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1.  Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway 
Oncogene  2012;32(23):2836-2847.
Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer and is especially implicated in the development and progression of colorectal cancer. The key effector protein of the canonical Wnt pathway is β-catenin, which functions with T-cell factor/lymphoid enhancer factor to activate expression of Wnt target genes. In this study, we used a new functional screen based on cell survival in the presence of cDNAs encoding proteins that activate the Wnt pathway thus identifying novel Wnt signaling components. Here we identify carboxypeptidase E (|CPE) and its splice variant, ΔN-CPE, as novel regulators of the Wnt pathway. We show that whereas ΔN-CPE activates the Wnt signal, the full-length CPE (F-CPE) protein is an inhibitor of Wnt/β-catenin signaling. F-CPE forms a complex with the Wnt3a ligand and the Frizzled receptor. Moreover, F-CPE disrupts disheveled-induced signalosomes that are important for transducing the Wnt signal and reduces β-catenin protein levels and activity. Taken together, our data indicate that F-CPE and ΔN-CPE regulate the canonical Wnt signaling pathway negatively and positively, respectively, and demonstrate that this screening approach can be a rapid means for isolation of novel Wnt signaling components.
doi:10.1038/onc.2012.308
PMCID: PMC3676431  PMID: 22824791
Wnt signaling; carboxypeptidase E (CPE); β-catenin; functional screen
2.  Development and Evaluation of a Genetic Risk Score for Obesity 
Biodemography and social biology  2013;59(1):10.1080/19485565.2013.774628.
Background
Results from genome-wide association studies (GWAS) represent a potential resource for etiological and treatment research. GWAS of obesity-related phenotypes have been especially successful. To translate this success into a research tool, we developed and tested a “genetic risk score” (GRS) that summarizes an individual’s genetic predisposition to obesity.
Methods
Different GWAS of obesity-related phenotypes report different sets of single nucleotide polymorphisms (SNPs) as the best genomic markers of obesity risk. Therefore, we applied a 3-stage approach that pooled results from multiple GWAS to select SNPs to include in our GRS: The 3 stages are (1) Extraction. SNPs with evidence of association are compiled from published GWAS; (2) Clustering. SNPs are grouped according to patterns of linkage disequilibrium; (3) Selection. Tag SNPs are selected from clusters that meet specific criteria. We applied this 3-stage approach to results from 16 GWAS of obesity-related phenotypes in European-descent samples to create a GRS. We then tested the GRS in the Atherosclerosis Risk in the Communities (ARIC) Study cohort (N=10,745, 55% female, 77% white, 23% African American).
Results
Our 32-locus GRS was a statistically significant predictor of body mass index (BMI) and obesity among ARIC whites (for BMI, r=0.13, p<1×10−30; for obesity, area under the receiver operating characteristic curve (AUC)=0.57 [95% CI 0.55–0.58]). The GRS improved prediction of obesity (as measured by delta-AUC and integrated discrimination index) when added to models that included demographic and geographic information. FTO- and MC4R-linked SNPs, and a non-genetic risk assessment consisting of a socioeconomic index (p<0.01 for all comparisons). The GRS also predicted increased mortality risk over 17 years of follow-up. The GRS performed less well among African Americans.
Conclusions
The obesity GRS derived using our 3-stage approach is not useful for clinical risk prediction, but may have value as a tool for etiological and treatment research.
doi:10.1080/19485565.2013.774628
PMCID: PMC3671353  PMID: 23701538
3.  Chronic bullying victimization across school transitions: The role of genetic and environmental influences 
Development and psychopathology  2013;25(2):10.1017/S0954579412001095.
We investigated the antecedents and consequences of chronic victimization by bullies across a school transition using a genetically sensitive longitudinal design. Data were from the Environmental Risk Longitudinal Twin Study (E-Risk), an epidemiological cohort of 2,232 children. We used mothers’ and children’s reports of bullying victimization during primary school and early secondary school. Children who experienced frequent victimization at both time points were classed as “chronic victims” and were found to have an increased risk for mental health problems and academic difficulties compared to children who were bullied only in primary school, children bullied for the first time in secondary school, and never-bullied children. Biometric analyses revealed that stability in victimization over this period was influenced primarily by genetic and shared environmental factors. Regression analyses showed that children’s early characteristics such as preexistent adjustment difficulties and IQ predicted chronic versus transitory victimization. Family risk factors for chronic victimization included socioeconomic disadvantage, low maternal warmth, and maltreatment. Our results suggest that bullying intervention programs should consider the role of the victims’ behaviors and family background in increasing vulnerability to chronic victimization. Our study highlights the importance of widening antibullying interventions to include families to reduce the likelihood of children entering a pathway toward chronic victimization.
doi:10.1017/S0954579412001095
PMCID: PMC3881278  PMID: 23627948
4.  Polygenic risk accelerates the developmental progression to heavy, persistent smoking and nicotine dependence: Evidence from a 4-Decade Longitudinal Study 
JAMA psychiatry (Chicago, Ill.)  2013;70(5):534-542.
OBJECTIVE
To test how genomic loci identified in genome-wide association studies (GWAS) influence the developmental progression of smoking behavior.
DESIGN
A 38-year prospective longitudinal study of a representative birth-cohort.
SETTING
The Dunedin Multidisciplinary Health and Development Study, New Zealand.
PARTICIPANTS
N=1037 male and female study members.
MAIN EXPOSURES
We assessed genetic risk with a multi-locus genetic risk score (GRS). The GRS was composed of single-nucleotide polymorphisms identified in three meta-analyses of GWAS of smoking quantity phenotypes.
OUTCOME MEASURES
Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerstrom Test of Nicotine Dependence), and cessation difficulties were evaluated at eight assessments spanning ages 11-38 years.
RESULTS
Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that two adolescent developmental phenotypes—early conversion to daily smoking and rapid progression to heavy smoking--mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history.
CONCLUSIONS
Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers.
doi:10.1001/jamapsychiatry.2013.736
PMCID: PMC3644004  PMID: 23536134
5.  Functional macrophage heterogeneity in a mouse model of autoimmune CNS pathology 
Functional macrophage heterogeneity is well appreciated outside the CNS in wound healing and cancer, and was recently also demonstrated in several CNS compartments following “sterile” insults. Yet, such heterogeneity was largely overlooked in the context of inflammatory autoimmune pathology, in which macrophages were mainly associated with disease induction and propagation. Here, we show the diversity of monocyte-derived macrophages along the course of experimental autoimmune uveitis (EAU), an inflammatory condition affecting the ocular system, serving a model for CNS autoimmune pathology. Disease induction resulted in the appearance of a distinct myeloid population in the retina, and in the infiltration of monocyte-derived macrophages that were absent from control eyes. During the disease course, the frequency of CX3CR1high infiltrating macrophages that express markers associated with inflammation-resolving activity was increased, along with a decrease in the frequency of inflammation-associated, Ly6C+ macrophages. Inhibition of monocyte infiltration at the induction phase of EAU prevented disease onset, while monocyte depletion at the resolution phase resulted in a decrease in Foxp3+ regulatory T cells, and in exacerbated disease. Thus, monocyte-derived macrophages display distinct phenotypes throughout the disease course, even in an immune-induced pathology, reflecting their differential roles in disease induction and resolution.
doi:10.4049/jimmunol.1202076
PMCID: PMC3626074  PMID: 23447691
6.  The social environment and walking behavior among low-income housing residents 
Walking, both for leisure and for travel/errands, counts towards meeting physical activity recommendations. Both social and physical neighborhood environmental features may encourage or inhibit walking. This study examined social capital, perceived safety, and disorder in relation to walking behavior among a population of low-income housing residents. Social and physical disorder were assessed by systematic social observation in the area surrounding 20 low-income housing sites in greater-Boston. A cross-sectional survey of 828 residents of these housing sites provided data on walking behavior, socio-demographics, and individual-level social capital and perceived safety of the areas in and around the housing site. Community social capital and safety were calculated by aggregating individual scores to the level of the housing site. Generalized estimating equations were used to estimate prevalence rate ratios for walking less than 10 minutes per day for a) travel/errands, b) leisure and c) both travel/errands and leisure. 21.8% of participants walked for travel/ errands less than 10 minutes per day, 34.8% for leisure, and 16.8% for both kinds of walking. In fully adjusted models, those who reported low individual-level social capital and safety also reported less overall walking and less walking for travel/errands. Unexpectedly, those who reported low social disorder also reported less walking for leisure, and those who reported high community social capital also walked less for all outcomes. Physical disorder and community safety were not associated with walking behavior. For low-income housing residents, neighborhood social environmental variables are unlikely the most important factors in determining walking behavior. Researchers should carefully weigh the respective limitations of subjective and objective measures of the social environment when linking them to health outcomes.
doi:10.1016/j.socscimed.2012.11.030
PMCID: PMC3578154  PMID: 23312303
USA; Environment; Social capital; Safety; Social disorder; Physical activity; Low-income housing
7.  Magnetic resonance-guided focused ultrasound treatment of facet joint pain: summary of preclinical phase 
Study design
A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted to test the feasibility, safety, and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for treating facet joint pain.
Objective
The goal of the current study was to develop a novel method for accurate and safe noninvasive facet joint ablation using MRgFUS.
Summary of background data
Facet joints are a common source of chronic back pain. Direct facet joint interventions include medial branch nerve ablation and intra-articular injections, which are widely used, but limited in the short and long term. MRgFUS is a breakthrough technology that enables accurate delivery of high-intensity focused ultrasound energy to create a localized temperature rise for tissue ablation, using MR guidance for treatment planning and real-time feedback.
Methods
We validated the feasibility, safety, and efficacy of MRgFUS for facet joint ablation using the ExAblate 2000® System (InSightec Ltd., Tirat Carmel, Israel) and confirmed the system's ability to ablate the edge of the facet joint and all terminal nerves innervating the joint. A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted.
Results
The experiments showed that targeting the facet joint with energies of 150–450 J provides controlled and accurate heating at the facet joint edge without penetration to the vertebral body, spinal canal, or root foramina. Treating with reduced diameter of the acoustic beam is recommended since a narrower beam improves access to the targeted areas.
Conclusions
MRgFUS can safely and effectively target and ablate the facet joint. These results are highly significant, given that this is the first study to demonstrate the potential of MRgFUS to treat facet joint pain.
doi:10.1186/2050-5736-2-9
PMCID: PMC4036610  PMID: 24921048
Chronic back pain; Facet joints; MRgFUS; Pain palliation
8.  The Detection of Motion by Blind Subjects With the Epiretinal 60-Electrode (Argus II) Retinal Prosthesis 
JAMA ophthalmology  2013;131(2):183-189.
Objective
To investigate the ability of 28 blind subjects implanted with a 60-electrode Argus II (Second Sight Medical Products Inc) retinal prosthesis system to detect the direction of a moving object.
Methods
Blind subjects (bare light perception or worse in both eyes) with retinitis pigmentosa were implanted with the Argus II prosthesis as part of a phase 1/2 feasibility study at multiple clinical sites worldwide. The experiment measured their ability to detect the direction of motion of a high-contrast moving bar on a flatscreen monitor in 3 conditions: with the prosthesis system on and a 1-to-1 mapping of spatial information, with the system off, and with the system on but with randomly scrambled spatial information.
Results
Fifteen subjects (54%) were able to perform the task significantly better with their prosthesis system than they were with their residual vision, 2 subjects had significantly better performance with their residual vision, and no difference was found for 11 subjects. Of the 15 better-performing subjects, 11 were available for follow-up testing, and 10 of them had significantly better performance with normal rather than with scrambled spatial information.
Conclusions
This work demonstrates that blind subjects implanted with the Argus II retinal prosthesis were able to perform a motion detection task they could not do with their native vision, confirming that electrical stimulation of the retina provides spatial information from synchronized activation of multiple electrodes.
doi:10.1001/2013.jamaophthalmol.221
PMCID: PMC3924899  PMID: 23544203
9.  Deformation of Filamentous Escherichia coli Cells in a Microfluidic Device: A New Technique to Study Cell Mechanics 
PLoS ONE  2014;9(1):e83775.
The mechanical properties of bacterial cells are determined by their stress-bearing elements. The size of typical bacterial cells, and the fact that different time and length scales govern their behavior, necessitate special experimental techniques in order to probe their mechanical properties under various spatiotemporal conditions. Here, we present such an experimental technique to study cell mechanics using hydrodynamic forces in a microfluidic device. We demonstrate the application of this technique by calculating the flexural rigidity of non-growing Escherichia coli cells. In addition, we compare the deformation of filamentous cells under growing and non-growing conditions during the deformation process. We show that, at low forces, the force needed to deform growing cells to the same extent as non-growing cells is approximately two times smaller. Following previous works, we interpret these results as the outcome of the difference between the elastic response of non-growing cells and the plastic-elastic response of growing cells. Finally, we observe some heterogeneity in the response of individual cells to the applied force. We suggest that this results from the individuality of different bacterial cells.
doi:10.1371/journal.pone.0083775
PMCID: PMC3879274  PMID: 24392095
10.  Autophagy and selective deployment of Atg proteins in antiviral defense 
International Immunology  2012;25(1):1-10.
A repertoire of mechanisms in the autophagy system combats viral infections.
Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy-related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors.
doi:10.1093/intimm/dxs101
PMCID: PMC3534236  PMID: 23042773
autophagy; dendritic cells; innate immunity; T-cell responses; virus infection
11.  Immune Privilege and the Philosophy of Immunology 
doi:10.3389/fimmu.2014.00110
PMCID: PMC3959614  PMID: 24678312
immune privilege; tolerance; immune suppression; eye; regulatory cells
12.  Interaction of FKBP5 Gene Variants and Adverse Life Events in Predicting Depression Onset: Results From a 10-Year Prospective Community Study 
The American journal of psychiatry  2011;168(10):10.1176/appi.ajp.2011.10111577.
Objective
The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress horm one system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode.
Method
The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14–24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping.
Results
While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study.
Conclusions
These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.
doi:10.1176/appi.ajp.2011.10111577
PMCID: PMC3856576  PMID: 21865530
13.  Sleep Problems in Childhood Predict Neuropsychological Functioning in Adolescence 
Pediatrics  2009;123(4):10.1542/peds.2008-0825.
OBJECTIVES
Our goal was to examine the association between parent-rated sleep problems during childhood and neuropsychological functioning during adolescence.
PARTICIPANTS AND METHODS
Longitudinal prospective data on an entire birth cohort from Dunedin, New Zealand, were obtained. One thousand thirty-seven children were enrolled in the study (52% male). Parents reported on sleep problems when the study members were 5, 7, and 9 years of age. Neuropsychological functioning was assessed by using 7 tests when the participants were 13 years of age.
RESULTS
After adjusting for gender and socioeconomic status, persistent sleep problems during childhood predicted scores on 2 neuropsychological tests: the copy score of the Rey-Osterrieth Complex Figure Test and 2 measures of performance on the Halstead Trail Making Test. These results were substantively replicated when sleep was assessed at the 5- and 9-year (but not 7-year) assessments separately.
CONCLUSIONS
Sleep problems during childhood may be associated with certain aspects of neuropsychological functioning during adolescence. This adds to the growing body of literature suggesting that childhood sleep problems may be a risk indicator of later difficulties.
doi:10.1542/peds.2008-0825
PMCID: PMC3826614  PMID: 19336377
sleep; neuropsychological; longitudinal; prospective
14.  The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases 
Nucleic Acids Research  2013;42(D1):D459-D471.
The MetaCyc database (MetaCyc.org) is a comprehensive and freely accessible database describing metabolic pathways and enzymes from all domains of life. MetaCyc pathways are experimentally determined, mostly small-molecule metabolic pathways and are curated from the primary scientific literature. MetaCyc contains >2100 pathways derived from >37 000 publications, and is the largest curated collection of metabolic pathways currently available. BioCyc (BioCyc.org) is a collection of >3000 organism-specific Pathway/Genome Databases (PGDBs), each containing the full genome and predicted metabolic network of one organism, including metabolites, enzymes, reactions, metabolic pathways, predicted operons, transport systems and pathway-hole fillers. Additions to BioCyc over the past 2 years include YeastCyc, a PGDB for Saccharomyces cerevisiae, and 891 new genomes from the Human Microbiome Project. The BioCyc Web site offers a variety of tools for querying and analysis of PGDBs, including Omics Viewers and tools for comparative analysis. New developments include atom mappings in reactions, a new representation of glycan degradation pathways, improved compound structure display, better coverage of enzyme kinetic data, enhancements of the Web Groups functionality, improvements to the Omics viewers, a new representation of the Enzyme Commission system and, for the desktop version of the software, the ability to save display states.
doi:10.1093/nar/gkt1103
PMCID: PMC3964957  PMID: 24225315
15.  Obsessions and Compulsions in the Community: Prevalence, Interference, Help-Seeking, Developmental Stability, and Co-Occurring Psychiatric Conditions 
The American journal of psychiatry  2009;166(3):10.1176/appi.ajp.2008.08071006.
Objective
It is unclear how many people in the community have obsessions and compulsions and associated levels of interference. It is also unknown what variables predict help-seeking for these symptoms, whether they are developmentally stable, and whether they increase the risk of mental disorders.
Method
The authors analyzed data from the prospective longitudinal Dunedin study of an unselected birth cohort. The presence of obsessions and compulsions and mental disorders was assessed using the Diagnostic Interview Schedule (DIS) at ages 11, 26, and 32. Data on interference and help-seeking were obtained at ages 26 and 32.
Results
Obsessions and compulsions were frequent in individuals with mental disorders other than obsessive-compulsive disorder (OCD) and among people without mental disorders. Even in the latter group, these symptoms caused significant interference. The presence of anxiety/depression and of obsessions (particularly aggressive and shameful thoughts), but not compulsions, was associated with help-seeking. Harm/checking was the most prevalent symptom dimension. Symptom dimensions were temporally stable and associated with increased comorbidity. Obsessive-compulsive symptoms at age 11 predicted a high risk of an adult OCD diagnosis as well as elevated adult symptom dimensions.
Conclusions
Obsessions and compulsions are common in the adult population, have their roots in childhood, and are associated with interference, risk for disorders, and help-seeking. Subclinical obsessions and compulsions should be taken into account in research, intervention, and DSM-V.
doi:10.1176/appi.ajp.2008.08071006
PMCID: PMC3818089  PMID: 19188283
16.  Blunted Cortisol Responses to Stress Signal Social and Behavioral Problems Among Maltreated/Bullied 12-Year-Old Children 
Biological psychiatry  2011;70(11):10.1016/j.biopsych.2011.06.017.
Background
Evidence from animal and human studies suggests that early-life stress such as physical maltreatment has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and is associated with blunted HPA axis reactivity in adulthood. Few studies have investigated whether blunted HPA axis reactivity observed in children exposed to early-life stress signals social, emotional, and behavioral problems.
Methods
Participants were 190 12-year-old children (50.5% males) recruited from the Environmental Risk Longitudinal Twin Study, a nationally representative 1994 to 1995 cohort of families with twins. Cortisol responses to psychosocial stress were measured in maltreated/ bullied (n = 64) and comparison children (n = 126). We ascertained maltreatment and bullying victimization using mothers’ reports and assessed children’s social, emotional, and behavioral problems at ages 5 and 12 using mothers’ and teachers’ reports.
Results
Piecewise multilevel growth curve analyses indicated that maltreated/bullied and comparison children showed distinct cortisol responses to stress. Specifically, maltreated/bullied children had lower cortisol responses than comparison children who exhibited a significant increase. Lower cortisol responses were, in turn, associated with more social and behavioral problems among maltreated/bullied children.
Conclusions
These findings provide support for the influence of childhood harm on blunted HPAaxis reactivity and its potential impacton children’s functioning. Our findings emphasize the need to integrate stress biomarkers in guiding prevention efforts for young victims.
doi:10.1016/j.biopsych.2011.06.017
PMCID: PMC3816750  PMID: 21839988
Behavioral problems; bullying; cortisol; HPA axis; maltreatment; social problems
17.  Rodent Models of Experimental Autoimmune Uveitis 
Methods in molecular biology (Clifton, N.J.)  2012;900:10.1007/978-1-60761-720-4_22.
The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions.
doi:10.1007/978-1-60761-720-4_22
PMCID: PMC3810964  PMID: 22933083
Uveitis; Uveoretinitis; EAU; Autoimmunity; T cells; Tolerance; Th1; Th2; IRBP; S-Ag
18.  Effects of cannabis on lung function: a population-based cohort study 
The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n=1,037).
Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance.
Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance.
Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.
doi:10.1183/09031936.00065009
PMCID: PMC3805041  PMID: 19679602
Cannabis; cohort study; marijuana; respiratory function; smoking; tobacco
19.  F11R Expression upon Hypoxia Is Regulated by RNA Editing 
PLoS ONE  2013;8(10):e77702.
F11R is a cell adhesion molecule found on the surface of human platelets. It plays a role in platelet aggregation, cell migration and cell proliferation. F11R is subjected to RNA editing, a post-transcriptional modification which affects RNA structure, stability, localization, translation and splicing. RNA editing in the 3'UTR of F11R and RNA levels are increased upon hypoxia. We therefore set to examine if RNA editing plays a role in the increase of F11R RNA seen upon hypoxic conditions. We show that ADAR1, but not ADAR2, takes part in the editing of F11R however editing alone is not sufficient for obtaining an elevation in RNA levels. In addition we show that hyper-edited mature mRNAs are retained in the nucleus and are associated with p54nrb. We therefore conclude that hypoxia-induced edited RNAs of F11R are preferentially stabilized and accumulate in the nucleus preventing their export to the cytoplasm for translation. This mechanism may be used by additional proteins in the cell as part of the cell's effort to reduce metabolism upon hypoxic stress.
doi:10.1371/journal.pone.0077702
PMCID: PMC3797694  PMID: 24147060
20.  Systematic social observation of children’s neighborhoods using Google Street View: a reliable and cost-effective method 
Background
Children growing up in poor versus affluent neighborhoods are more likely to spend time in prison, develop health problems and die at an early age. The question of how neighborhood conditions influence our behavior and health has attracted the attention of public health officials and scholars for generations. Online tools are now providing new opportunities to measure neighborhood features and may provide a cost effective way to advance our understanding of neighborhood effects on child health.
Method
A virtual systematic social observation (SSO) study was conducted to test whether Google Street View could be used to reliably capture the neighborhood conditions of families participating in the Environmental-Risk (E-Risk) Longitudinal Twin Study. Multiple raters coded a subsample of 120 neighborhoods and convergent and discriminant validity was evaluated on the full sample of over 1,000 neighborhoods by linking virtual SSO measures to: (a) consumer based geo-demographic classifications of deprivation and health, (b) local resident surveys of disorder and safety, and (c) parent and teacher assessments of children’s antisocial behavior, prosocial behavior, and body mass index.
Results
High levels of observed agreement were documented for signs of physical disorder, physical decay, dangerousness and street safety. Inter-rater agreement estimates fell within the moderate to substantial range for all of the scales (ICCs ranged from .48 to .91). Negative neighborhood features, including SSO-rated disorder and decay and dangerousness corresponded with local resident reports, demonstrated a graded relationship with census-defined indices of socioeconomic status, and predicted higher levels of antisocial behavior among local children. In addition, positive neighborhood features, including SSO-rated street safety and the percentage of green space, were associated with higher prosocial behavior and healthy weight status among children.
Conclusions
Our results support the use of Google Street View as a reliable and cost effective tool for measuring both negative and positive features of local neighborhoods.
doi:10.1111/j.1469-7610.2012.02565.x
PMCID: PMC3537178  PMID: 22676812
Systematic social observation; Google Street View; neighborhood disorder; neighborhood deprivation; antisocial behavior; body mass index
21.  The relationship between diet and perceived and objective access to supermarkets among low-income housing residents 
Social science & medicine (1982)  2012;75(7):1254-1262.
In the U.S., supermarkets serve as an important source of year-round produce (Chung & Myers, 1999), and yet access to supermarkets may be scarce in “food deserts,” or poor, urban areas that lack sources of healthy, affordable food (Cummins & Macintyre, 2002). This study examined objective distance to the nearest supermarket and participant-report of supermarket access in relation to fruit and vegetable intake. Street-network distance to the closest supermarket was calculated using GIS mapping. Perceived access was assessed by a survey question asking whether participants had a supermarket within walking distance of home. Cross-sectional survey data were collected from 828 low-income housing residents in three urban areas in greater-Boston. Generalized estimating equations were used to estimate the association between perceived and objective supermarket access and diet. Fruit and vegetable consumption was low (2.63 servings/day). Results suggest that most low-income housing residents in greater-Boston do not live in “food deserts,” as the average distance to a supermarket was 0.76 km (range 0.13–1.22 km). Distance to a supermarket was not associated with fruit and vegetable intake (p = 0.22). Perceived supermarket access was strongly associated with increased fruit and vegetable intake (0.5 servings/day) after controlling for socio-demographic covariates (p < 0.0001). Patterns of mismatch between perceived and objective measures revealed that mismatch between the two measures were high (31.45%). Those who did not report a supermarket within walking distance from home despite the objective presence of a supermarket within 1 km consumed significantly fewer fruits and vegetables (0.56 servings/day) than those with a supermarket who reported one, even after controlling for socio-demographic variables (p = 0.0008). Perceived measures of the food environment may be more strongly related to dietary behaviors than objective ones, and may incorporate components of food access not captured in objective measures.
doi:10.1016/j.socscimed.2012.05.014
PMCID: PMC3739049  PMID: 22727742
USA; Food access; Neighborhood; Low-income housing; Health behaviors; Perceived measures; Objective measures
22.  Arguable Assumptions, Debatable Conclusions 
Biological psychiatry  2009;67(4):e19-e23.
doi:10.1016/j.biopsych.2009.07.041
PMCID: PMC3784000  PMID: 20006323
23.  Age-dependent effects of microglial inhibition in vivo on Alzheimer’s disease neuropathology using bioactive-conjugated iron oxide nanoparticles 
Background
Tau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease, Pick’s disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice.
Methods
Here we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin γ377-395 peptide conjugated to iron oxide (γ-Fe2O3) nanoparticles of 21 ± 3.5 nm diameter.
Results
Stabilization of the peptide by its covalent conjugation to the γ-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin γ377-395 peptide-nanoparticle conjugate.
Conclusions
These results demonstrate a differential effect of microglial activity on tau pathology using the fibrin γ377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation.
doi:10.1186/1477-3155-11-32
PMCID: PMC3851539  PMID: 24059692
Tau; Microglia; Tangle; Fibrin γ377-395 peptide; Iron oxide nanoparticles
24.  Etiological and Clinical Features of Childhood Psychotic Symptoms 
Archives of general psychiatry  2010;67(4):328-338.
Context
It has been reported that childhood psychotic symptoms are common in the general population and may signal neurodevelopmental processes that lead to schizophrenia. However, it is not clear whether these symptoms are associated with the same extensive risk factors established for adult schizophrenia.
Objective
To examine the construct validity of children’s self-reported psychotic symptoms by testing whether these symptoms share the risk factors and clinical features of adult schizophrenia.
Design
Prospective, longitudinal cohort study of a nationally representative birth cohort in Great Britain.
Participants
A total of 2232 twelve-year-old children followed up since age 5 years (retention, 96%).
Main Outcome Measure
Children’s self-reported hallucinations and delusions.
Results
Children’s psychotic symptoms are familial and heritable and are associated with social risk factors (eg, urbanicity); cognitive impairments at age 5; home-rearing risk factors (eg, maternal expressed emotion); behavioral, emotional, and educational problems at age 5; and comorbid conditions, including self-harm.
Conclusions
The results provide a comprehensive picture of the construct validity of children’s self-reported psychotic symptoms. For researchers, the findings indicate that children who have psychotic symptoms can be recruited for neuroscience research to determine the pathogenesis of schizophrenia. For clinicians, the findings indicate that psychotic symptoms in childhood are often a marker of an impaired developmental process and should be actively assessed.
doi:10.1001/archgenpsychiatry.2010.14
PMCID: PMC3776482  PMID: 20368509
25.  The local food environment and diet: A systematic review 
Health & place  2012;18(5):1172-1187.
Despite growing attention to the problem of obesogenic environments, there has not been a comprehensive review evaluating the food environment-diet relationship. This study aims to evaluate this relationship in the current literature, focusing specifically on the method of exposure assessment (GIS, survey, or store audit). This study also explores 5 dimensions of “food access” (availability, accessibility, affordability, accommodation, acceptability) using a conceptual definition proposed by Penchansky and Thomas (1981). Articles were retrieved through a systematic keyword search in Web of Science and supplemented by the reference lists of included studies. Thirty-eight studies were reviewed and categorized by the exposure assessment method and the conceptual dimensions of access it captured. GIS-based measures were the most common measures, but were less consistently associated with diet than other measures. Few studies examined dimensions of affordability, accommodation, and acceptability. Because GIS-based measures on their own may not capture important non-geographic dimensions of access, a set of recommendations for future researchers is outlined.
doi:10.1016/j.healthplace.2012.05.006
PMCID: PMC3684395  PMID: 22717379
Food environment; diet; measurement; GIS; survey; store audit

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