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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.  Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife? 
Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.
Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.
Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.
Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.
Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
doi:10.1164/rccm.201402-0370OC
PMCID: PMC4214127  PMID: 24956257
asthma; telomere; aging; longitudinal; developmental phenotype
3.  Comparative genomic analysis of clinical and environmental Vibrio vulnificus isolates revealed biotype 3 evolutionary relationships 
In 1996 a common-source outbreak of severe soft tissue and bloodstream infections erupted among Israeli fish farmers and fish consumers due to changes in fish marketing policies. The causative pathogen was a new strain of Vibrio vulnificus, named biotype 3, which displayed a unique biochemical and genotypic profile. Initial observations suggested that the pathogen erupted as a result of genetic recombination between two distinct populations. We applied a whole genome shotgun sequencing approach using several V. vulnificus strains from Israel in order to study the pan genome of V. vulnificus and determine the phylogenetic relationship of biotype 3 with existing populations. The core genome of V. vulnificus based on 16 draft and complete genomes consisted of 3068 genes, representing between 59 and 78% of the whole genome of 16 strains. The accessory genome varied in size from 781 to 2044 kbp. Phylogenetic analysis based on whole, core, and accessory genomes displayed similar clustering patterns with two main clusters, clinical (C) and environmental (E), all biotype 3 strains formed a distinct group within the E cluster. Annotation of accessory genomic regions found in biotype 3 strains and absent from the core genome yielded 1732 genes, of which the vast majority encoded hypothetical proteins, phage-related proteins, and mobile element proteins. A total of 1916 proteins (including 713 hypothetical proteins) were present in all human pathogenic strains (both biotype 3 and non-biotype 3) and absent from the environmental strains. Clustering analysis of the non-hypothetical proteins revealed 148 protein clusters shared by all human pathogenic strains; these included transcriptional regulators, arylsulfatases, methyl-accepting chemotaxis proteins, acetyltransferases, GGDEF family proteins, transposases, type IV secretory system (T4SS) proteins, and integrases. Our study showed that V. vulnificus biotype 3 evolved from environmental populations and formed a genetically distinct group within the E-cluster. The unique epidemiological circumstances facilitated disease outbreak and brought this genotype to the attention of the scientific community.
doi:10.3389/fmicb.2014.00803
PMCID: PMC4295529  PMID: 25642229
aquaculture; microbial genome; Vibrio vulnificus; whole genome shotgun sequences; evolution; core genome; accessory genome
4.  Inositol-Related Gene Knockouts Mimic Lithium's Effect on Mitochondrial Function 
Neuropsychopharmacology  2013;39(2):319-328.
The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.
doi:10.1038/npp.2013.194
PMCID: PMC3870788  PMID: 23924600
animal models; bipolar disorder; depression; unipolar/bipolar; DNA microarrays; inositol; knockout mice; lithium; psychiatry & behavioral sciences; Psychopharmacology; lithium; bipolar disorder; inositol; DNA microarrays; knockout mice; mitochondria
5.  Neuropsychological Decline in Schizophrenia from the Premorbid to Post-Onset Period: Evidence from a Population-Representative Longitudinal Study 
Objective
Despite widespread belief that neuropsychological decline is a cardinal feature of the progression from the premorbid to the chronic form of schizophrenia, few longitudinal studies have examined change in neuropsychological functioning from before to after the onset of schizophrenia. We addressed the following unresolved questions: Is neuropsychological decline generalized versus confined to particular mental functions? Is neuropsychological decline unique to schizophrenia? Do individuals with schizophrenia also have cognitive problems in everyday life?
Method
Participants were members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand between 1972-73 and followed prospectively to age 38, with 95% retention. Assessment of IQ and other specific neuropsychological functions was conducted at ages 7-13, before the onset of schizophrenia, and again at age 38. Informants also reported on cognitive problems at age 38.
Results
Individuals with schizophrenia showed decline in IQ as well as a range of different mental functions, particularly those tapping processing speed, learning, executive functioning, and motor functioning. There was little evidence of decline in verbal abilities or delayed memory, however, and the developmental progression of deficits in schizophrenia differed across mental functions. Processing speed deficits increased gradually from childhood to beyond the early teen years, whereas verbal deficits emerged early but remained static through midlife. Neuropsychological decline was specific to schizophrenia, as no evidence of decline was apparent among individuals with persistent depression, children with mild cognitive impairment, individuals matched on childhood risk factors for schizophrenia, and psychiatrically healthy individuals. Informants also reported cognitive problems for individuals diagnosed with schizophrenia.
Conclusion
There is substantial neuropsychological decline in schizophrenia from the premorbid to post-onset period, but the extent and developmental progression of decline varies across mental functions. Findings suggest that different pathophysiological mechanisms might underlie deficits in different mental functions.
doi:10.1176/appi.ajp.2013.12111438
PMCID: PMC3947263  PMID: 24030246
6.  Microvascular Abnormality in Schizophrenia as Shown by Retinal Imaging  
The American journal of psychiatry  2013;170(12):10.1176/appi.ajp.2013.13020234.
Objective
Retinal and cerebral microvessels are structurally and functionally homologous, but, unlike cerebral microvessels, retinal microvessels can be noninvasively measured in vivo via retinal imaging. Here we test the hypothesis that individuals with schizophrenia show microvascular abnormality and evaluate the utility of retinal imaging as a tool for future schizophrenia research.
Methods
Participants were members of the Dunedin Study, a population-representative cohort followed from birth with 95% retention. Study members underwent retinal imaging at age 38 years. We assessed retinal arteriolar and venular caliber for all members of the cohort, including individuals who developed schizophrenia.
Results
Study members who developed schizophrenia were distinguished by wider retinal venules, suggesting microvascular abnormality reflective of insufficient brain oxygen supply. Analyses that controlled for confounding health conditions suggested that wider retinal venules are not simply an artifact of co-occurring health problems in schizophrenia patients. Wider venules were also associated with a dimensional measure of adult psychosis symptoms and with psychosis symptoms reported in childhood.
Conclusions
Findings provide initial support for the hypothesis that individuals with schizophrenia show microvascular abnormality. Moreover, results suggest that the same vascular mechanisms underlie subthreshold symptoms and clinical disorder and that these associations may begin early in life. These findings highlight the promise of retinal imaging as a tool for understanding the pathogenesis of schizophrenia.
doi:10.1176/appi.ajp.2013.13020234
PMCID: PMC3857729  PMID: 24030514
7.  Results of a pilot intervention to improve health and safety for healthcare workers 
Objective
To test the feasibility of a multicomponent pilot intervention to improve worker safety and wellness in two Boston hospitals.
Methods
The 3-month intervention was conducted on seven hospital units. Pre (374 workers) and post (303 workers) surveys assessed changes in safety/ergonomic behaviors and practices, and social support. Wellness outcomes included self-reported pain/aching in specific body areas (musculoskeletal disorders, or MSDs) and physical activity (PA).
Results
Pain was reported frequently (81%), and PA averaged 4h per week. There was a post-intervention increase in safe patient handling (p <0.0001), safety practices (p = 0.0004), ergonomics (p = 0.009), and supervisor support (p = 0.01), but no changes in MSDs or PA.
Conclusions
Safe patient handling, ergonomics, and safety practices are good targets for worker safety and wellness interventions; longer intervention periods may reduce risk of MSDs.
doi:10.1097/JOM.0b013e3182a7e65a
PMCID: PMC3858503  PMID: 24270297
musculoskeletal symptoms; physical activity; safe patient handling; healthcare; intervention
8.  Draft Genome Sequence of Fish Pathogenic Vibrio vulnificus Biotype 2 
Genome Announcements  2014;2(6):e01224-14.
Vibrio vulnificus is a marine pathogen capable of causing severe soft tissue infections and septicemia in humans. V. vulnificus biotype 2 is the etiological agent of fish vibriosis. We describe here the first draft genome sequence of V. vulnificus biotype 2, strain ES-7601, isolated from an infected eel in Japan.
doi:10.1128/genomeA.01224-14
PMCID: PMC4246164  PMID: 25428972
9.  School, Neighborhood, and Family Factors Are Associated With Children's Bullying Involvement: A Nationally Representative Longitudinal Study 
Objective
To test whether school, neighborhood, and family factors are independently associated with children's involvement in bullying, over and above their own behaviors that may increase their risk for becoming involved in bullying.
Method
We examined bullying in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994Y1995 birth cohort of 2,232 children. We used mother and teacher reports to identify children who experienced bullying between the ages of 5 and 7 years either as victims, bullies, or bully-victims. We collected information about school characteristics from the Department for Children, Schools and Families. We collected reports from mothers about children's neighborhood and home environments and reports from mothers and teachers about children's internalizing and externalizing problems when they were 5 years old.
Results
Multinomial logistic regressions showed that over and above other socioenvironmental factors and children's behavior problems, school size was associated with an increased risk for being a victim of bullying, problems with neighbors was associated with an increased risk for being a bully-victim, and family factors (e.g., child maltreatment, domestic violence) were associated with all groups of children involved in bullying.
Conclusions
Socioenvironmental factors are associated with children's risk for becoming involved in bullying over and above their own behaviors. Intervention programs aimed at reducing bullying should extend their focus beyond schools to include local communities and families.
doi:10.1097/CHI.0b013e31819cb017
PMCID: PMC4231780  PMID: 19325496
bullying; victimization; risk factors; children
10.  Mental Health Context of Food Insecurity: a Representative Cohort of Families With Young Children 
Pediatrics  2009;124(4):e564-e572.
OBJECTIVE
Children from food-insecure families (ie, families that lack access to sufficient, safe, and nutritious food) are at risk for developmental problems. Food insecurity disproportionately occurs among low–socioeconomic status (SES) and low-income families; however, interventions that supplement families’ income or diet have not eradicated food insecurity. This may be because food insecurity is also related to nonfinancial factors such as the presence of maternal mental health problems. To clarify whether addressing mothers’ mental health problems may be a promising strategy for reducing the burden of food insecurity, we tested the hypothesis that low-SES families are especially vulnerable to food insecurity when the mother experiences depression, alcohol or drug abuse, psychosis spectrum disorder, or domestic violence.
METHODS
We used data from a nationally representative cohort of 1116 British families (the Environmental Risk Longitudinal Study). Food insecurity, family SES, maternal mental health and exposure to domestic violence, and children’s behavioral outcomes were measured by using validated methods.
RESULTS
Overall, 9.7% of study families were food-insecure. Among low-SES families, controlling for income variation, food insecurity cooccurred with maternal depression (odds ratio [OR]: 2.82 [95% confidence interval (CI): 1.62–4.93]), psychosis spectrum disorder (OR: 4.01 [95% CI: 2.03–7.94]), and domestic violence (OR: 2.36 [95% CI: 1.18– 4.73]). In addition, food insecurity predicted elevated rates of children’s behavior problems.
CONCLUSIONS
Among families with young children, food insecurity is frequent, particularly when the mother experiences mental health problems. This suggests that interventions that improve women’s mental health may also contribute to decreasing the burden of food insecurity and its impact on the next generation.
doi:10.1542/peds.2009-0583
PMCID: PMC4231784  PMID: 19786424
food insecurity; mental health; socioeconomic factors; families; longitudinal study
11.  Mothers and Children as Informants of Bullying Victimization: Results from an Epidemiological Cohort of Children 
Stressful events early in life can affect children’s mental health problems. Collecting valid and reliable information about children’s bad experiences is important for research and clinical purposes. This study aimed to (1) investigate whether mothers and children provide valid reports of bullying victimization, (2) examine the inter-rater reliability between the two informants, (3) test the predictive validity of their reports with children’s emotional and behavioral problems and (4) compare the genetic and environmental etiology of bullying victimization as reported by mothers and children. We assessed bullying victimization in the Environmental-Risk (E-Risk) Longitudinal Twin Study, a nationally-representative sample of 1,116 families with twins. We collected reports from mothers and children during private interviews, including detailed narratives. Findings showed that we can rely on mothers and children as informants of bullying victimization: both informants provided information which adhered to the definition of bullying as involving repeated hurtful actions between peers in the presence of a power imbalance. Although mothers and children modestly agreed with each other about who was bullied during primary and secondary school, reports of bullying victimization from both informants were similarly associated with children’s emotional and behavioral problems and provided similar estimates of genetic and environmental influences. Findings from this study suggest that collecting information from multiple informants is ideal to capture all instances of bullying victimization. However, in the absence of child self-reports, mothers can be considered as a viable alternative, and vice versa.
doi:10.1007/s10802-010-9463-5
PMCID: PMC4231790  PMID: 20938734
Informant; Bullying victimization; Agreement; Validity; Reliability
12.  Is Obesity Associated With a Decline in Intelligence Quotient During the First Half of the Life Course? 
American Journal of Epidemiology  2013;178(9):1461-1468.
Cross-sectional studies have found that obesity is associated with low intellectual ability and neuroimaging abnormalities in adolescence and adulthood. Some have interpreted these associations to suggest that obesity causes intellectual decline in the first half of the life course. We analyzed data from a prospective longitudinal study to test whether becoming obese was associated with intellectual decline from childhood to midlife. We used data from the ongoing Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort study of 1,037 children in New Zealand who were followed prospectively from birth (1972–1973) through their fourth decade of life with a 95% retention rate. Intelligence quotient (IQ) was measured in childhood and adulthood. Anthropometric measurements were taken at birth and at 12 subsequent in-person assessments. As expected, cohort members who became obese had lower adulthood IQ scores. However, obese cohort members exhibited no excess decline in IQ. Instead, these cohort members had lower IQ scores since childhood. This pattern remained consistent when we accounted for children's birth weights and growth during the first years of life, as well as for childhood-onset obesity. Lower IQ scores among children who later developed obesity were present as early as 3 years of age. We observed no evidence that obesity contributed to a decline in IQ, even among obese individuals who displayed evidence of the metabolic syndrome and/or elevated systemic inflammation.
doi:10.1093/aje/kwt135
PMCID: PMC3813310  PMID: 24029684
cognitive aging; intellectual decline; intelligence quotient; IQ decline; life course; longitudinal study; metabolic syndrome; obesity
14.  Five-year predictive validity of DSM-IV conduct disorder research diagnosis in 4½–5-year-old children 
Objective
This longitudinal study of a non-referred, population-based sample tested the 5-year predictive validity of the DSM-IV conduct disorder (CD) research diagnosis in children 4½–5 years of age.
Method
In the E-Risk Study, a representative birth cohort of 2,232 children, mothers were interviewed and teachers completed mailed questionnaires to assess children’s past 6-month CD symptoms. A follow-up assessment was conducted when children were 10 years old.
Results
CD-diagnosed 5-year-olds were significantly more likely than controls to have behavioural and educational difficulties at age 10. Increased risk for age-10 educational difficulties persisted after controlling for age-5 IQ and ADHD diagnosis. Although the majority of CD-diagnosed 5-year-olds had no CD symptoms at age 10, findings suggest that these “remitted” children continued to experience behavioural and educational problems 5 years later despite their apparent remission from CD.
Conclusions
DSM-IV CD symptoms validly identify preschool-aged children who continue to have behavioural and educational problems in middle-childhood.
doi:10.1007/s00787-008-0729-1
PMCID: PMC4212821  PMID: 19165535
conduct disorder; preschool; predictive validity; epidemiology; nosology
15.  The Protective Effects of Neighborhood Collective Efficacy on British Children Growing Up in Deprivation: A Developmental Analysis 
Developmental psychology  2009;45(4):942-957.
This article reports on the influence of neighborhood-level deprivation and collective efficacy on children’s antisocial behavior between the ages of 5 and 10 years. Latent growth curve modeling was applied to characterize the developmental course of antisocial behavior among children in the E-Risk Longitudinal Twin Study, an epidemiological cohort of 2,232 children. Children in deprived versus affluent neighborhoods had higher levels of antisocial behavior at school entry (24.1 vs. 20.5, p < .001) and a slower rate of decline from involvement in antisocial behavior between the ages of 5 and 10 (−0.54 vs. −0.78, p < .01). Neighborhood collective efficacy was negatively associated with levels of antisocial behavior at school entry (r =−.10, p < .01) but only in deprived neighborhoods; this relationship held after controlling for neighborhood problems and family-level factors. Collective efficacy did not predict the rate of change in antisocial behavior between the ages of 5 and 10. Findings suggest that neighborhood collective efficacy may have a protective effect on children living in deprived contexts.
doi:10.1037/a0016162
PMCID: PMC4212822  PMID: 19586172
antisocial behavior; collective efficacy; neighborhoods; protective factors; latent growth curve modeling
16.  Specificity of childhood psychotic symptoms for predicting schizophrenia by 38 years of age: a birth cohort study 
Psychological medicine  2013;43(10):2077-2086.
Background
Childhood psychotic symptoms have been used as a subclinical phenotype of schizophrenia in etiological research and as a target for preventative interventions. However, recent studies have cast doubt on the specificity of these symptoms for schizophrenia, suggesting alternative outcomes such as anxiety and depression. Using a prospective longitudinal birth cohort we investigated whether childhood psychotic symptoms predicted a diagnosis of schizophrenia or other psychiatric disorders by 38 years of age.
Method
Participants were drawn from a birth cohort of 1037 children from Dunedin, New Zealand, who were followed prospectively to 38 years of age (96% retention rate). Structured clinical interviews were administered at age 11 to assess psychotic symptoms and study members underwent psychiatric assessments at ages 18, 21, 26, 32 and 38 to obtain past-year DSM-III-R/IV diagnoses and self-reports of attempted suicides since adolescence.
Results
Psychotic symptoms at age 11 predicted elevated rates of research diagnoses of schizophrenia and post-traumatic stress disorder (PTSD) and also suicide attempts by age 38, even when controlling for gender, social class and childhood psychopathology. No significant associations were found for persistent anxiety, persistent depression, mania or persistent substance dependence. Very few of the children presenting with age-11 psychotic symptoms were free from disorder by age 38.
Conclusions
Childhood psychotic symptoms were not specific to a diagnosis of schizophrenia in adulthood and thus future studies of early symptoms should be cautious in extrapolating findings only to this clinical disorder. However, these symptoms may be useful as a marker of adult mental health problems more broadly.
doi:10.1017/S0033291712003091
PMCID: PMC3758773  PMID: 23302254
Childhood; longitudinal; post-traumatic stress disorder; psychosis; suicide
17.  Genetics in Population Health Science: Strategies & Opportunities 
American journal of public health  2013;103(0 1):S73-S83.
Translational research is needed to leverage discoveries from the frontiers of genome science to improve public health. So far, public health researchers have largely ignored genetic discoveries, while geneticists have ignored important aspects of population health science. This mutual neglect should end. In this article, we discuss 3 areas where public health researchers can help to advance translation: (1) Risk Assessment: Investigate genetic profiles as components in composite risk assessments; (2) Targeted Intervention: Conduct life-course longitudinal studies to understand when genetic risks manifest in development and whether intervention during sensitive periods can have lasting effects; and (3) Understanding Environmental Causation: Collaborate with geneticists on gene-environment interaction research. We illustrate with examples from our own research on obesity and smoking.
doi:10.2105/AJPH.2012.301139
PMCID: PMC3786748  PMID: 23927511
18.  Identification of male-specific amh duplication, sexually differentially expressed genes and microRNAs at early embryonic development of Nile tilapia (Oreochromis niloticus) 
BMC Genomics  2014;15(1):774.
Background
The probable influence of genes and the environment on sex determination in Nile tilapia suggests that it should be regarded as a complex trait. Detection of sex determination genes in tilapia has both scientific and commercial importance. The main objective was to detect genes and microRNAs that were differentially expressed by gender in early embryonic development.
Results
Artificial fertilization of Oreochromis niloticus XX females with either sex-reversed ΔXX males or genetically-modified YY ‘supermales’ resulted in all-female and all-male embryos, respectively. RNA of pools of all-female and all-male embryos at 2, 5 and 9 dpf were used as template for a custom Agilent eArray hybridization and next generation sequencing. Fifty-nine genes differentially expressed between genders were identified by a false discovery rate of p < 0.05. The most overexpressed genes were amh and tspan8 in males, and cr/20β-hsd, gpa33, rtn4ipl and zp3 in females (p < 1 × 10−9). Validation of gene expression using qPCR in embryos and gonads indicated copy number variation in tspan8, gpa33, cr/20β-hsd and amh. Sequencing of amh identified a male-specific duplication of this gene, denoted amhy, differing from the sequence of amh by a 233 bp deletion on exonVII, hence lacking the capability to encode the protein motif that binds to the transforming growth factor beta receptor (TGF-β domain). amh and amhy segregated in the mapping family in full concordance with SD-linked marker on LG23 signifying the QTL for SD. We discovered 831 microRNAs in tilapia embryos of which nine had sexually dimorphic expression patterns by a false discovery rate of p < 0.05. An up-regulated microRNA in males, pma-mir-4585, was characterized with all six predicted target genes including cr/20β-hsd, down-regulated in males.
Conclusions
This study reports the first discovery of sexually differentially expressed genes and microRNAs at a very early stage of tilapia embryonic development, i.e. from 2 dpf. Genes with sexually differential expression patterns are enriched for copy number variation. A novel male-specific duplication of amh, denoted amhy, lacking the TGF-β domain was identified and mapped to the QTL region on LG23 for SD, thus indicating its potential role in SD.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-774) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-774
PMCID: PMC4176596  PMID: 25199625
Sex-determination; Gene expression; MicroRNA; CNV; Tilapia; Embryo; amh; amhy; cr/20β-hsd
20.  Polygenic risk and the development and course of asthma: Evidence from a 4-decade longitudinal study 
The lancet. Respiratory medicine  2013;1(6):453-461.
BACKGROUND
Genome-wide association studies (GWAS) have discovered loci that predispose to asthma. To integrate these new discoveries with emerging models of asthma pathobiology, research is needed to test how genetic discoveries relate to developmental and biological characteristics of asthma.
METHODS
We derived a multi-locus profile of genetic risk from published GWAS of asthma case status. We then tested associations between this “genetic risk score” and developmental and biological characteristics of asthma in a population-based long-running birth cohort, the Dunedin Longitudinal Study (n=1,037). We evaluated asthma onset, persistence, atopy, airway hyperresponsiveness, incompletely reversible airflow obstruction, and asthma-related school and work absenteeism and hospitalization during 9 prospective assessments spanning ages 9–38 years, when 95% of surviving cohort members were seen.
INTERPRETATION
Cohort members at higher genetic risk experienced asthma onset earlier in life (HR=1.12 [1.01–1.26]). Childhood-onset asthma cases at higher genetic risk were more likely to become life-course-persistent asthma cases (RR=1.36 [1.14–1.63]). Asthma cases at higher genetic risk more often manifested atopy (RR=1.07 [1.01–1.14]), airway hyperresponsiveness (RR=1.16 [1.03–1.32]), and incompletely reversible airflow obstruction (RR=1.28 [1.04–1.57]). They were also more likely to miss school or work due to asthma (IRR=1.38 [1.02–1.86]) and to be hospitalized with breathing problems (HR=1.38 [1.07–1.79]). Genotypic information about asthma risk was independent of and additive to information derived from cohort members’ family histories of asthma.
CONCLUSIONS
Findings from this population study confirm that GWAS-discoveries for asthma associate with a childhood-onset phenotype and advance asthma genetics beyond the original GWAS-discoveries in three ways: (1) We show that genetic risks predict which childhood-onset asthma cases remit and which become life-course-persistent cases, although these predictions are not sufficiently sensitive or specific to support immediate clinical translation; (2) We elucidate a biological profile of the asthma that arises from these genetic risks: asthma characterized by atopy and airway hyperresponsiveness and leading to incompletely reversible airflow obstruction; and (3) We describe the real-life impact of GWAS-discoveries by quantifying genetic associations with missed school and work and hospitalization.
doi:10.1016/S2213-2600(13)70101-2
PMCID: PMC3899706  PMID: 24429243
21.  Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen 
Journal of autoimmunity  2013;44:21-33.
Despite presence of circulating retina-specific T cells in healthy individuals, ocular immune privilege usually averts development of autoimmune uveitis. To study the breakdown of immune privilege and development of disease, we generated transgenic (Tg) mice that express a T cell receptor (TCR) specific for interphotoreceptor retinoid-binding protein (IRBP), which serves as an autoimmune target in uveitis induced by immunization. Three lines of TCR Tg mice, with different levels of expression of the transgenic R161 TCR and different proportions of IRBP-specific CD4+ T cells in their peripheral repertoire, were successfully established. Importantly, two of the lines rapidly developed spontaneous uveitis, reaching 100% incidence by 2 and 3 months of age, respectively, whereas the third appeared “poised” and only developed appreciable disease upon immune perturbation. Susceptibility roughly paralleled expression of the R161 TCR. In all three lines, peripheral CD4+ T cells displayed a naïve phenotype, but proliferated in vitro in response to IRBP and elicited uveitis upon adoptive transfer. In contrast, CD4+ T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells that appeared to have been peripherally converted from conventional CD4+ T cells rather than thymically derived. Thus, R161 mice provide a new and valuable model of spontaneous autoimmune disease that circumvents the limitations of active immunization and adjuvants, and allows to study basic mechanisms involved in maintenance and breakdown of immune homeostasis affecting immunologically privileged sites such as the eye.
doi:10.1016/j.jaut.2013.06.003
PMCID: PMC3743101  PMID: 23810578
Autoimmune uveitis; Immune privilege; TCR transgenic mouse; Spontaneous disease
22.  Prospective Developmental Subtypes of Alcohol Dependence from Age 18 to 32 Years: Implications for Nosology, Etiology, and Intervention 
Development and psychopathology  2013;25(3):785-800.
The purpose of the present study was to identify child and adult correlates that differentiate (a) individuals with persistent alcohol dependence from individuals with developmentally-limited alcohol dependence and (b) individuals with adult-onset alcohol dependence from individuals who never diagnose. Participants are 1,037 members of the Dunedin longitudinal study, a birth cohort followed prospectively from birth until age 32. Past-year DSM-IV alcohol dependence diagnoses were ascertained with structured diagnostic interviews at ages 18, 21, 26, and 32. Individuals were classified as developmentally-limited, persistent, or adult-onset subtypes based on their time-ordered pattern of diagnoses. The persistent subtype generally exhibited the worst scores on all correlates, including family psychiatric history, adolescent and adult externalizing and internalizing problems, adolescent and adult substance use, adult quality of life, and coping strategies. The prospective predictors that distinguished them from the developmentally-limited subtype involved family liability, adolescent negative affectivity, daily alcohol use, and frequent marijuana use. Furthermore, young people who developed the persistent subtype of alcohol dependence were distinguished from the developmentally-limited subtype by an inability to reduce drinking and by continued use despite problems, already by age 18. The adult-onset group members were virtually indistinguishable from ordinary cohort members as children or adolescents, but, in adulthood, adult-onset cases were distinguished by problems with depression, substance use, stress, and strategies for coping with stress. Information about age-of-onset and developmental course is fundamental for identifying subtypes of alcohol dependence. Subtype-specific etiologies point to targeted prevention and intervention efforts based on characteristics of each subtype.
doi:10.1017/S0954579413000175
PMCID: PMC3725643  PMID: 23880392
Alcohol; subtypes; development; longitudinal
23.  The challenge of constructing, classifying and representing metabolic pathways 
FEMS microbiology letters  2013;345(2):85-93.
Scientists, educators, and students benefit from having free and centralized access to the wealth of metabolic information that has been gathered over the decades. Curators of the MetaCyc database work to present this information in an easily understandable pathway-based framework. MetaCyc is used not only as an encyclopedic resource for metabolic information but also as a template for the pathway prediction software that generates pathway/genome databases for thousands of organisms with sequenced genomes (available at www.biocyc.org). Curators need to define pathway boundaries and classify pathways within a broader pathway ontology to maximize the utility of the pathways to both users and the pathway prediction software. These seemingly simple tasks pose several challenges. This review describes these challenges as well as the criteria that need to be considered, and the rules that have been developed by MetaCyc curators as they make decisions regarding the representation and classification of metabolic pathway information in MetaCyc. The functional consequences of these decisions in regard to pathway prediction in new species are also discussed.
doi:10.1111/1574-6968.12194
PMCID: PMC4026850  PMID: 23746312
metabolic pathway; metabolic database; MetaCyc; pathway prediction
24.  Metabolite and transcript profiling of berry skin during fruit development elucidates differential regulation between Cabernet Sauvignon and Shiraz cultivars at branching points in the polyphenol pathway 
BMC Plant Biology  2014;14:188.
Background
Grapevine berries undergo complex biochemical changes during fruit maturation, many of which are dependent upon the variety and its environment. In order to elucidate the varietal dependent developmental regulation of primary and specialized metabolism, berry skins of Cabernet Sauvignon and Shiraz were subjected to gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) based metabolite profiling from pre-veraison to harvest. The generated dataset was augmented with transcript profiling using RNAseq.
Results
The analysis of the metabolite data revealed similar developmental patterns of change in primary metabolites between the two cultivars. Nevertheless, towards maturity the extent of change in the major organic acid and sugars (i.e. sucrose, trehalose, malate) and precursors of aromatic and phenolic compounds such as quinate and shikimate was greater in Shiraz compared to Cabernet Sauvignon. In contrast, distinct directional projections on the PCA plot of the two cultivars samples towards maturation when using the specialized metabolite profiles were apparent, suggesting a cultivar-dependent regulation of the specialized metabolism. Generally, Shiraz displayed greater upregulation of the entire polyphenol pathway and specifically higher accumulation of piceid and coumaroyl anthocyanin forms than Cabernet Sauvignon from veraison onwards. Transcript profiling revealed coordinated increased transcript abundance for genes encoding enzymes of committing steps in the phenylpropanoid pathway. The anthocyanin metabolite profile showed F3′5′H-mediated delphinidin-type anthocyanin enrichment in both varieties towards maturation, consistent with the transcript data, indicating that the F3′5′H-governed branching step dominates the anthocyanin profile at late berry development. Correlation analysis confirmed the tightly coordinated metabolic changes during development, and suggested a source-sink relation between the central and specialized metabolism, stronger in Shiraz than Cabernet Sauvignon. RNAseq analysis also revealed that the two cultivars exhibited distinct pattern of changes in genes related to abscisic acid (ABA) biosynthesis enzymes.
Conclusions
Compared with CS, Shiraz showed higher number of significant correlations between metabolites, which together with the relatively higher expression of flavonoid genes supports the evidence of increased accumulation of coumaroyl anthocyanins in that cultivar. Enhanced stress related metabolism, e.g. trehalose, stilbene and ABA in Shiraz berry-skin are consistent with its relatively higher susceptibility to environmental cues.
doi:10.1186/s12870-014-0188-4
PMCID: PMC4222437  PMID: 25064275
Metabolite profiling; Grape berry metabolism; Grapevine; Transcript analysis; Metabolomics; GC-MS; LC-MS
25.  Aldolase positively regulates of the canonical Wnt signaling pathway 
Molecular Cancer  2014;13:164.
The Wnt signaling pathway is an evolutionary conserved system, having pivotal roles during animal development. When over-activated, this signaling pathway is involved in cancer initiation and progression. The canonical Wnt pathway regulates the stability of β-catenin primarily by a destruction complex containing a number of different proteins, including Glycogen synthase kinase 3β (GSK-3β) and Axin, that promote proteasomal degradation of β-catenin. As this signaling cascade is modified by various proteins, novel screens aimed at identifying new Wnt signaling regulators were conducted in our laboratory. One of the different genes that were identified as Wnt signaling activators was Aldolase C (ALDOC). Here we report that ALDOC, Aldolase A (ALDOA) and Aldolase B (ALDOB) activate Wnt signaling in a GSK-3β-dependent mechanism, by disrupting the GSK-3β-Axin interaction and targeting Axin to the dishevelled (Dvl)-induced signalosomes that positively regulate the Wnt pathway thus placing the Aldolase proteins as novel Wnt signaling regulators.
doi:10.1186/1476-4598-13-164
PMCID: PMC4094682  PMID: 24993527
Wnt signaling; Aldolase; β-catenin; GSK-3β

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