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1.  Expression of cytochrome P450 CYP81A6 in rice: tissue specificity, protein subcellular localization, and response to herbicide application*  
The cytochrome P450 gene CYP81A6 confers tolerance to bentazon and metsulfuron-methyl, two selective herbicides widely used for weed control in rice and wheat fields. Knockout mutants of CYP81A6 are highly susceptible to both herbicides. The present study aimed to characterize the CYP81A6 expression in rice. Quantitative real-time polymerase chain reaction (PCR) analyses demonstrated that foliar treatment of bentazon (500 mg/L) greatly induced expression of CYP81A6 in both wild-type (Jiazhe B) and its knockout mutant (Jiazhe mB): a 10-fold increase at 9 h before returning to basal levels at 24 h in Jiazhe B, while in the mutant the expression level rose to >20-fold at 12 h and maintained at such high level up to 24 h post exposure. In contrast, metsulfuron-methyl (500 mg/L) treatment did not affect the expression of CYP81A6 in Jiazhe B within 80 h; thereafter the expression peaked at 120 h and returned gradually to basal levels by Day 6. We suggest that a metabolite of metsulfuron-methyl, 1H-2,3-benzothiazin-4-(3H)-one-2,2-dioxide, is likely to be responsible for inducing CYP81A6 expression, rather than the metsulfuron-methyl itself. Use of a promoter-GUS reporter construct (CYP81A6Pro::GUS) demonstrated that CYP81A6 was constitutively expressed throughout the plant, with the highest expression in the upper surfaces of leaves. Subcellular localization studies in rice protoplasts showed that CYP81A6 was localized in the endoplasmic reticulum. These observations advance our understanding of CYP81A6 expression in rice, particularly its response to the two herbicides.
doi:10.1631/jzus.B1400168
PMCID: PMC4322422  PMID: 25644466
CYP81A6; Bentazon; Metsulfuron-methyl; Expression induction; Xenobiotics
2.  Stochastic Particle Barcoding for Single-Cell Tracking and Multiparametric Analysis 
This study presents stochastic particle barcoding (SPB), a method for tracking cell identity across bioanalytical platforms. In this approach, single cells or small collections of cells are co-encapsulated within an enzymatically-degradable hydrogel block along with a random collection of fluorescent beads, whose number, color, and position encode the identity of the cell, enabling samples to be transferred in bulk between single-cell assay platforms without losing the identity of individual cells. The application of SPB was demonstrated for transferring cells from a subnanoliter protein secretion/phenotyping array platform into a microtiter plate, with re-identification accuracies in the plate assay of 96±2%. Encapsulated cells were recovered by digesting the hydrogel, allowing subsequent genotyping and phenotyping of cell lysates. Finally, a model scaling was developed to illustrate how different parameters affect the accuracy of SPB and to motivate scaling of the method to 1,000's of unique blocks.
doi:10.1002/smll.201401369
PMCID: PMC4303509  PMID: 25180800
barcodes; cells; hydrogels; labeling; lab-on-a-chip devices
3.  Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells 
Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, non-immunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of pre-existing alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC class-I deficient and class I/class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC class-I deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a TCR-independent manner, of class I-deficient donor cells.
doi:10.1111/ajt.12525
PMCID: PMC4045013  PMID: 24304495
Bone marrow transplantation; indirect alloreactivity; tolerance; CD8 T cells
4.  Trihelix transcription factor GT-4 mediates salt tolerance via interaction with TEM2 in Arabidopsis 
BMC Plant Biology  2014;14(1):339.
Background
Trihelix transcription factor family is plant-specific and plays important roles in developmental processes. However, their function in abiotic stress response is largely unclear.
Results
We studied one member GT-4 from Arabidopsis in relation to salt stress response. GT-4 expression is induced by salt stress and GT-4 protein is localized in nucleus and cytoplasm. GT-4 acts as a transcriptional activator and its C-terminal end is the activation domain. The protein can bind to the cis-elements GT-3 box, GT-3b box and MRE4. GT-4 confers enhanced salt tolerance in Arabidopsis likely through direct binding to the promoter and activation of Cor15A, in addition to possible regulation of other relevant genes. The gt-4 mutant shows salt sensitivity. TEM2, a member of AP2/ERF family was identified to interact with GT-4 in yeast two-hybrid, BiFC and Co-IP assays. Loss-of-function of TEM2 exerts no significant difference on salt tolerance or Cor15A expression in Arabidopsis. However, double mutant gt-4/tem2 shows greater sensitivity to salt stress and lower transcript level of Cor15A than gt-4 single mutant. GT-4 plus TEM2 can synergistically increase the promoter activity of Cor15A.
Conclusions
GT-4 interacts with TEM2 and then co-regulates the salt responsive gene Cor15A to improve salt stress tolerance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0339-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-014-0339-7
PMCID: PMC4267404  PMID: 25465615
Salt stress; Trihelix transcription factor; GT-4; TEM2
5.  Factorial Structure of the Brief Symptom Inventory (BSI)-18 among Chinese Drug Users 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.06.017.
BACKGROUND
Although the Brief Symptom Inventory-18 (BSI-18) has been widely used for mental health screenings in both clinical and non-clinical populations, the validation of its application to Chinese populations has been very limited. The objective of this research is to assess the factorial structure of the BSI-18 within a Chinese drug using population.
METHODS AND RESULTS
A total sample of 303 drug users recruited via Respondent Driven Sampling (RDS) from Changsha, China was used for the study. Our results show: 1) The BSI-18 item scores are highly skewed; 2) With dichotomous items measures (1-problem at least moderately caused respondent discomfort during the past week; 0-otherwise), our findings support the designed 3-factor solution of the BSI-18 (somatization, depression, and anxiety); 3) The BSI-18 has a hierarchical factorial structure with 3 first-order factors and an underlying second-order factor (general psychological distress); 4) Tentative support should also be given to a single dimension of general psychological distress in Chinese drug using populations. Our study recommends a useful alternative approach for evaluating the factorial structure of the BSI-18 – i.e. CFA with dichotomous item measures. Both the total BSI-18 score and the three subscales (SOM, DEP, and ANX) can be used in applications of the BSI-18.
CONCLUSION
Overall, our findings suggest the BSI-18 is useful with Chinese drug users, and shows potential for use with non-Western and substance using populations more generally.
doi:10.1016/j.drugalcdep.2013.06.017
PMCID: PMC3818478  PMID: 23906998
BSI-18; psychological distress; confirmatory factor analysis; drug users; China
6.  Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse 
The Journal of Neuroscience  2014;34(16):5649-5657.
Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.
doi:10.1523/JNEUROSCI.4564-13.2014
PMCID: PMC3988415  PMID: 24741055
extrasynaptic glutamate receptor; glutamate spillover; glutamate uptake; heroin self-administration; nucleus accumbens; relapse
7.  Development of a Double Antibody Sandwich ELISA for West Nile Virus Detection Using Monoclonal Antibodies against Non-Structural Protein 1 
PLoS ONE  2014;9(10):e108623.
The early diagnosis of West Nile virus (WNV) infection is important for successful clinical management and epidemiological control. The non-structural protein 1 (NS1) of flavivirus, a highly conserved and secreted glycoprotein, is abundant in the serum of flavivirus-infected patients and represents a useful early diagnostic marker. We developed a WNV-specific NS1 antigen-capture ELISA using two mouse monoclonal antibodies (MAbs) that recognised distinct epitopes of the NS1 protein of WNV as capture and detection antibodies. The antigen-capture ELISA displayed exclusive specificity to WNV without cross-reaction with other related members of the flavivirus family, including the dengue virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Additionally, the specificity was presented as no false positive in normal (0/1003) and DENV-infected (0/107) human serum specimens. The detection limit of the antigen-capture ELISA was as low as 15 pg/ml of recombinant WNV NS1 protein (rWNV-NS1) and 6.1 plaque-forming units (PFU)/0.1 ml of WNV-infected culture supernatant. In mice infected with WNV, the NS1 protein was readily detected in serum as early as one day after WNV infection, prior to the development of clinical signs of the disease. The sensitivity of the NS1 capture ELISA (93.7%) was significantly higher (79.4%) than that of real-time reverse transcription polymerase chain reaction in 63 serum samples from WNV-infected mice (p = 0.035). This newly developed NS1 antigen-capture ELISA with high sensitivity and specificity could be used as an efficient method for the early diagnosis of WNV infection in animals or humans.
doi:10.1371/journal.pone.0108623
PMCID: PMC4193763  PMID: 25303282
8.  A latent class analysis of external barriers to drug treatment in China 
Drug treatment services of varying types have been scaled up in China over the past decade. Yet, barriers to treatment remain among the population of drug users in China. In this paper, we use a person-centered approach to examine external barriers to drug treatment among a sample of Chinese drug users. Specifically, we used a latent class analysis to determine a typology of external barriers to treatment among a sample of 262 drug users. The results of the analyses suggest three-classes of drug users with respect to their perceptions of external barriers to treatment – Major Barriers, Low Barriers, and Systems-level Barriers – indicating that drug users are a heterogeneous population on this matter. Age and types of drugs used were predictors of class membership. In this regard, different tactics must be utilized in order to successfully reach this wide ranging group of individuals.
doi:10.1016/j.jsat.2013.05.004
PMCID: PMC3742624  PMID: 23827260
9.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
Background Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods Using extant longitudinal birth cohorts (n = 19) with data on birthweight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
doi:10.1093/ije/dyt109
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood
10.  Enhancement of osseointegration of polyethylene terephthalate artificial ligament by coating of silk fibroin and depositing of hydroxyapatite 
Background
Application of artificial ligament in anterior cruciate ligament reconstruction is one of the research focuses of sports medicine but the biological tendon–bone healing still remains a problem. The preliminary study of hydroxyapatite (HAP) coating on the polyethylene terephthalate (PET) surface could effectively induce the osteoblast differentiation, but the tendon–bone healing was still not stable. As a green synthesis process, the biomimetic mineralization can simulate the natural bone growth in vitro and in vivo.
Methods
HAP crystals were grown under the guide of silk fibroin (SF) PET surface by biomimetic route. Several techniques including scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy were utilized for proving the introduction of both SF and HAP. The viability and osseointegration of bone marrow stromal cells on the surface of three kinds of ligament, including PET group (non-coating group), PET+SF group (SF-coating group), and PET+SF+HAP group (combined HAP- and SF-coating group), were analyzed by CCK-8 assays and alkaline phosphatase (ALP) detection. Seventy-two mature male New Zealand rabbits were randomly divided into three groups. Among them, 36 rabbits were sacrificed for mechanical testing, and histological examination for the others.
Results
The SF and SF+HAP were successfully coated on the surface of PET fiber. The CCK-8 assay showed that the cell proliferation on PET+SF+HAP group was better than the other two groups from 24 to 120 hours. After 14 days of culture, the cells in the PET+SF+HAP group delivered higher levels of ALP than the other two groups. After 3 days of culture, the expression level of integrin β1 in the PET+SF+HAP group and PET+SF group were higher than in the PET group. The mean load to failure and the stiffness value of the PET+SF+HAP group were both higher than the other two groups. Hematoxylin and eosin staining showed that new bone tissue formation was only found in the PET+SF+HAP group 8 weeks postoperatively. Masson staining showed that in the PET+SF+HAP group 8 weeks postoperatively, the PET fibers were almost completely encircled by collagen. Histomorphometric analysis showed that the width of the graft–bone interface in the PET+SF+HAP group was narrower than that in the other two groups 4 and 8 weeks postoperatively. The mRNA level of BMP-7 in the PET+SF+HAP groups was significantly higher than those in the other two groups 4 and 8 weeks postoperatively.
Conclusion
The study showed that the combined SF and HAP coating by biomimetic route on the surface of PET artificial ligament could induce graft osseointegration in the bone tunnel, providing theoretical and experimental foundation for manufacturing novel artificial ligaments meeting the clinical needs.
doi:10.2147/IJN.S69137
PMCID: PMC4189703  PMID: 25302023
biomineralization; tendon–bone healing; ligament reconstruction
11.  SHP-1 is a target of regorafenib in colorectal cancer 
Oncotarget  2014;5(15):6243-6251.
Regorafenib is an inhibitor of multiple protein kinases which exerts antitumor and antimetastatic activities in metastatic colorectal cancer (CRC). SH2 domain-containing phosphatase 1 (SHP-1) is reported to have tumor suppressive potential because it acts as a negative regulator of p-STAT3Tyr705 signaling. However, little is known about the mechanism regarding regorafenib affects SHP-1 tyrosine phosphatase activity and leads to apoptosis and tumor suppression in CRC. Here, we found that regorafenib triggered apoptotic cell death and significantly enhanced SHP-1 activity, which dramatically decreased the phosphorylated form of STAT3 at Tyr705 (p-STAT3Tyr705). Importantly, regorafenib augmented SHP-1 activity by direct disruption of the association between N-SH2 and catalytic PTP domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 blocked the effect of regorafenib-induced SHP-1 activity, growth inhibition and a decrease of p-STAT3Tyr705 expression, suggesting that regorafenib triggers a conformational change in SHP-1 by relieving its autoinhibition. In vivo assay showed that regorafenib significantly inhibited xenograft growth and decreased p-STAT3Tyr705 expression but induced higher SHP-1 activity. Collectively, regorafenib is a novel SHP-1 agonist exerts superior anti-tumor effects by enhancing SHP-1 activity that directly targets p-STAT3Tyr705. Small molecule-enhancement of SHP-1 activity may be a promising therapeutic approach for CRC treatment.
PMCID: PMC4171626  PMID: 25071018
SHP-1; Regorafenib; Colorectal cancer; STAT3; Apoptosis
12.  Cytomegalovirus immune reconstitution inflammatory syndrome manifesting as acute appendicitis in an HIV-infected patient 
BMC Infectious Diseases  2014;14:313.
Background
Appendicitis occurs with increased frequency in HIV infected compared to HIV uninfected persons. CMV-related appendicitis specifically presents with typical appendicitis symptoms including surgical abdomen, fever and leukocytosis and may have a more severe course with higher mortality than other types of infective appendicitis. We report the first case of CMV appendicitis as a manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS).
Case presentation
The patient was a 38 year old woman with a recent diagnosis of HIV infection who complained of right lower quadrant pain, anorexia, nausea and fevers two weeks after initiating antiretroviral therapy. Acute appendicitis was suspected and the patient underwent an appendectomy. Pathologic examination of the resected appendiceal tissue demonstrated inflammation with perforation and cytopathic changes typical of CMV that were positive for CMV by immunostain. This presentation of CMV abruptly after antiretroviral therapy initiation with a pronounced cellular infiltration of the tissue, is consistent with CMV-IRIS presenting as appendicitis.
Conclusions
Appendicitis can be a rare manifestation of CMV-IRIS in HIV-infected patients who start antiretroviral therapy. Evaluation of appendiceal tissue for cytopathic changes and CMV should be considered in acute appendicitis in HIV infected persons.
doi:10.1186/1471-2334-14-313
PMCID: PMC4057562  PMID: 24910267
Cytomegalovirus; Immune reconstitution inflammatory syndrome; Opportunistic infections; HIV
13.  Emerging concepts in haematopoietic cell transplantation 
Nature reviews. Immunology  2012;12(6):403-416.
Haematopoietic cell transplantation (HCT) is the most widely used cellular therapy. It is the only known cure for some hematologic malignancies and has recently been used for additional indications, such as allograft tolerance induction and treatment of autoimmune diseases. Recent advances have enabled HCT in a wider range of patients with improved outcomes. This Review summarizes the latest developments in this therapy, focusing on issues that will impact future advancement.
doi:10.1038/nri3226
PMCID: PMC4006975  PMID: 22627859
14.  Efficacy and safety of ondansetron in preventing postanesthesia shivering: a meta-analysis of randomized controlled trials 
BMC Anesthesiology  2014;14:12.
Background
Shivering is a very common complication in the postanesthesia period. Increasing studies have reported ondansetron may be effective in prevention of postanesthesia shivering (PAS). However, the results remained controversial; hence we conducted a meta-analysis of randomized controlled trials to evaluate the efficacy and safety of ondansetron on the prevention of postanesthesia shivering.
Methods
PubMed and Embase databases were searched to identify the eligible randomized controlled trials assessing the effect of ondansetron on the prevention of PAS. Results were expressed as risk ratios (RRs) with accompanying 95% confidence intervals (CIs). The meta-analysis was performed with fixed-effect model or random-effect model according to the heterogeneity.
Results
Six trials including 533 subjects were included. Compared with placebo, ondansetron was associated with a significant reduction of PAS (RR 0.43, 95% CI, 0.27-0.70), without an increased risk of bradycardia (RR 0.37, 95% CI, 0.12-1.15). Compared with meperidine, no difference was observed in the incidence of PAS (RR 0.68, 95% CI, 0.39-1.19) and bradycardia (RR 2.0, 95% CI, 0.38-10.64).
Conclusions
Ondansetron has a preventive effect on PAS without a paralleled side effect of bradycardia.
doi:10.1186/1471-2253-14-12
PMCID: PMC3945808  PMID: 24588846
Qndansetron; Postanesthesia shivering; Meta-analysis
15.  Radiation Dose in the Thyroid and the Thyroid Cancer Risk Attributable to CT Scans for Pediatric Patients in One General Hospital of China 
Objective: To quantify the radiation dose in the thyroid attributable to different CT scans and to estimate the thyroid cancer risk in pediatric patients. Methods: The information about pediatric patients who underwent CT scans was abstracted from the radiology information system in one general hospital between 1 January 2012 and 31 December 2012. The radiation doses were calculated using the ImPACT Patient Dosimetry Calculator and the lifetime attributable risk (LAR) of thyroid cancer incidence was estimated based on the National Academies Biologic Effects of Ionizing Radiation VII model. Results: The subjects comprised 922 children, 68% were males, and received 971 CT scans. The range of typical radiation dose to the thyroid was estimated to be 0.61–0.92 mGy for paranasal sinus CT scans, 1.10–2.45 mGy for head CT scans, and 2.63–5.76 mGy for chest CT scans. The LAR of thyroid cancer were as follows: for head CT, 1.1 per 100,000 for boys and 8.7 per 100,000 for girls; for paranasal sinus CT scans, 0.4 per 100,000 for boys and 2.7 per 100,000 for girls; for chest CT scans, 2.1 per 100,000 for boys and 14.1 per 100,000 for girls. The risk of thyroid cancer was substantially higher for girls than for the boys, and from chest CT scans was higher than that from head or paransal sinus CT scans. Conclusions: Chest CT scans caused higher thyroid dose and the LAR of thyroid cancer incidence, compared with paransal sinus or head CT scans. Therefore, physicians should pay more attention to protect the thyroid when children underwent CT scans, especially chest CT scans.
doi:10.3390/ijerph110302793
PMCID: PMC3987004  PMID: 24608902
cancer risk; pediatric CT; radiation dose
16.  The Nogo-C2/Nogo Receptor Complex Regulates the Morphogenesis of Zebrafish Lateral Line Primordium through Modulating the Expression of dkk1b, a Wnt Signal Inhibitor 
PLoS ONE  2014;9(1):e86345.
The fish lateral line (LL) is a mechanosensory system closely related to the hearing system of higher vertebrates, and it is composed of several neuromasts located on the surface of the fish. These neuromasts can detect changes in external water flow, to assist fish in maintaining a stationary position in a stream. In the present study, we identified a novel function of Nogo/Nogo receptor signaling in the formation of zebrafish neuromasts. Nogo signaling in zebrafish, like that in mammals, involves three ligands and four receptors, as well as three co-receptors (TROY, p75, and LINGO-1). We first demonstrated that Nogo-C2, NgRH1a, p75, and TROY are able to form a Nogo-C2 complex, and that disintegration of this complex causes defective neuromast formation in zebrafish. Time-lapse recording of the CldnB::lynEGFP transgenic line revealed that functional obstruction of the Nogo-C2 complex causes disordered morphogenesis, and reduces rosette formation in the posterior LL (PLL) primordium during migration. Consistent with these findings, hair-cell progenitors were lost from the PLL primordium in p75, TROY, and Nogo-C2/NgRH1a morphants. Notably, the expression levels of pea3, a downstream marker of Fgf signaling, and dkk1b, a Wnt signaling inhibitor, were both decreased in p75, TROY, and Nogo-C2/NgRH1a morphants; moreover, dkk1b mRNA injection could rescue the defects in neuromast formation resulting from knockdown of p75 or TROY. We thus suggest that a novel Nogo-C2 complex, consisting of Nogo-C2, NgRH1a, p75, and TROY, regulates Fgf signaling and dkk1b expression, thereby ensuring stable organization of the PLL primordium.
doi:10.1371/journal.pone.0086345
PMCID: PMC3897714  PMID: 24466042
17.  Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice 
Acta Pharmacologica Sinica  2014;35(1):124-134.
Aim:
To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice.
Methods:
Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses.
Results:
Plumbagin (2.5–20 μmol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 μmol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2–3 weeks and reduced the tumor volume by 44%–74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts.
Conclusion:
Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells.
doi:10.1038/aps.2013.152
PMCID: PMC4075744  PMID: 24384612
plumbagin; naphthoquinone; breast cancer; lytic lesion; osteoclast; bone microenvironment; apoptosis; in vivo imaging
18.  Non-alloreactive T Cells Prevent Donor Lymphocyte Infusion-Induced Graft-vs.-Host Disease by Controlling Microbial Stimuli 
In mice, graft-versus-host reactions (GVHR), associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras (MCs). However, GVHD sometimes occurrs after DLI in established mixed chimeric patients. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell-depleted hematopoietic cell transplantation is slow, resulting in lymphopenia at the time of DLI. We demonstrate here that T cell lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of non-alloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a Treg-independent mechanism, but not by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by Treg-depleted, non-alloreactive T cells. Finally, thymectomized mixed chimeras showed increased GVHD following delayed DLI. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, T cell lymphopenia is a risk factor for GVHD in MCs receiving delayed DLI and suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of T cells to control microbial infections.
doi:10.4049/jimmunol.1200045
PMCID: PMC3524834  PMID: 23136200
19.  Birth Status, Child Growth, and Adult Outcomes in Low- and Middle-Income Countries☆ 
The Journal of Pediatrics  2013;163(6):1740-1746.e4.
Objective
To assess the impact of being born preterm or small for gestational age (SGA) on several adult outcomes.
Study design
We analyzed data for 4518 adult participants in 5 birth cohorts from Brazil, Guatemala, India, the Philippines, and South Africa.
Results
In the study population, 12.8% of males and 11.9% of females were born preterm, and 26.8% of males and 22.4% of females were born term but SGA. Adults born preterm were 1.11 cm shorter (95% CI, 0.57-1.65 cm), and those born term but SGA were 2.35 cm shorter (95% CI, 1.93-2.77 cm) compared with those born at term and appropriate size for gestational age. Blood pressure and blood glucose level did not differ by birth category. Compared with those born term and at appropriate size for gestational age, schooling attainment was 0.44 years lower (95% CI, 0.17-0.71 years) in those born preterm and 0.41 years lower (95% CI, 0.20-0.62 years) in those born term but SGA.
Conclusion
Being born preterm or term but SGA is associated with persistent deficits in adult height and schooling, but is not related to blood pressure or blood glucose level in low- and middle-income settings. Increased postnatal growth is associated with gains in height and schooling regardless of birth status, but not with increases in blood pressure or blood glucose level.
doi:10.1016/j.jpeds.2013.08.012
PMCID: PMC3849851  PMID: 24064150
AGA, Appropriate for gestational age; BMI, Body mass index; GA, Gestational age; IFG, Impaired fasting glucose; LGA, Large for gestational age; LMP, Last menstrual period; SGA, Small for gestational age
20.  A Comparative Study of Theoretical Graph Models for Characterizing Structural Networks of Human Brain 
Previous studies have investigated both structural and functional brain networks via graph-theoretical methods. However, there is an important issue that has not been adequately discussed before: what is the optimal theoretical graph model for describing the structural networks of human brain? In this paper, we perform a comparative study to address this problem. Firstly, large-scale cortical regions of interest (ROIs) are localized by recently developed and validated brain reference system named Dense Individualized Common Connectivity-based Cortical Landmarks (DICCCOL) to address the limitations in the identification of the brain network ROIs in previous studies. Then, we construct structural brain networks based on diffusion tensor imaging (DTI) data. Afterwards, the global and local graph properties of the constructed structural brain networks are measured using the state-of-the-art graph analysis algorithms and tools and are further compared with seven popular theoretical graph models. In addition, we compare the topological properties between two graph models, namely, stickiness-index-based model (STICKY) and scale-free gene duplication model (SF-GD), that have higher similarity with the real structural brain networks in terms of global and local graph properties. Our experimental results suggest that among the seven theoretical graph models compared in this study, STICKY and SF-GD models have better performances in characterizing the structural human brain network.
doi:10.1155/2013/201735
PMCID: PMC3863486  PMID: 24369454
21.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
International journal of epidemiology  2013;42(5):10.1093/ije/dyt109.
Background
Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods
Using extant longitudinal birth cohorts (n = 19) with data on birth-weight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results
We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions
This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
doi:10.1093/ije/dyt109
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood
22.  Attitudes Toward Psychiatry as a Prospective Career among Medical Students in Their Pre-Clinical Year in China- A Pilot Study 
PLoS ONE  2013;8(9):e73395.
Objective
To understand the attitudes among medical students in China toward different medical specialties and to find the factors that influenced their choice of career in psychiatry.
Methods
A questionnaire was developed and administered to 287 medical students at the Xiangya Medical College, Central South University in Changsha, China. All the students were asked to rate the importance of five possible factors in choosing a specialty as a vocation: the ability to help patients, interesting and challenging work, lifestyle factors, financial reward, and prestige.
Results
Students reported negative perceptions of psychiatry in regard to all five possible factors that were important in choosing a specialty as a vocation, especially in financial reward and prestige.
Conclusions
Medical students in China have negative attitudes toward psychiatry as a career. Some negative beliefs about psychiatry seem to be due to erroneous or insufficient knowledge that could be corrected during the course of medical education. Some negative attitudes were unlikely to be completely changed until the mental health system in China improves.
doi:10.1371/journal.pone.0073395
PMCID: PMC3759458  PMID: 24023869
23.  Bony defect repair in rabbit using hybrid rapid prototyping polylactic-co-glycolic acid/β-tricalciumphosphate collagen I/apatite scaffold and bone marrow mesenchymal stem cells 
Indian Journal of Orthopaedics  2013;47(4):388-394.
Background:
In bone tissue engineering, extracellular matrix exerts critical influence on cellular interaction with porous biomaterial and the apatite playing an important role in the bonding process of biomaterial to bone tissue. The aim of this study was to observe the therapeutic effects of hybrid rapid prototyping (RP) scaffolds comprising polylactic-co-glycolic acid (PLGA), β-tricalciumphosphate (β-TCP), collagen I and apatite (PLGA/β-TCP-collagen I/apatite) on segmental bone defects in conjunction with combination with bone marrow mesenchymal stem cells (BMSCs).
Materials and Methods:
BMSCs were seeded into the hybrid RP scaffolds to repair 15 mm defect in the radius of rabbits. Radiograph, microcomputed tomography and histology were used to evaluate new bone formation.
Results:
Radiographic analysis done from 12 to 36 weeks postoperative period demonstrated that new bone formed at the radial defect site and continues to increase until the medullary cavity is recanalized and remodelling is complete. The bone defect remained unconnected in the original RP scaffolds (PLGA/β-TCP) during the whole study. Histological observations conformed to the radiographic images. In hybrid RP scaffold group, woven bone united the radial defect at 12 weeks and consecutively remodeled into lamellar bone 24 weeks postoperation and finally matured into cortical bone with normal marrow cavity after another 12 weeks. No bone formation but connective tissue has been detected in RP scaffold at the same time.
Conclusion:
Collagen I/apatite sponge composite coating could improve new bone formation in vivo. The hybrid RP scaffold of PLGA/β-TCP skeleton with collagen I/apatite sponge composite coating is a promising candidate for bone tissue engineering.
doi:10.4103/0019-5413.114927
PMCID: PMC3745694  PMID: 23960284
Apatite; bone tissue engineering; collagen I; hybrid scaffolds; segmental bone defect
24.  A new treatment for cognitive disorders related to in utero exposure to alcohol★ 
Neural Regeneration Research  2013;8(18):1702-1713.
Maternal alcohol consumption during pregnancy has detrimental effects on fetal central nervous system development. Maternal alcohol consumption prior to and during pregnancy significantly affects cognitive functions in offspring, which may be related to changes in cyclin-dependent kinase 5 because it is associated with modulation of synaptic plasticity and impaired learning and memory. In this study, we examined adult offspring in a maternal alcohol consumption model in rats. Y-maze test results showed that in utero exposure to alcohol impairs learning and memory capacities. Cyclin-dependent kinase 5 mRNA and protein expressions in the hippocampus of the offspring were significantly elevated, as assayed by quantitative real-time PCR and reverse transcription-PCR, immunofluorescence, and immuno-precipitation. Our experimental findings strongly suggest that altered cyclin-dependent kinase 5 may mediate impaired learning and memory in adult rats that were exposed to alcohol by maternal consumption while in utero.
doi:10.3969/j.issn.1673-5374.2013.18.008
PMCID: PMC4145914  PMID: 25206467
neural regeneration; neurogenesis; pregnancy; ethanol; hippocampus; development; offspring; learning and memory; cyclin-dependent kinase 5; grants-supported paper; neuroregeneration
25.  Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4 
PLoS ONE  2013;8(6):e65404.
Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD+ binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.
doi:10.1371/journal.pone.0065404
PMCID: PMC3675114  PMID: 23762361

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