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1.  Medication of l-tetrahydropalmatine Significantly Ameliorates Opiate Craving and Increases the Abstinence Rate in Heroin Users: A Pilot Study 
Acta pharmacologica Sinica  2008;29(7):781-788.
Drug addiction is a chronic brain disease with constant relapse requiring long-term treatment. New pharmacological strategies focus on the development of an effective anti-relapse drug. This study examines the effects of levo-Tetrahydropalmatine (l-THP) on reducing heroin craving and increasing the abstinence rate among heroin-dependent subjects
One hundred twenty heroin-dependent subjects participated in the randomized, double-blinded, and placebo-controlled study using l-THP treatment. The participants remained in a ward during a four-week period of l-THP treatment, followed by four weeks of observation after treatment. Subjects were followed for three months after discharge. Outcome measures are the measured severity of the protracted abstinence withdrawal syndrome (PAWS) and the abstinence rate.
Four weeks of l-THP treatment significantly ameliorated the severity of PAWS—specifically, somatic syndrome, mood states, insomnia, and drug craving, in comparison to the placebo group. Based on the three-month follow-up observation, participants who survived the initial two weeks of the l-THP medication and remained in the trial program, had a significantly higher abstinence rate of 47.8% (95% CI: 33-67%) than those of 15.2 % in the placebo group (95% CI:7-25%), according to a log-rank test (P < 0.0005).
l-THP significantly ameliorated PAWS, especially reduced drug craving. Furthermore, it increased the abstinence rate among heroin users. These results support the potential use of l-THP for treatment of heroin addiction.
PMCID: PMC4535343  PMID: 18565275
Heroin addiction; l-Tetrahydropalmatine; Abstinence rate; Relapse
2.  Factors related to Psychosocial Barriers to Drug Treatment among Chinese Drug Users 
Addictive behaviors  2014;39(8):1265-1271.
Although substance abuse treatment has been considerably scaled up in China, impediments to accessing these services remain among drug users. The authors examine the primary psychosocial barriers to drug treatment in this population and evaluate factors associated with these barriers. Barriers to accessing drug treatment were measured using the Barriers to Treatment Inventory (BTI). A Structural Equation Model was used to examine whether the internal barriers were associated with treatment history and frequent methamphetamine use as well as how demographic characteristics influence such barriers. We found four primary factors of internal barriers to drug treatment – absence of problem, negative social support, fear of treatment, and privacy concerns – to fit well. Demographic factors, notably age and employment status, indirectly influence barriers to treatment via other factors. Frequency of methamphetamine use and drug treatment history are directly associated with the absence of problem and negative social support dimensions of the BTI, and it is through these pathways that demographic factors such as age and employment status shape barriers to treatment. The findings indicate that perceived absence of a problem and negative social support are the barriers most influenced by the personal domains of Chinese drug users’ lives. Efforts to engage drug users in China about drug treatment options may consider how these barriers are differentially perceived in order to effectively reach this population.
PMCID: PMC4075974  PMID: 24813554
drug treatment; barriers; China
3.  Three SAUR proteins SAUR76, SAUR77 and SAUR78 promote plant growth in Arabidopsis 
Scientific Reports  2015;5:12477.
Ethylene perceived by a family of five receptors regulates many developmental processes in Arabidopsis. Here we conducted the yeast two-hybrid assay to screen for additional unidentified proteins that interact with subfamily II ethylene receptor ETR2. Three SAUR proteins, named SAUR76, 77 and 78, were identified to associate with both ETR2 and EIN4 in different assays. Interaction of SAUR76 and SAUR78 with ETR2 was further verified by co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays. Expressions of SAUR76-78 are induced by auxin and ethylene treatments. Compared with wild type, SAUR-overexpressing plants exhibit reduced ethylene sensitivity, while SAUR-RNAi lines exhibit enhanced ethylene sensitivity. Overexpressing the three SAURs partially complements the phenotype of subfamily II ethylene receptor loss-of-function double mutant etr2-3ein4-4, which has increased ethylene response and small cotyledon and rosette. saur76 mutation partially suppresses the reduced ethylene sensitivity of etr2-2. SAUR76/78 proteins are regulated by 26S proteasome system and larger tag increases their protein stability. These findings suggest that SAUR76-78 may affect ethylene receptor signaling and promote plant growth in Arabidopsis.
PMCID: PMC4513569  PMID: 26207341
4.  A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking 
Nature Communications  2015;6:7675.
We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.
Cue-based therapies for treating drug addiction have proven to be only partially effective. Here the authors demonstrate a new memory retrieval based treatment protocol for drug addiction that results in long-lasting inhibition of drug seeking behavior in rodents.
PMCID: PMC4510700  PMID: 26169171
5.  Incidence of Second Primary Malignancies Following Colorectal Cancer: A Distinct Pattern of Occurrence Between Colon and Rectal Cancers and Association of Co-Morbidity with Second Primary Malignancies in a Population-Based Cohort of 98,876 Patients in Taiwan 
Medicine  2015;94(26):e1079.
The purpose of this study is to determine the features of second primary malignancies (SPMs) among patients with prior colorectal cancer (CRC) using a nationwide population-based dataset.
Patients with CRC newly diagnosed between 1996 and 2011, and >1 year of follow-up were recruited from the Taiwan National Health Insurance database. Standardized incidence ratios (SIRs) of SPMs in patients with CRC were calculated.
During the 16-year study period, 4259 SPMs developed among 98,876 CRC patients. The median duration of follow-up was 4.03 years. The SIR for all SPMs was 1.13 (95% confidence interval = 1.10–1.17). Compared with the general population, a higher incidence of thyroid, prostate, ovarian, and hematologic malignancies developed among patients with colon cancer, whereas the risk for bone and soft tissue cancers increased among patients with rectal cancer. The risk for breast, bladder, kidney, lung, and uterine cancers was significantly higher in patients with colon and rectal cancers than the general population. The risk for liver and biliary tract cancers declined in patients with rectal cancer. Based on multivariate analysis among patients with CRC, age ≥70 years, men, chronic obstructive pulmonary disease (COPD), cirrhosis, and dyslipidemia were independent predictors of an SPM.
In conclusion, patients with CRC were at increased risk for a second cancer. The pattern of SPMs was distinct between patients with colon and rectal cancer. Age, men, COPD, cirrhosis, and dyslipidemia were independent risk factors for SPMs. Surveillance and education should be provided for survivors with respect to risk for SPMs.
PMCID: PMC4504576  PMID: 26131831
6.  The Prognostic Role of Para-Aortic Lymph Nodes in Patients with Colorectal Cancer: Is It Regional or Distant Disease? 
PLoS ONE  2015;10(6):e0130345.
Visible para-aortic lymph nodes of ≥2 mm in size are common metastatic patterns of colorectal cancer (CRC) seen on imaging. Their prognostic value, however, remains inconclusive. We aimed to assess the prognostic role of visible para-aortic lymph nodes (PALNs).
Patients with confirmed pathologic diagnosis of CRC were enrolled. Correlations among clinicopathologic variables were analyzed using the χ2 test. The Cox proportional hazards model was applied for univariate and multivariate analyses. Survival was estimated using the Kaplan-Meier method and log-rank test. A prognostic model for visible PALNs in CRC patients was established.
In total, 4527 newly diagnosed CRC patients were enrolled. Patients with visible PALNs had inferior overall survival compared to those without visible PALNs (5-year overall survival, 67% vs. 76%, P = 0.015). Lymphovascular invasion (LVI) (hazard ratio = 1.865, P = 0.015); nodal disease (pN+) status (hazard ratio = 2.099, P = 0.006); elevated preoperative serum carcinoembryonic antigen (CEA) levels (hazard ratio = 2.263, P < 0.001); and visible PALNs ≥10 mm (hazard ratio = 1.638, P = 0.031) were independent prognostic factors for patients with visible PALNs. If each prognostic factor scored one point, 5-year overall survival of lower- (prognostic score 0–1), intermediate- (prognostic score 2), and high- (prognostic score 3–4) risk groups were, 78%. 54%, and 25% respectively (P < 0.001).
The prognostic model, which included LVI, pN+ status, preoperative serum CEA level, and the size of visible PALNs, could effectively distinguish the outcome of patients with visible PALNs.
PMCID: PMC4482546  PMID: 26115511
7.  Correction: Development of SSR Markers and Genetic Diversity in White Birch (Betula platyphylla) 
PLoS ONE  2015;10(6):e0129758.
PMCID: PMC4452386  PMID: 26030921
8.  Identification of candidate flavonoid pathway genes using transcriptome correlation network analysis in ripe strawberry (Fragaria × ananassa) fruits 
Journal of Experimental Botany  2015;66(15):4455-4467.
This work in strawberry fruit predicts new genes relevant to a key metabolic pathway using correlation analysis, and then demonstrates their function in a rapid and effective transient assay.
New modulators of the strawberry flavonoid pathway were identified through correlation network analysis. The transcriptomes of red, ripe fruit from two parental lines and 14 of their progeny were compared, and uncharacterized transcripts matching the expression patterns of known flavonoid-pathway genes were identified. Fifteen transcripts corresponded with putative transcription factors, and several of these were examined experimentally using transient expression in developing fruits. The results suggest that two of the newly-identified regulators likely contribute to discrete nodes of the flavonoid pathway. One increases only LEUCOANTHOCYANIDIN REDUCTASE (LAR) and FLAVONOL 3’-HYDROXYLASE (F3’H) transcript accumulation upon overexpression. Another affects LAR and FLAVONOL SYNTHASE (FLS) after overexpression. The third putative transcription factor appears to be a universal regulator of flavonoid-pathway genes, as many pathway transcripts decrease in abundance when this gene is silenced. This report demonstrates that such systems-level approaches may be especially powerful when connected to an effective transient expression system, helping to provide rapid and strong evidence of gene function in key fruit-ripening processes.
PMCID: PMC4507756  PMID: 25979996
Anthocyanin; coexpresssion; flavonoid; fruit ripening; strawberry; transcriptome.
9.  Development of SSR Markers and Genetic Diversity in White Birch (Betula platyphylla) 
PLoS ONE  2015;10(4):e0125235.
In order to study genetic diversity of white birch (Betula platyphylla), 544 primer pairs were designed based on the genome-wide Solexa sequences. Among them, 215 primer pairs showed polymorphism between five genotypes and 111 primer pairs that presented clear visible bands in genotyping 41 white birch plants that were collected from 6 different geographical regions. A total of 717 alleles were obtained at 111 loci with a range of 2 to 12 alleles per locus. The results of statistic analysis showed that polymorphic frequency of the alleles ranged from 17% to 100% with a mean of 55.85%; polymorphism information content (PIC) of the loci was from 0.09 to 0.58 with a mean of 0.30; and gene diversity between the tested genotypes was from 0.01 to 0.66 with a mean of 0.36. The results also indicated that major allele frequency ranged from 0.39 to 1.00 with an mean of 0.75; expected heterozygosity from 0.22 to 0.54 with a mean of 0.46; observed heterozygosity from 0.02 to 0.95 with a mean of 0.26; Nei's index from 0.21 to 0.54 with a mean of 0.46; and Shannon's Information from 0.26 to 0.87 with a mean of 0.66. The 41 white birch genotypes at the 111 selected SSR loci showed low to moderate similarity (0.025-0.610), indicating complicated genetic diversity among the white birch collections. The UPGMA-based clustering analysis of the allelic constitution of 41 white birch genotypes at 111 SSR loci suggested that the six different geographical regions can be further separated into four clusters at a similarity coefficient of 0.22. Genotypes from Huanren and Liangshui provenances were grouped into Cluster I, genotypes from Xiaobeihu and Qingyuan provenances into Cluster II, genotypes from Finland provenance into Cluster III, and genotypes from Maoershan into Cluster IV. The information provided in this study could help for genetic improvement and germplasm conservation, evaluation and utilization in white birch tree breeding program.
PMCID: PMC4414481  PMID: 25923698
10.  Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an independent prognostic marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy 
BMC Cancer  2015;15:301.
The impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored. We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy.
We examined CIP2A expression by immunohistochemistry (IHC) and used direct sequencing to identify the mutational status of KRAS exon 2 (codon 12 and 13). The association between CIP2A expression, KRAS genotype, clinicopathological parameters and survival were examined by the Kaplan–Meier method and the Cox proportional hazards model. A combination of immunoblotting and proliferation assays were employed to elucidate the role of CIP2A in signal transduction pathways in wild-type KRAS Caco-2 cells.
A total of 220 colorectal cancer patients who had undergone colorectal liver metastasectomy were included in the study. The mutant KRAS genotype was associated with CIP2A overexpression. CIP2A expression was an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy (relative risk = 1.873, P = 0.019). Targeted silencing of CIP2A in Caco-2 cells (wild-type KRAS) led to decreased expression of pERK/ERK and decreased cell proliferation. Overexpression of mutant KRAS G12D in Caco-2 cells led to an increase in CIP2A expression and cell proliferation. In Caco-2 cells with the KRAS G12D, KRAS overexpression preserved the regulation effect of CIP2A in KRAS and abrogated the impact of CIP2A regulation on pERK/ERK and cell proliferation. CIP2A inhibition also increased the efficacy of cetuximab in Caco-2 cells.
CIP2A is an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.
PMCID: PMC4404594  PMID: 25896895
CIP2A; Colorectal neoplasm; KRAS; Liver; Metastasectomy
11.  Prelimbic Cortex and Ventral Tegmental Area Modulate Synaptic Plasticity Differentially in Nucleus Accumbens During Cocaine-Reinstated Drug Seeking 
Neuropsychopharmacology  2013;39(5):1169-1177.
Addictive drug use causes long-lasting changes in synaptic strength and dendritic spine morphology in the nucleus accumbens that might underlie the vulnerability to relapse. Although activity in mesocorticolimbic circuitry is required for reinstating cocaine seeking, its role in reinstatement-associated synaptic plasticity is not well characterized. Using rats extinguished from cocaine self-administration, we found potentiated synaptic strength (assessed as the AMPA/NMDA current amplitude ratio) and increased spine head diameter in medium spiny neurons in the accumbens core (NAcore). The basal changes in synaptic strength and morphology in cocaine-extinguished animals were further augmented during cocaine-induced reinstatement. Two NAcore afferents contributing to cocaine reinstatement are glutamatergic inputs from the prelimbic prefrontal cortex (PL) and dopamine from the ventral tegmental area (VTA). Pharmacological inhibition of either PL or VTA prevented cocaine-primed reinstatement. However, inhibiting the PL further potentiated AMPA/NMDA and spine head diameter, while inactivating the VTA or the combined systemic administration of dopamine D1 and D2 antagonists prevented the increase in AMPA/NMDA and spine diameter induced by cocaine priming. These data indicate that neuronal activity in the VTA and associated dopamine receptor stimulation is necessary for the synaptic potentiation in the NAcore during cocaine-induced reinstatement. Although activity in the PL was necessary for reinstatement, it inhibited synaptic potentiation initiated by an acute cocaine injection. Thus, although the PL and VTA differentially regulate the direction of synaptic plasticity induced by a cocaine-priming injection, coordinated synaptic potentiation by both NAcore afferents is necessary for cocaine-induced relapse.
PMCID: PMC3957111  PMID: 24232172
addiction & substance abuse; dopamine; glutamate; neurocircuitry; plasticity; cocaine self-administration; synaptic plasticity; reinstatement; prefrontal cortex; accumbens core
12.  Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts1 
Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate here that SW THY generates all human T cell subsets, including Tregs, in similar numbers as human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34+ cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to non-donor human and pig antigens. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naïve-type Tregs compared to HU THY-genereated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8+ T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells and reduced responses to protein antigens. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.
PMCID: PMC3983999  PMID: 24591363
13.  Fermentation Characteristics and Lactic Acid Bacteria Succession of Total Mixed Ration Silages Formulated with Peach Pomace 
The objective of this study was to assess the use of peach pomace in total mixed ration (TMR) silages and clarify the differences in aerobic stability between TMR and TMR silages caused by lactic acid bacteria (LAB). The TMR were prepared using peach pomace, alfalfa hay or Leymus chinensis hay, maize meal, soybean meal, cotton meal, limestone, a vitamin-mineral supplement, and salt in a ratio of 6.0:34.0:44.4:7.0:5.0:2.5:1.0:0.1 on a dry matter (DM) basis. Fermentation quality, microbial composition, and the predominant LAB were examined during ensiling and aerobic deterioration. The results indicated that the TMR silages with peach pomace were well fermented, with low pH and high lactic acid concentrations. The aerobic stability of TMR silages were significantly higher than that of TMR. Compared with TMR silages with alfalfa hay, TMR silage with Leymus chinensis hay was much more prone to deterioration. Although the dominant LAB were not identical in TMR, the same dominant species, Lactobacillus buchneri and Pediococcus acidilactici, were found in both types of TMR silages after 56 d of ensiling, and they may play an important role in the aerobic stability of TMR silages.
PMCID: PMC4341099  PMID: 25656205
Aerobic Stabilization; Lactic Acid Bacteria; Peach Pomace; Total Mixed Ration Silage
14.  Stress-Induced Sensitization To Cocaine: Actin Cytoskeleton Remodeling Within Mesocorticolimbic Nuclei 
The European journal of neuroscience  2012;36(8):3103-3117.
This study investigated the consequence of repeated stress on actin cytoskeleton remodeling in the nucleus accumbens (NAc) and prefrontal cortex (Pfc), and the involvement of this remodeling in the expression of stress-induced motor cross-sensitization with cocaine. Wistar rats were restrained daily (2 hours) for 7 days and, three weeks later, their NAc and Pfc were dissected 45 min after acute saline or cocaine (30 mg/kg i.p.). F-actin, actin-binding proteins (ABP) and GluR1 were quantified by western blotting, and dendritic spines and PSD size measured by electron microscopy. In the NAc from the stress plus cocaine group we observed a decrease in the phosphorylation of two ABPs, cofilin and cortactin, and an increase in the PSD size and the surface expression of GluR1, consistent with a more highly branched actin cytoskeleton. The Pfc also showed evidence of increased actin polymerization after stress as an increase was observed in Arp2, and in the number of spines. Inhibiting actin cycling and polymerization with latrunculin A into the NAc, but not the Pfc, inhibited the expression of cross-sensitization to cocaine (15 mg/kg i.p.) and restored the expression of GluR1 to control levels. This study shows that a history of repeated stress alters the ability of a subsequent cocaine injection to modulate dendritic spine morphology, actin dynamics and GluR1 expression in the NAc. Furthermore, by regulating GluR1 expression in the NAc, elevated actin cycling contributes to the expression of cross-sensitization between stress and cocaine, while stress-induced changes in the Pfc were not associated with cross-sensitization.
PMCID: PMC4346257  PMID: 22882295
F-actin; actin binding proteins; dendritic spines; AMPA receptors; latrunculin A
15.  ALDH2 is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural Chinese sample 
Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 600 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum p = 4.73×10-8) and two AD-related phenotypes: flushing response (minimum p = 4.75×10-26) and maximum drinks in a 24-hour period (minimum p = 1.54×10-16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9% and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females – despite familial enrichment for AD – for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally-mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.
PMCID: PMC4149216  PMID: 24277619
Alcohol Dependence; Maximum Drinks; Flushing Response; Genome-Wide Association; Aldehyde Dehydrogenase
16.  Sleeping problems in Chinese illicit drug dependent subjects 
BMC Psychiatry  2015;15:28.
Illicit drug use/dependence has been recognized as a major problem. Clinical studies demonstrate that poor sleep quality is associated with increased frequency of drug use and relapse. However, few studies have addressed the issue of sleep quality among illicit drug dependent subjects.
This cross-sectional study explored sleep quality in drug dependent subjects in China. We studied 2178 illicit drug dependent subjects from drug rehabilitation centres in Changsha and 2236 non-drug-using subjects, all of whom completed the self-report Pittsburgh Sleep Quality Index (PSQI).
We found that the prevalence of sleep disturbance was much higher in drug users (68.5%, PSQI >5; specifically, 80.24% in heroin users, 54.16% in methamphetamine users and 81.98% in ketamine users with PSQI >5) than non-users (26.4%, PSQI >5). Drug users had approximately twice the sleep latency than nondrug users (37.7 minutes V.S 18.4 minutes). Although drug users and non-users reported similar sleep duration (about 7.4 hours), drug users showed poorer subjective sleep quality and habitual sleep efficiency. They reported more sleep disturbance and need for sleep medications, more daytime dysfunction and poorer subjective sleep quality compared with nondrug users. The total PSQI score positively correlated with the duration of drug use (rp = 0.164, p < 0.001). We also found a link between sleep problems and cigarette smoking, alcohol drinking, and duration of drug use.
Poor sleep quality is common among illicit drug dependent subjects. Long-term substance users had more sleep problems. Future research aiming at quantifying the benefits of treatment interventions should not neglect the influence of sleep problems. Gaining more insight into the impact of sleep quality on the addiction treatment could also help to target future intervention measures more effectively.
PMCID: PMC4337091  PMID: 25884573
Sleep problems; Sleep quality; Illicit drug dependent subjects; Self-reported survey
17.  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.
PMCID: PMC4322422  PMID: 25644466
CYP81A6; Bentazon; Metsulfuron-methyl; Expression induction; Xenobiotics
18.  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.
PMCID: PMC4303509  PMID: 25180800
barcodes; cells; hydrogels; labeling; lab-on-a-chip devices
19.  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.
PMCID: PMC4045013  PMID: 24304495
Bone marrow transplantation; indirect alloreactivity; tolerance; CD8 T cells
20.  Trihelix transcription factor GT-4 mediates salt tolerance via interaction with TEM2 in Arabidopsis 
BMC Plant Biology  2014;14:339.
Trihelix transcription factor family is plant-specific and plays important roles in developmental processes. However, their function in abiotic stress response is largely unclear.
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.
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.
PMCID: PMC4267404  PMID: 25465615
Salt stress; Trihelix transcription factor; GT-4; TEM2
21.  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.
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.
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.
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.
PMCID: PMC3818478  PMID: 23906998
BSI-18; psychological distress; confirmatory factor analysis; drug users; China
22.  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.
PMCID: PMC3988415  PMID: 24741055
extrasynaptic glutamate receptor; glutamate spillover; glutamate uptake; heroin self-administration; nucleus accumbens; relapse
23.  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.
PMCID: PMC4193763  PMID: 25303282
24.  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.
PMCID: PMC3742624  PMID: 23827260
25.  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.
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood

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