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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.  CHILDHOOD TO EARLY MID-LIFE SYSTOLIC BLOOD PRESSURE TRAJECTORIES: EARLY LIFE PREDICTORS, EFFECT MODIFIERS, AND ADULT CARDIOVASCULAR OUTCOMES 
Hypertension  2015;66(6):1108-1115.
Previous studies examining blood pressure change over time have modelled an “average” population trajectory. Recent research among older adults suggests there may be subgroups with different blood pressure trajectories. Identifying subgroups at risk of developing adult hypertension early in life can inform effective risk reduction efforts. We sought to identify different systolic blood pressure trajectories from childhood, their correlated risk factors and early midlife cardiovascular outcomes. Blood pressure data at ages 7, 11, 18, 26, 32 and 38 years from a longitudinal, representative birth cohort study (n=975) were used to identify four distinct trajectory groups via group-based trajectory modeling: ‘normal’ (21.8%), ‘high-normal’ (43.3%), ‘prehypertensive’ (31.6%), and ‘hypertensive’ (4.2%). The categories refer to blood pressure beginning at age 7 and most recently measured at age 38. Family history of high blood pressure (OR=43.23, 95% CI 5.27, 354.65), male gender (OR=109.48, 95% CI=26.82, 446.96), being first born (OR=2.5 95% CI=1.00, 8.69) and low birthweight (OR=2.79, 95% CI 2.49, 3.09) were associated with hypertensive group membership (compared to the normal group). Higher body mass index and cigarette smoking resulted in increasing blood pressure across trajectories, particularly for the higher blood pressure groups. Prehypertensive and hypertensive trajectory groups had worse cardiovascular outcomes by early midlife. Harmful blood pressure trajectories are identifiable in childhood, associated with both antecedent and modifiable risk factors over time, and predict adult cardiovascular disease risk. Early detection, subsequent targeted prevention and/or intervention may reduce the lifecourse burden associated with higher blood pressure.
doi:10.1161/HYPERTENSIONAHA.115.05831
PMCID: PMC4646716  PMID: 26558818
blood pressure; follow-up studies; hypertension; pediatrics; risk factor; high blood pressure
3.  Successful customer intercept interview recruitment outside small and midsize urban food retailers 
BMC Public Health  2016;16:1050.
Background
Customer intercept interviews are increasingly used to characterize food purchases at retail food outlets and restaurants; however, methodological procedures, logistical issues and response rates using intercept methods are not well described in the food environment literature. The aims of this manuscript were to 1) describe the development and implementation of a customer intercept interview protocol in a large, NIH-funded study assessing food purchases in small and midsize food retailers in Minneapolis and St. Paul, Minnesota, 2) describe intercept interview response rates by store type and environmental factors (e.g., neighborhood socioeconomic status, day/time, weather), and 3) compare demographic characteristics (e.g., gender, race/ethnicity) of participants versus non-participants.
Methods
After a pilot phase involving 28 stores, a total of 616 interviews were collected from customers exiting 128 stores in fall 2014. The number of eligible customers encountered per hour (a measure of store traffic), participants successfully recruited per hour, and response rates were calculated overall and by store type, neighborhood socio-economic status, day and time of data collection, and weather. Response rates by store type, neighborhood socio-economic status, time and day of data collection, and weather, and characteristics of participants and non-participants were compared using chi-square tests.
Results
The overall response rate was 35 %, with significantly higher response rates at corner/small grocery stores (47 %) and dollar stores (46 %) compared to food-gas marts (32 %) and pharmacies (26 %), and for data collection between 4:00–6:00 pm on weekdays (40 %) compared to weekends (32 %). The distribution of race/ethnicity, but not gender, differed between participants and non-participants (p < 0.01), with greater participation rates among those identified as Black versus White.
Conclusions
Customer intercept interviews can be successfully used to recruit diverse samples of customers at small and midsize food retailers. Future community-based studies using customer intercept interviews should collect data sufficient to report response rates and consider potential differences between the racial/ethnic composition of the recruited sample and the target population.
doi:10.1186/s12889-016-3717-2
PMCID: PMC5050669  PMID: 27716142
Research design in epidemiology; Measurement; Nutrition; Health promotion; Diet
4.  Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence from a 4-decade longitudinal cohort study 
The American journal of psychiatry  2015;172(10):967-977.
Objective
Despite a prevailing assumption that adult ADHD is a childhood-onset neurodevelopmental disorder, no prospective-longitudinal study has described the childhoods of the adult-ADHD population. We report follow-back analyses of ADHD cases diagnosed in adulthood, alongside follow-forward analyses of ADHD cases diagnosed in childhood, in one cohort.
Method
Participants belonged to a representative birth cohort of 1,037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 38, with 95% retention. Symptoms of ADHD, associated clinical features, comorbid disorders, neuropsychological deficits, GWAS-derived polygenic risk, and life impairment indicators were assessed. Data sources were participants, parents, teachers, informants, neuropsychological testing, and administrative records. Adult ADHD diagnoses used DSM5 criteria, apart from onset-age and cross-setting corroboration, which were study outcomes.
Results
As expected, the childhood-ADHD group showed 6% prevalence, male excess, childhood comorbid disorders, neurocognitive deficits, polygenic risk, and, despite having outgrown their ADHD diagnosis, residual adult life impairment. As expected, the adult-ADHD group showed 3% prevalence, gender balance, adult substance dependence, adult life impairment, and treatment contact. Unexpectedly, the childhood-ADHD and adult-ADHD groups comprised virtually non-overlapping sets; 90% of adult-ADHD cases lacked a history of childhood ADHD. Also unexpectedly, the adult-ADHD group did not show tested neuropsychological deficits in childhood or adulthood, nor did they show polygenic risk for childhood ADHD.
Conclusion
Findings raise the possibility that adults presenting with the ADHD symptom picture may not have a childhood-onset neurodevelopmental disorder. If this finding is replicated, then the disorder's place in the classification system must be reconsidered, and research must investigate the etiology of adult ADHD.
doi:10.1176/appi.ajp.2015.14101266
PMCID: PMC4591104  PMID: 25998281
5.  Living alongside more affluent neighbors predicts greater involvement in antisocial behavior among low-income boys 
Background
The creation of economically mixed communities has been proposed as one way to improve the life outcomes of children growing up in poverty. However, whether low-income children benefit from living alongside more affluent neighbors is unknown.
Method
Prospectively gathered data on over 1,600 children from the Environmental Risk (E-Risk) Longitudinal Twin Study living in urban environments is used to test whether living alongside more affluent neighbors (measured via high-resolution geo-spatial indices) predicts low-income children’s antisocial behavior (reported by mothers and teachers at the ages of 5, 7, 10, and 12).
Results
Results indicated that low-income boys (but not girls) surrounded by more affluent neighbors had higher levels of antisocial behavior than their peers embedded in concentrated poverty. The negative effect of growing up alongside more affluent neighbors on low-income boys’ antisocial behavior held across childhood and after controlling for key neighborhood and family-level factors.
Conclusions
Findings suggest that efforts to create more economically mixed communities for children, if not properly supported, may have iatrogenic effects on boys’ antisocial behavior.
doi:10.1111/jcpp.12380
PMCID: PMC4790437  PMID: 25611118
Children’s antisocial behavior; socioeconomic status; economic inequality; neighborhood poverty; economically mixed communities; sex differences
6.  Measuring Users’ Receptivity Toward an Integral Intervention Model Based on mHealth Solutions for Patients With Treatment-Resistant Schizophrenia (m-RESIST): A Qualitative Study 
JMIR mHealth and uHealth  2016;4(3):e112.
Background
Despite the theoretical potential of mHealth solutions in the treatment of patients with schizophrenia, there remains a lack of technological tools in clinical practice.
Objective
The aim of this study was to measure the receptivity of patients, informal carers, and clinicians to a European integral intervention model focused on patients with persistent positive symptoms: Mobile Therapeutic Attention for Patients with Treatment-Resistant Schizophrenia (m-RESIST).
Methods
Before defining the system requirements, a qualitative study of the needs of outpatients with treatment-resistant schizophrenia was carried out in Spain, Israel, and Hungary. We analyzed the opinions of patients, informal carers, and clinicians concerning the services originally intended to be part of the solution. A total of 9 focus groups (72 people) and 35 individual interviews were carried out in the 3 countries, using discourse analysis as the framework.
Results
A webpage and an online forum were perceived as suitable to get both reliable information on the disease and support. Data transmission by a smart watch (monitoring), Web-based visits, and instant messages (clinical treatment) were valued as ways to improve contact with clinicians. Alerts were appreciated as reminders of daily tasks and appointments. Avoiding stressful situations for outpatients, promoting an active role in the management of the disease, and maintaining human contact with clinicians were the main suggestions provided for improving the effectiveness of the solution.
Conclusions
Positive receptivity toward m-RESIST services is related to its usefulness in meeting user needs, its capacity to empower them, and the possibility of maintaining human contact.
doi:10.2196/mhealth.5716
PMCID: PMC5062002  PMID: 27682896
mHealth solution; treatment-resistant schizophrenia; intervention model; qualitative research; needs assessment
7.  A transcriptional time-course analysis of oral vs. aboral whole-body regeneration in the Sea anemone Nematostella vectensis 
BMC Genomics  2016;17(1):718.
Background
The ability of regeneration is essential for the homeostasis of all animals as it allows the repair and renewal of tissues and body parts upon normal turnover or injury. The extent of this ability varies greatly in different animals with the sea anemone Nematostella vectensis, a basal cnidarian model animal, displaying remarkable whole-body regeneration competence.
Results
In order to study this process in Nematostella we performed an RNA-Seq screen wherein we analyzed and compared the transcriptional response to bisection in the wound-proximal body parts undergoing oral (head) or aboral (tail) regeneration at several time points up to the initial restoration of the basic body shape. The transcriptional profiles of regeneration responsive genes were analyzed so as to define the temporal pattern of differential gene expression associated with the tissue-specific oral and aboral regeneration. The identified genes were characterized according to their GO (gene ontology) assignations revealing groups that were enriched in the regeneration process with particular attention to their affiliation to the major developmental signaling pathways. While some of the genes and gene groups thus analyzed were previously known to be active in regeneration, we have also revealed novel and surprising candidate genes such as cilia-associated genes that likely participate in this important developmental program.
Conclusions
This work highlighted the main groups of genes which showed polarization upon regeneration, notably the proteinases, multiple transcription factors and the Wnt pathway genes that were highly represented, all displaying an intricate temporal balance between the two sides. In addition, the evolutionary comparison performed between regeneration in different animal model systems may reveal the basic mechanisms playing a role in this fascinating process.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3027-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-3027-1
PMCID: PMC5015328  PMID: 27605362
Regeneration; Head vs. tail regeneration; Nematostella vectensis; Major axis polarization; Wnt pathway; Metalloproteinase; Homeobox genes; Cilia
8.  Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site 
Immunity  2015;43(2):343-353.
Summary
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine, and was independent of the endogenous retinal autoantigen. Our findings not only have implications for etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes may be a more common trigger of autoimmune diseases than is currently appreciated.
doi:10.1016/j.immuni.2015.07.014
PMCID: PMC4544742  PMID: 26287682
9.  Immune Mechanisms in Inflammatory and Degenerative Eye Disease 
Trends in immunology  2015;36(6):354-363.
It has recently been recognized that pathology of age-associated degenerative eye diseases such as adult macular degeneration (AMD), glaucoma and diabetic retinopathy, have strong immunological underpinnings. Attempts have been made to extrapolate to age-related degenerative disease insights from inflammatory processes associated with non-infectious uveitis, but these have not yet been sufficiently informative. Here we review recent findings on the immune processes underlying uveitis and those that have been shown to contribute to AMD, discussing in this context parallels and differences between overt inflammation and para-inflammation in the eye. We propose that mechanisms associated with ocular immune privilege, in combination with paucity of age-related antigen(s) within the target tissue, dampen what could otherwise be overt inflammation and result in the para-inflammation that characterizes age-associated neurodegenerative disease.
doi:10.1016/j.it.2015.04.003
PMCID: PMC4563859  PMID: 25981967
10.  Why Are Children in Urban Neighborhoods at Increased Risk for Psychotic Symptoms? Findings From a UK Longitudinal Cohort Study 
Schizophrenia Bulletin  2016;42(6):1372-1383.
Background:
Urban upbringing is associated with a 2-fold adulthood psychosis risk, and this association replicates for childhood psychotic symptoms. No study has investigated whether specific features of urban neighborhoods increase children’s risk for psychotic symptoms, despite these early psychotic phenomena elevating risk for schizophrenia and other psychiatric disorders in adulthood.
Methods:
Analyses were conducted on over 2000 children from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of UK-born twins. Neighborhood-level characteristics were assessed for each family via: a geodemographic discriminator indexing neighborhood-level deprivation, postal surveys of over 5000 residents living alongside the children, and in-home interviews with the children’s mothers. Children were interviewed about psychotic symptoms at age 12. Analyses were adjusted for important family-level confounders including socioeconomic status (SES), psychiatric history, and maternal psychosis.
Results:
Urban residency at age-5 (OR = 1.80, 95% CI = 1.16–2.77) and age-12 (OR = 1.76, 95% CI = 1.15–2.69) were both significantly associated with childhood psychotic symptoms, but not with age-12 anxiety, depression, or antisocial behavior. The association was not attributable to family SES, family psychiatric history, or maternal psychosis, each implicated in childhood mental health. Low social cohesion, together with crime victimization in the neighborhood explained nearly a quarter of the association between urbanicity and childhood psychotic symptoms after considering family-level confounders.
Conclusions:
Low social cohesion and crime victimization in the neighborhood partly explain why children in cities have an elevated risk of developing psychotic symptoms. Greater understanding of the mechanisms leading from neighborhood-level exposures to psychotic symptoms could help target interventions for emerging childhood psychotic symptoms.
doi:10.1093/schbul/sbw052
PMCID: PMC5049530  PMID: 27153864
childhood psychotic symptoms; neighborhood characteristics; social cohesion; psychosis; urbanicity
11.  Social jetlag, obesity and metabolic disorder: investigation in a cohort study 
BACKGROUND
Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction.
METHODS
We studied participants from the population-representative Dunedin Longitudinal Study (N = 1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes.
RESULTS
Our analysis was restricted to N = 815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation.
CONCLUSIONS
The findings are consistent with the possibility that ‘living against our internal clock’ may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.
doi:10.1038/ijo.2014.201
PMCID: PMC4422765  PMID: 25601363
12.  Cardiorespiratory Fitness and Cognitive Function in Midlife: Neuroprotection or Neuroselection? 
Annals of neurology  2015;77(4):607-617.
Objective
To determine if better cognitive functioning at midlife among more physically fit individuals reflects “neuroprotection,” in which fitness protects against age-related cognitive decline, or “neuroselection,” in which children with higher cognitive functioning select into more active lifestyles.
Methods
Children in the Dunedin Longitudinal Study (N=1,037) completed the Wechsler Intelligence Scales and the Trail-Making, Rey-Delayed-Recall, and Grooved-Pegboard tasks as children and again at midlife (age-38). Adult cardiorespiratory fitness was assessed using a submaximal exercise test to estimate maximum-oxygen-consumption-adjusted-for-body-weight in milliliters/minute/kilogram (VO2max). We tested if more-fit individuals had better cognitive functioning than their less-fit counterparts (which could be consistent with neuroprotection), and if better childhood cognitive functioning predisposed to better adult cardiorespiratory fitness (neuroselection). Finally, we examined possible mechanisms of neuroselection.
Results
Participants with better cardiorespiratory fitness had higher cognitive test scores at midlife. However, fitness-associated advantages in cognitive functioning were present already in childhood. After accounting for childhood-baseline performance on the same cognitive tests, there was no association between cardiorespiratory fitness and midlife cognitive functioning. Socioeconomic and health advantages in childhood, and healthier lifestyles during young adulthood explained most of the association between childhood cognitive functioning and adult cardiorespiratory fitness.
Interpretation
We found no evidence for a neuroprotective effect of cardiorespiratory fitness as of midlife. Instead, children with better cognitive functioning are selecting into healthier lives. Fitness interventions may enhance cognitive functioning. But, observational and experimental studies testing neuroprotective effects of physical fitness should consider confounding by neuroselection.
doi:10.1002/ana.24356
PMCID: PMC4376580  PMID: 25601795
13.  Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis 
Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal antigen IRBP is a model of human autoimmune uveitis. We examined whether T regulatory (Treg) cells found in uveitic eyes are (i) IRBP specific, (ii) functionally suppressive, and (iii) play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3+ Treg to T effector (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Treg (CD4+Foxp3+) and up to 60% of Teff (CD4+FoxP3−) cells were IRBP-specific, while in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teff from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Treg and Teff cells. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3+ Tregs play a role in the natural resolution of uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye.
doi:10.4049/jimmunol.1402650
PMCID: PMC4459505  PMID: 25716996
14.  Dissecting Stages of Human Kidney Development and Tumorigenesis with Surface Markers Affords Simple Prospective Purification of Nephron Stem Cells 
Scientific Reports  2016;6:23562.
When assembling a nephron during development a multipotent stem cell pool becomes restricted as differentiation ensues. A faulty differentiation arrest in this process leads to transformation and initiation of a Wilms’ tumor. Mapping these transitions with respective surface markers affords accessibility to specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark human renal progenitor populations. Herein, using cell sorting, RNA sequencing, in vitro studies with serum-free media and in vivo xenotransplantation we demonstrate a sequential map that links human kidney development and tumorigenesis; In nephrogenesis, NCAM1+CD133− marks SIX2+ multipotent renal stem cells transiting to NCAM1+CD133+ differentiating segment-specific SIX2− epithelial progenitors and NCAM1−CD133+ differentiated nephron cells. In tumorigenesis, NCAM1+CD133− marks SIX2+ blastema that includes the ALDH1+ WT cancer stem/initiating cells, while NCAM1+CD133+ and NCAM1−CD133+ specifying early and late epithelial differentiation, are severely restricted in tumor initiation capacity and tumor self-renewal. Thus, negative selection for CD133 is required for defining NCAM1+ nephron stem cells in normal and malignant nephrogenesis.
doi:10.1038/srep23562
PMCID: PMC4810363  PMID: 27020553
15.  Complete Genome Sequence of Turicibacter sp. Strain H121, Isolated from the Feces of a Contaminated Germ-Free Mouse 
Genome Announcements  2016;4(2):e00114-16.
Turicibacter bacteria are commonly detected in the gastrointestinal tracts and feces of humans and animals, but their phylogeny, ecological role, and pathogenic potential remain unclear. We present here the first complete genome sequence of Turicibacter sp. strain H121, which was isolated from the feces of a mouse line contaminated following germ-free derivation.
doi:10.1128/genomeA.00114-16
PMCID: PMC4807225  PMID: 27013036
16.  NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis 
The Journal of Experimental Medicine  2015;212(10):1739-1752.
DCs recruit NK cells to the draining lymph node where they interact with DC creating a positive feedback loop of IL-27 and IFNγ production, which is ultimately limited by IL-10. This innate NK-DC axis controls the development of the adaptive response and dampens induction of autoimmunity.
IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ+/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ–IL-27 axis.
doi:10.1084/jem.20141678
PMCID: PMC4577839  PMID: 26347474
17.  Streptococcus pneumoniae Cell-Wall-Localized Phosphoenolpyruvate Protein Phosphotransferase Can Function as an Adhesin: Identification of Its Host Target Molecules and Evaluation of Its Potential as a Vaccine 
PLoS ONE  2016;11(3):e0150320.
In Streptococcus pneumonia, phosphoenolpyruvate protein phosphotransferase (PtsA) is an intracellular protein of the monosaccharide phosphotransferase systems. Biochemical and immunostaining methods were applied to show that PtsA also localizes to the bacterial cell-wall. Thus, it was suspected that PtsA has functions other than its main cytoplasmic enzymatic role. Indeed, recombinant PtsA and anti-rPtsA antiserum were shown to inhibit adhesion of S. pneumoniae to cultured human lung adenocarcinoma A549 cells. Screening of a combinatorial peptide library expressed in a filamentous phage with rPtsA identified epitopes that were capable of inhibiting S. pneumoniae adhesion to A549 cells. The insert peptides in the phages were sequenced, and homologous sequences were found in human BMPER, multimerin1, protocadherin19, integrinβ4, epsin1 and collagen type VIIα1 proteins, all of which can be found in A549 cells except the latter. Six peptides, synthesized according to the homologous sequences in the human proteins, specifically bound rPtsA in the micromolar range and significantly inhibited pneumococcal adhesion in vitro to lung- and tracheal-derived cell lines. In addition, the tested peptides inhibited lung colonization after intranasal inoculation of mice with S. pneumoniae. Immunization with rPtsA protected the mice against a sublethal intranasal and a lethal intravenous pneumococcal challenge. In addition, mouse anti rPtsA antiserum reduced bacterial virulence in the intravenous inoculation mouse model. These findings showed that the surface-localized PtsA functions as an adhesin, PtsA binding peptides derived from its putative target molecules can be considered for future development of therapeutics, and rPtsA should be regarded as a candidate for vaccine development.
doi:10.1371/journal.pone.0150320
PMCID: PMC4798226  PMID: 26990554
18.  Modified ground-truthing: an accurate and cost-effective food environment validation method for town and rural areas 
Background
A major concern in food environment research is the lack of accuracy in commercial business listings of food stores, which are convenient and commonly used. Accuracy concerns may be particularly pronounced in rural areas. Ground-truthing or on-site verification has been deemed the necessary standard to validate business listings, but researchers perceive this process to be costly and time-consuming. This study calculated the accuracy and cost of ground-truthing three town/rural areas in Minnesota, USA (an area of 564 miles, or 908 km), and simulated a modified validation process to increase efficiency without comprising accuracy. For traditional ground-truthing, all streets in the study area were driven, while the route and geographic coordinates of food stores were recorded.
Results
The process required 1510 miles (2430 km) of driving and 114 staff hours. The ground-truthed list of stores was compared with commercial business listings, which had an average positive predictive value (PPV) of 0.57 and sensitivity of 0.62 across the three sites. Using observations from the field, a modified process was proposed in which only the streets located within central commercial clusters (the 1/8 mile or 200 m buffer around any cluster of 2 stores) would be validated. Modified ground-truthing would have yielded an estimated PPV of 1.00 and sensitivity of 0.95, and would have resulted in a reduction in approximately 88 % of the mileage costs.
Conclusions
We conclude that ground-truthing is necessary in town/rural settings. The modified ground-truthing process, with excellent accuracy at a fraction of the costs, suggests a new standard and warrants further evaluation.
doi:10.1186/s12966-016-0360-3
PMCID: PMC4794836  PMID: 26988710
Food environment; Validation; Cost-effectiveness; Accuracy; Ground-truthing
19.  Committed to work but vulnerable: Self-perceptions and mental health in NEET 18-year-olds from a contemporary British cohort 
Background
Labour market disengagement among youths has lasting negative economic and social consequences, yet is poorly understood. We compared four types of work-related self-perceptions, as well as vulnerability to mental health and substance abuse problems, among youths not in education, employment, or training (NEET) and among their peers.
Methods
Participants were from the Environmental Risk (E-Risk) longitudinal study, a nationally representative U.K. cohort of 2,232 twins born in 1994–95. We measured commitment to work, job-search effort, professional/technical skills, “soft” skills (e.g., teamwork, decision-making, communication), optimism about getting ahead, and mental health and substance-use disorders at age 18. We also examined childhood mental health.
Results
At age 18, 11.6% of participants were NEET. NEET participants reported themselves as committed to work and searching for jobs with greater diligence than their non-NEET peers. However, they reported fewer “soft” skills (B = −0.98, p < .001) and felt less optimistic about their likelihood of getting ahead in life (B = −2.41, p < .001). NEET youths also had higher rates of concurrent mental health and substance-abuse problems, but these did not explain the relationship with work-related self-perceptions. Nearly 60% of NEET (vs. 35% of non-NEET) youths had already experienced ≥1 mental health problem in childhood/adolescence. Associations of NEET status with concurrent mental health problems were independent of pre-existing mental health vulnerability.
Conclusions
Our findings indicate that while NEET is clearly an economic and mental health issue, it does not appear to be a motivation issue. Alongside skills, work-related self-perceptions and mental-health problems may be targets for intervention and service provision among this high-risk population.
doi:10.1111/jcpp.12459
PMCID: PMC4789764  PMID: 26791344
20.  Measuring adolescents’ exposure to victimization: The Environmental Risk (E-Risk) Longitudinal Twin Study 
Development and psychopathology  2015;27(4 Pt 2):1399-1416.
This paper presents mutlilevel findings on adolescents’ victimization exposure from a large longitudinal cohort of twins. Data were obtained from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) followed to 18 years of age (with 93% retention). To assess adolescent victimization we combined best practices in survey research on victimization with optimal approaches to measuring life stress and traumatic experiences, and introduce a reliable system for coding severe victimization. One in three children experienced at least one type of severe victimization during adolescence (crime victimization, peer/sibling victimization, internet/mobile phone victimization, sexual victimization, family violence, maltreatment, or neglect), and most types of victimization were more prevalent amongst children from low socioeconomic backgrounds. Exposure to multiple victimization types was common, as was re-victimization; over half of those physically maltreated in childhood were also exposed to severe physical violence in adolescence. Biometric twin analyses revealed that environmental factors had the greatest influence on most types of victimization, while severe physical maltreatment from caregivers during adolescence was predominantly influenced by heritable factors. The findings from this study showcase how distinct levels of victimization measurement can be harmonized in large-scale studies of health and development.
doi:10.1017/S0954579415000838
PMCID: PMC4778729  PMID: 26535933
adolescence; assessment; gene-environment correlation; maltreatment; violence
21.  Disparities persist in nutrition policies and practices in Minnesota secondary schools 
Access to healthy foods among secondary school students is patterned by individual-level socioeconomic status, but few studies have examined how school nutrition policies and practices are patterned by school-level characteristics. The objective of this study was to examine school nutrition policies and practices by school characteristics (location, racial/ethnic composition and free/reduced priced lunch eligibility [FRPL]) in Minnesota secondary schools between 2008 and 2012. Data from the 2008 to 2012 Minnesota School Health Profiles survey were used to assess school nutrition policies and practices, and National Center for Educational Statistics (NCES) data were used for school characteristics (n = 505 secondary schools). Nutrition policies and practices included: 1) the availability of low-nutrient, energy dense (LNED) items, 2) strategies to engage students in healthy eating, and 3) restrictions on advertisements of LNED products in areas around the school. Among school-level characteristics, school location was most strongly related to school nutrition policies. Across all years, city schools were less likely than town/rural schools to have vending machines/school stores [prevalence difference (PD)=13.7, 95% confidence interval (CI) -25.0,-2.3], and less likely to sell sports drinks (PD= -36.3, 95% CI: -51.8, -20.7). City schools were also more likely to prohibit advertisements for LNED products in school buildings (PD=17.7, 95% CI: 5.5, 29.9) and on school grounds (PD=15.6, 95% CI: 1.7, 29.5). Between 2008 and 2012 the prevalence of some healthy eating policies/practices (limiting salty snacks, offering taste testing, banning unhealthy food advertisements in school publications) declined in city schools only, where these policies/practices had previously been more common. Monitoring of these trends is needed to understand the impact of these policies on student outcomes across school settings.
doi:10.1016/j.jand.2014.08.029
PMCID: PMC4344858  PMID: 25441964
Nutritional policies; secondary schools; health disparities; adolescent obesity; rural health
22.  Is Toxoplasma Gondii Infection Related to Brain and Behavior Impairments in Humans? Evidence from a Population-Representative Birth Cohort 
PLoS ONE  2016;11(2):e0148435.
Background
Toxoplasma gondii (T. gondii) is a protozoan parasite present in around a third of the human population. Infected individuals are commonly asymptomatic, though recent reports have suggested that infection might influence aspects of the host’s behavior. In particular, Toxoplasma infection has been linked to schizophrenia, suicide attempt, differences in aspects of personality and poorer neurocognitive performance. However, these studies are often conducted in clinical samples or convenience samples.
Methods/Results
In a population-representative birth-cohort of individuals tested for presence of antibodies to T. gondii (N = 837) we investigated the association between infection and four facets of human behavior: neuropsychiatric disorder (schizophrenia and major depression), poor impulse control (suicidal behavior and criminality), personality, and neurocognitive performance. Suicide attempt was marginally more frequent among individuals with T. gondii seropositivity (p = .06). Seropositive individuals also performed worse on one out of 14 measures of neuropsychological function.
Conclusion
On the whole, there was little evidence that T. gondii was related to increased risk of psychiatric disorder, poor impulse control, personality aberrations or neurocognitive impairment.
doi:10.1371/journal.pone.0148435
PMCID: PMC4757034  PMID: 26886853
23.  The Development of a Novel qPCR Assay-Set for Identifying Fecal Contamination Originating from Domestic Fowls and Waterfowl in Israel 
The emerging microbial source tracking (MST) methodologies aim to identify fecal contamination originating from domestic and wild animals, and from humans. Avian MST is especially challenging, primarily because the Aves class includes both domesticated and wild species with highly diverse habitats and dietary characteristics. The quest for specific fecal bacterial MST markers can be difficult with respect to attaining sufficient assay sensitivity and specificity. The present study utilizes high throughput sequencing (HTS) to screen bacterial 16S rRNA genes from fecal samples collected from both domestic and wild avian species. Operational taxonomic unit (OTU) analysis was then performed, from which sequences were retained for downstream quantitative polymerase chain reaction (qPCR) marker development. Identification of unique avian host DNA sequences, absent in non-avian hosts, was then carried out using a dedicated database of bacterial 16S rRNA gene taken from the Ribosomal Database Project. Six qPCR assays were developed targeting the 16S rRNA gene of Lactobacillus, Gallibacterium, Firmicutes, Fusobacteriaceae, and other bacteria. Two assays (Av4143 and Av163) identified most of the avian fecal samples and demonstrated sensitivity values of 91 and 70%, respectively. The Av43 assay only identified droppings from battery hens and poultry, whereas each of the other three assays (Av24, Av13, and Av216) identified waterfowl species with lower sensitivities values. The development of an MST assay-panel, which includes both domestic and wild avian species, expands the currently known MST analysis capabilities for decoding fecal contamination.
doi:10.3389/fmicb.2016.00145
PMCID: PMC4756122  PMID: 26925034
birds; fecal contamination; HTS; MST; qPCR
24.  Characterization of a New Epitope of IRBP That Induces Moderate to Severe Uveoretinitis in Mice With H-2b Haplotype 
Purpose
Experimental autoimmune uveitis (EAU) induced in mice using the retinal antigen interphotoreceptor retinoid binding protein (IRBP) is an animal model for posterior uveitis in humans. However, EAU induced by native IRBP protein or its widely used epitope amino acid residues 1 to 20 of human IRBP (hIRBP1-20) is inconsistent, often showing low scores and incidence. We found an urgent need to identify a better pathogenic epitope for the C57BL/6 strain.
Methods
Mice were immunized with uveitogenic peptides or with native bovine IRBP. Clinical and histological disease and associated immunological responses were evaluated. Truncated and substituted peptides, as well as bioinformatic analyses, were used to identify critical major histocompatibility complex (MHC)/T cell receptor (TCR) contact residues and the minimal core epitope.
Results
The new uveitogenic epitope of IRBP, amino acid residues 651 to 670 of human IRBP (LAQGAYRTAVDLESLASQLT [hIRBP651-670]) is uveitogenic for mice of the H-2b haplotype and elicits EAU with a higher severity and incidence in C57BL/6 mice than the previously characterized hIRBP1-20 epitope. Using truncated and substituted peptides, as well as bioinformatic analysis, we identified the critical contact residues with MHC/TCR and defined the minimal core epitope. This made it possible to design MHC tetramers and use them to detect epitope-specific T cells in the uveitic eye and in lymphoid organs of hIRBP651-670–immunized mice.
Conclusions
Data suggest that hIRBP651-670 is an epitope naturally processed from a conserved region of native IRBP, potentially explaining its relatively high uveitogenicity. This epitope should be useful for basic and preclinical studies of uveitis in the C57BL/6 model and gives access to genetically engineered mice available on this background.
A novel epitope of IRBP, uveitogenic in C57BL/6 and other H-2b haplotype mice, has been characterized. It provides an alternative to the relatively weakly uveitogenic peptide hIRBP1-20 for this most widely used mouse strain.
doi:10.1167/iovs.15-17280
PMCID: PMC4544201  PMID: 26284549
autoimmune; EAU; IRBP; H-2b mice
25.  Octanol-assisted liposome assembly on chip 
Nature Communications  2016;7:10447.
Liposomes are versatile supramolecular assemblies widely used in basic and applied sciences. Here we present a novel microfluidics-based method, octanol-assisted liposome assembly (OLA), to form monodisperse, cell-sized (5–20 μm), unilamellar liposomes with excellent encapsulation efficiency. Akin to bubble blowing, an inner aqueous phase and a surrounding lipid-carrying 1-octanol phase is pinched off by outer fluid streams. Such hydrodynamic flow focusing results in double-emulsion droplets that spontaneously develop a side-connected 1-octanol pocket. Owing to interfacial energy minimization, the pocket splits off to yield fully assembled solvent-free liposomes within minutes. This solves the long-standing fundamental problem of prolonged presence of residual oil in the liposome bilayer. We demonstrate the unilamellarity of liposomes with functional α-haemolysin protein pores in the membrane and validate the biocompatibility by inner leaflet localization of bacterial divisome proteins (FtsZ and ZipA). OLA offers a versatile platform for future analytical tools, delivery systems, nanoreactors and synthetic cells.
A broad application of liposomes calls for high throughout techniques to produce them in a controlled and fast manner. Here, Deshpande et al. show a microfluidic approach using alcohol-based lipid-carrying material to generate monodisperse and unilamellar liposomes within a just few minutes.
doi:10.1038/ncomms10447
PMCID: PMC4735860  PMID: 26794442

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