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1.  Age and Dark Rearing Bidirectionally Regulate the Level and Laminar Pattern of Expression of Abelson Interacting Protein 2 (Abi-2), a Novel Candidate Visual Cortical Plasticity Gene 
Electrophysiological studies indicate that cat visual cortical critical period neuronal plasticity peaks around 5 weeks and largely disappears by 20 weeks. Dark rearing slows this time course. Normal cats are more plastic than dark reared cats at 5 weeks but the opposite is true at 20 weeks. Thus, a stringent criterion for identifying genes controlling neuronal plasticity is that normal and dark rearing produce opposite direction differences in expression between young and older animals. Differential display PCR identified Abelson interacting protein 2 (Abi-2) as a candidate plasticity gene regulated according to this criterion. Western blotting showed bidirectional regulation of Abi-2 protein levels in cats and mice that was specific to visual cortex and did not occur in frontal cortex. Immunohistochemistry indicated developmental changes in Abi-2 laminar expression in cat visual cortex. Dark rearing altered laminar expression such that at 5 weeks dark reared cats were similar to 1 week normally reared cats and at 20 weeks, dark reared cats were similar to 5–10 week normally reared animals. The effect of dark rearing on both Abi-2 expression levels and laminar expression patterns was to slow the normal developmental process, the same effect seen on physiologically assessed plasticity in visual cortex.
doi:10.1007/s12031-013-0037-1
PMCID: PMC3797860  PMID: 23828391
Visual Deprivation; Visual Development; differential display PCR; Neuronal Plasticity
2.  Injection Drug Users’ Involvement In Drug Economy: Dynamics of Sociometric and Egocentric Social Networks 
Connections (Toronto, Ont.)  2013;33(1):24-34.
The purpose of this analysis was to examine the effect of social network cohesiveness on drug economy involvement, and to test whether this relationship is mediated by drug support network size in a sample of active injection drug users. Involvement in the drug economy was defined by self-report of participation in at least one of the following activities: selling drugs, holding drugs or money for drugs, providing street security for drug sellers, cutting/packaging/cooking drugs, selling or renting drug paraphernalia (e.g., pipes, tools, rigs), and injecting drugs in others’ veins. The sample consists of 273 active injection drug users in Baltimore, Maryland who reported having injected drugs in the last 6 months and were recruited through either street outreach or by their network members. Egocentric drug support networks were assessed through a social network inventory at baseline. Sociometric networks were built upon the linkages by selected matching characteristics, and k-plex rank was used to characterize the level of cohesiveness of the individual to others in the social network. Although no direct effect was observed, structural equation modeling indicated k-plex rank was indirectly associated with drug economy involvement through drug support network size. These findings suggest the effects of large-scale sociometric networks on injectors’ drug economy involvement may occur through their immediate egocentric networks. Future harm reduction programs for injection drug users (IDUs) should consider providing programs coupled with economic opportunities to those drug users within a cohesive network subgroup. Moreover, individuals with a high connectivity to others in their network may be optimal individuals to train for diffusing HIV prevention messages.
PMCID: PMC4193503  PMID: 25309015
3.  Maintenance of Large Numbers of Virus Genomes in Human Cytomegalovirus-Infected T98G Glioblastoma Cells 
Journal of Virology  2014;88(7):3861-3873.
ABSTRACT
After infection, human cytomegalovirus (HCMV) persists for life. Primary infections and reactivation of latent virus can both result in congenital infection, a leading cause of central nervous system birth defects. We previously reported long-term HCMV infection in the T98G glioblastoma cell line (1). HCMV infection has been further characterized in T98Gs, emphasizing the presence of HCMV DNA over an extended time frame. T98Gs were infected with either HCMV Towne or AD169-IE2-enhanced green fluorescent protein (eGFP) strains. Towne infections yielded mixed IE1 antigen-positive and -negative (Ag+/Ag−) populations. AD169-IE2-eGFP infections also yielded mixed populations, which were sorted to obtain an IE2− (Ag−) population. Viral gene expression over the course of infection was determined by immunofluorescent analysis (IFA) and reverse transcription-PCR (RT-PCR). The presence of HCMV genomes was determined by PCR, nested PCR (n-PCR), and fluorescence in situ hybridization (FISH). Compared to the HCMV latency model, THP-1, Towne-infected T98Gs expressed IE1 and latency-associated transcripts for longer periods, contained many more HCMV genomes during early passages, and carried genomes for a greatly extended period of passaging. Large numbers of HCMV genomes were also found in purified Ag− AD169-infected cells for the first several passages. Interestingly, latency transcripts were observed from very early times in the Towne-infected cells, even when IE1 was expressed at low levels. Although AD169-infected Ag− cells expressed no detectable levels of either IE1 or latency transcripts, they also maintained large numbers of genomes within the cell nuclei for several passages. These results identify HCMV-infected T98Gs as an attractive new model in the study of the long-term maintenance of virus genomes in the context of neural cell types.
IMPORTANCE Our previous work showed that T98G glioblastoma cells were semipermissive to HCMV infection; virus trafficked to the nucleus, and yet only a proportion of cells stained positive for viral antigens, thus allowing continual subculturing and passaging. The cells eventually transitioned to a state where viral genomes were maintained without viral antigen expression or virion production. Here we report that during long-term T98G infection, large numbers of genomes were maintained within all of the cells' nuclei for the first several passages (through passage 4 [P4]), even in the presence of continual cellular division. Surprisingly, genomes were maintained, albeit at a lower level, through day 41. This is decidedly longer than in any other latency model system that has been described to date. We believe that this system offers a useful model to aid in unraveling the cellular components involved in viral genome maintenance (and presumably replication) in cells carrying long-term latent genomes in a neural context.
doi:10.1128/JVI.01166-13
PMCID: PMC3993548  PMID: 24453365
4.  MAE-FMD: Multi-agent evolutionary method for functional module detection in protein-protein interaction networks 
BMC Bioinformatics  2014;15(1):325.
Background
Studies of functional modules in a Protein-Protein Interaction (PPI) network contribute greatly to the understanding of biological mechanisms. With the development of computing science, computational approaches have played an important role in detecting functional modules.
Results
We present a new approach using multi-agent evolution for detection of functional modules in PPI networks. The proposed approach consists of two stages: the solution construction for agents in a population and the evolutionary process of computational agents in a lattice environment, where each agent corresponds to a candidate solution to the detection problem of functional modules in a PPI network. First, the approach utilizes a connection-based encoding scheme to model an agent, and employs a random-walk behavior merged topological characteristics with functional information to construct a solution. Next, it applies several evolutionary operators, i.e., competition, crossover, and mutation, to realize information exchange among agents as well as solution evolution. Systematic experiments have been conducted on three benchmark testing sets of yeast networks. Experimental results show that the approach is more effective compared to several other existing algorithms.
Conclusions
The algorithm has the characteristics of outstanding recall, F-measure, sensitivity and accuracy while keeping other competitive performances, so it can be applied to the biological study which requires high accuracy.
doi:10.1186/1471-2105-15-325
PMCID: PMC4262229  PMID: 25265982
Computational biology; Protein-protein interaction network; Functional module detection; Multi-agent evolution
5.  Ligusticum wallichii Extract Inhibited the Expression of IL-1β after AMI in Rats 
This study investigated the effects of Ligusticum wallichii on IL-1β expression in myocardium and central nervous system after AMI. AMI rat was administrated with Ligusticum wallichii extract. A series of assays were used to detect the effects of Ligusticum wallichii extract on infarct size, left ventricular ejection fraction, expression of TLR-4, NF-κB, and IL-1β in myocardium, IL-1β expression in serum and hypothalamus, and NPY expression in hypothalamus. We observed that Ligusticum wallichii extract improved the left ventricular ejection fraction and reduced infarct area enlargement after AMI, by inhibiting the expression of IL-1β in myocardium, serum, and hypothalamus. Ligusticum wallichii extract reduced the expression of IL-1β in myocardium by regulating TLR4-NF-κB signaling pathway and inhibited IL-1β in hypothalamus by regulating NPY mRNA expression.
doi:10.1155/2014/620359
PMCID: PMC4150451  PMID: 25202335
6.  Ginsenoside Rb1 Protects Neonatal Rat Cardiomyocytes from Hypoxia/Ischemia Induced Apoptosis and Inhibits Activation of the Mitochondrial Apoptotic Pathway 
Aim. To investigate the effect of Ginsenoside Rb1 (GS-Rb1) on hypoxia/ischemia (H/I) injury in cardiomyocytes in vitro and the mitochondrial apoptotic pathway mediated mechanism. Methods. Neonatal rat cardiomyocytes (NRCMs) for the H/I groups were kept in DMEM without glucose and serum, and were placed into a hypoxic jar for 24 h. GS-Rb1 at concentrations from 2.5 to 40 µM was given during hypoxic period for 24 h. NRCMs injury was determined by MTT and lactate dehydrogenase (LDH) leakage assay. Cell apoptosis, ROS accumulation, and mitochondrial membrane potential (MMP) were assessed by flow cytometry. Cytosolic translocation of mitochondrial cytochrome c and Bcl-2 family proteins were determined by Western blot. Caspase-3 and caspase-9 activities were determined by the assay kit. Results. GS-Rb1 significantly reduced cell death and LDH leakage induced by H/I. It also reduced H/I induced NRCMs apoptosis induced by H/I, in accordance with a minimal reactive oxygen species (ROS) burst. Moreover, GS-Rb1 markedly decreased the translocation of cytochrome c from the mitochondria to the cytosol, increased the Bcl-2/ Bax ratio, and preserved mitochondrial transmembrane potential (ΔΨm). Its administration also inhibited activities of caspase-9 and caspase-3. Conclusion. Administration of GS-Rb1 during H/I in vitro is involved in cardioprotection by inhibiting apoptosis, which may be due to inhibition of the mitochondrial apoptotic pathway.
doi:10.1155/2014/149195
PMCID: PMC4120487  PMID: 25120573
7.  “Drinking buddies” and alcohol dependence symptoms among African American men and women in Baltimore, MD 
Drug and alcohol dependence  2012;128(0):123-129.
BACKGROUND
Social network characteristics have been found to be associated with a variety of risky behaviors, including alcohol consumption. This study assessed the relationships between the characteristics of drinking buddies and alcohol dependence symptoms among a sample of African American men and women.
METHODS
This is a cross-sectional study using baseline data from 721 impoverished African American men and women participating in an HIV prevention study in Baltimore, MD. Alcohol dependence symptoms were assessed through the Alcohol Use Disorders Identification Test (AUDIT) and was defined as AUDIT score>=13 for females and AUDIT score>=15 for males. Logistic regression models with generalized estimating equations (GEE) using network member as the unit of analysis were conducted to assess the associations between the gender or relationship (i.e,, kin, non-kin or sex partner) of the drinking buddies and the participants’ alcohol dependence symptoms.
RESULTS
Approximately 22% of the participants had alcohol dependence symptoms. Among male participants, alcohol dependence symptoms were associated with having drinking buddies who were sex partners (AOR: 2.41, 95%CI: 1.32, 4.39) or who were female (AOR: 2.29, 95%CI: 1.29, 4.05). Among female participants, association between the presence of drinking buddy and alcohol dependence symptoms did not depend on the types of relationship or the gender of the drinking buddy.
CONCLUSIONS
Social network characteristics with respect to alcohol dependence symptoms vary according to the type of relationship or the gender of the drinking buddies, especially among men. Gender-specific norm-based interventions may be a useful strategy to decrease drink problems.
doi:10.1016/j.drugalcdep.2012.08.016
PMCID: PMC4019971  PMID: 22999417
Alcohol dependence symptoms; African American; social networks; drinking buddy
8.  Factors associated with drinking alcohol before visiting female sex workers among men in Sichuan Province, China 
AIDS and behavior  2013;17(2):568-573.
Alcohol use in commercial sex is highly prevalent globally and alcohol use in conjunction with sexual activity might increase the probability of risky behaviors, and. In the current study, we explored individual and contextual factors associated with drinking alcohol before visiting female sex workers (FSWs) among 560 male clients in Sichuan province, China. A cross-sectional survey was conducted in Sichuan province, China. Over one-fifth (21.1%) of the participants reported always using alcohol before having sex with FSWs. As compared to those who reported not always drinking alcohol before having sex with FSWs, male clients who reported always drinking alcohol before having sex with FSWs had higher income, were more likely to have main sex partners, to drink alcohol daily, to report minor depressive symptoms and were more likely to visit FSWs with friends rather than by themselves. Results from this study highlight the importance of addressing alcohol use among men who pay for sex in China. Future interventions should promote alcohol-related norms in reducing the harms associated with consuming alcohol.
doi:10.1007/s10461-012-0260-8
PMCID: PMC4017933  PMID: 22806054
alcohol use; risky sexual behaviors; commercial sex; HIV; China
9.  Significance of Ubiquitin Carboxy-Terminal Hydrolase L1 Elevations in Athletes after Sub-Concussive Head Hits 
PLoS ONE  2014;9(5):e96296.
The impact of sub-concussive head hits (sub-CHIs) has been recently investigated in American football players, a population at risk for varying degrees of post-traumatic sequelae. Results show how sub-CHIs in athletes translate in serum as the appearance of reporters of blood-brain barrier disruption (BBBD), how the number and severity of sub-CHIs correlate with elevations of putative markers of brain injury is unknown. Serum brain injury markers such as UCH-L1 depend on BBBD. We investigated the effects of sub-CHIs in collegiate football players on markers of BBBD, markers of cerebrospinal fluid leakage (serum beta 2-transferrin) and markers of brain damage. Emergency room patients admitted for a clinically-diagnosed mild traumatic brain injury (mTBI) were used as positive controls. Healthy volunteers were used as negative controls. Specifically this study was designed to determine the use of UCH-L1 as an aid in the diagnosis of sub-concussive head injury in athletes. The extent and intensity of head impacts and serum values of S100B, UCH-L1, and beta-2 transferrin were measured pre- and post-game from 15 college football players who did not experience a concussion after a game. S100B was elevated in players experiencing the most sub-CHIs; UCH-L1 levels were also elevated but did not correlate with S100B or sub-CHIs. Beta-2 transferrin levels remained unchanged. No correlation between UCH-L1 levels and mTBI were measured in patients. Low levels of S100B were able to rule out mTBI and high S100B levels correlated with TBI severity. UCH-L1 did not display any interpretable change in football players or in individuals with mild TBI. The significance of UCH-L1 changes in sub-concussions or mTBI needs to be further elucidated.
doi:10.1371/journal.pone.0096296
PMCID: PMC4012998  PMID: 24806476
10.  INFORMAL SOCIAL SUPPORT AND DEPRESSION AMONG AFRICAN AMERICAN MEN WHO HAVE SEX WITH MEN 
Journal of community psychology  2013;41(4):10.1002/jcop.21548.
Men who have sex with men (MSM) experience greater mental health problems as compared with heterosexual populations. Informal social support plays a critical role in emotional well-being. The primary goal of this article is to examine the relationship between depressive symptoms and received social support from family, friends, and sex partners within the social network from a sample of 188 African American MSM in Baltimore, Maryland. We found that receiving emotional support from a family member or a sex partner was associated with reduced odds of having depressive symptoms. Receiving financial support from a family member or a friend was associated with increased odds of having depressive symptoms. The results suggest the importance of emotional support provided by family and sex partner in mental health and the potential value of training African American MSM in skills to enhance the quality of the relationships.
doi:10.1002/jcop.21548
PMCID: PMC3736997  PMID: 23935226
11.  Genetic Analysis of Diversity within a Chinese Local Sugarcane Germplasm Based on Start Codon Targeted Polymorphism 
BioMed Research International  2014;2014:468375.
In-depth information on sugarcane germplasm is the basis for its conservation and utilization. Data on sugarcane molecular markers are limited for the Chinese sugarcane germplasm collections. In the present study, 20 start codon targeted (SCoT) marker primers were designed to assess the genetic diversity among 107 sugarcane accessions within a local sugarcane germplasm collection. These primers amplified 176 DNA fragments, of which 163 were polymorphic (92.85%). Polymorphic information content (PIC) values ranged from 0.783 to 0.907 with a mean of 0.861. Unweighted pair group method of arithmetic averages (UPGMA) cluster analysis of the SCoT marker data divided the 107 sugarcane accessions into six clusters at 0.674 genetic similarity coefficient level. Relatively abundant genetic diversity was observed among ROC22, ROC16, and ROC10, which occupied about 80% of the total sugarcane acreage in China, indicating their potential breeding value on Mainland China. Principal component analysis (PCA) partitioned the 107 sugarcane accessions into two major groups, the Domestic Group and the Foreign Introduction Group. Each group was further divided based on institutions, where the sugarcane accessions were originally developed. The knowledge of genetic diversity among the local sugarcane germplasm provided foundation data for managing sugarcane germplasm, including construction of a core collection and regional variety distribution and subrogation.
doi:10.1155/2014/468375
PMCID: PMC3980922  PMID: 24779012
12.  Acute toxicity of nickel nanoparticles in rats after intravenous injection 
This study was carried out to add scientific data in regard to the use of metallic nanoparticles in nanomedicine. The acute toxicity of nickel (Ni) nanoparticles (50 nm), intravenously injected through the dorsal penile vein of Sprague Dawley rats was evaluated in this study. Fourteen days after injection, Ni nanoparticles induced liver and spleen injury, lung inflammation, and caused cardiac toxicity. These results indicate that precautionary measures should be taken with regard to the use of Ni nanoparticles or Ni compounds in nanomedicine.
doi:10.2147/IJN.S56212
PMCID: PMC3958504  PMID: 24648736
nickel; nanoparticles; intravenous; acute toxicity
13.  Injection drug users' and their risk networks experiences of and attitudes toward drug dealer violence in Baltimore, Maryland 
Background
A large portion of violence associated with drug use is due to drug dealing. These analyses sought to examine injection drug users' attitudes and experiences of drug dealer violence.
Methods
The current study used the 18-month follow up data of STEP into Action (STEP) study, an HIV prevention intervention among drug injectors and their risk network members conducted in Baltimore, Maryland. Four scales assessed acceptability of drug dealer violence, willingness to talk to drug users about avoiding drug dealer violence, social norms about reporting drug dealer violence, and intentions to report drug dealer violence to the police.
Results
Many (44%) of the 373 participants reported witnessing drug dealers' acts of violence within the prior 6 months. Although the majority of participants disagreed with statements on the acceptability of dealers using violence, only a minority indicated that they would call the police if they observed dealer violence. Most participants indicated that they would be interested in talking to drug users about how to avoid violent dealers. Males were more likely to report that violence was acceptable, whereas African Americans were less likely to condone violence. Those who were homeless and had higher incomes were more likely to report witnessing drug dealer violence.
Conclusions
These results suggest that it may be feasible to train current and former drug users and their risk network members in methods to promote violence reduction among drug dealers.
doi:10.1016/j.drugpo.2012.07.007
PMCID: PMC3519954  PMID: 22959117
violence; drug dealer; injection drug users
14.  Syndemics of syphilis, HCV infection, and methamphetamine use along the east coast of China 
BMC Public Health  2014;14:172.
Background
An upsurge in club drug use has been observed in recent years in some cities of China, especially methamphetamine, which is quickly replacing heroin to become the most widespread drug across the nation. This study investigated the type of drugs used, syphilis and hepatitis C virus (HCV) infection and the correlates for syphilis, HCV and unprotected commercial sex behavior among drug users in two cities along the east coast of China.
Methods
A cross-sectional survey conducted in 2010 provided demographics, sexual and drug use behaviors, HIV knowledge and the utilization of intervention services among drug users. Blood samples were tested for HIV, syphilis, and HCV infection.
Results
Of 805 eligible participants, 0.2% were infected with HIV, 3.7% with HCV, and 9.6% with syphilis. Of the participants, 96.6% were methamphetamine users, 11.9% reported ever having used ≥2 types of these drugs, and 11.4% reported ever injecting drugs. In the multivariable logistic regression analysis, participants infected with syphilis were more likely to be female (adjusted odds ratio (AOR)=2.8, 95% confidence interval (CI): 1.2-6.5), have ever had commercial sex in the past 12 months (AOR=2.0, 95% CI: 1.0-3.9), be infected with HCV (AOR=12.1, 95% CI: 4.1-20.3) and less likely to have ever had sex with regular partners in the past 12 months (AOR=0.2, 95% CI: 0.1-0.6). Participants infected with HCV were more likely to have ever injected drugs (AOR=2.7, 95% CI: 1.1-6.5) and be infected with syphilis (AOR=8.0, 95% CI: 3.5-18.0). Participants who had unprotected sex with commercial sex partners in the last sexual encounter were more likely to be female (AOR=2.9, 95% CI:1.7-4.9), have middle school or lower level education (AOR=3.4, 95% CI:2.0-5.5), never have received intervention in the last year (AOR=2.1, 95%CI:1.2-3.6) and be infected with syphilis (AOR=4.2, 95% CI:2.4-7.4).
Conclusions
Methamphetamine is the predominant drug used among the drug users, the prevalence of syphilis and HCV infection are alarmingly high, and unprotected commercial sex was common among this group. The findings highlight the need for effective, multifaceted interventions addressing sexual and drug use-related risky behaviors among this group. Further research is needed to better understand the causal pathway of the syndemics.
doi:10.1186/1471-2458-14-172
PMCID: PMC3936988  PMID: 24533587
Syphilis; HCV; Methamphetamine; Sexual behavior; Drug user
15.  The epidemiology of finding a dead body: reports from inner-city Baltimore, Maryland US 
Community mental health journal  2013;49(1):106-109.
In the US, there are no national statistics on encountering a dead body, which can be viewed as a measure of community health and a stressful life event. Participants for an HIV prevention intervention targeting drug users were recruited in areas of inner-city Baltimore, Maryland .Nine hundred and fifty one respondents, most with a history of drug use, were asked “have you ever found a dead body?” and 17.0% reported they had. Leading causes of death were: violence (37%), natural causes (22.2%), drug overdose (21.6%), accidental death (3.1%), and suicide (2.5%). In multivariate logistic models, respondents with longer history of drug use and more roles in a drug economy were more likely to be exposed to a dead body. The study results suggest that this population has a high level of experiences with mortality associated with violence and drugs. To obtain a better understanding of community health, future studies should assess not only morbidity and mortality, but also how death and illness is experienced by the community.
doi:10.1007/s10597-012-9492-3
PMCID: PMC3406247  PMID: 22297618
Urban Health; Mortality; Drug use; Violence; Mental Health
16.  Noninvasive Assessments of Optic Nerve Neurodegeneration in Transgenic Mice With Isolated Optic Neuritis 
Purpose.
To determine if phosphorylated neurofilament heavy chain (pNF-H) released into the bloodstream and the pattern ERG are noninvasive indicators of neurodegeneration in experimental optic neuritis.
Methods.
Serum from Myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor–positive (TCR+) transgenic mice that develop isolated optic neuritis usually without any other characteristic lesions of inflammation or demyelination in the spinal cord and littermates negative for the transgene were assayed for the presence of serum phosphorylated neurofilament H (pNF-H). In vivo measurements of optic nerve and retinal ganglion cell injury were assessed by magnetic resonance imaging (MRI), optical coherence tomography (OCT), and pattern electroretinogram (PERG). Automated two dimensional fluorescence differential in-gel electrophoresis (2D-DIGE) of pooled optic nerve samples, light, and transmission electron micrographs were used to evaluate optic atrophy postmortem.
Results.
We found an almost 3-fold elevation in serum pNF-H levels in MOG+ mice relative to MOG-littermates (P = 0.02). 2D-DIGE revealed a 3-fold reduction in optic nerve neurofilaments. Visual function assessed by the PERG was reduced by one-quarter (P = 0.033) and latencies increased by 38% (P = 0.036). MOG+ mice with the lowest PERG amplitudes had optic nerve atrophy visualized by MRI. Optic nerve diameters were reduced by one-third (P = 0.0001) and axon counts reduced by more than two-thirds. Histopathology of the spinal cords was normal.
Conclusions.
Elevated serum pNF-H levels and the PERG are useful markers of neurodegeneration of the optic nerve in isolated experimental optic neuritis. Our findings suggest that elevations of this axonal protein in patients with optic neuritis who had a poor visual outcome are likely also due to demise of optic nerve axons.
OCT detects RNFL loss after axons die off. In this report, we show elevated serum pNF-H levels are due to isolated optic neuritis, suggesting this biomarker may be useful for selecting at initial presentation optic neuritis patients in need of neuroprotection to prevent irreversible visual loss.
doi:10.1167/iovs.13-11899
PMCID: PMC3700386  PMID: 23722393
optic neuritis; neuroophthalmology; neurodegeneration; axonal degeneration; neurofilaments
17.  Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation 
Aim. The aim of the present study was to investigate the effect of cornel iridoid glycoside (CIG) on tau hyperphosphorylation induced by wortmannin (WT) and GF-109203X (GFX) and the underlying mechanisms. Methods. Human neuroblastoma SK-N-SH cells were preincubated with CIG (50, 100, and 200 µg/ml, resp.) for 24 h and then exposed to 10 µM WT and 10 µM GFX for 3 h after washing out CIG. Immunohistochemistry was used to observe the microtubular cytoskeleton of the cultured cells. Western blotting was used to measure the phosphorylation level of tau protein, glycogen synthase kinase 3β (GSK-3β), and protein phosphatase 2A (PP2A). The activity of PP2A was detected by a biochemical assay. Results. Preincubation of CIG significantly attenuated the WT/GFX-induced tau hyperphosphorylation at the sites of Thr205, Thr212, Ser214, Thr217, Ser396, and PHF-1 and improved the damage of morphology and microtubular cytoskeleton of the cells. CIG did not prevent the decrease in p-AKT-ser473 and p-GSK-3β-ser9 induced by WT/GFX. However, CIG significantly elevated the activity of PP2A by reducing the demethylation of PP2A catalytic subunit (PP2Ac) at Leu309 and the ratio of PME-1/LCMT in the WT/GFX-treated cells. The results suggest that CIG may be beneficial to the treatment of AD.
doi:10.1155/2013/108486
PMCID: PMC3880719  PMID: 24454482
18.  A Pilot Study of Novel Biomarkers in Neonates With Hypoxic-Ischemic Encephalopathy 
Pediatric research  2010;68(6):10.1203/PDR.0b013e3181f85a03.
Severe hypoxic-ischemic encephalopathy (HIE) is a devastating condition that can lead to mortality and long-term disabilities in term newborns. No rapid and reliable laboratory test exists to assess the degree of neuronal injury in these patients. We propose two possible biomarkers: 1) phosphorylated axonal neurofilament heavy chain (pNF-H) protein, one of the major subunits of neurofilaments, found only in axonal cytoskeleton of neurons and 2) Ubiquitin C-terminal hydrolase 1 (UCHL1 protein) that is heavily and specifically concentrated in neuronal perikarya and dendrites. High-serum pNF-H and UCHL1 levels are reported in subarachnoid hemorrhage and traumatic brain injury, suggesting that they are released into blood following neuronal injury. We hypothesized that serum pNF-H and UCHL1 were higher in neonates with moderate-to-severe HIE than in healthy neonates. A time-limited enrollment of 14 consecutive patients with HIE and 14 healthy controls was performed. UCHL1 and pNF-H were correlated with clinical data and brain MRI. UCHL1 and pNF-H serum levels were higher in HIE versus controls. UCHL1 showed correlation with the 10-min Apgar score, and pNF-H showed correlation with abnormal brain MRI. Our findings suggest that serum UCHL1 and pNF-H could be explored as diagnostic and prognostic tools in neonatal HIE.
doi:10.1203/PDR.0b013e3181f85a03
PMCID: PMC3851011  PMID: 20736881
19.  Acute Toxicity of Intravenously Administered Titanium Dioxide Nanoparticles in Mice 
PLoS ONE  2013;8(8):e70618.
Background
With a wide range of applications, titanium dioxide (TiO2) nanoparticles (NPs) are manufactured worldwide in large quantities. Recently, in the field of nanomedicine, intravenous injection of TiO2 nanoparticulate carriers directly into the bloodstream has raised public concerns on their toxicity to humans.
Methods
In this study, mice were injected intravenously with a single dose of TiO2 NPs at varying dose levels (0, 140, 300, 645, or 1387 mg/kg). Animal mortality, blood biochemistry, hematology, genotoxicity and histopathology were investigated 14 days after treatment.
Results
Death of mice in the highest dose (1387 mg/kg) group was observed at day two after TiO2 NPs injection. At day 7, acute toxicity symptoms, such as decreased physical activity and decreased intake of food and water, were observed in the highest dose group. Hematological analysis and the micronucleus test showed no significant acute hematological or genetic toxicity except an increase in the white blood cell (WBC) count among mice 645 mg/kg dose group. However, the spleen of the mice showed significantly higher tissue weight/body weight (BW) coefficients, and lower liver and kidney coefficients in the TiO2 NPs treated mice compared to control. The biochemical parameters and histological tissue sections indicated that TiO2 NPs treatment could induce different degrees of damage in the brain, lung, spleen, liver and kidneys. However, no pathological effects were observed in the heart in TiO2 NPs treated mice.
Conclusions
Intravenous injection of TiO2 NPs at high doses in mice could cause acute toxicity effects in the brain, lung, spleen, liver, and kidney. No significant hematological or genetic toxicity was observed.
doi:10.1371/journal.pone.0070618
PMCID: PMC3738549  PMID: 23950972
20.  Clinical and experimental studies regarding the expression and diagnostic value of carcinoembryonic antigen-related cell adhesion molecule 1 in non-small-cell lung cancer 
BMC Cancer  2013;13:359.
Background
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in non-small-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Methods
The expression of the serum CEACAM1 was determined by enzyme-linked immunosorbent assay. The protein expression and the location of CEACAM1 in tumours were observed by immunohistochemical staining. The CEACAM1 mRNA levels in tumour and normal adjacent tissues were measured using quantitative real-time PCR, and the expression patterns and the rate of CEACAM1-S and CEACAM1-L were analysed by reverse transcription-PCR.
Results
Serum CEACAM1 levels were significantly higher in NSCLC patients compared with that from normal healthy controls (P <0.0001). 17 patients (81%) among 21 showed high expression of CEACAM1 by immunohistochemical staining. Although no significant differences were found between tumour and normal tissues on mRNA expression levels of CEACAM1 (P >0.05), the CEACAM1-S and the CEACAM1-S/L (S: L) ratios were significantly higher in tumour than normal tissues (P <0.05).
Conclusions
Our data indicated that the serum levels of CEACAM1 could discriminate lung cancer patients from health donors and that CEACAM1 might be a useful marker in early diagnosis of NSCLC. Moreover, our results showed that the expression patterns of CEACAM1 isoforms could be changed during oncogenesis, even when total CEACAM1 in tumour tissues did not show significant changes. Our study suggested that the expression ratios of CEACAM1-S/CEACAM1-L might be a better diagnostic indicator in NSCLC than the quantitative changes of CEACAM1.
doi:10.1186/1471-2407-13-359
PMCID: PMC3728234  PMID: 23885995
Carcinoembryonic antigen-related cell adhesion molecule 1; Non-small-cell lung carcinomas; Enzyme-linked immunosorbent assay; Receiver operating characteristic curve
21.  Coupling Hippocampal Neurogenesis to Brain pH through Proneurogenic Small Molecules That Regulate Proton Sensing G Protein-Coupled Receptors 
ACS Chemical Neuroscience  2012;3(7):557-568.
Acidosis, a critical aspect of central nervous system (CNS) pathophysiology and a metabolic corollary of the hypoxic stem cell niche, could be an expedient trigger for hippocampal neurogenesis and brain repair. We recently tracked the function of our isoxazole stem cell-modulator small molecules (Isx) through a chemical biology-target discovery strategy to GPR68, a proton (pH) sensing G protein-coupled receptor with no known function in brain. Isx and GPR68 coregulated neuronal target genes such as Bex1 (brain-enriched X-linked protein-1) in hippocampal neural progenitors (HCN cells), which further amplified GPR68 signaling by producing metabolic acid in response to Isx. To evaluate this proneurogenic small molecule/proton signaling circuit in vivo, we explored GPR68 and BEX1 expression in brain and probed brain function with Isx. We localized proton-sensing GPR68 to radial processes of hippocampal type 1 neural stem cells (NSCs) and, conversely, localized BEX1 to neurons. At the transcriptome level, Isx demonstrated unrivaled proneurogenic activity in primary hippocampal NSC cultures. In vivo, Isx pharmacologically targeted type 1 NSCs, promoting neurogenesis in young mice, depleting the progenitor pool without adversely affecting hippocampal learning and memory function. After traumatic brain injury, cerebral cortical astrocytes abundantly expressed GPR68, suggesting an additional role for proton-GPCR signaling in reactive astrogliosis. Thus, probing a novel proneurogenic synthetic small molecule’s mechanism-of-action, candidate target, and pharmacological activity, we identified a new GPR68 regulatory pathway for integrating neural stem and astroglial cell functions with brain pH.
doi:10.1021/cn300025a
PMCID: PMC3400383  PMID: 22860225
Small molecules; acidosis; G protein-coupled receptors; hippocampal neurogenesis; traumatic brain injury
22.  A Regulatory Pathway, Ecdysone-Transcription Factor Relish-Cathepsin L, Is Involved in Insect Fat Body Dissociation 
PLoS Genetics  2013;9(2):e1003273.
Insect fat body is the organ for intermediary metabolism, comparable to vertebrate liver and adipose tissue. Larval fat body is disintegrated to individual fat body cells and then adult fat body is remodeled at the pupal stage. However, little is known about the dissociation mechanism. We find that the moth Helicoverpa armigera cathepsin L (Har-CL) is expressed heavily in the fat body and is released from fat body cells into the extracellular matrix. The inhibitor and RNAi experiments demonstrate that Har-CL functions in the fat body dissociation in H. armigera. Further, a nuclear protein is identified to be transcription factor Har-Relish, which was found in insect immune response and specifically binds to the promoter of Har-CL gene to regulate its activity. Har-Relish also responds to the steroid hormone ecdysone. Thus, the dissociation of the larval fat body is involved in the hormone (ecdysone)-transcription factor (Relish)-target gene (cathepsin L) regulatory pathway.
Author Summary
Insect fat body is the intermediary metabolism organ and the main source of hemolymph components, and it is crucial for insect development and metamorphosis. However, molecular mechanism for the fat body remodeling is almost unknown other than in Drosophila melanogaster. A pupal diapause species the cotton bollworm, Helicoverpa armigera (Har), is a useful model to study individual or tissue remodeling, because larval fat body will remain integral in diapause-type pupae for months, whereas the dissociation of larval fat body will start on day 0 after pupation in nondiapause-type ones. Here, we find that H. armigera cathepsin L (Har-CL) is released from fat body cells into the extracellular matrix for tissue dissociation. A nuclear protein is identified to be transcription factor Har-Relish, which regulates the promoter activity of Har-CL gene. Har-Relish also responds to the steroid hormone ecdysone. Thus, a new regulatory mechanism, ecdysone-Relish-cathepsin L signaling pathway, is involved in the larval fat body dissociation.
doi:10.1371/journal.pgen.1003273
PMCID: PMC3573115  PMID: 23459255
23.  Involvement of Organic Cation Transporter-3 and Plasma Membrane Monoamine Transporter in Serotonin Uptake in Human Brain Vascular Smooth Muscle Cells 
The serotonin (5-HT) uptake system is supposed to play a crucial part in vascular functions by “fine-tuning” the local concentration of 5-HT in the vicinity of 5-HT2 receptors in vascular smooth muscle cells. In this study, the mechanism of 5-HT uptake in human brain vascular smooth muscle cells (HBVSMCs) was investigated. [3H]5-HT uptake in HBVSMCs was Na+-independent. Kinetic analyses of [3H]5-HT uptake in HBVSMCs revealed a Km of 50.36 ± 10.2 mM and a Vmax of 1033.61 ± 98.86 pmol/mg protein/min. The specific serotonin re-uptake transporter (SERT) inhibitor citalopram, the specific norepinephrine transporter (NET) inhibitor desipramine, and the dopamine transporter (DAT) inhibitor GBR12935 inhibited 5-HT uptake in HBVSMCs with IC50 values of 97.03 ± 40.10, 10.49 ± 5.98, and 2.80 ± 1.04 μM, respectively. These IC50 values were 100-fold higher than data reported by other authors, suggesting that those inhibitors were not blocking their corresponding transporters. Reverse transcription-polymerase chain reaction results demonstrated the presence of mRNA for organic cation transporter (OCT)-3 and plasma membrane monoamine transporter (PMAT), but the absence of OCT-1, OCT-2, SERT, NET, and DAT. siRNA knockdown of OCT-3 and PMAT specifically attenuated 5-HT uptake in HBVSMCs. It is concluded that 5-HT uptake in HBVSMCs was mediated predominantly by a low-affinity and Na+-independent mechanism. The most probable candidates are OCT-3 and PMAT, but not the SERT.
doi:10.3389/fphar.2013.00014
PMCID: PMC3569667  PMID: 23407616
serotonin; organic cation transporter; monoamine transporter; vascular smooth muscle cells
24.  Experiencing Violence as a Predictor of Drug Use Relapse among Former Drug Users in Baltimore, Maryland 
The purpose of this study was to examine experiencing violence as a predictor of subsequent drug relapse among a sample of former crack, cocaine, and heroin users in Baltimore, MD, USA. The sample consists of 228 former drug users in Baltimore who were recruited through street outreach. Mixed-effects models were used to examine experiencing violence as a predictor of drug relapse at follow-up after adjusting for clustering of responses among participants living in the same census block. Using longitudinal data, we found that experiencing violence in the past year predicted drug relapse at 2-year follow-up among former drug users. Results indicate experiencing violence is a determinant of drug use relapse and highlight the importance of addressing the fundamental issues of violence experienced in inner-city communities. Addressing the extent of recent violence among drug treatment participants, providing coping skills, and reducing community violence are strategies that may address the link between violence and drug relapse.
doi:10.1007/s11524-011-9610-5
PMCID: PMC3232408  PMID: 21877254
Violence; Drug relapse; Drug users; Inner city
25.  Results of a Randomized Controlled Trial of a Peer Mentor HIV/STI prevention intervention for women over an 18month follow-up 
AIDS and behavior  2011;15(8):1654-1663.
Despite numerous behavioral interventions designed for women, rates of HIV and STIs are increasing. Interventions are needed that reach a large number of at-risk individuals. This study was a randomized clinical trial of a HIV/STI behavioral intervention conducted in Baltimore, MD, USA. Heterosexual women (n=169) completed a baseline and 3 semiannual follow-up visits. Participants were randomized into a standard of care comparison condition or a Peer Mentor condition. At the 6-month follow-up, Peer Mentors were less likely to have multiple sex partners [AOR: 0.28 (95% CI: 0.13, 0.63)]. At the 18 month follow-up assessment, Peer Mentors increased their condom use during vaginal [AOR: 0.47 (95% CI: 0.25, 0.87)] and anal sex [AOR: 0.24 (95% CI: 0.09, 0.68)] as well as with main [AOR: 0.41 (95% CI: 0.21, 0.77)] and non-main partners [AOR: 0.33 (95% CI: 0.14, 0.79]. Peer education is a sustainable approach to change risky sexual behaviors.
doi:10.1007/s10461-011-9943-9
PMCID: PMC3158274  PMID: 21468659

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