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1.  Healthy for Life: A Randomized Trial Examining Physical Activity Outcomes and Psychosocial Mediators 
Background
Researchers theorize that interventions increase physical activity by influencing key theory-based mediators (e.g., behavioral processes). However, few studies have been adequately powered to examine the importance of mediators.
Purpose
This study examined both physical activity behavior and psychosocial mediators in a randomized trial specifically powered to detect mediation.
Methods
Healthy, sedentary adults (n=448; 70% Caucasian, 87% women, mean age was 43) were randomly assigned to either a six-month print-based theory tailored physical activity intervention (n=224) or a six-month health/wellness contact control arm (n=224).
Results
The print intervention arm exhibited greater increases in physical activity than the control arm at six and 12 months (p<.05). Additionally, behavioral processes were found to be an important mediator of physical activity behavior.
Conclusions
It is important for researchers and practitioners to focus on increasing behavioral strategies for physical activity adoption. Future studies should examine other potential mediators of physical activity.
doi:10.1007/s12160-012-9439-5
PMCID: PMC3597765  PMID: 23229158
Exercise; Physical Activity; Mediators; Intervention Studies
2.  The role of estrogen receptor beta in transplacental cancer prevention by indole-3-carbinol 
In the present study, the efficacy of indole-3-carbinol (I3C), a key bioactive component of cruciferous vegetables, for prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[def,p]chrysene (DBC) was evaluated using an estrogen receptor beta (ERβ) knockout mouse model. I3C was provided either through the maternal diet coincident with carcinogen exposure during pregnancy or directly to offspring post initiation with DBC. I3C was effective at reducing T-cell acute lymphoblastic lymphoma/leukemia (T-ALL)-related mortality in offspring only if provided via the maternal diet, although a gender difference in the role of ERβ in mediating this response was evident. In female offspring, chemoprevention of T-ALL by maternal dietary I3C required expression of ERβ; survival in Esr2 wild-type and heterozygous female offspring was >90% compared to 66% in Esr2 null females. Alternatively, ERβ status did not significantly impact the transplacental chemoprevention by I3C in males. The possible role of ERβ in mediating lung carcinogenesis or chemoprevention by I3C was similarly complicated. Lung tumor incidence was unaltered by either dietary intervention, whereas lung tumor multiplicity was substantially reduced in Esr2 null females on the control diet and marginally lower in Esr2 null males exposed to I3C via the maternal diet compared to their wild-type and heterozygous counterparts. These findings suggest that I3C may act via ERβ to prevent or suppress DBC-initiated transplacental carcinogenesis, but that the involvement of this receptor appears to differ depending on the cancer type and gender of the offspring.
doi:10.1158/1940-6207.CAPR-12-0311
PMCID: PMC3618583  PMID: 23447562
Cancer prevention; indole-3-carbinol; estrogen receptor beta; T-cell acute lymphoblastic leukemia; lung carcinogenesis; polycyclic aromatic hydrocarbon
3.  Practice Based Versus Telemedicine Based Collaborative Care for Depression in Rural Federally Qualified Health Centers: A Pragmatic Randomized Comparative Effectiveness Trial 
The American journal of psychiatry  2013;170(4):10.1176/appi.ajp.2012.12050696.
Objective
Practice Based Collaborative Care is a complex evidence-based practice that is difficult to implement in smaller primary care practices lacking on-site mental health staff. Telemedicine Based Collaborative Care virtually co-locates and integrates mental health providers into primary care settings. The objective of this multi-site randomized pragmatic comparative effectiveness trial was to compare the outcomes of patients randomized to Practice Based versus Telemedicine Based Collaborative Care.
Method
From 2007–2009, patients at Federally Qualified Health Centers serving medically underserved populations were screened for depression, and 364 patients screening positive were enrolled and followed for 18 months. Those randomized to Practice Based Collaborative Care received evidence-based care from an on-site primary care provider and nurse care manager. Those randomized to Telemedicine Based Collaborative Care received evidence-based care from an on-site primary care provider and off-site telephone nurse care manager, telephone pharmacist, tele-psychologist and tele-psychiatrist. The primary clinical outcomes were treatment response, remission and changes in depression severity
Results
There were significant group main effects for both response (OR=7.74, CI95=3.94–15.20, p<0.0001) and remission (OR=12.69, CI95=4.81–33.46, p<0.0001) and a significant overall group by time interaction effect for Hopkins Symptom Checklist depression severity (χ23=40.51, p<0.0001) with greater reductions in depression severity observed over time for those randomized to Telemedicine Based Collaborative Care. Improvements in outcomes appeared to be attributable to higher fidelity to the collaborative care evidence-base in the Telemedicine Based group.
Conclusions
Contracting with an off-site Telemedicine Based Collaborative Care team yields better outcomes than implementing Practice Based Collaborative Care with locally available staff.
doi:10.1176/appi.ajp.2012.12050696
PMCID: PMC3816374  PMID: 23429924
4.  Investigating the feasibility of scale up and automation of human induced pluripotent stem cells cultured in aggregates in feeder free conditions☆ 
Journal of Biotechnology  2014;173(100):53-58.
Highlights
•First published protocol for scalable automation of hiPSC in feeder-free conditions.•Successful transfer of hiPSC between sites representative of research and manufacture.•Comparability between manual and automated expansion protocols for hiPSC.
The transfer of a laboratory process into a manufacturing facility is one of the most critical steps required for the large scale production of cell-based therapy products. This study describes the first published protocol for scalable automated expansion of human induced pluripotent stem cell lines growing in aggregates in feeder-free and chemically defined medium. Cells were successfully transferred between different sites representative of research and manufacturing settings; and passaged manually and using the CompacT SelecT automation platform. Modified protocols were developed for the automated system and the management of cells aggregates (clumps) was identified as the critical step. Cellular morphology, pluripotency gene expression and differentiation into the three germ layers have been used compare the outcomes of manual and automated processes.
doi:10.1016/j.jbiotec.2013.12.009
PMCID: PMC3969287  PMID: 24440272
Induced pluripotent stem cells; Feeder free; Automation; Scale up; Manufacturing
5.  Association between parental psychopathology and suicidal behavior among adult offspring: results from the cross-sectional South African Stress and Health survey 
BMC Psychiatry  2014;14:65.
Background
Prior studies have demonstrated a link between parental psychopathology and offspring suicidal behavior. However, it remains unclear what aspects of suicidal behavior among adult offspring are predicted by specific parental mental disorders, especially in Africa. This study set out to investigate the association between parental psychopathology and suicidal behavior among their adult offspring in a South African general population sample.
Method
Parental psychopathology and suicidal behavior in offspring were assessed using structured interviews among 4,315 respondents from across South Africa. The WHO CIDI was used to collect data on suicidal behavior, while the Family History Research Diagnostic Criteria Interview was used to assess prior parental psychopathology. Bivariate and multivariate survival models tested the associations between the type and number parental mental disorders (including suicide) and lifetime suicidal behavior in the offspring. Associations between a range of parental disorders and the onset of subsequent suicidal behavior (suicidal ideation, plans, and attempts) among adult offspring were tested.
Results
The presence of parental psychopathology significantly increased the odds of suicidal behavior among their adult offspring. More specifically, parental panic disorder was associated with offspring suicidal ideation, while parental panic disorder, generalized anxiety disorder and suicide were significantly associated with offspring suicide attempts. Among those with suicidal ideation, none of the tested forms of parental psychopathology was associated with having suicide plans or attempts. There was a dose–response relationship between the number of parental disorders and odds of suicidal ideation.
Conclusions
Parental psychopathology increases the odds of suicidal behavior among their adult offspring in the South African context, replicating results found in other regions. Specific parental disorders predicted the onset and persistence of suicidal ideation or attempts in their offspring. Further research into these associations is recommended in order to determine the mechanisms through which parent psychopathology increases the odds of suicidal behavior among offspring.
doi:10.1186/1471-244X-14-65
PMCID: PMC3944470  PMID: 24592882
Suicide; Parental psychopathology; South Africa
6.  Epigenetic inactivation of endothelin-2 (ET-2) and ET-3 in colon cancer 
Endothelin-1 (ET-1) and its receptors are overexpressed in human cancers, but much less is known about the roles of ET-2 and ET-3 in cancer etiology. We sought to examine human and rat colon tumors for dysregulation of ET-2 and ET3 expression, and determine the underlying mechanisms. Human primary colon cancers and carcinogen-induced rat colon tumors were subjected to real-time RT-PCR, immunoblotting, and immunohistochemistry; EDN2 and EDN3 genes were examined by methylation-specific PCR, bisulfite sequencing, and pyrosequencing; and forced expression of ET-2 and ET-3 was conducted in human colon cancer cells followed by real-time cell migration and invasion assays. Rat and human colon tumors had markedly reduced expression of ET-2 and ET-3 mRNA and protein compared with matched controls. Mechanistic studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers, and in a panel of human colon cancer cell lines. Forced expression of ET-2 and ET-3 attenuated significantly the migration and invasion of human colon cancer cells. We conclude that epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. Current therapeutic strategies target overexpressed members of the ET axis via small molecule inhibitors and receptor antagonists, but this work supports a complementary approach based on the re-expression of ET-2 and ET-3 as natural antagonists of ET-1 in colon cancer.
doi:10.1002/ijc.27762
PMCID: PMC3500448  PMID: 22865632
Colorectal Cancer; DNA methylation; Endothelin Axis; Epigenetics
7.  Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury 
Cardiovascular Research  2012;97(3):432-442.
Aims
We have reported that either toll-like receptor 4 deficiency (TLR4−/−) or TLR2 modulation protects against myocardial ischaemia/reperfusion (I/R) injury. The mechanisms involve attenuation of I/R-induced nuclear factor KappaB (NF-κB) activation. MicroRNA-146a (miR-146a) has been reported to target interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), resulting in inhibiting NF-κB activation. This study examined the role of microRNA-146a in myocardial I/R injury.
Methods and results
We constructed lentivirus expressing miR-146a (LmiR-146a). LmiR-146a was transfected into mouse hearts through the right common carotid artery. The lentivirus vector (LmiR-Con) served as vector control. Untransfected mice served as I/R control. Sham operation served as sham control. Seven days after transfection, the hearts were subjected to ischaemia (60 min) followed by reperfusion (4 h). Myocardial infarct size was analysed by triphenyltetrazolium chloride (TTC) staining. In separate experiments, the hearts were subjected to ischaemia (60 min) followed by reperfusion for up to 7 days. Cardiac function was measured by echocardiography prior to I/R, 3 and 7 days after myocardial I/R. LmiR-146a transfection significantly decreased I/R-induced myocardial infarct size by 55% and prevented I/R-induced decreases in ejection fraction (EF%) and fractional shortening (%FS). LmiR-146a transfection attenuated I/R-induced myocardial apoptosis and caspase-3/7 and -8 activities. LmiR-146a transfection suppresses IRAK1 and TRAF6 expression in the myocardium. In addition, transfection of LmiR-146a prevented I/R-induced NF-κB activation and inflammatory cytokine production.
Conclusions
MicroRNA-146a protects the myocardium from I/R injury. The mechanisms may involve attenuation of NF-κB activation and inflammatory cytokine production by suppressing IRAK1 and TRAF6.
doi:10.1093/cvr/cvs356
PMCID: PMC3567787  PMID: 23208587
MicroRNA-146a myocardial I/R; Toll-like receptors; NF-κB activation
8.  Application of a Fuzzy Neural Network Model in Predicting Polycyclic Aromatic Hydrocarbon- Mediated Perturbations of the Cyp1b1 Transcriptional Regulatory Network in Mouse Skin 
Toxicology and applied pharmacology  2012;267(2):192-199.
Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave one out cross-validation. Predictions were within 1 log2 fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights.
doi:10.1016/j.taap.2012.12.011
PMCID: PMC3626406  PMID: 23274566
PAHs; modeling; mixtures; Cyp1b1; skin Ahrr
9.  Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression 
Leukemia  2012;27(5):1080-1089.
We have previously identified a tyrosine kinase-independent, guanine nucleotide exchange factor (GEF) activity that is contained within the region of p210 BCR/ABL that distinguishes it from p190 BCR/ABL. In the current study we have compared the transforming activity of p190 BCR/ABL, p210 BCR/ABL, and a mutant that lacks GEF activity (p210 BCR/ABL(S509A)). In cell-based, ex vivo, and murine bone marrow transplantation assays (BMT) the transforming activity of p210 BCR/ABL(S509A) mimics p190 BCR/ABL, and is distinct from p210 BCR/ABL. Thus, in the BMT assay, the p190 BCR/ABL and p210 BCR/ABL(S509A) transplanted mice exhibit a more rapid onset of disease than mice transplanted with p210 BCR/ABL. The reduced disease latency is associated with erythroid hyperplasia in the absence of anemia, and expansion of the MEP, CMP and GMP populations, producing a phenotype that is similar to acute myeloid leukemia (AML-M6). The disease phenotype is readily transplantable into secondary recipients. This is consistent with ex vivo clonogenicity assays where p210 BCR/ABL preferentially supports the growth of CFU-GM, while p190 BCR/ABL and the mutant preferentially support the growth of BFU-E. These results suggest that the GEF activity that distinguishes p210 BCR/ABL from p190 BCR/ABL actively regulates disease progression.
doi:10.1038/leu.2012.351
PMCID: PMC3931524  PMID: 23207522
Chronic myelogenous leukemia; p210 BCR/ABL; RhoGEF domain; Rho GTPase
10.  Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism 
Cancer research  2012;73(4):1340-1351.
Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235, PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony-formation in leukemic but not normal CD34+ cells. Notably, increased lethality was observed in 4/6 primary AML specimens. Responding, but not non-responding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly down-regulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2 or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown, or Mcl-1 over-expression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or shRNA knockdown of GSK3α/β significantly attenuated Mcl-1 down-regulation and decreased apoptosis. In a systemic AML xenograft model, dual tet-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 anti-leukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 co-administration significantly diminished tumor growth, down-regulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that anti-leukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 down-regulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3α/β, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3-mimetics warrants attention in AML, particularly in the setting of basal AKT activation and/or addiction.
doi:10.1158/0008-5472.CAN-12-1365
PMCID: PMC3578060  PMID: 23243017
PI3K; Bcl-2; Bcl-xL; apoptosis; leukemia
11.  Benefit of Long-Term Dual Anti-Platelet Therapy in Patients Treated with Drug-Eluting Stents: From the NHLBI Dynamic Registry 
The American journal of cardiology  2012;111(4):486-492.
The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an important, unanswered question. This study was designed to evaluate the association of varying durations of DAPT on clinical outcomes after DES implantation for the treatment of coronary artery disease. Using the National Heart, Lung and Blood Institute (NHLBI) Dynamic Registry, patients enrolled in the last two waves after index percutaneous coronary intervention (PCI) with DES and who were event free at time of landmark analysis were included. Landmark analysis was performed at 12 and 24 months after PCI and patients stratified according to continued use of DAPT or not. Subjects were evaluated for rates of death, myocardial infarction (MI) and stent thrombosis (ST) at 4 years from their index procedure. The number of evaluable patients was 2157 and 1918 for the 12- and 24-month landmarks, respectively. In both landmark analyses, there was a significantly lower 4-year rate of death/MI in the group that continued DAPT compared to the group that did not (12-month: 10.5% vs. 14.5%, p=0.01; 24-month: 5.7% vs. 8.6%, p=0.02). Beneficial differences in the group that continued on DAPT were preserved after multivariate and propensity adjustment. There were no significant differences in definite stent thrombosis in either landmark analysis. In conclusion, at 12-months and 24-months following DES implantation, continued use of DAPT, was associated with lower 4-year risk of death and myocardial infarction.
doi:10.1016/j.amjcard.2012.10.030
PMCID: PMC3579582  PMID: 23211356
Coronary disease; Stents; Mortality; Thrombosis
12.  Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium 
Visual neuroscience  2013;30(3):55-64.
Cathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mreg dsu/dsu mouse, we observe increased basal laminin. Loss of the Mreg dsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.
doi:10.1017/S0952523813000096
PMCID: PMC3912860  PMID: 23611523
Retinal pigment epithelium; Cathepsin-D processing; Phagocytosis; Protease secretion
13.  SR-A deficiency reduces myocardial ischemia/reperfusion injury; involvement of increased microRNA-125b expression in macrophages 
Biochimica et biophysica acta  2012;1832(2):336-346.
The macrophage scavenger receptor class A (SR-A) participates in the innate immune and inflammatory responses. This study examined the role of macrophage SR-A in myocardial ischemia/reperfusion (I/R) injury and hypoxia/reoxygenation (H/R)-induced cell damage. SR-A−/− and WT mice were subjected to ischemia (45 min) followed by reperfusion for up to 7 days. SR-A−/− mice showed smaller myocardial infarct size and better cardiac function than did WT I/R mice. SR-A deficiency attenuated I/R-induced myocardial apoptosis by preventing p53-mediated Bak-1 apoptotic signaling. The levels of microRNA-125b in SR-A−/− heart were significantly greater than in WT myocardium. SR-A is predominantly expressed on macrophages. To investigate the role of SR-A macrophages in H/R-induced injury, we isolated peritoneal macrophages from SR-A deficient (SR-A−/−) and wild type (WT) mice. Macrophages were subjected to hypoxia followed by reoxygenation. H/R markedly increased NF-κB binding activity as well as KC and MCP-1 production in WT macrophages but not in SR-A−/− macrophages. H/R induced caspase-3/7 and -8 activities and cell death in WT macrophages, but not in SR-A−/− macrophages. The levels of miR-125b in SR-A−/− macrophages were significantly higher than in WT macrophages. Transfection of WT macrophages with miR-125b mimics attenuated H/R-induced caspase-3/7 and -8 activities and H/R-decreased viability, and prevented H/R-increased p-53, Bak-1 and Bax expression. The data suggest that SR-A deficiency attenuates myocardial I/R injury by targeting p53-mediated apoptotic signaling. SR-A−/− macrophages contain high levels of miR-125b which may play a role in the protective effect of SR-A deficiency on myocardial I/R injury and H/R-induced cell damage.
doi:10.1016/j.bbadis.2012.10.012
PMCID: PMC3534792  PMID: 23123599
microRNA-125b; Macrophage SR-A; hypoxia/reoxygenation; Myocardial I/R injury; apoptosis
14.  Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus 
Gene therapy  2013;20(8):824-833.
Usher 1 patients are born profoundly deaf and then develop retinal degeneration. Thus they are readily identified prior to the onset of retinal degeneration, making gene therapy a viable strategy to prevent their blindness. Here, we have investigated the use of adeno-associated viruses (AAV) for the delivery of the Usher 1B gene, MYO7A, to retinal cells in cell culture and in Myo7a-null mice. MYO7A cDNA, under control of a smCBA promoter, was packaged in single AAV2 and AAV5 vectors, and as two overlapping halves in dual AAV2 vectors. The 7.9-kb smCBA-MYO7A exceeds the capacity of an AAV vector; packaging of such oversized constructs into single AAV vectors may involve fragmentation of the gene. Nevertheless, the AAV2 and AAV5 single vector preparations successfully transduced photoreceptor and RPE cells, resulting in functional, full-length MYO7A protein and correction of mutant phenotypes, suggesting successful homologous recombination of gene fragments. With discrete, conventional-sized dual AAV2 vectors, full-length MYO7A was detected, but the level of protein expression was variable, and only a minority of cells showed phenotype correction. Our results show that MYO7A therapy with AAV2 or AAV5 single vectors is efficacious, however, the dual AAV2 approach proved to be less effective.
doi:10.1038/gt.2013.3
PMCID: PMC3640772  PMID: 23344065
Usher syndrome; gene therapy; adeno-associated virus; retina; RPE; MYO7A
15.  Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways 
Endocrine-Related Cancer  2014;21(1):85-99.
Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors.
doi:10.1530/ERC-13-0181
PMCID: PMC3869950  PMID: 24189182
anosmin-1; Kallmann syndrome; brain tumor; integrins; matrix metalloproteinases; meta-analysis; tumor microenvironment
16.  Rho GTPases in hematopoietic stem cell functions 
Current opinion in hematology  2009;16(4):249-254.
Purpose of review
Rho GTPases are key molecular switches controlling the transduction of external signals to cytoplasmic and nuclear effectors. In the last few years, the development of genetic and pharmacological tools has allowed a more precise definition of the specific roles of Rho GTPases in hematopoietic stem cells (HSCs) and progeny of these cells. Rho GTPases are now known to be crucial in HSCs response to hematopoietic microenvironment cues. This article will review the known HSC functions, which are regulated by Rho GTPases.
Recent findings
This review analyzes the latest data on how different Rho GTPases control adhesion, migration, retention, proliferation, survival, senescence and oncogenic transformation of HSCs and relates these new findings to the physiological functions of these cells.
Summary
The development of small molecule inhibitors with ability to interfere Rho GTPase activation by guanine nucleotide exchange factors offers new therapeutic strategies to manipulate the function of HSCs.
doi:10.1097/MOH.0b013e32832c4b80
PMCID: PMC3908896  PMID: 19417647
bone marrow retention; Cdc42; engraftment; hematopoietic stem cells and progenitors; leukemia; Rac; Rho GTPases
17.  Episodic Memory and Episodic Future Thinking Impairments in High-Functioning Autism Spectrum Disorder: An Underlying Difficulty With Scene Construction or Self-Projection? 
Neuropsychology  2013;28(1):55-67.
Objective: There appears to be a common network of brain regions that underlie the ability to recall past personal experiences (episodic memory) and the ability to imagine possible future personal experiences (episodic future thinking). At the cognitive level, these abilities are thought to rely on “scene construction” (the ability to bind together multimodal elements of a scene in mind—dependent on hippocampal functioning) and temporal “self-projection” (the ability to mentally project oneself through time—dependent on prefrontal cortex functioning). Although autism spectrum disorder (ASD) is characterized by diminished episodic memory, it is unclear whether episodic future thinking is correspondingly impaired. Moreover, the underlying basis of such impairments (difficulties with scene construction, self-projection, or both) is yet to be established. The current study therefore aimed to elucidate these issues. Method: Twenty-seven intellectually high-functioning adults with ASD and 29 age- and IQ-matched neurotypical comparison adults were asked to describe (a) imagined atemporal, non-self-relevant fictitious scenes (assessing scene construction), (b) imagined plausible self-relevant future episodes (assessing episodic future thinking), and (c) recalled personally experienced past episodes (assessing episodic memory). Tests of narrative ability and theory of mind were also completed. Results: Performances of participants with ASD were significantly and equally diminished in each condition and, crucially, this diminution was independent of general narrative ability. Conclusions: Given that participants with ASD were impaired in the fictitious scene condition, which does not involve self-projection, we suggest the underlying difficulty with episodic memory/future thinking is one of scene construction.
doi:10.1037/neu0000005
PMCID: PMC3906795  PMID: 24015827
autism spectrum disorder; episodic memory; episodic future thinking; scene construction; self-projection
18.  Spatial Navigation Impairments Among Intellectually High-Functioning Adults With Autism Spectrum Disorder: Exploring Relations With Theory of Mind, Episodic Memory, and Episodic Future Thinking 
Journal of Abnormal Psychology  2013;122(4):1189-1199.
Research suggests that spatial navigation relies on the same neural network as episodic memory, episodic future thinking, and theory of mind (ToM). Such findings have stimulated theories (e.g., the scene construction and self-projection hypotheses) concerning possible common underlying cognitive capacities. Consistent with such theories, autism spectrum disorder (ASD) is characterized by concurrent impairments in episodic memory, episodic future thinking, and ToM. However, it is currently unclear whether spatial navigation is also impaired. Hence, ASD provides a test case for the scene construction and self-projection theories. The study of spatial navigation in ASD also provides a test of the extreme male brain theory of ASD, which predicts intact or superior navigation (purportedly a systemizing skill) performance among individuals with ASD. Thus, the aim of the current study was to establish whether spatial navigation in ASD is impaired, intact, or superior. Twenty-seven intellectually high-functioning adults with ASD and 28 sex-, age-, and IQ-matched neurotypical comparison adults completed the memory island virtual navigation task. Tests of episodic memory, episodic future thinking, and ToM were also completed. Participants with ASD showed significantly diminished performance on the memory island task, and performance was positively related to ToM and episodic memory, but not episodic future thinking. These results suggest that (contra the extreme male brain theory) individuals with ASD have impaired survey-based navigation skills—that is, difficulties generating cognitive maps of the environment—and adds weight to the idea that scene construction/self-projection are impaired in ASD. The theoretical and clinical implications of these results are discussed.
doi:10.1037/a0034819
PMCID: PMC3906800  PMID: 24364620
autism spectrum disorder; episodic memory; episodic future thinking; spatial navigation; theory of mind
19.  Diminished Time-Based, but Undiminished Event-Based, Prospective Memory Among Intellectually High-Functioning Adults With Autism Spectrum Disorder: Relation to Working Memory Ability 
Neuropsychology  2013;28(1):30-42.
Objective: Prospective memory (PM) is the ability to remember to carry out an intended action. Working memory is the ability to store information in mind while processing potentially distracting information. The few previous studies of PM in autism spectrum disorder (ASD) have yielded inconsistent findings. Studies of working memory ability in ASD have suggested a selective impairment of “visual working memory.” However, it remains unclear whether any such impairment is the result of diminished (domain-specific; visual/verbal) storage capacity or diminished (domain-general) processing capacity. We aim to clarify these issues and explore the relation between PM and working memory in ASD. Method: Seventeen adults with ASD and 17 age- and IQ-matched comparison participants completed experimental measures of both event-based (perform action x when event y occurs) and time-based (perform action a at time b) PM, plus a self-report measure of PM skills. Participants also completed a working memory test battery. Results: Participants with ASD self-reported diminished PM skill, and showed diminished performance on the time-based, but not event-based, PM task. On the working memory test battery, visual but not verbal storage capacity was diminished among participants with ASD, as was processing ability. Whereas visual storage was associated with event-based PM task performance among comparison participants, verbal storage was associated among ASD participants. Conclusions: ASD appears to involve a selective deficit in time-based PM and a selective difficulty with aspects of working memory that depend on the storage of visual information. However, event-based PM may be achieved through compensatory strategies in ASD.
doi:10.1037/neu0000008
PMCID: PMC3906801  PMID: 24128041
autism; prospective memory; working memory; short-term memory (STM); complex span
20.  Effects of Sulforaphane and 3,3′-Diindolylmethane on Genome-Wide Promoter Methylation in Normal Prostate Epithelial Cells and Prostate Cancer Cells 
PLoS ONE  2014;9(1):e86787.
Epigenetic changes, including aberrant DNA methylation, result in altered gene expression and play an important role in carcinogenesis. Phytochemicals such as sulforaphane (SFN) and 3,3′-diindolylmethane (DIM) are promising chemopreventive agents for the treatment of prostate cancer. Both have been shown to induce re-expression of genes, including tumor suppressor genes silenced in cancer cells, via modulation of epigenetic marks including DNA methylation. However, it remained unclear the effects SFN and DIM on DNA methylation at a genomic scale. The goal of this study was to determine the genome-wide effects of SFN and DIM on promoter methylation in normal prostate epithelial cells and prostate cancer cells. Both SFN and DIM treatment decreased DNA methyltransferase expression in normal prostate epithelial cells (PrEC), and androgen-dependent (LnCAP) and androgen-independent (PC3) prostate cancer cells. The effects of SFN and DIM on promoter methylation profiles in normal PrEC, LnCAP and PC3 prostate cancer cells were determined using methyl-DNA immunoprecipitation followed by genome-wide DNA methylation array. We showed widespread changes in promoter methylation patterns, including both increased and decreased methylation, in all three prostate cell lines in response to SFN or DIM treatments. In particular, SFN and DIM altered promoter methylation in distinct sets of genes in PrEC, LnCAP, and PC3 cells, but shared similar gene targets within a single cell line. We further showed that SFN and DIM reversed many of the cancer-associated methylation alterations, including aberrantly methylated genes that are dysregulated or are highly involved in cancer progression. Overall, our data suggested that both SFN and DIM are epigenetic modulators that have broad and complex effects on DNA methylation profiles in both normal and cancerous prostate epithelial cells. Results from our study may provide new insights into the epigenetic mechanisms by which SFN and DIM exert their cancer chemopreventive effects.
doi:10.1371/journal.pone.0086787
PMCID: PMC3899342  PMID: 24466240
21.  The association between substance use and common mental disorders in young adults: results from the South African Stress and Health (SASH) Survey 
The Pan African Medical Journal  2014;17(Suppl 1):11.
Introduction
Although substance use is commonly associated with mental disorders, limited data on this association are available from low and middle income countries such as South Africa. The aims of the study were i) to determine patterns of substance use in young adults, ii) to identify trends of common psychiatric disorders in relation to use of specific substances, and iii) to determine whether specific psychiatric disorders were associated with use of specific substances in the South African population.
Methods
Data were drawn from the South African Stress and Health (SASH) study, a nationally-representative, cross-sectional survey of South African households that forms part of a World Health Organisation (WHO) World Mental Health (WMH) initiative to standardise information on the global burden of mental illness and its correlates. Data from a subset (n = 1766; aged 18 to 30 years) of the SASH sample of 4351 individuals were analysed. The Composite International Diagnostic Interview Version 3 (CIDI 3.0) was used to elicit basic demographic details and information regarding mental illness and substance use. Multiple regression analyses, adjusted for age and gender, were used to identify associations between mental disorders and substance use.
Results
Significant associations were found between substance use and mood and anxiety disorders, with a particularly strong relationship between cannabis use and mental disorder.
Conclusion
The results are consistent with those from previous studies, and reinforce the argument that comorbid substance use and mental disorders constitute a major public health burden.
doi:10.11694/pamj.supp.2014.17.1.3328
PMCID: PMC3946226  PMID: 24624244
SASH; comorbidity; mental disorders; substance use
22.  Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens 
Cofactor-independent phosphoglycerate mutase (iPGAM) is essential for the growth of C. elegans but is absent from humans, suggesting its potential as a drug target in parasitic nematodes such as Brugia malayi, a cause of lymphatic filariasis (LF). iPGAM's active site is small and hydrophilic, implying that it may not be druggable, but another binding site might permit allosteric inhibition. As a comprehensive assessment of iPGAM's druggability, high-throughput screening (HTS) was conducted at two different locations: ∼220,000 compounds were tested against the C. elegans iPGAM by Genzyme Corporation, and ∼160,000 compounds were screened against the B. malayi iPGAM at the National Center for Drug Screening in Shanghai. iPGAM's catalytic activity was coupled to downstream glycolytic enzymes, resulting in NADH consumption, as monitored by a decline in visible-light absorbance at 340 nm. This assay performed well in both screens (Z′-factor >0.50) and identified two novel inhibitors that may be useful as chemical probes. However, these compounds have very modest potency against the B. malayi iPGAM (IC50 >10 µM) and represent isolated singleton hits rather than members of a common scaffold. Thus, despite the other appealing properties of the nematode iPGAMs, their low druggability makes them challenging to pursue as drug targets. This study illustrates a “druggability paradox” of target-based drug discovery: proteins are generally unsuitable for resource-intensive HTS unless they are considered druggable, yet druggability is often difficult to predict in the absence of HTS data.
Author Summary
Parasitic worms like Brugia malayi cause widespread lymphatic filariasis (LF) in southeast Asia and sub-Saharan Africa. The adult worms causing most of the symptoms of LF are difficult to treat with existing drugs. As a possible step toward new LF drugs, we searched for inhibitors of the B. malayi cofactor-independent phosphoglycerate mutase (iPGAM), an enzyme thought to be critical to survival and development of this parasite. Despite testing over 100,000 compounds at each of two screening centers, we found only two compounds that consistently inhibited the B. malayi enzyme more strongly than the cofactor-dependent enzyme found in humans. These compounds have limited potency and are not especially great starting points for drug development. The 3-dimensional structure of iPGAM suggests that the active site is difficult to access from the surrounding solvent, which may partly explain our very low yield of inhibitors. We conclude that iPGAM may not be an ideal drug target in B. malayi or related organisms because it is difficult to inhibit with druglike compounds.
doi:10.1371/journal.pntd.0002628
PMCID: PMC3886921  PMID: 24416464
23.  Informing Disease Models with Temporal and Spatial Contact Structure among GPS-Collared Individuals in Wild Populations 
PLoS ONE  2014;9(1):e84368.
Contacts between hosts are essential for transmission of many infectious agents. Understanding how contacts, and thus transmission rates, occur in space and time is critical to effectively responding to disease outbreaks in free-ranging animal populations. Contacts between animals in the wild are often difficult to observe or measure directly. Instead, one must infer contacts from metrics such as proximity in space and time. Our objective was to examine how contacts between white-tailed deer (Odocoileus virginianus) vary in space and among seasons. We used GPS movement data from 71 deer in central New York State to quantify potential direct contacts between deer and indirect overlap in space use across time and space. Daily probabilities of direct contact decreased from winter (0.05–0.14), to low levels post-parturition through summer (0.00–0.02), and increased during the rut to winter levels. The cumulative distribution for the spatial structure of direct and indirect contact probabilities around a hypothetical point of occurrence increased rapidly with distance for deer pairs separated by 1,000 m – 7,000 m. Ninety-five percent of the probabilities of direct contact occurred among deer pairs within 8,500 m of one another, and 99% within 10,900 m. Probabilities of indirect contact accumulated across greater spatial extents: 95% at 11,900 m and 99% at 49,000 m. Contacts were spatially consistent across seasons, indicating that although contact rates differ seasonally, they occur proportionally across similar landscape extents. Distributions of contact probabilities across space can inform management decisions for assessing risk and allocating resources in response.
doi:10.1371/journal.pone.0084368
PMCID: PMC3883651  PMID: 24409293
24.  CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: involving activation of PI3K/Akt signaling 
Biochimica et biophysica acta  2012;1832(1):96-104.
Background
Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury.
Methods
Male C57BL/6 mice were treated with either CpG-ODN, control-ODN, or inhibitory CpG-ODN (iCpG-ODN) one hr prior to myocardial ischemia (60 min) followed by reperfusion. Untreated mice served as I/R control (n=10/each group). Infarct size was determined by TTC straining. Cardiac function was examined by echocardiography before and after myocardial I/R up to 14 days.
Results
CpG-ODN administration significantly decreased infarct size by 31.4% and improved cardiac function after myocardial I/R up to 14 days. Neither control-ODN nor iCpG-ODN altered I/R-induced myocardial infarction and cardiac dysfunction. CpG-ODN attenuated I/R-induced myocardial apoptosis and prevented I/R-induced decrease in Bcl2 and increase in Bax levels in the myocardium. CpG-ODN increased Akt and GSK-3β phosphorylation in the myocardium. In vitro data suggested that CpG-ODN treatment induced TLR9 tyrosine phosphorylation and promoted an association between TLR9 and the p85 subunit of PI3K. Importantly, PI3K/Akt inhibition and Akt kinase deficiency abolished CpG-ODN-induced cardioprotection.
Conclusion
The CpG-ODN, the TLR9 ligand, induces protection against myocardial I/R injury. The mechanisms involve activation of the PI3K/At signaling pathway.
doi:10.1016/j.bbadis.2012.08.008
PMCID: PMC3518630  PMID: 22917564
Myocardial I/R; TLR9; PI3K/Akt signaling; Apoptosis
25.  The Association between Optimism and Serum Antioxidants in the Midlife in the United States Study 
Psychosomatic medicine  2012;75(1):2-10.
Objective
Psychological and physical health are often conceptualized as the absence of disease, but less research addresses positive psychological and physical functioning. For example, optimism has been linked with reduced disease risk and biological dysfunction, but very little research has examined associations with markers of healthy biological functioning. Thus, we investigated the association between two indicators of positive health: optimism and serum antioxidants.
Methods
The cross-sectional association between optimism and antioxidant concentrations was examined in 982 men and women from the Midlife in the United States study. Primary measures included self-reported optimism (assessed with the revised Life Orientation Test) and serum concentrations of nine different antioxidants (carotenoids and Vitamin E). Regression analyses examined the relationship between optimism and antioxidant concentrations in models adjusted for demographics, health status, and health behaviors.
Results
For every standard deviation increase in optimism, carotenoid concentrations increased by 3–13% in age-adjusted models. Controlling for demographic characteristics and health status attenuated this association. Fruit and vegetable consumption and smoking status were identified as potential pathways underlying the association between optimism and serum carotenoids. Optimism was not significantly associated with Vitamin E.
Conclusions
Optimism was associated with greater carotenoid concentrations and this association was partially explained by diet and smoking status. The direction of effects cannot be conclusively determined. Effects may be bidirectional given that optimists are likely to engage in health behaviors associated with more serum antioxidants, and more serum antioxidants are likely associated with better physical health that enhances optimism.
doi:10.1097/PSY.0b013e31827c08a9
PMCID: PMC3539819  PMID: 23257932
optimism; antioxidants; carotenoids; vitamin E

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