of calycosin on HUVECs. Calycosin are considered to be able to activate MLCP through promoting the generation of NO, decreasing PMLC, suppressing the cytoskeleton remodeling caused by activation of Rho/ROCK pathway and inhibiting AKT pathway by decreasing VEGF, VEGF R2 and PI3K level.
Calycosin protected HUVEC from LPS-induced endothelial injury, possibly through suppression of Rho/ROCK pathway and regulation of AKT pathway.
PMCID: PMC4562353  PMID: 26346982
Calycosin-7-O-β-D-glucoside; HUVECs; Rho/ROCK pathway; AKT pathway
4.  The CO2 Storage Capacity of the Intercalated Diaminoalkane Graphene Oxides: A Combination of Experimental and Simulation Studies 
To study the effect of interlayer spacing of pillared graphene oxides (GOs) on CO2 uptake, we have obtained CO2 isotherms with respect to the interlayer distance of pillared graphene oxide by both experimental and simulation methods. Interlayer distances of GO were modulated by intercalation of three kinds of diaminoalkanes with a different number of carbon atoms (NH2(CH2)nNH2, n = 4, 8, and 12) as pillars. The intercalated GOs (IGOs) and their reduced products (RIGOs) are characterized using a variety of approaches such as X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and N2 adsorption. Gas adsorption performance shows that the CO2 uptake of IGOs and RIGOs decrease with the increase of the interlayer distance at low pressure, while at high pressure, the adsorption capacity of IGO-12 has a larger growth than those of both IGO-4 and IGO-8 and surpasses them at 30 bar. The contribution of the electrostatics to CO2 adsorption is larger than that of van der Waals force at low pressures, whereas for the high pressures, the adsorption is dominated by van der Waals force.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-015-1026-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4529426  PMID: 26253866
Intercalated graphite oxides; CO2 adsorption; Grand canonical Monte Carlo simulation
5.  Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells 
The Journal of Clinical Investigation  2015;125(5):2007-2020.
Rapidly cycling fetal and neonatal hematopoietic stem cells (HSCs) generate a pool of quiescent adult HSCs after establishing hematopoiesis in the bone marrow. We report an essential role for the trithorax group gene absent, small, or homeotic 1-like (Ash1l) at this developmental transition. Emergence and expansion of Ash1l-deficient fetal/neonatal HSCs were preserved; however, in young adult animals, HSCs were profoundly depleted. Ash1l-deficient adult HSCs had markedly decreased quiescence and reduced cyclin-dependent kinase inhibitor 1b/c (Cdkn1b/1c) expression and failed to establish long-term trilineage bone marrow hematopoiesis after transplantation to irradiated recipients. Wild-type HSCs could efficiently engraft when transferred to unirradiated, Ash1l-deficient recipients, indicating increased availability of functional HSC niches in these mice. Ash1l deficiency also decreased expression of multiple Hox genes in hematopoietic progenitors. Ash1l cooperated functionally with mixed-lineage leukemia 1 (Mll1), as combined loss of Ash1l and Mll1, but not isolated Ash1l or Mll1 deficiency, induced overt hematopoietic failure. Our results uncover a trithorax group gene network that controls quiescence, niche occupancy, and self-renewal potential in adult HSCs.
PMCID: PMC4463197  PMID: 25866973
Hematology; Stem cells; Transplantation
6.  Protective Effects of Hong Shan Capsule against Lethal Total-Body Irradiation-Induced Damage in Wistar Rats 
Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage.
PMCID: PMC4581280  PMID: 26274957
Hong Shan capsule (HSC); lethal total-body irradiation; radioprotection; gene expression; signaling pathways
7.  Spontaneous restoration of transplantation tolerance after acute rejection 
Nature Communications  2015;6:7566.
Transplantation is a cure for end-stage organ failure but, in the absence of pharmacological immunosuppression, allogeneic organs are acutely rejected. Such rejection invariably results in allosensitization and accelerated rejection of secondary donor-matched grafts. Transplantation tolerance can be induced in animals and a subset of humans, and enables long-term acceptance of allografts without maintenance immunosuppression. However, graft rejection can occur long after a state of transplantation tolerance has been acquired. When such an allograft is rejected, it has been assumed that the same rules of allosensitization apply as to non-tolerant hosts and that immunological tolerance is permanently lost. Using a mouse model of cardiac transplantation, we show that when Listeria monocytogenes infection precipitates acute rejection, thus abrogating transplantation tolerance, the donor-specific tolerant state re-emerges, allowing spontaneous acceptance of a donor-matched second transplant. These data demonstrate a setting in which the memory of allograft tolerance dominates over the memory of transplant rejection.
An infection can break the immune tolerance of a transplanted organ, resulting in its rejection. Here the authors show that the immunological memory of transplantation tolerance dominates over the memory of allograft rejection, so that another organ transplanted later can be spontaneously accepted.
PMCID: PMC4498267  PMID: 26151823
8.  Cryptochromes and Hormone Signal Transduction under Near-Zero Magnetic Fields: New Clues to Magnetic Field Effects in a Rice Planthopper 
PLoS ONE  2015;10(7):e0132966.
Although there are considerable reports of magnetic field effects (MFE) on organisms, very little is known so far about the MFE-related signal transduction pathways. Here we establish a manipulative near-zero magnetic field (NZMF) to investigate the potential signal transduction pathways involved in MFE. We show that exposure of migratory white-backed planthopper, Sogatella furcifera, to the NZMF results in delayed egg and nymphal development, increased frequency of brachypterous females, and reduced longevity of macropterous female adults. To understand the changes in gene expression underlying these phenotypes, we examined the temporal patterns of gene expression of (i) CRY1 and CRY2 as putative magnetosensors, (ii) JHAMT, FAMeT and JHEH in the juvenile hormone pathway, (iii) CYP307A1 in the ecdysone pathway, and (iv) reproduction-related Vitellogenin (Vg). The significantly altered gene expression of CRY1 and CRY2 under the NZMF suggest their developmental stage-specific patterns and potential upstream location in magnetic response. Gene expression patterns of JHAMT, JHEH and CYP307A1 were consistent with the NZMF-triggered delay in nymphal development, higher proportion of brachypterous female adults, and the shortened longevity of macropterous female adults, which show feasible links between hormone signal transduction and phenotypic MFE. By conducting manipulative NZMF experiments, our study suggests an important role of the geomagnetic field (GMF) in modulating development and physiology of insects, provides new insights into the complexity of MFE-magnetosensitivity interactions, and represents an initial but crucial step forward in understanding the molecular basis of cryptochromes and hormone signal transduction involved in MFE.
PMCID: PMC4501744  PMID: 26173003
9.  A Pterin-Dependent Signaling Pathway Regulates a Dual-Function Diguanylate Cyclase-Phosphodiesterase Controlling Surface Attachment in Agrobacterium tumefaciens 
mBio  2015;6(4):e00156-15.
The motile-to-sessile transition is an important lifestyle switch in diverse bacteria and is often regulated by the intracellular second messenger cyclic diguanylate monophosphate (c-di-GMP). In general, high c-di-GMP concentrations promote attachment to surfaces, whereas cells with low levels of signal remain motile. In the plant pathogen Agrobacterium tumefaciens, c-di-GMP controls attachment and biofilm formation via regulation of a unipolar polysaccharide (UPP) adhesin. The levels of c-di-GMP in A. tumefaciens are controlled in part by the dual-function diguanylate cyclase-phosphodiesterase (DGC-PDE) protein DcpA. In this study, we report that DcpA possesses both c-di-GMP synthesizing and degrading activities in heterologous and native genetic backgrounds, a binary capability that is unusual among GGDEF-EAL domain-containing proteins. DcpA activity is modulated by a pteridine reductase called PruA, with DcpA acting as a PDE in the presence of PruA and a DGC in its absence. PruA enzymatic activity is required for the control of DcpA and through this control, attachment and biofilm formation. Intracellular pterin analysis demonstrates that PruA is responsible for the production of a novel pterin species. In addition, the control of DcpA activity also requires PruR, a protein encoded directly upstream of DcpA with a predicted molybdopterin-binding domain. PruR is hypothesized to be a potential signaling intermediate between PruA and DcpA through an as-yet-unidentified mechanism. This study provides the first prokaryotic example of a pterin-mediated signaling pathway and a new model for the regulation of dual-function DGC-PDE proteins.
Pathogenic bacteria often attach to surfaces and form multicellular communities called biofilms. Biofilms are inherently resilient and can be difficult to treat, resisting common antimicrobials. Understanding how bacterial cells transition to the biofilm lifestyle is essential in developing new therapeutic strategies. We have characterized a novel signaling pathway that plays a dominant role in the regulation of biofilm formation in the model pathogen Agrobacterium tumefaciens. This control pathway involves small metabolites called pterins, well studied in eukaryotes, but this is the first example of pterin-dependent signaling in bacteria. The described pathway controls levels of an important intracellular second messenger (cyclic diguanylate monophosphate) that regulates key bacterial processes such as biofilm formation, motility, and virulence. Pterins control the balance of activity for an enzyme that both synthesizes and degrades the second messenger. These findings reveal a complex, multistep pathway that modulates this enzyme, possibly identifying new targets for antibacterial intervention.
PMCID: PMC4488946  PMID: 26126849
10.  Contraception and Unintended Pregnancy among Unmarried Female University Students: A Cross-sectional Study from China 
PLoS ONE  2015;10(6):e0130212.
This study aims to understand the level of contraceptive knowledge and attitudes towards contraception, and then to explore the association between the contraceptive behavior and unintended pregnancy in unmarried female university students in China. A cross-sectional study was conducted of university students in 49 universities across 7 cities in China from September 2007 to January 2008. We distributed 74,800 questionnaires, of which 69,842 were returned. In this paper, the data from 35,383 unmarried female university students were analyzed. The prevalence of sexual intercourse in unmarried female university students was 10.2%. The prevalence of unintended pregnancy in those sexually active female university students, was 31.8%. Among students with pregnancy, 53.5% experienced two or more pregnancies. 28.3% of the students with sexual intercourse reported that they always adopted contraceptive methods, and of those 82.9% chose to use male condoms. The majority (83.9%) of students with unintended pregnancy chose to terminate the latest pregnancy by surgical abortion or medical abortion. The contraceptive knowledge level of students who experienced unintended pregnancy was lower than those who did not. In China, about one third of unmarried female students with sexual intercourse experience unintended pregnancy. A variety of contraceptive methods are adopted, but the frequency of contraceptive use is low. Most of unmarried female students who experienced unintended pregnancy would choose to terminate the pregnancy with surgical or medical abortion. University students, especially the ones who have experienced unintended pregnancy, lack contraceptive and reproductive health knowledge.
PMCID: PMC4474598  PMID: 26091505
11.  Successful Treatment of Idiopathic Eosinophilic Peritonitis by Oral Corticosteroid Therapy in a Continuous Ambulatory Peritoneal Dialysis Patient 
Eosinophilic peritonitis is a well-described complication of peritoneal dialysis and is often associated with either a reaction to the dialysis system constituent (tubing, sterilant or solution) or an underlying bacterial or fungal reaction. We report a case of eosinophilic peritonitis, which is treated by oral prednisone acetate therapy. A 43-year-old female patient developed end-stage renal disease and underwent continuous ambulatory peritoneal dialysis for 2.5 years. The patient received 2,000 ml of 1.5% dialysis solution (PD2) with three exchanges daily and 2,000 ml of 2.5% PDF overnight (PD2). She went to the consultation because of a constant turbid peritoneal dialysis effluent for 3 months without abdominal pain. Repeated peritoneal effluent samples showed an elevated white blood cell count of 500 cells/mm3, with 87% eosinophils. The peripheral blood test revealed a white blood cell count of 3.8 × 109/l, with 32.2% eosinophils. Etiology like bacterial and fungal infection was excluded by peritoneal fluid culture. Turbidness persisted in spite of diagnostic antibiotic treatment. Given the fact that we found a significant elevation of eosinophils in the peripheral blood and an absolute increase in the eosinophil count of >30/mm3 in dialysis fluid (up to 400/mm3 in our patient), obvious dialysate effluent turbidness, negative results of repeated peritoneal fluid cultures, inefficacy of antibiotic therapy, and negativity of serum tumor and immunological markers, we drew the conclusion that the patient had idiopathic eosinophilic peritonitis. Oral corticosteroid was administered at once (20 mg prednisone acetate daily), which was gradually weaned off and stopped over an 8-week period. Afterwards, the dialysis effluent became clear, and the cytological analysis showed that the white blood cell count decreased to 1 × 106/l, with no eosinophils. This case reminds us that the diagnosis of eosinophilic peritonitis should be considered when repeated cultures are always negative and the turbidness of peritoneal dialysis effluent persists in spite of an antibiotic therapy.
PMCID: PMC4519605  PMID: 26266243
Idiopathic eosinophilic peritonitis; Continuous ambulatory peritoneal dialysis; Turbidness; Corticosteroid therapy
12.  Design of Asymmetric Particles Containing a Charged Interior and a Neutral Surface Charge: Comparative Study on in Vivo Circulation of Polyelectrolyte Microgels 
Lowering the modulus of hydrogel particles could enable them to bypass in vivo physical barriers that would otherwise filter particles with similar size but higher modulus. Incorporation of electrolyte moieties into the polymer network of hydrogel particles to increase the swelling ratio is a straightforward and quite efficient way to decrease the modulus. In addition, charged groups in hydrogel particles can also help secure cargoes. However, the distribution of charged groups on the surface of a particle can accelerate the clearance of particles. Herein, we developed a method to synthesize highly swollen microgels of precise size with near-neutral surface charge while retaining interior charged groups. A strategy was employed to enable a particle to be highly cross-linked with very small mesh size, and subsequently PEGylated to quench the exterior amines only without affecting the internal amines. Acidic degradation of the cross-linker allows for swelling of the particles to microgels with a desired size and deformability. The microgels fabricated demonstrated extended circulation in vivo compared to their counterparts with a charged surface, and could potentially be utilized in in vivo applications including as oxygen carriers or nucleic acid scavengers.
PMCID: PMC4227716  PMID: 24941029
13.  Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis 
Scientific Reports  2015;5:11251.
The differential expression of microRNAs (miRNAs) in plasma of gastric cancer (GC) patients may serve as a diagnostic biomarker. A total of 33 miRNAs were identified through the initial screening phase (3 GC pools vs. 1 normal control (NC) pool) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel (miRCURY-Ready-to-Use-PCR-Human-panel-I + II-V1.M). By qRT-PCR, these miRNAs were further assessed in training (30 GC VS. 30 NCs) and testing stages (71 GC VS. 61 NCs). We discovered a plasma miRNA signature including five up-regulated miRNAs (miR-185, miR-20a, miR-210, miR-25 and miR-92b), and this signature was evaluated to be a potential diagnostic marker of GC. The areas under the receiver operating characteristic curve of the signature were 0.86, 0.74 and 0.87 for the training, testing and the external validation stages (32 GC VS. 18 NCs), respectively. The five miRNAs were consistently dysregulated in GC tissues (n = 30). Moreover, miR-185 was decreased while miR-20a, miR-210 and miR-92b were increased in arterial plasma (n = 38). However, none of the miRNAs in the exosomes showed different expression between 10 GC patients and 10 NCs. In conclusion, we identified a five-miRNA signature in the peripheral plasma which could serve as a non-invasive biomarker in detection of GC.
PMCID: PMC4462022  PMID: 26059512
14.  Prognostic Value and Clinicopathology Significance of MicroRNA-200c Expression in Cancer: A Meta-Analysis 
PLoS ONE  2015;10(6):e0128642.
MiR-200c has been shown to be related to cancer formation and progression. However, the prognostic and clinicopathologic significance of miR-200c expression in cancer remain inconclusive. We carried out this systematic review and meta-analysis to investigate the prognostic value of miR-200c expression in cancer. Pooled hazard ratios (HRs) of miR-200c for overall survival (OS) and progression-free survival (PFS) were calculated to measure the effective value of miR-200c expression on prognosis. The association between miR-200c expression and clinical significance was measured by odds ratios (ORs). Twenty-three studies were included in our meta-analysis. We found that miR-200c was not significantly correlated with OS (HR = 1.41, 95%Cl: 0.95-2.10; P = 0.09) and PFS (HR = 1.12, 95%Cl: 0.68-1.84; P = 0.67) in cancer. In our subgroup analysis, higher expression of miR-200c was significantly associated with poor OS in blood (HR = 2.10, 95%CI: 1.52-2.90, P<0.00001). Moreover, in clinicopathology analysis, miR-200c expression in blood was significantly associated with TNM stage, lymph node metastasis and distant metastasis. MiR-200c may have the potential to become a new blood biomarker to monitor cancer prognosis and progression.
PMCID: PMC4452703  PMID: 26035744
15.  Predicting Attitudes toward Press- and Speech Freedom across the U.S.A.: A Test of Climato-Economic, Parasite Stress, and Life History Theories 
PLoS ONE  2015;10(6):e0125241.
National surveys reveal notable individual differences in U.S. citizens’ attitudes toward freedom of expression, including freedom of the press and speech. Recent theoretical developments and empirical findings suggest that ecological factors impact censorship attitudes in addition to individual difference variables (e.g., education, conservatism), but no research has compared the explanatory power of prominent ecological theories. This study tested climato-economic, parasite stress, and life history theories using four measures of attitudes toward censoring the press and offensive speech obtained from two national surveys in the U.S.A. Neither climate demands nor its interaction with state wealth—two key variables for climato-economic theory—predicted any of the four outcome measures. Interstate parasite stress significantly predicted two, with a marginally significant effect on the third, but the effects became non-significant when the analyses were stratified for race (as a control for extrinsic risks). Teenage birth rates (a proxy of human life history) significantly predicted attitudes toward press freedom during wartime, but the effect was the opposite of what life history theory predicted. While none of the three theories provided a fully successful explanation of individual differences in attitudes toward freedom of expression, parasite stress and life history theories do show potentials. Future research should continue examining the impact of these ecological factors on human psychology by further specifying the mechanisms and developing better measures for those theories.
PMCID: PMC4451980  PMID: 26030736
16.  Development of genetic tools for Myceliophthora thermophila 
BMC Biotechnology  2015;15:35.
The thermophilic filamentous fungus Myceliophthora thermophila has many suitable characteristics for industrial biotechnology and could be a promising new chassis system for synthetic biology, particularly the ATCC 42464 strain, whose genome was sequenced in 2011. However, metabolic engineering of this strain using genetic approaches has not been reported owing to a lack of genetic tools for this organism.
In the present study, we developed a high efficiency Agrobacterium tumefaciens mediated transformation system for M. thermophila, including an approach for targeted gene deletion using green fluorescence protein (GFP) as a marker for selection. Up to 145 transformants per 105 conidia were obtained in one transformation plate. Moreover, a ku70 deletion mutant was constructed in the ATCC 42464 background using the tools developed in present study and subsequently characterized. The ku70 deletion construct was designed using resistance to phosphinothricin as the selection marker. Additionally, a GFP-encoding cassette was incorporated that allowed for the selection of site-specific (no fluorescence) or ectopic (fluorescence) integration of the ku70 construct. Transformants with ectopically integrated ku70 deletion constructs were therefore identified using the fluorescent signal of GFP. PCR and Southern blotting analyses of non-fluorescent putative ku70 deletion transformants revealed all 11 tested transformants to be correct deletions. The deletion frequency in a pool of 116 transformants analyzed was 58 %. Moreover, the homologous rate improved about 3 folds under ku70 mutant using the pyrG as a test gene to disrupt in M. thermophila.
We successfully developed an efficient transformation and target gene disruption approach for M. thermophila ATCC 42464 mediated by A. tumefaciens. The tools and the ku70 deletion strain developed here should advance the development of M. thermophila as an industrial host through metabolic engineering and accelerate the elucidation of the mechanism of rapid cellulose degradation in this thermophilic fungus.
PMCID: PMC4446196  PMID: 26013561
Myceliophthora thermophila; Agrobacterium tumefaciens; genetic transformation; ku70
17.  A Virulence Essential CRN Effector of Phytophthora capsici Suppresses Host Defense and Induces Cell Death in Plant Nucleus 
PLoS ONE  2015;10(5):e0127965.
Phytophthora capsici is a soil-borne plant pathogen with a wide range of hosts. The pathogen secretes a large array of effectors during infection of host plants, including Crinkler (CRN) effectors. However, it remains largely unknown on the roles of these effectors in virulence especially in P. capsici. In this study, we identified a cell death-inducing CRN effector PcCRN4 using agroinfiltration approach. Transient expression of PcCRN4 gene induced cell death in N. benthamiana, N. tabacum and Solanum lycopersicum. Overexpression of the gene in N. benthamiana enhanced susceptibility to P. capsici. Subcellular localization results showed that PcCRN4 localized to the plant nucleus, and the localization was required for both of its cell death-inducing activity and virulent function. Silencing PcCRN4 gene in P. capsici significantly reduced pathogen virulence. The expression of the pathogenesis-related gene PR1b in N. benthamiana was significantly induced when plants were inoculated with PcCRN4-silenced P. capsici transformant compared to the wilt-type. Callose deposits were also abundant at sites inoculated with PcCRN4-silenced transformant, indicating that silencing of PcCRN4 in P. capsici reduced the ability of the pathogen to suppress plant defenses. Transcriptions of cell death-related genes were affected when PcCRN4-silenced line were inoculated on Arabidopsis thaliana, suggesting that PcCRN4 may induce cell death by manipulating cell death-related genes. Overall, our results demonstrate that PcCRN4 is a virulence essential effector and it needs target to the plant nucleus to suppress plant immune responses.
PMCID: PMC4444017  PMID: 26011314
18.  Better short-term efficacy of treating severe flail chest with internal fixation surgery compared with conservative treatments 
The objective of the study is to provide evidence for selecting the best treatment approach for severe flail chest by comparing surgical and conservative treatments.
This is a retrospective study in which 32 patients with severe flail chest were treated in the Fujian Provincial Hospital (China) between July 2007 and July 2012 with surgical internal rib fixation (n = 17) or conservative treatments (n = 15). Mechanical ventilation time, intensive care unit (ICU) stay time, pulmonary infection, antibiotic treatment duration, acute physiology and chronic health evaluation II (APACHE II) scores 7 and 14 days after trauma, rate of tracheostomy, and rate of endotracheal re-intubation were compared.
One patient died in the conservative treatment group. Better short-term outcomes were observed in the surgery group, such as total mechanical ventilation time (10.5 ± 3.7 vs. 13.7 ± 4.4 days, P = 0.03), ICU stay (15.9 ± 5.0 vs. 19.6 ± 5.0 days, P = 0.05), pulmonary infection rate (58.8 % vs. 93.3 %, P = 0.02), and APACHE II scores on the 14th day (6.5 ± 3.8 vs. 10.1 ± 4.7, P = 0.02). No difference was observed in the therapeutic time of antibiotics, rate of tracheostomy, and the rate of endotracheal re-intubation between the two groups.
Results suggest that internal fixation surgery resulted in better outcomes in the management of severe flail chest compared with conservative treatments.
PMCID: PMC4443506  PMID: 26003405
Flail chest; Surgery; Internal fixation; Trauma; Conservative treatment
19.  Synergistic Effect of S224P and N383D Substitutions in the PA of H5N1 Avian Influenza Virus Contributes to Mammalian Adaptation 
Scientific Reports  2015;5:10510.
The adaptation of H5N1 avian influenza viruses to human poses a great threat to public health. Previous studies indicate the adaptive mutations in viral polymerase of avian influenza viruses are major contributors in overcoming the host species barrier, with the majority of mammalian adaptive mutations occurring in the PB2 protein. However, the adaptive mutations in the PA protein of the H5N1 avian influenza virus are less defined and poorly understood. In this study, we identified the synergistic effect of the PA/224P + 383D of H5N1 avian influenza viruses and its ability to enhance the pathogenicity and viral replication in a mammalian mouse model. Interestingly, the signature of PA/224P + 383D mainly exists in mammalian isolates of the H5N1 influenza virus and pdmH1N1 influenza virus, providing a potential pathway for the natural adaptation to mammals which imply the effects of natural adaptation to mammals. Notably, the mutation of PA/383D, which is highly conserved in avian influenza viruses, increases the polymerase activity in both avian and human cells, and may have roles in maintaining the avian influenza virus in their avian reservoirs, and jumping species to infect humans.
PMCID: PMC4441148  PMID: 26000865
20.  Biodistribution and Trafficking of Hydrogel Nanoparticles in Adult Mosquitoes 
PLoS Neglected Tropical Diseases  2015;9(5):e0003745.
Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes.
Methodology/Principal Findings
PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract.
Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector lethal cargoes for mosquito control.
Author Summary
Emerging insecticide resistance in disease vectors is of great public health concern. Discovery of new targets and novel strategies for insecticidal interventions to control vector borne diseases is a public health imperative. Nanotechnology offers great potential for molecular genetic investigations and for delivery of effector molecules for control of disease vectors. We have developed a tool box of hydrogel nanoparticles (NPs) with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector lethal cargoes to adult mosquitoes. Nanotechnology will likely be useful for molecular investigations and potential control of the arthropod vectors of other neglected tropical diseases.
PMCID: PMC4440717  PMID: 25996505
21.  Biodistribution and Toxicity Studies of PRINT Hydrogel Nanoparticles in Mosquito Larvae and Cells 
PLoS Neglected Tropical Diseases  2015;9(5):e0003735.
Mosquito-borne diseases continue to remain major threats to human and animal health and impediments to socioeconomic development. Increasing mosquito resistance to chemical insecticides is a great public health concern, and new strategies/technologies are necessary to develop the next-generation of vector control tools. We propose to develop a novel method for mosquito control that employs nanoparticles (NPs) as a platform for delivery of mosquitocidal dsRNA molecules to silence mosquito genes and cause vector lethality. Identifying optimal NP chemistry and morphology is imperative for efficient mosquitocide delivery. Toward this end, fluorescently labeled polyethylene glycol NPs of specific sizes, shapes (80 nm x 320 nm, 80 nm x 5000 nm, 200 nm x 200 nm, and 1000 nm x 1000 nm) and charges (negative and positive) were fabricated by Particle Replication in Non-Wetting Templates (PRINT) technology. Biodistribution, persistence, and toxicity of PRINT NPs were evaluated in vitro in mosquito cell culture and in vivo in Anopheles gambiae larvae following parenteral and oral challenge. Following parenteral challenge, the biodistribution of the positively and negatively charged NPs of each size and shape was similar; intense fluorescence was observed in thoracic and abdominal regions of the larval body. Positively charged NPs were more associated with the gastric caeca in the gastrointestinal tract. Negatively charged NPs persisted through metamorphosis and were observed in head, body and ovaries of adults. Following oral challenge, NPs were detected in the larval mid- and hindgut. Positively charged NPs were more efficiently internalized in vitro than negatively charged NPs. Positively charged NPs trafficked to the cytosol, but negatively charged NPs co-localized with lysosomes. Following in vitro and in vivo challenge, none of the NPs tested induced any cytotoxic effects.
Author Summary
There is an urgent need for new interventions and novel insecticides to control mosquito vectors of human disease agents. Nanoparticle-based strategies have been explored extensively as means to deliver a molecule of interest for medical applications (e.g., antigens, drugs, nucleic acids, etc.) to particular tissues and cells in mammalian systems. Our particular application of interest is to use nanoparticles as a platform to deliver nucleic-acid based mosquitocidal molecules. As a first step to developing nanoparticle delivery for molecular vector control, we investigated the physicochemical properties of PRINT hydrogel nanoparticles with respect to their biodistribution, persistence and safety in Anopheles gambiae mosquito larvae and in cell culture. This technology could be applied to studies of pathobiology and physiology in any vector species, with the benefit that the particles can be tailored to move to and target specific delivery of a cargo to a particular organ system and even sub-cellular location. Therefore, this technology and specific information about where the particles go and with what affinity sets the stage of describing a platform that has tremendous potential use in vector control and disease transmission intervention.
PMCID: PMC4440723  PMID: 25996390
22.  Chromodomain protein Tcd1 is required for macronuclear genome rearrangement and repair in Tetrahymena 
Scientific Reports  2015;5:10243.
The survival of an organism’s progeny depends on the maintenance of its genome. Programmed DNA rearrangement and repair in Tetrahymena occur during the differentiation of the developing somatic macronuclear genome from the germ line micronuclear genome. Tetrahymena chromodomain protein (Tcd1) exhibited dynamic localization from the parental to the developing macronuclei. In the developing macronuclei, Tcd1 colocalized with Pdd1 and H3K9me3. Furthermore, Tcd1 colocalized with Pdd1 in the conjusome and “donut structure” of DNA elimination heterochromatin region. During the growth and conjugation stages, TCD1 knockout cells appeared normal and similar to wild-type strains. In addition, these knockout cells proceeded to the 2MAC-1MIC stage. However, the progeny of the TCD1 knockout cells did not grow upon return to SPP medium and eventually died. The deletion of the internal elimination sequence R element was partially disrupted in the developing new macronuclei. Gamma H2A staining showed that Tcd1 loss induced the accumulation of DNA double-strand breaks and the failure of genome repair. These results suggest that the chromodomain protein Tcd1 is required for the rearrangement and repair of new macronuclear genome in Tetrahymena.
PMCID: PMC4437310  PMID: 25989344
23.  Preschoolers’ Understanding of Merit in Two Asian Societies 
PLoS ONE  2015;10(5):e0114717.
Recent research in moral psychology have suggested that children make judgments about distributive justice early on in development, and in particular they appear to be able to use merit when distributing the benefits of a collective action. This prediction has recently been validated in various western cultures but it is unknown whether it also applies to more collectivistic cultures, in which the group might be favoured over the individual, and need over merit. Here, we investigate merit-based distributions among 81 children belonging to two Asian societies, China and Japan (mean age = 5.0 years). In line with the idea that children’s moral psychology develops early, we found that Chinese and Japanese children are able to use merit to distribute the benefits of a collective action.
PMCID: PMC4430231  PMID: 25970346
24.  Electroacupuncture inhibits weight gain in diet-induced obese rats by activating hypothalamicLKB1-AMPK signaling 
Electroacupuncture (EA) is reported to be an effective treatment for obesity, but its mechanism is unclear. This study aimed to investigate the relationship between hypothalamic LKB1-AMPK-ACC signaling and EA.
Fifty male Sprague–Dawley rats were divided into two groups fed either chow (chow-fed group) or high-fat diet (HF group). After 4 weeks of feeding, obese rats in the HF group (defined as weighing 20 % or more than rats in the chow-fed group) were randomly allocated into an EA or Diet-induced obesity (DIO) group. The EA group was given EA on bilateral ST25–ST36 for 4 weeks, while the DIO group received no further intervention. Body weight of the chow-fed, DIO, and EA groups were measured weekly. mRNA and protein levels of the hypothalamic LKB1-AMPK-ACC signaling pathway were detected using real-time (RT)-PCR and western blot, respectively.
After 4 weeks of EA treatment, the weight growth trend of rats in the EA group was inhibited compared with those in the DIO group. RT-PCR and western blotting showed that EA upregulated the transcription of Adenosine 5′-monophosphate -activated protein kinase α2 (AMPKα2), promoted protein expression of Liver kinase B1 (LKB1) and AMPKα1, and inhibited acetyl-CoA carboxylase (ACC) protein expression in the hypothalamus.
This study suggests that hypothalamic LKB1-AMPK-ACC signaling plays an important role in EA treatment for obesity.
PMCID: PMC4485871  PMID: 25963634
Obesity; Electroacupuncture; AMPK; LKB1; ACC
25.  Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells 
Oncotarget  2015;6(13):10893-10907.
Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1α (HIF-1α) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1α treatment. Blocking the SDF-1α/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells.
PMCID: PMC4484427  PMID: 25843954
non-small cell lung cancer (NSCLC); ionizing radiation; reactive oxygen species (ROS); CXCR4; invasiveness

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