Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection.

PubMed

Steinrueck, Magdalena; Guet, Călin C

2017-07-25

How the organization of genes on a chromosome shapes adaptation is essential for understanding evolutionary paths. Here, we investigate how adaptation to rapidly increasing levels of antibiotic depends on the chromosomal neighborhood of a drug-resistance gene inserted at different positions of the Escherichia coli chromosome. Using a dual-fluorescence reporter that allows us to distinguish gene amplifications from other up-mutations, we track in real-time adaptive changes in expression of the drug-resistance gene. We find that the relative contribution of several mutation types differs systematically between loci due to properties of neighboring genes: essentiality, expression, orientation, termination, and presence of duplicates. These properties determine rate and fitness effects of gene amplification, deletions, and mutations compromising transcriptional termination. Thus, the adaptive potential of a gene under selection is a system-property with a complex genetic basis that is specific for each chromosomal locus, and it can be inferred from detailed functional and genomic data.

Targeted Advertising, Promotion, and Price For Menthol Cigarettes in California High School Neighborhoods

PubMed Central

Schleicher, Nina C.; Dauphinee, Amanda L.; Fortmann, Stephen P.

2012-01-01

Objectives: To describe advertising, promotions, and pack prices for the leading brands of menthol and nonmenthol cigarettes near California high schools and to examine their associations with school and neighborhood demographics. Methods: In stores (n = 407) within walking distance (0.8 km [1/2 mile]) of California high schools (n = 91), trained observers counted ads for menthol and nonmenthol cigarettes and collected data about promotions and prices for Newport and Marlboro, the leading brand in each category. Multilevel modeling examined the proportion of all cigarette advertising for any menthol brand, the proportion of stores with sales promotions, and the lowest advertised pack price in relation to store types and school/neighborhood demographics. Results: For each 10 percentage point increase in the proportion of Black students, the proportion of menthol advertising increased by 5.9 percentage points (e.g., from an average of 25.7%–31.6%), the odds of a Newport promotion were 50% higher (95% CI = 1.01, 2.22), and the cost of Newport was 12 cents lower (95% CI = −0.18, −0.06). By comparison, the odds of a promotion and the price for Marlboro, the leading brand of nonmenthol cigarettes, were unrelated to any school or neighborhood demographics. Conclusions: In high school neighborhoods, targeted advertising exposes Blacks to more promotions and lower prices for the leading brand of menthol cigarettes. This evidence contradicts the manufacturer’s claims that the availability of its promotions is not based on race/ethnicity. It also highlights the need for tobacco control policies that would limit disparities in exposure to retail marketing for cigarettes. PMID:21705460

COGNAT: a web server for comparative analysis of genomic neighborhoods.

PubMed

Klimchuk, Olesya I; Konovalov, Kirill A; Perekhvatov, Vadim V; Skulachev, Konstantin V; Dibrova, Daria V; Mulkidjanian, Armen Y

2017-11-22

In prokaryotic genomes, functionally coupled genes can be organized in conserved gene clusters enabling their coordinated regulation. Such clusters could contain one or several operons, which are groups of co-transcribed genes. Those genes that evolved from a common ancestral gene by speciation (i.e. orthologs) are expected to have similar genomic neighborhoods in different organisms, whereas those copies of the gene that are responsible for dissimilar functions (i.e. paralogs) could be found in dissimilar genomic contexts. Comparative analysis of genomic neighborhoods facilitates the prediction of co-regulated genes and helps to discern different functions in large protein families. We intended, building on the attribution of gene sequences to the clusters of orthologous groups of proteins (COGs), to provide a method for visualization and comparative analysis of genomic neighborhoods of evolutionary related genes, as well as a respective web server. Here we introduce the COmparative Gene Neighborhoods Analysis Tool (COGNAT), a web server for comparative analysis of genomic neighborhoods. The tool is based on the COG database, as well as the Pfam protein families database. As an example, we show the utility of COGNAT in identifying a new type of membrane protein complex that is formed by paralog(s) of one of the membrane subunits of the NADH:quinone oxidoreductase of type 1 (COG1009) and a cytoplasmic protein of unknown function (COG3002). This article was reviewed by Drs. Igor Zhulin, Uri Gophna and Igor Rogozin.

A Systematic Review of Neighborhood Disparities in Point-of-Sale Tobacco Marketing

PubMed Central

Henriksen, Lisa; Rose, Shyanika W.; Moreland-Russell, Sarah; Ribisl, Kurt M.

2015-01-01

We systematically reviewed evidence of disparities in tobacco marketing at tobacco retailers by sociodemographic neighborhood characteristics. We identified 43 relevant articles from 893 results of a systematic search in 10 databases updated May 28, 2014. We found 148 associations of marketing (price, placement, promotion, or product availability) with a neighborhood demographic of interest (socioeconomic disadvantage, race, ethnicity, and urbanicity). Neighborhoods with lower income have more tobacco marketing. There is more menthol marketing targeting urban neighborhoods and neighborhoods with more Black residents. Smokeless tobacco products are targeted more toward rural neighborhoods and neighborhoods with more White residents. Differences in store type partially explain these disparities. There are more inducements to start and continue smoking in lower-income neighborhoods and in neighborhoods with more Black residents. Retailer marketing may contribute to disparities in tobacco use. Clinicians should be aware of the pervasiveness of these environmental cues. PMID:26180986

A Systematic Review of Neighborhood Disparities in Point-of-Sale Tobacco Marketing.

PubMed

Lee, Joseph G L; Henriksen, Lisa; Rose, Shyanika W; Moreland-Russell, Sarah; Ribisl, Kurt M

2015-09-01

We systematically reviewed evidence of disparities in tobacco marketing at tobacco retailers by sociodemographic neighborhood characteristics. We identified 43 relevant articles from 893 results of a systematic search in 10 databases updated May 28, 2014. We found 148 associations of marketing (price, placement, promotion, or product availability) with a neighborhood demographic of interest (socioeconomic disadvantage, race, ethnicity, and urbanicity). Neighborhoods with lower income have more tobacco marketing. There is more menthol marketing targeting urban neighborhoods and neighborhoods with more Black residents. Smokeless tobacco products are targeted more toward rural neighborhoods and neighborhoods with more White residents. Differences in store type partially explain these disparities. There are more inducements to start and continue smoking in lower-income neighborhoods and in neighborhoods with more Black residents. Retailer marketing may contribute to disparities in tobacco use. Clinicians should be aware of the pervasiveness of these environmental cues.

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

Gene-by-social-environment interaction (GxSE) between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma-exposed women.

PubMed

Lowe, Sarah R; Pothen, John; Quinn, James W; Rundle, Andrew; Bradley, Bekh; Galea, Sandro; Ressler, Kerry J; Koenen, Karestan C

2015-11-15

Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women. Female participants (N=1361) were recruited from a public hospital, and completed measures of PTS and MD symptoms and provided DNA samples. Participants' home addresses were mapped onto 300 neighborhoods (2010 census tracts), and data on crime within neighborhoods was collected. Multilevel models detected a significant GxSE between rs2267735 and neighborhood crime for MD symptoms (p=.01). Having two copies of the risk (C) allele was associated with higher MD symptoms for participants living in high-crime neighborhoods. At least six limitations are noteworthy: (1) low statistical power; (2) use of self-report symptom inventories; (3) lack of information on symptom onset; (4) homogeneous sample from a single metropolitan area; (5) non-specific index of crime; and (6) use of census tracts to define neighborhoods. The results provide further evidence of GxSEs for psychiatric outcomes among trauma-exposed populations. Further investigations of genetic factors for trauma-related psychopathology should include careful assessments of the social environment. Copyright © 2015 Elsevier B.V. All rights reserved.

Gene-by-social-environment interaction (GxSE) between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma-exposed women

PubMed Central

Lowe, Sarah R.; Pothen, John; Quinn, James W.; Rundle, Andrew; Bradley, Bekh; Galea, Sandro; Ressler, Kerry J.; Koenen, Karestan C.

2015-01-01

Background Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women. Methods Female participants (N = 1361) were recruited from a public hospital, and completed measures of PTS and MD symptoms and provided DNA samples. Participants’ home addresses were mapped onto 300 neighborhoods (2010 census tracts), and data on crime within neighborhoods was collected. Results Multilevel models detected a significant GxSE between rs2267735 and neighborhood crime for MD symptoms (p = .01). Having two copies of the risk (C) allele was associated with higher MD symptoms for participants living in high-crime neighborhoods. Limitations At least six limitations are noteworthy: (1) low statistical power; (2) use of self-report symptom inventories; (3) lack of information on symptom onset; (4) homogeneous sample from a single metropolitan area; (5) non-specific index of crime; and (6) use of census tracts to define neighborhoods. Conclusions The results provide further evidence of GxSEs for psychiatric outcomes among trauma-exposed populations. Further investigations of genetic factors for trauma-related psychopathology should include careful assessments of the social environment. PMID:26334183

Training Neighborhood Residents to Conduct a Survey

ERIC Educational Resources Information Center

Back, Susan Malone; Tseng, Wan-Chun; Li, Jiaqi; Wang, Yuanhua; Phan, Van Thanh; Yeter, Ibrahim Halil

2015-01-01

As a requirement for a federal neighborhood revitalization grant, the authors trained resident interviewers and coordinated the conduct of more than 1000 door-to-door interviews of a stratified random sample. The targeted area was a multiethnic, lower income neighborhood that continues to experience the effects of past segregation. Monitoring and…

Rural Neighborhood Walkability: Implications for Assessment.

PubMed

Kegler, Michelle C; Alcantara, Iris; Haardörfer, Regine; Gemma, Alexandra; Ballard, Denise; Gazmararian, Julie

2015-06-16

Physical activity levels, including walking, are lower in the southern U.S., particularly in rural areas. This study investigated the concept of rural neighborhood walkability to aid in developing tools for assessing walkability and to identify intervention targets in rural communities. Semi-structured interviews were conducted with physically active adults (n = 29) in rural Georgia. Mean age of participants was 55.9 years; 66% were male, 76% were white, and 24% were African American. Participants drew maps of their neighborhoods and discussed the relevance of typical domains of walkability to their decisions to exercise. Comparative analyses were conducted to identify major themes. The majority felt the concept of neighborhood was applicable and viewed their neighborhood as small geographically (less than 0.5 square miles). Sidewalks were not viewed as essential for neighborhood-based physical activity and typical destinations for walking were largely absent. Destinations within walking distance included neighbors' homes and bodies of water. Views were mixed on whether shade, safety, dogs, and aesthetics affected decisions to exercise in their neighborhoods. Measures of neighborhood walkability in rural areas should acknowledge the small size of self-defined neighborhoods, that walking in rural areas is likely for leisure time exercise, and that some domains may not be relevant.

About miRNAs, miRNA seeds, target genes and target pathways.

PubMed

Kehl, Tim; Backes, Christina; Kern, Fabian; Fehlmann, Tobias; Ludwig, Nicole; Meese, Eckart; Lenhof, Hans-Peter; Keller, Andreas

2017-12-05

miRNAs are typically repressing gene expression by binding to the 3' UTR, leading to degradation of the mRNA. This process is dominated by the eight-base seed region of the miRNA. Further, miRNAs are known not only to target genes but also to target significant parts of pathways. A logical line of thoughts is: miRNAs with similar (seed) sequence target similar sets of genes and thus similar sets of pathways. By calculating similarity scores for all 3.25 million pairs of 2,550 human miRNAs, we found that this pattern frequently holds, while we also observed exceptions. Respective results were obtained for both, predicted target genes as well as experimentally validated targets. We note that miRNAs target gene set similarity follows a bimodal distribution, pointing at a set of 282 miRNAs that seems to target genes with very high specificity. Further, we discuss miRNAs with different (seed) sequences that nonetheless regulate similar gene sets or pathways. Most intriguingly, we found miRNA pairs that regulate different gene sets but similar pathways such as miR-6886-5p and miR-3529-5p. These are jointly targeting different parts of the MAPK signaling cascade. The main goal of this study is to provide a general overview on the results, to highlight a selection of relevant results on miRNAs, miRNA seeds, target genes and target pathways and to raise awareness for artifacts in respective comparisons. The full set of information that allows to infer detailed results on each miRNA has been included in miRPathDB, the miRNA target pathway database (https://mpd.bioinf.uni-sb.de).

A multilevel prediction of physiological response to challenge: Interactions among child maltreatment, neighborhood crime, endothelial nitric oxide synthase gene (eNOS), and GABA(A) receptor subunit alpha-6 gene (GABRA6).

PubMed

Lynch, Michael; Manly, Jody Todd; Cicchetti, Dante

2015-11-01

Physiological response to stress has been linked to a variety of healthy and pathological conditions. The current study conducted a multilevel examination of interactions among environmental toxins (i.e., neighborhood crime and child maltreatment) and specific genetic polymorphisms of the endothelial nitric oxide synthase gene (eNOS) and GABA(A) receptor subunit alpha-6 gene (GABRA6). One hundred eighty-six children were recruited at age 4. The presence or absence of child maltreatment as well as the amount of crime that occurred in their neighborhood during the previous year were determined at that time. At age 9, the children were brought to the lab, where their physiological response to a cognitive challenge (i.e., change in the amplitude of the respiratory sinus arrhythmia) was assessed and DNA samples were collected for subsequent genotyping. The results confirmed that complex Gene × Gene, Environment × Environment, and Gene × Environment interactions were associated with different patterns of respiratory sinus arrhythmia reactivity. The implications for future research and evidence-based intervention are discussed.

Work and Home Neighborhood Design and Physical Activity.

PubMed

Carlson, Jordan A; Frank, Lawrence D; Ulmer, Jared; Conway, Terry L; Saelens, Brian E; Cain, Kelli L; Sallis, James F

2018-01-01

To investigate relations of perceived worksite neighborhood environments to total physical activity and active transportation, over and above home neighborhood built environments. Observational epidemiologic study. Baltimore, Maryland-Washington, DC, and Seattle-King County, Washington metropolitan areas. One thousand eighty-five adults (mean age = 45.0 [10.2]; 46% women) recruited from 32 neighborhoods stratified by high/low neighborhood income and walkability. The Neighborhood Environment Walkability Survey assessed perceptions of worksite and home neighborhood environments. Accelerometers assessed total moderate-to-vigorous physical activity (MVPA). The International Physical Activity Questionnaire assessed total active transportation and active transportation to and around work. Mixed-effects regression tested relations of home and worksite neighborhood environments to each physical activity outcome, adjusted for demographics. Home and worksite mixed land use and street connectivity had the most consistent positive associations with physical activity outcomes. Worksite traffic and pedestrian safety were also associated with multiple physical activity outcomes. The worksite neighborhood explained additional variance in physical activity outcomes than explained by the home neighborhood. Worksite and home neighborhood environments interacted in explaining active transportation to work, with the greatest impacts occurring when both neighborhoods were activity supportive. Both worksite and home neighborhood environments were independently related to total MVPA and active transportation. Community design policies should target improving the physical activity supportiveness of worksite neighborhood environments and integrating commercial and residential development.

Neighborhood alcohol outlet density and genetic influences on alcohol use: evidence for gene-environment interaction.

PubMed

Slutske, Wendy S; Deutsch, Arielle R; Piasecki, Thomas M

2018-05-07

Genetic influences on alcohol involvement are likely to vary as a function of the 'alcohol environment,' given that exposure to alcohol is a necessary precondition for genetic risk to be expressed. However, few gene-environment interaction studies of alcohol involvement have focused on characteristics of the community-level alcohol environment. The goal of this study was to examine whether living in a community with more alcohol outlets would facilitate the expression of the genetic propensity to drink in a genetically-informed national survey of United States young adults. The participants were 2434 18-26-year-old twin, full-, and half-sibling pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Participants completed in-home interviews in which alcohol use was assessed. Alcohol outlet densities were extracted from state-level liquor license databases aggregated at the census tract level to derive the density of outlets. There was evidence that the estimates of genetic and environmental influences on alcohol use varied as a function of the density of alcohol outlets in the community. For example, the heritability of the frequency of alcohol use for those residing in a neighborhood with ten or more outlets was 74% (95% confidence limits = 55-94%), compared with 16% (95% confidence limits = 0-34%) for those in a neighborhood with zero outlets. This moderating effect of alcohol outlet density was not explained by the state of residence, population density, or neighborhood sociodemographic characteristics. The results suggest that living in a neighborhood with many alcohol outlets may be especially high-risk for those individuals who are genetically predisposed to frequently drink.

Neighborhood disadvantage, neighborhood safety and cardiometabolic risk factors in African Americans: biosocial associations in the Jackson Heart study.

PubMed

Clark, Cheryl R; Ommerborn, Mark J; Hickson, DeMarc A; Grooms, Kya N; Sims, Mario; Taylor, Herman A; Albert, Michelle A

2013-01-01

We examined associations between neighborhood socioeconomic disadvantage, perceived neighborhood safety and cardiometabolic risk factors, adjusting for health behaviors and socioeconomic status (SES) among African Americans. Study participants were non-diabetic African Americans (n = 3,909) in the baseline examination (2000-2004) of the Jackson Heart Study. We measured eight risk factors: the metabolic syndrome, its five components, insulin resistance and cardiovascular inflammation. We assessed neighborhood socioeconomic disadvantage with US Census 2000 data. We assessed perceived neighborhood safety, health behaviors and SES via survey. We used generalized estimating equations to estimate associations with a random intercept model for neighborhood effects. After adjustment for health behaviors and SES, neighborhood socioeconomic disadvantage was associated with the metabolic syndrome in women (PR 1.13, 95% CI 1.01, 1.27). Lack of perceived safety was associated with elevated glucose (OR 1.36, 95% CI 1.03, 1.80) and waist circumference (PR 1.06, 95% CI 1.02, 1.11) among women, and with elevated glucose (PR 1.30, 95% CI 1.02, 1.66) and insulin resistance (PR 1.25, 95% CI 1.08, 1.46) among men. Neighborhood socioeconomic disadvantage and perceived safety should be considered as targets for intervention to reduce cardiometabolic risks among African Americans.

Neighborhood Disadvantage, Neighborhood Safety and Cardiometabolic Risk Factors in African Americans: Biosocial Associations in the Jackson Heart Study

PubMed Central

Clark, Cheryl R.; Ommerborn, Mark J.; Hickson, DeMarc A.; Grooms, Kya N.; Sims, Mario; Taylor, Herman A.; Albert, Michelle A.

2013-01-01

Objective We examined associations between neighborhood socioeconomic disadvantage, perceived neighborhood safety and cardiometabolic risk factors, adjusting for health behaviors and socioeconomic status (SES) among African Americans. Methods Study participants were non-diabetic African Americans (n = 3,909) in the baseline examination (2000–2004) of the Jackson Heart Study. We measured eight risk factors: the metabolic syndrome, its five components, insulin resistance and cardiovascular inflammation. We assessed neighborhood socioeconomic disadvantage with US Census 2000 data. We assessed perceived neighborhood safety, health behaviors and SES via survey. We used generalized estimating equations to estimate associations with a random intercept model for neighborhood effects. Results After adjustment for health behaviors and SES, neighborhood socioeconomic disadvantage was associated with the metabolic syndrome in women (PR 1.13, 95% CI 1.01, 1.27). Lack of perceived safety was associated with elevated glucose (OR 1.36, 95% CI 1.03, 1.80) and waist circumference (PR 1.06, 95% CI 1.02, 1.11) among women, and with elevated glucose (PR 1.30, 95% CI 1.02, 1.66) and insulin resistance (PR 1.25, 95% CI 1.08, 1.46) among men. Conclusions Neighborhood socioeconomic disadvantage and perceived safety should be considered as targets for intervention to reduce cardiometabolic risks among African Americans. PMID:23691005

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes.

PubMed

Osato, Naoki

2018-01-19

Transcriptional target genes show functional enrichment of genes. However, how many and how significantly transcriptional target genes include functional enrichments are still unclear. To address these issues, I predicted human transcriptional target genes using open chromatin regions, ChIP-seq data and DNA binding sequences of transcription factors in databases, and examined functional enrichment and gene expression level of putative transcriptional target genes. Gene Ontology annotations showed four times larger numbers of functional enrichments in putative transcriptional target genes than gene expression information alone, independent of transcriptional target genes. To compare the number of functional enrichments of putative transcriptional target genes between cells or search conditions, I normalized the number of functional enrichment by calculating its ratios in the total number of transcriptional target genes. With this analysis, native putative transcriptional target genes showed the largest normalized number of functional enrichments, compared with target genes including 5-60% of randomly selected genes. The normalized number of functional enrichments was changed according to the criteria of enhancer-promoter interactions such as distance from transcriptional start sites and orientation of CTCF-binding sites. Forward-reverse orientation of CTCF-binding sites showed significantly higher normalized number of functional enrichments than the other orientations. Journal papers showed that the top five frequent functional enrichments were related to the cellular functions in the three cell types. The median expression level of transcriptional target genes changed according to the criteria of enhancer-promoter assignments (i.e. interactions) and was correlated with the changes of the normalized number of functional enrichments of transcriptional target genes. Human putative transcriptional target genes showed significant functional enrichments. Functional

Targeted gene insertion for molecular medicine.

PubMed

Voigt, Katrin; Izsvák, Zsuzsanna; Ivics, Zoltán

2008-11-01

Genomic insertion of a functional gene together with suitable transcriptional regulatory elements is often required for long-term therapeutical benefit in gene therapy for several genetic diseases. A variety of integrating vectors for gene delivery exist. Some of them exhibit random genomic integration, whereas others have integration preferences based on attributes of the targeted site, such as primary DNA sequence and physical structure of the DNA, or through tethering to certain DNA sequences by host-encoded cellular factors. Uncontrolled genomic insertion bears the risk of the transgene being silenced due to chromosomal position effects, and can lead to genotoxic effects due to mutagenesis of cellular genes. None of the vector systems currently used in either preclinical experiments or clinical trials displays sufficient preferences for target DNA sequences that would ensure appropriate and reliable expression of the transgene and simultaneously prevent hazardous side effects. We review in this paper the advantages and disadvantages of both viral and non-viral gene delivery technologies, discuss mechanisms of target site selection of integrating genetic elements (viruses and transposons), and suggest distinct molecular strategies for targeted gene delivery.

Rural neighborhoods and child aggression.

PubMed

Bowen, Natasha K; Wretman, Christopher J

2014-12-01

Structural equation modeling with latent variables was used to evaluate the direct and mediated effects of a neighborhood risk factor (negative teen behaviors) on the parent-report aggressive behavior of 213 students in grades 3 through 5 attending a school in a low-income, rural community. Contagion and social control hypotheses were examined as well as hypotheses about whether the neighborhood served as a microsystem or exosystem for rural pre-adolescents. Analyses took into account the clustering of students and ordinal nature of the data. Findings suggest that rural neighborhoods may operate as both a microsystem and exosystem for children, with direct contagion effects on their aggressive behaviors as well as indirect social control effects through parenting practices. Direct effects on aggression were also found for parenting practices and child reports of friends' negative behaviors. Pre-adolescence may be a transitional stage, when influences of the neighborhood on child behavior begin to compete with influences of caregivers. Findings can inform the timing and targets of violence prevention in rural communities.

Perceived Neighborhood Social Cohesion and Myocardial Infarction

PubMed Central

Kim, Eric S.; Hawes, Armani M.; Smith, Jacqui

2015-01-01

Background The main strategy for alleviating heart disease has been to target individuals and encourage them to change their health behaviors. Though important, emphasis on individuals has diverted focus and responsibility away from neighborhood characteristics, which also strongly influence people’s behaviors. Although a growing body of research has repeatedly demonstrated strong associations between neighborhood characteristics and cardiovascular health, it has typically focused on negative neighborhood characteristics. Only a few studies have examined the potential health enhancing effects of positive neighborhood characteristics, such as perceived neighborhood social cohesion. Methods Using multiple logistic regression models, we tested whether higher perceived neighborhood social cohesion was associated with lower incidence of myocardial infarction. Prospective data from the Health and Retirement Study—a nationally representative panel study of American adults over the age of 50—were used to analyze 5,276 participants with no history of heart disease. Respondents were tracked for four years and analyses adjusted for relevant sociodemographic, behavioral, biological, and psychosocial factors. Results In a model that adjusted for age, gender, race, marital status, education, and total wealth, each standard deviation increase in perceived neighborhood social cohesion was associated with a 22% reduced odds of myocardial infarction (OR = 0.78, 95% CI, 0.63–0.94. The association between perceived neighborhood social cohesion and myocardial infarction remained even after adjusting for behavioral, biological, and psychosocial covariates. Conclusions Higher perceived neighborhood social cohesion may have a protective effect against myocardial infarction. PMID:25135074

Neighborhood Disparities in the Restaurant Food Environment.

PubMed

Martinez-Donate, Ana P; Espino, Jennifer Valdivia; Meinen, Amy; Escaron, Anne L; Roubal, Anne; Nieto, Javier; Malecki, Kristen

2016-11-01

Restaurant meals account for a significant portion of the American diet. Investigating disparities in the restaurant food environment can inform targeted interventions to increase opportunities for healthy eating among those who need them most. To examine neighborhood disparities in restaurant density and the nutrition environment within restaurants among a statewide sample of Wisconsin households. Households (N = 259) were selected from the 2009-2010 Survey of the Health of Wisconsin (SHOW), a population-based survey of Wisconsin adults. Restaurants in the household neighborhood were enumerated and audited using the Nutrition Environment Measures Survey for Restaurants (NEMS-R). Neighborhoods were defined as a 2- and 5-mile street-distance buffer around households in urban and non-urban areas, respectively. Adjusted linear regression models identified independent associations between sociodemographic household characteristics and neighborhood restaurant density and nutrition environment scores. On average, each neighborhood contained approximately 26 restaurants. On average, restaurants obtained 36.1% of the total nutrition environment points. After adjusting for household characteristics, higher restaurant density was associated with both younger and older household average age (P < .05), all white households (P = .01), and urban location (P < .001). Compared to rural neighborhoods, urban and suburban neighborhoods had slightly higher (ie, healthier) nutrition environment scores (P < .001). The restaurant food environment in Wisconsin neighborhoods varies by age, race, and urbanicity, but offers ample room for improvement across socioeconomic groups and urbanicity levels. Future research must identify policy and environmental interventions to promote healthy eating in all restaurants, especially in young and/or rural neighborhoods in Wisconsin.

Dynamics of 1α,25-dihydroxyvitamin D3-dependent chromatin accessibility of early vitamin D receptor target genes.

PubMed

Seuter, Sabine; Pehkonen, Petri; Heikkinen, Sami; Carlberg, Carsten

2013-12-01

The signaling cascade of the transcription factor vitamin D receptor (VDR) is triggered by its specific ligand 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). In this study we demonstrate that in THP-1 human monocytic leukemia cells 87.4% of the 1034 most prominent genome-wide VDR binding sites co-localize with loci of open chromatin. At 165 of them 1α,25(OH)2D3 strongly increases chromatin accessibility and has at further 217 sites weaker effects. Interestingly, VDR binding sites in 1α,25(OH)2D3-responsive chromatin regions are far more often composed of direct repeats with 3 intervening nucleotides (DR3s) than those in ligand insensitive regions. DR3-containing VDR sites are enriched in the neighborhood of genes that are involved in controling cellular growth, while non-DR3 VDR binding is often found close to genes related to immunity. At the example of six early VDR target genes we show that the slope of their 1α,25(OH)2D3-induced transcription correlates with the basal chromatin accessibility of their major VDR binding regions. However, the chromatin loci controlling these genes are indistinguishable in their VDR association kinetics. Taken together, ligand responsive chromatin loci represent dynamically regulated contact points of VDR with the genome, from where it controls early 1α,25(OH)2D3 target genes. © 2013.

Neighborhood crime and depressive symptoms among African American women: Genetic moderation and epigenetic mediation of effects.

PubMed

Lei, Man-Kit; Beach, Steven R H; Simons, Ronald L; Philibert, Robert A

2015-12-01

Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.

NEIGHBORHOOD CRIME AND DEPRESSIVE SYMPTOMS AMONG AFRICAN AMERICAN WOMEN: GENETIC MODERATION AND EPIGENETIC MEDIATOIN OF EFFECTS

PubMed Central

Lei, Man-Kit; Beach, Steven R. H.; Simons, Ronald L.; Philibert, Robert A.

2015-01-01

Introduction Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. Objective The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. Methods Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). Results Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. Conclusion The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms. PMID:26513121

Evolving phage vectors for cell targeted gene delivery.

PubMed

Larocca, David; Burg, Michael A; Jensen-Pergakes, Kristen; Ravey, Edward Prenn; Gonzalez, Ana Maria; Baird, Andrew

2002-03-01

We adapted filamentous phage vectors for targeted gene delivery to mammalian cells by inserting a mammalian reporter gene expression cassette (GFP) into the vector backbone and fusing the pIII coat protein to a cell targeting ligand (i.e. FGF2, EGF). Like transfection with animal viral vectors, targeted phage gene delivery is concentration, time, and ligand dependent. Importantly, targeted phage particles are specific for the appropriate target cell surface receptor. Phage have distinct advantages over existing gene therapy vectors because they are simple, economical to produce at high titer, have no intrinsic tropism for mammalian cells, and are relatively simple to genetically modify and evolve. Initially transduction by targeted phage particles was low resulting in foreign gene expression in 1-2% of transfected cells. We increased transduction efficiency by modifying both the transfection protocol and vector design. For example, we stabilized the display of the targeting ligand to create multivalent phagemid-based vectors with transduction efficiencies of up to 45% in certain cell lines when combined with genotoxic treatment. Taken together, these studies establish that the efficiency of phage-mediated gene transfer can be significantly improved through genetic modification. We are currently evolving phage vectors with enhanced cell targeting, increased stability, reduced immunogenicity and other properties suitable for gene therapy.

Targeting gene therapy to cancer: a review.

PubMed

Dachs, G U; Dougherty, G J; Stratford, I J; Chaplin, D J

1997-01-01

In recent years the idea of using gene therapy as a modality in the treatment of diseases other than genetically inherited, monogenic disorders has taken root. This is particularly obvious in the field of oncology where currently more than 100 clinical trials have been approved worldwide. This report will summarize some of the exciting progress that has recently been made with respect to both targeting the delivery of potentially therapeutic genes to tumor sites and regulating their expression within the tumor microenvironment. In order to specifically target malignant cells while at the same time sparing normal tissue, cancer gene therapy will need to combine highly selective gene delivery with highly specific gene expression, specific gene product activity, and, possibly, specific drug activation. Although the efficient delivery of DNA to tumor sites remains a formidable task, progress has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods. In this report emphasis will be placed on targeted rather than high-efficiency delivery, although those would need to be combined in the future for effective therapy. To date delivery has been targeted to tumor-specific and tissue-specific antigens, such as epithelial growth factor receptor, c-kit receptor, and folate receptor, and these will be described in some detail. To increase specificity and safety of gene therapy further, the expression of the therapeutic gene needs to be tightly controlled within the target tissue. Targeted gene expression has been analyzed using tissue-specific promoters (breast-, prostate-, and melanoma-specific promoters) and disease-specific promoters (carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC). Alternatively, expression could be regulated externally with the use of radiation-induced promoters or tetracycline-responsive elements. Another novel possibility that will be

Zinc-finger protein-targeted gene regulation: Genomewide single-gene specificity

PubMed Central

Tan, Siyuan; Guschin, Dmitry; Davalos, Albert; Lee, Ya-Li; Snowden, Andrew W.; Jouvenot, Yann; Zhang, H. Steven; Howes, Katherine; McNamara, Andrew R.; Lai, Albert; Ullman, Chris; Reynolds, Lindsey; Moore, Michael; Isalan, Mark; Berg, Lutz-Peter; Campos, Bradley; Qi, Hong; Spratt, S. Kaye; Case, Casey C.; Pabo, Carl O.; Campisi, Judith; Gregory, Philip D.

2003-01-01

Zinc-finger protein transcription factors (ZFP TFs) can be designed to control the expression of any desired target gene, and thus provide potential therapeutic tools for the study and treatment of disease. Here we report that a ZFP TF can repress target gene expression with single-gene specificity within the human genome. A ZFP TF repressor that binds an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene gives a >10-fold reduction in CHK2 mRNA and protein. This level of repression was sufficient to generate a functional phenotype, as demonstrated by the loss of DNA damage-induced CHK2-dependent p53 phosphorylation. We determined the specificity of repression by using DNA microarrays and found that the ZFP TF repressed a single gene (CHK2) within the monitored genome in two different cell types. These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics. PMID:14514889

Neighborhood Poverty. Policy Implications in Studying Neighborhoods. Volume II.

ERIC Educational Resources Information Center

Brooks-Gunn, Jeanne, Ed.; Duncan, Greg J., Ed.; Aber, J. Lawrence, Ed.

Volume 2 of the "Neighborhood Poverty" series incorporates empirical data on neighborhood poverty into discussions of policy and program development. The chapters are: (1) "Ecological Perspectives on the Neighborhood Context of Urban Poverty: Past and Present" (Robert J. Sampson and Jeffrey D. Morenoff); (2) "The Influence of Neighborhoods on…

Targeted polymeric nanoparticles for cancer gene therapy

PubMed Central

Kim, Jayoung; Wilson, David R.; Zamboni, Camila G.; Green, Jordan J.

2015-01-01

In this article, advances in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed. Characterization and evaluation of biomaterials, targeting ligands, and transcriptional elements are each discussed. Advances in biomaterials have driven improvements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific cancer cells, and the design of transcriptional elements has enabled selective DNA expression specific to the cancer cells. Together, these features have improved the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors to treat cancer. As polymeric nanoparticles can be designed to be biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral platforms, they have significant potential for clinical use. Results of polymeric gene therapy in clinical trials and future directions for the engineering of nanoparticle systems for targeted cancer gene therapy are also presented. PMID:26061296

Gene targeting in mosquito cells: a demonstration of 'knockout' technology in extrachromosomal gene arrays

PubMed Central

Eggleston, Paul; Zhao, Yuguang

2001-01-01

Background Gene targeting would offer a number of advantages over current transposon-based strategies for insect transformation. These include freedom from both position effects associated with quasi-random integration and concerns over transgene instability mediated by endogenous transposases, independence from phylogenetic restrictions on transposon mobility and the ability to generate gene knockouts. Results We describe here our initial investigations of gene targeting in the mosquito. The target site was a hygromycin resistance gene, stably maintained as part of an extrachromosomal array. Using a promoter-trap strategy to enrich for targeted events, a neomycin resistance gene was integrated into the target site. This resulted in knockout of hygromycin resistance concurrent with the expression of high levels of neomycin resistance from the resident promoter. PCR amplification of the targeted site generated a product that was specific to the targeted cell line and consistent with precise integration of the neomycin resistance gene into the 5' end of the hygromycin resistance gene. Sequencing of the PCR product and Southern analysis of cellular DNA subsequently confirmed this molecular structure. Conclusions These experiments provide the first demonstration of gene targeting in mosquito tissue and show that mosquito cells possess the necessary machinery to bring about precise integration of exogenous sequences through homologous recombination. Further development of these procedures and their extension to chromosomally located targets hold much promise for the exploitation of gene targeting in a wide range of medically and economically important insect species. PMID:11513755

Subjective neighborhood assessment and physical inactivity: An examination of neighborhood-level variance.

PubMed

Prochaska, John D; Buschmann, Robert N; Jupiter, Daniel; Mutambudzi, Miriam; Peek, M Kristen

2018-06-01

Research suggests a linkage between perceptions of neighborhood quality and the likelihood of engaging in leisure-time physical activity. Often in these studies, intra-neighborhood variance is viewed as something to be controlled for statistically. However, we hypothesized that intra-neighborhood variance in perceptions of neighborhood quality may be contextually relevant. We examined the relationship between intra-neighborhood variance of subjective neighborhood quality and neighborhood-level reported physical inactivity across 48 neighborhoods within a medium-sized city, Texas City, Texas using survey data from 2706 residents collected between 2004 and 2006. Neighborhoods where the aggregated perception of neighborhood quality was poor also had a larger proportion of residents reporting being physically inactive. However, higher degrees of disagreement among residents within neighborhoods about their neighborhood quality was significantly associated with a lower proportion of residents reporting being physically inactive (p=0.001). Our results suggest that intra-neighborhood variability may be contextually relevant in studies seeking to better understand the relationship between neighborhood quality and behaviors sensitive to neighborhood environments, like physical activity. Copyright © 2017 Elsevier Inc. All rights reserved.

Defining Neighborhood Boundaries for Urban Health Research

PubMed Central

Weiss, Linda; Ompad, Danielle; Galea, Sandro; Vlahov, David

2008-01-01

The body of literature exploring neighborhood effects on health has increased rapidly in recent years, yet a number of methodological concerns remain, including preferred methods for identification and delineation of study neighborhoods. In research combining census or other publicly available data with surveys of residents and/or street-level observations, questions regarding neighborhood definition take on added significance. Neighborhoods must be identified and delineated in such a way as to optimize quality and availability of data from each of these sources. IMPACT, a multi-level study examining associations between features of the urban environment and mental health, drug use, and sexual behavior, utilized a multi-step neighborhood definition process including development of census block group maps, review of land use and census tract data, and field visits and observation in each of the targeted communities. Field observations were guided by a pre-identified list of environmental features focused on the potential for recruitment (e.g. pedestrian volume); characteristics commonly used to define neighborhood boundaries (e.g. obstructions to pedestrian traffic, changes in land use), and characteristics that have been associated in the literature with health behaviors and health outcomes (such as housing type, maintenance and use of open spaces). This process, implemented in February through July 2005, proved feasible and offered the opportunity to identify neighborhoods appropriate to study objectives and to collect descriptive information that can be used as a context for understanding study results. PMID:17543706

The Mechanism of Gene Targeting in Human Somatic Cells

PubMed Central

Kan, Yinan; Ruis, Brian; Lin, Sherry; Hendrickson, Eric A.

2014-01-01

Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells. PMID:24699519

Simple Monitoring of Gene Targeting Efficiency in Human Somatic Cell Lines Using the PIGA Gene

PubMed Central

Karnan, Sivasundaram; Konishi, Yuko; Ota, Akinobu; Takahashi, Miyuki; Damdindorj, Lkhagvasuren; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2012-01-01

Gene targeting in most of human somatic cell lines has been labor-intensive because of low homologous recombination efficiency. The development of an experimental system that permits a facile evaluation of gene targeting efficiency in human somatic cell lines is the first step towards the improvement of this technology and its application to a broad range of cell lines. In this study, we utilized phosphatidylinositol glycan anchor biosynthesis class A (PIGA), a gene essential for the synthesis of glycosylphosphatidyl inositol (GPI) anchors, as a reporter of gene targeting events in human somatic cell lines. Targeted disruption of PIGA was quantitatively detected with FLAER, a reagent that specifically binds to GPI anchors. Using this PIGA-based reporter system, we successfully detected adeno-associated virus (AAV)-mediated gene targeting events both with and without promoter-trap enrichment of gene-targeted cell population. The PIGA-based reporter system was also capable of reproducing previous findings that an AAV-mediated gene targeting achieves a remarkably higher ratio of homologous versus random integration (H/R ratio) of targeting vectors than a plasmid-mediated gene targeting. The PIGA-based system also detected an approximately 2-fold increase in the H/R ratio achieved by a small negative selection cassette introduced at the end of the AAV-based targeting vector with a promoter-trap system. Thus, our PIGA-based system is useful for monitoring AAV-mediated gene targeting and will assist in improving gene targeting technology in human somatic cell lines. PMID:23056640

Neighborhood Influences on Vehicle-Pedestrian Crash Severity.

PubMed

Toran Pour, Alireza; Moridpour, Sara; Tay, Richard; Rajabifard, Abbas

2017-12-01

Socioeconomic factors are known to be contributing factors for vehicle-pedestrian crashes. Although several studies have examined the socioeconomic factors related to the location of the crashes, limited studies have considered the socioeconomic factors of the neighborhood where the road users live in vehicle-pedestrian crash modelling. This research aims to identify the socioeconomic factors related to both the neighborhoods where the road users live and where crashes occur that have an influence on vehicle-pedestrian crash severity. Data on vehicle-pedestrian crashes that occurred at mid-blocks in Melbourne, Australia, was analyzed. Neighborhood factors associated with road users' residents and location of crash were investigated using boosted regression tree (BRT). Furthermore, partial dependence plots were applied to illustrate the interactions between these factors. We found that socioeconomic factors accounted for 60% of the 20 top contributing factors to vehicle-pedestrian crashes. This research reveals that socioeconomic factors of the neighborhoods where the road users live and where the crashes occur are important in determining the severity of the crashes, with the former having a greater influence. Hence, road safety countermeasures, especially those focussing on the road users, should be targeted at these high-risk neighborhoods.

Incorporating Neighborhood Choice in a Model of Neighborhood Effects on Income.

PubMed

van Ham, Maarten; Boschman, Sanne; Vogel, Matt

2018-05-09

Studies of neighborhood effects often attempt to identify causal effects of neighborhood characteristics on individual outcomes, such as income, education, employment, and health. However, selection looms large in this line of research, and it has been argued that estimates of neighborhood effects are biased because people nonrandomly select into neighborhoods based on their preferences, income, and the availability of alternative housing. We propose a two-step framework to disentangle selection processes in the relationship between neighborhood deprivation and earnings. We model neighborhood selection using a conditional logit model, from which we derive correction terms. Driven by the recognition that most households prefer certain types of neighborhoods rather than specific areas, we employ a principle components analysis to reduce these terms into eight correction components. We use these to adjust parameter estimates from a model of subsequent neighborhood effects on individual income for the unequal probability that a household chooses to live in a particular type of neighborhood. We apply this technique to administrative data from the Netherlands. After we adjust for the differential sorting of households into certain types of neighborhoods, the effect of neighborhood income on individual income diminishes but remains significant. These results further emphasize that researchers need to be attuned to the role of selection bias when assessing the role of neighborhood effects on individual outcomes. Perhaps more importantly, the persistent effect of neighborhood deprivation on subsequent earnings suggests that neighborhood effects reflect more than the shared characteristics of neighborhood residents: place of residence partially determines economic well-being.

The effect of neighborhood disadvantage, social ties, and genetic variation on the antisocial behavior of African American women: A multilevel analysis

PubMed Central

LEI, MAN-KIT; SIMONS, RONALD L.; EDMOND, MARY BOND; SIMONS, LESLIE GORDON; CUTRONA, CAROLYN E.

2015-01-01

Social disorganization theory posits that individuals who live in disadvantaged neighborhoods are more likely to engage in antisocial behavior than are those who live in advantaged neighborhoods and that neighborhood disadvantage asserts this effect through its disruptive impact on social ties. Past research on this framework has been limited in two respects. First, most studies have concentrated on adolescent males. In contrast, the present study focused on a sample of adult African American females. Second, past research has largely ignored individual-level factors that might explain why people who grow up in disadvantaged neighborhoods often do not engage in antisocial behavior. We investigated the extent to which genetic variation contributes to heterogeneity of response to neighborhood conditions. We found that the impact of neighborhood disadvantage on antisocial behavior was mediated by neighborhood social ties. Further, the analysis indicated that the effects of neighborhood disadvantage and social ties on antisocial behavior were moderated by genetic polymorphisms. Examination of these moderating effects provided support for the differential susceptibility model of Gene×Environment. The effect of Gene×Neighborhood Disadvantage on antisocial behavior was mediated by the effect of Gene×Neighborhood Social Ties, providing support for an expanded view of social disorganization theory. PMID:24713449

The effect of neighborhood disadvantage, social ties, and genetic variation on the antisocial behavior of African American women: a multilevel analysis.

PubMed

Lei, Man-Kit; Simons, Ronald L; Edmond, Mary Bond; Simons, Leslie Gordon; Cutrona, Carolyn E

2014-11-01

Social disorganization theory posits that individuals who live in disadvantaged neighborhoods are more likely to engage in antisocial behavior than are those who live in advantaged neighborhoods and that neighborhood disadvantage asserts this effect through its disruptive impact on social ties. Past research on this framework has been limited in two respects. First, most studies have concentrated on adolescent males. In contrast, the present study focused on a sample of adult African American females. Second, past research has largely ignored individual-level factors that might explain why people who grow up in disadvantaged neighborhoods often do not engage in antisocial behavior. We investigated the extent to which genetic variation contributes to heterogeneity of response to neighborhood conditions. We found that the impact of neighborhood disadvantage on antisocial behavior was mediated by neighborhood social ties. Further, the analysis indicated that the effects of neighborhood disadvantage and social ties on antisocial behavior were moderated by genetic polymorphisms. Examination of these moderating effects provided support for the differential susceptibility model of Gene × Environment. The effect of Gene × Neighborhood Disadvantage on antisocial behavior was mediated by the effect of Gene × Neighborhood Social Ties, providing support for an expanded view of social disorganization theory.

Targeted gene flow for conservation.

PubMed

Kelly, Ella; Phillips, Ben L

2016-04-01

Anthropogenic threats often impose strong selection on affected populations, causing rapid evolutionary responses. Unfortunately, these adaptive responses are rarely harnessed for conservation. We suggest that conservation managers pay close attention to adaptive processes and geographic variation, with an eye to using them for conservation goals. Translocating pre-adapted individuals into recipient populations is currently considered a potentially important management tool in the face of climate change. Targeted gene flow, which involves moving individuals with favorable traits to areas where these traits would have a conservation benefit, could have a much broader application in conservation. Across a species' range there may be long-standing geographic variation in traits or variation may have rapidly developed in response to a threatening process. Targeted gene flow could be used to promote natural resistance to threats to increase species resilience. We suggest that targeted gene flow is a currently underappreciated strategy in conservation that has applications ranging from the management of invasive species and their impacts to controlling the impact and virulence of pathogens. © 2015 Society for Conservation Biology.

Active living neighborhoods: is neighborhood walkability a key element for Belgian adolescents?

PubMed

De Meester, Femke; Van Dyck, Delfien; De Bourdeaudhuij, Ilse; Deforche, Benedicte; Sallis, James F; Cardon, Greet

2012-01-04

In adult research, neighborhood walkability has been acknowledged as an important construct among the built environmental correlates of physical activity. Research into this association has only recently been extended to adolescents and the current empirical evidence is not consistent. This study investigated whether neighborhood walkability and neighborhood socioeconomic status (SES) are associated with physical activity among Belgian adolescents and whether the association between neighborhood walkability and physical activity is moderated by neighborhood SES and gender. In Ghent (Belgium), 32 neighborhoods were selected based on GIS-based walkability and SES derived from census data. In total, 637 adolescents (aged 13-15 year, 49.6% male) participated in the study. Physical activity was assessed using accelerometers and the Flemish Physical Activity Questionnaire. To analyze the associations between neighborhood walkability, neighborhood SES and individual physical activity, multivariate multi-level regression analyses were conducted. Only in low-SES neighborhoods, neighborhood walkability was positively associated with accelerometer-based moderate to vigorous physical activity and the average activity level expressed in counts/minute. For active transport to and from school, cycling for transport during leisure time and sport during leisure time no association with neighborhood walkability nor, with neighborhood SES was found. For walking for transport during leisure time a negative association with neighborhood SES was found. Gender did not moderate the associations of neighborhood walkability and SES with adolescent physical activity. Neighborhood walkability was related to accelerometer-based physical activity only among adolescent boys and girls living in low-SES neighborhoods. The relation of built environment to adolescent physical activity may depend on the context.

Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy

PubMed Central

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-01

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration. PMID:25606974

Bacteriophage-derived vectors for targeted cancer gene therapy.

PubMed

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-19

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration.

The impact of housing rehabilitation on local neighborhoods: the case of small community development organizations.

PubMed

Smith, Marvin M; Hevener, Christy Chung

2011-01-01

Across the nation, nonprofit organizations located in poor and declining neighborhoods are promoting homeownership in the hopes that their efforts will stave off decline and contribute to neighborhood stability. A common homeownership strategy among nonprofits is to acquire boarded-up or deteriorated homes at a low price, rehabilitate them, and then sell them at an affordable price. As these programs continue, nonprofit organizations want to show quantitatively that neighborhood revitalization works—that the funds devoted to an area stabilize neighborhoods or, even more, that they initiate a surge of continued upward progress. But, unlike their larger counterparts, smaller community development organizations are usually at a disadvantage in undertaking such an evaluation. This study will help illustrate what might be done. It focuses on the case of St. Joseph's Carpenter Society (SJCS) in Camden, New Jersey and assesses the quantitative impact that SJCS has on its target neighborhoods. A three-tiered approach is adopted that ranges from a target and comparison area analysis, to regression analysis of SJCS's impact on local housing prices, and finally to an examination of the relative market performance of SJCS's houses. All told, the analysis suggests that SJCS's rehabilitation and homeownership education activities appear to have a positive influence on the neighborhoods in its target area.

Active living neighborhoods: is neighborhood walkability a key element for Belgian adolescents?

PubMed Central

2012-01-01

Background In adult research, neighborhood walkability has been acknowledged as an important construct among the built environmental correlates of physical activity. Research into this association has only recently been extended to adolescents and the current empirical evidence is not consistent. This study investigated whether neighborhood walkability and neighborhood socioeconomic status (SES) are associated with physical activity among Belgian adolescents and whether the association between neighborhood walkability and physical activity is moderated by neighborhood SES and gender. Methods In Ghent (Belgium), 32 neighborhoods were selected based on GIS-based walkability and SES derived from census data. In total, 637 adolescents (aged 13-15 year, 49.6% male) participated in the study. Physical activity was assessed using accelerometers and the Flemish Physical Activity Questionnaire. To analyze the associations between neighborhood walkability, neighborhood SES and individual physical activity, multivariate multi-level regression analyses were conducted. Results Only in low-SES neighborhoods, neighborhood walkability was positively associated with accelerometer-based moderate to vigorous physical activity and the average activity level expressed in counts/minute. For active transport to and from school, cycling for transport during leisure time and sport during leisure time no association with neighborhood walkability nor, with neighborhood SES was found. For walking for transport during leisure time a negative association with neighborhood SES was found. Gender did not moderate the associations of neighborhood walkability and SES with adolescent physical activity. Conclusions Neighborhood walkability was related to accelerometer-based physical activity only among adolescent boys and girls living in low-SES neighborhoods. The relation of built environment to adolescent physical activity may depend on the context. PMID:22216923

Neighborhood Jams.

ERIC Educational Resources Information Center

Zingher, Gary

1995-01-01

Examines the role of the neighborhood in books for children and young adults. Discusses community characteristics, historical fiction, "special and scary places," neighborhoods in conflict and harmony, and the neighborhood as a memory base. Presents activities including animated maps, games, murals, small group dramas, and storytelling.…

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

Hazardous Waste Site Remediation, Neighborhood Change, and Neighborhood Quality.

PubMed Central

Greenberg, M; Schneider, D

1994-01-01

We tested the hypothesis that neighborhoods with hazardous waste sites may no longer be undesirable places to live if they have been at least partly remediated. We collected 377 questionnaires (42% response rate) administered from within one-half mile of the number 1, 4, and 12 hazardous waste sites on the National Priority List (Superfund). These neighborhoods were rated higher quality than neighborhoods with unremediated hazardous waste sites and about the same as neighborhoods in northern New Jersey and the United States as a whole. Newer residents considered these formerly tainted areas to be opportunities to upgrade their housing and living conditions. Long-term residents retained the negative image of the blemished neighborhood. Images p542-a PMID:9679112

Positive Neighborhood Norms Buffer Ethnic Diversity Effects on Neighborhood Dissatisfaction, Perceived Neighborhood Disadvantage, and Moving Intentions.

PubMed

Van Assche, Jasper; Asbrock, Frank; Roets, Arne; Kauff, Mathias

2018-05-01

Positive neighborhood norms, such as strong local networks, are critical to people's satisfaction with, perceived disadvantage of, and intentions to stay in their neighborhood. At the same time, local ethnic diversity is said to be detrimental for these community outcomes. Integrating both frameworks, we tested whether the negative consequences of diversity occur even when perceived social norms are positive. Study 1 ( N = 1,760 German adults) showed that perceptions of positive neighborhood norms buffered against the effects of perceived diversity on moving intentions via neighborhood satisfaction and perceived neighborhood disadvantage. Study 2 ( N = 993 Dutch adults) replicated and extended this moderated mediation model using other characteristics of diversity (i.e., objective and estimated minority proportions). Multilevel analyses again revealed consistent buffering effects of positive neighborhood norms. Our findings are discussed in light of the ongoing public and political debate concerning diversity and social and communal life.

Challenges and complications in neighborhood mapping: from neighborhood concept to operationalization

NASA Astrophysics Data System (ADS)

Deng, Yongxin

2016-07-01

This paper examines complications in neighborhood mapping and corresponding challenges for the GIS community, taking both a conceptual and a methodological perspective. It focuses on the social and spatial dimensions of the neighborhood concept and highlights their relationship in neighborhood mapping. Following a brief summary of neighborhood definitions, five interwoven factors are identified to be origins of neighborhood mapping difficulties: conceptual vagueness, uncertainty of various sources, GIS representation, scale, and neighborhood homogeneity or continuity. Existing neighborhood mapping methods are grouped into six categories to be assessed: perception based, physically based, inference based, preexisting, aggregated, and automated. Mapping practices in various neighborhood-related disciplines and applications are cited as examples to demonstrate how the methods work, as well as how they should be evaluated. A few mapping strategies for the improvement of neighborhood mapping are prescribed from a GIS perspective: documenting simplifications employed in the mapping procedure, addressing uncertainty sources, developing new data solutions, and integrating complementary mapping methods. Incorporation of high-resolution data and introduction of more GIS ideas and methods (such as fuzzy logic) are identified to be future opportunities.

Examination of the neighborhood activation theory in normal and hearing-impaired listeners.

PubMed

Dirks, D D; Takayanagi, S; Moshfegh, A; Noffsinger, P D; Fausti, S A

2001-02-01

Experiments were conducted to examine the effects of lexical information on word recognition among normal hearing listeners and individuals with sensorineural hearing loss. The lexical factors of interest were incorporated in the Neighborhood Activation Model (NAM). Central to this model is the concept that words are recognized relationally in the context of other phonemically similar words. NAM suggests that words in the mental lexicon are organized into similarity neighborhoods and the listener is required to select the target word from competing lexical items. Two structural characteristics of similarity neighborhoods that influence word recognition have been identified; "neighborhood density" or the number of phonemically similar words (neighbors) for a particular target item and "neighborhood frequency" or the average frequency of occurrence of all the items within a neighborhood. A third lexical factor, "word frequency" or the frequency of occurrence of a target word in the language, is assumed to optimize the word recognition process by biasing the system toward choosing a high frequency over a low frequency word. Three experiments were performed. In the initial experiments, word recognition for consonant-vowel-consonant (CVC) monosyllables was assessed in young normal hearing listeners by systematically partitioning the items into the eight possible lexical conditions that could be created by two levels of the three lexical factors, word frequency (high and low), neighborhood density (high and low), and average neighborhood frequency (high and low). Neighborhood structure and word frequency were estimated computationally using a large, on-line lexicon-based Webster's Pocket Dictionary. From this program 400 highly familiar, monosyllables were selected and partitioned into eight orthogonal lexical groups (50 words/group). The 400 words were presented randomly to normal hearing listeners in speech-shaped noise (Experiment 1) and "in quiet" (Experiment 2) as

Generation of novel resistance genes using mutation and targeted gene editing.

PubMed

Gal-On, Amit; Fuchs, Marc; Gray, Stewart

2017-10-01

Classical breeding for virus resistance is a lengthy process and is restricted by the availability of resistance genes. Precise genome editing is a 'dream technology' to improve plants for virus resistance and these tools have opened new and very promising ways to generate virus resistant plants by disrupting host susceptibility genes, or by increasing the expression of viral resistance genes. However, precise targets must be identified and their roles understood to minimize potential negative effects on the plant. Nonetheless, the opportunities for genome editing are expanding, as are the technologies to generate effective and broad-spectrum resistance against plant viruses. Here we provide insights into recent progress related to gene targets and gene editing technologies. Published by Elsevier B.V.

Core Promoter Functions in the Regulation of Gene Expression of Drosophila Dorsal Target Genes*

PubMed Central

Zehavi, Yonathan; Kuznetsov, Olga; Ovadia-Shochat, Avital; Juven-Gershon, Tamar

2014-01-01

Developmental processes are highly dependent on transcriptional regulation by RNA polymerase II. The RNA polymerase II core promoter is the ultimate target of a multitude of transcription factors that control transcription initiation. Core promoters consist of core promoter motifs, e.g. the initiator, TATA box, and the downstream core promoter element (DPE), which confer specific properties to the core promoter. Here, we explored the importance of core promoter functions in the dorsal-ventral developmental gene regulatory network. This network includes multiple genes that are activated by different nuclear concentrations of Dorsal, an NFκB homolog transcription factor, along the dorsal-ventral axis. We show that over two-thirds of Dorsal target genes contain DPE sequence motifs, which is significantly higher than the proportion of DPE-containing promoters in Drosophila genes. We demonstrate that multiple Dorsal target genes are evolutionarily conserved and functionally dependent on the DPE. Furthermore, we have analyzed the activation of key Dorsal target genes by Dorsal, as well as by another Rel family transcription factor, Relish, and the dependence of their activation on the DPE motif. Using hybrid enhancer-promoter constructs in Drosophila cells and embryo extracts, we have demonstrated that the core promoter composition is an important determinant of transcriptional activity of Dorsal target genes. Taken together, our results provide evidence for the importance of core promoter composition in the regulation of Dorsal target genes. PMID:24634215

In Situ Gene Therapy via AAV-CRISPR-Cas9-Mediated Targeted Gene Regulation.

PubMed

Moreno, Ana M; Fu, Xin; Zhu, Jie; Katrekar, Dhruva; Shih, Yu-Ru V; Marlett, John; Cabotaje, Jessica; Tat, Jasmine; Naughton, John; Lisowski, Leszek; Varghese, Shyni; Zhang, Kang; Mali, Prashant

2018-04-25

Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice. We also applied our platform for targeted in vivo gene-repression-mediated gene therapy for retinitis pigmentosa. Specifically, we engineered targeted repression of Nrl, a master regulator of rod photoreceptor determination, and demonstrated Nrl knockdown mediates in situ reprogramming of rod cells into cone-like cells that are resistant to retinitis pigmentosa-specific mutations, with concomitant prevention of secondary cone loss. Furthermore, we benchmarked our results from Nrl knockdown with those from in vivo Nrl knockout via gene editing. Taken together, our AAV-CRISPR-Cas9 platform for in vivo epigenome engineering enables a robust approach to target disease in a genomically scarless and potentially reversible manner. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Perceptions as the crucial link? The mediating role of neighborhood perceptions in the relationship between the neighborhood context and neighborhood cohesion.

PubMed

Laméris, Joran; Hipp, John R; Tolsma, Jochem

2018-05-01

This study examines the effects of neighborhood racial in-group size, economic deprivation and the prevalence of crime on neighborhood cohesion among U.S. whites. We explore to what extent residents' perceptions of their neighborhood mediate these macro-micro relationships. We use a recent individual-level data set, the American Social Fabric Study (2012/2013), enriched with contextual-level data from the U.S. Census Bureau (2010) and employ multi-level structural equation models. We show that the racial in-group size is positively related to neighborhood cohesion and that neighborhood cohesion is lower in communities with a high crime rate. Individuals' perceptions of the racial in-group size partly mediate the relationship between the objective racial in-group size and neighborhood cohesion. Residents' perceptions of unsafety from crime also appear to be a mediating factor, not only for the objective crime rate but also for the objective racial in-group size. This is in line with our idea that racial stereotypes link racial minorities to crime whereby neighborhoods with a large non-white population are perceived to be more unsafe. Residents of the same neighborhood differ in how they perceive the degree of economic decay of the neighborhood and this causes them to evaluate neighborhood cohesion differently, however perceptions of neighborhood economic decay do not explain the link between the objective neighborhood context and neighborhood cohesion. Copyright © 2018. Published by Elsevier Inc.

Problem-Solving Test: Targeted Gene Disruption

ERIC Educational Resources Information Center

Szeberenyi, Jozsef

2008-01-01

Mutational inactivation of a specific gene is the most powerful technique to analyze the biological function of the gene. This approach has been used for a long time in viruses, bacteria, yeast, and fruit fly, but looked quite hopeless in more complex organisms. Targeted inactivation of specific genes (also known as knock-out mutation) in mice is…

Neighborhood solutions for neighborhood problems: an empirically based violence prevention collaboration.

PubMed

Randall, J; Swenson, C C; Henggeler, S W

1999-12-01

Youth antisocial behavior is influenced, in part, by neighborhood context. Yet, rather than attempting to ameliorate factors contributing to youth antisocial behavior, service dollars are primarily devoted to expensive and often ineffective out-of-home placements. This article describes the development and implementation of a collaborative partnership designed to empower an economically disadvantaged neighborhood to address violent criminal behavior, substance abuse, and other serious antisocial problems of its youth while maintaining youth in the neighborhood. Through a collaboration between a university research center and neighborhood stakeholders, services are being provided to address the key priorities identified by neighborhood residents, and extensive efforts are being made to develop family and neighborhood contexts that are conducive to prosocial youth behavior.

Specific c-Jun target genes in malignant melanoma.

PubMed

Schummer, Patrick; Kuphal, Silke; Vardimon, Lily; Bosserhoff, Anja K; Kappelmann, Melanie

2016-05-03

A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.

Ghettoizing outdoor advertising: disadvantage and ad panel density in black neighborhoods.

PubMed

Kwate, Naa Oyo A; Lee, Tammy H

2007-01-01

This study investigated correlates of outdoor advertising panel density in predominantly African American neighborhoods in New York City. Research shows that black neighborhoods have more outdoor advertising space than white neighborhoods, and these spaces disproportionately market alcohol and tobacco advertisements. Thus, understanding the factors associated with outdoor advertising panel density has important implications for public health. We linked 2000 census data with property data at the census block group level to investigate two neighborhood-level determinants of ad density: income level and physical decay. Results showed that block groups were exposed to an average of four ad spaces per 1,000 residents and that vacant lot square footage was a significant positive predictor of ad density. An inverse relationship between median household income and ad density did not reach significance, suggesting that relative affluence did not protect black neighborhoods from being targeted for outdoor advertisements.

Ghettoizing Outdoor Advertising: Disadvantage and Ad Panel Density in Black Neighborhoods

PubMed Central

Lee, Tammy H.

2006-01-01

This study investigated correlates of outdoor advertising panel density in predominantly African American neighborhoods in New York City. Research shows that black neighborhoods have more outdoor advertising space than white neighborhoods, and these spaces disproportionately market alcohol and tobacco advertisements. Thus, understanding the factors associated with outdoor advertising panel density has important implications for public health. We linked 2000 census data with property data at the census block group level to investigate two neighborhood-level determinants of ad density: income level and physical decay. Results showed that block groups were exposed to an average of four ad spaces per 1,000 residents and that vacant lot square footage was a significant positive predictor of ad density. An inverse relationship between median household income and ad density did not reach significance, suggesting that relative affluence did not protect black neighborhoods from being targeted for outdoor advertisements. PMID:17146710

Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression

PubMed Central

Abruzzi, Katharine Compton; Rodriguez, Joseph; Menet, Jerome S.; Desrochers, Jennifer; Zadina, Abigail; Luo, Weifei; Tkachev, Sasha; Rosbash, Michael

2011-01-01

CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4–6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in prior RNA cycling studies. This is due in part to different RNA isoforms and to fly head tissue heterogeneity. CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation. PMID:22085964

Cross-lingual neighborhood effects in generalized lexical decision and natural reading.

PubMed

Dirix, Nicolas; Cop, Uschi; Drieghe, Denis; Duyck, Wouter

2017-06-01

The present study assessed intra- and cross-lingual neighborhood effects, using both a generalized lexical decision task and an analysis of a large-scale bilingual eye-tracking corpus (Cop, Dirix, Drieghe, & Duyck, 2016). Using new neighborhood density and frequency measures, the general lexical decision task yielded an inhibitory cross-lingual neighborhood density effect on reading times of second language words, replicating van Heuven, Dijkstra, and Grainger (1998). Reaction times for native language words were not influenced by neighborhood density or frequency but error rates showed cross-lingual neighborhood effects depending on target word frequency. The large-scale eye movement corpus confirmed effects of cross-lingual neighborhood on natural reading, even though participants were reading a novel in a unilingual context. Especially second language reading and to a lesser extent native language reading were influenced by lexical candidates from the nontarget language, although these effects in natural reading were largely facilitatory. These results offer strong and direct support for bilingual word recognition models that assume language-independent lexical access. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

STAT3 or USF2 Contributes to HIF Target Gene Specificity

PubMed Central

Pawlus, Matthew R.; Wang, Liyi; Murakami, Aya; Dai, Guanhai; Hu, Cheng-Jun

2013-01-01

The HIF1- and HIF2-mediated transcriptional responses play critical roles in solid tumor progression. Despite significant similarities, including their binding to promoters of both HIF1 and HIF2 target genes, HIF1 and HIF2 proteins activate unique subsets of target genes under hypoxia. The mechanism for HIF target gene specificity has remained unclear. Using siRNA or inhibitor, we previously reported that STAT3 or USF2 is specifically required for activation of endogenous HIF1 or HIF2 target genes. In this study, using reporter gene assays and chromatin immuno-precipitation, we find that STAT3 or USF2 exhibits specific binding to the promoters of HIF1 or HIF2 target genes respectively even when over-expressed. Functionally, HIF1α interacts with STAT3 to activate HIF1 target gene promoters in a HIF1α HLH/PAS and N-TAD dependent manner while HIF2α interacts with USF2 to activate HIF2 target gene promoters in a HIF2α N-TAD dependent manner. Physically, HIF1α HLH and PAS domains are required for its interaction with STAT3 while both N- and C-TADs of HIF2α are involved in physical interaction with USF2. Importantly, addition of functional USF2 binding sites into a HIF1 target gene promoter increases the basal activity of the promoter as well as its response to HIF2+USF2 activation while replacing HIF binding site with HBS from a HIF2 target gene does not change the specificity of the reporter gene. Importantly, RNA Pol II on HIF1 or HIF2 target genes is primarily associated with HIF1α or HIF2α in a STAT3 or USF2 dependent manner. Thus, we demonstrate here for the first time that HIF target gene specificity is achieved by HIF transcription partners that are required for HIF target gene activation, exhibit specific binding to the promoters of HIF1 or HIF2 target genes and selectively interact with HIF1α or HIF2α protein. PMID:23991099

Improving Mental Health Through the Regeneration of Deprived Neighborhoods: A Natural Experiment

PubMed Central

White, James; Greene, Giles; Farewell, Daniel; Dunstan, Frank; Rodgers, Sarah; Lyons, Ronan A.; Humphreys, Ioan; John, Ann; Webster, Chris; Phillips, Ceri J.; Fone, David

2017-01-01

Abstract Neighborhood-level interventions provide an opportunity to better understand the impact of neighborhoods on health. In 2001, the Welsh Government, United Kingdom, funded Communities First, a program of neighborhood regeneration delivered to the 100 most deprived of the 881 electoral wards in Wales. In this study, we examined the association between neighborhood regeneration and mental health. Information on regeneration activities in 35 intervention areas (n = 4,197 subjects) and 75 control areas (n = 6,695 subjects) was linked to data on mental health from a cohort study with assessments made in 2001 (before regeneration) and 2008 (after regeneration). Propensity score matching was used to estimate the change in mental health in intervention neighborhoods versus control neighborhoods. Baseline differences between intervention and control areas were of similar magnitude as produced by paired randomization of neighborhoods. Regeneration was associated with an improvement in the mental health of residents in intervention areas compared with control neighborhoods (β = 1.54, 95% confidence interval: 0.50, 2.59), suggesting a reduction in socioeconomic inequalities in mental health. There was a dose-response relationship between length of residence in regeneration neighborhoods and improvements in mental health (P-trend = 0.05). These results show that targeted regeneration of deprived neighborhoods can improve mental health. PMID:28486637

Multi-targeted priming for genome-wide gene expression assays.

PubMed

Adomas, Aleksandra B; Lopez-Giraldez, Francesc; Clark, Travis A; Wang, Zheng; Townsend, Jeffrey P

2010-08-17

Complementary approaches to assaying global gene expression are needed to assess gene expression in regions that are poorly assayed by current methodologies. A key component of nearly all gene expression assays is the reverse transcription of transcribed sequences that has traditionally been performed by priming the poly-A tails on many of the transcribed genes in eukaryotes with oligo-dT, or by priming RNA indiscriminately with random hexamers. We designed an algorithm to find common sequence motifs that were present within most protein-coding genes of Saccharomyces cerevisiae and of Neurospora crassa, but that were not present within their ribosomal RNA or transfer RNA genes. We then experimentally tested whether degenerately priming these motifs with multi-targeted primers improved the accuracy and completeness of transcriptomic assays. We discovered two multi-targeted primers that would prime a preponderance of genes in the genomes of Saccharomyces cerevisiae and Neurospora crassa while avoiding priming ribosomal RNA or transfer RNA. Examining the response of Saccharomyces cerevisiae to nitrogen deficiency and profiling Neurospora crassa early sexual development, we demonstrated that using multi-targeted primers in reverse transcription led to superior performance of microarray profiling and next-generation RNA tag sequencing. Priming with multi-targeted primers in addition to oligo-dT resulted in higher sensitivity, a larger number of well-measured genes and greater power to detect differences in gene expression. Our results provide the most complete and detailed expression profiles of the yeast nitrogen starvation response and N. crassa early sexual development to date. Furthermore, our multi-targeting priming methodology for genome-wide gene expression assays provides selective targeting of multiple sequences and counter-selection against undesirable sequences, facilitating a more complete and precise assay of the transcribed sequences within the genome.

Fe₃O₄ Nanoparticles in Targeted Drug/Gene Delivery Systems.

PubMed

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-02-23

Fe₃O₄ nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe₃O₄ NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe₃O₄ NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe₃O₄ NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe₃O₄ NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe₃O₄ NPs targeting drug/gene delivery systems.

Framing Ethnic Variations in Alcohol Outcomes from Biological Pathways to Neighborhood Context

PubMed Central

Chartier, Karen G.; Scott, Denise M.; Wall, Tamara L.; Covault, Jonathan; Karriker-Jaffe, Katherine J.; Mills, Britain A.; Luczak, Susan E.; Caetano, Raul; Arroyo, Judith A.

2013-01-01

Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. Those discussed are: 1) biological pathways to alcohol problems, 2) gene by stress interactions, 3) neighborhood disadvantage, stress, and access to alcohol, and 4) drinking cultures and contexts. These factors and their interrelationships are complex, requiring a multi-level perspective. The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multi-level research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. PMID:24483624

BLISTER Regulates Polycomb-Target Genes, Represses Stress-Regulated Genes and Promotes Stress Responses in Arabidopsis thaliana.

PubMed

Kleinmanns, Julia A; Schatlowski, Nicole; Heckmann, David; Schubert, Daniel

2017-01-01

HIGHLIGHTS The PRC2 interacting protein BLISTER likely acts downstream of PRC2 to silence Polycomb target genes and is a key regulator of specific stress responses in Arabidopsis . Polycomb group (PcG) proteins are key epigenetic regulators of development. The highly conserved Polycomb repressive complex 2 (PRC2) represses thousands of target genes by trimethylating H3K27 (H3K27me3). Plant specific PcG components and functions are largely unknown, however, we previously identified the plant-specific protein BLISTER (BLI) as a PRC2 interactor. BLI regulates PcG target genes and promotes cold stress resistance. To further understand the function of BLI , we analyzed the transcriptional profile of bli-1 mutants. Approximately 40% of the up-regulated genes in bli are PcG target genes, however, bli-1 mutants did not show changes in H3K27me3 levels at all tested genes, indicating that BLI regulates PcG target genes downstream of or in parallel to PRC2. Interestingly, a significant number of BLI regulated H3K27me3 target genes is regulated by the stress hormone absciscic acid (ABA). We further reveal an overrepresentation of genes responding to abiotic stresses such as drought, high salinity, or heat stress among the up-regulated genes in bli mutants. Consistently, bli mutants showed reduced desiccation stress tolerance. We conclude that the PRC2 associated protein BLI is a key regulator of stress-responsive genes in Arabidopsis : it represses ABA-responsive PcG target genes, likely downstream of PRC2, and promotes resistance to several stresses such as cold and drought.

Progress in gene targeting and gene therapy for retinitis pigmentosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farrar, G.J.; Humphries, M.M.; Erven, A.

1994-09-01

Previously, we localized disease genes involved in retinitis pigmentosa (RP), an inherited retinal degeneration, close to the rhodopsin and peripherin genes on 3q and 6p. Subsequently, we and others identified mutations in these genes in RP patients. Currently animal models for human retinopathies are being generated using gene targeting by homologous recombination in embryonic stem (ES) cells. Genomic clones for retinal genes including rhodopsin and peripherin have been obtained from a phage library carrying mouse DNA isogenic with the ES cell line (CC1.2). The peripherin clone has been sequenced to establish the genomic structure of the mouse gene. Targeting vectorsmore » for rhodopsin and peripherin including a neomycin cassette for positive selection and thymidine kinase genes enabling selection against random intergrants are under construction. Progress in vector construction will be presented. Simultaneously we are developing systems for delivery of gene therapies to retinal tissues utilizing replication-deficient adenovirus (Ad5). Efficacy of infection subsequent to various methods of intraocular injection and with varying viral titers is being assayed using an adenovirus construct containing a CMV promoter LacZ fusion as reporter and the range of tissues infected and the level of duration of LacZ expression monitored. Viral constructs with the LacZ reporter gene under the control of retinal specific promoters such as rhodopsin and IRBP cloned into pXCJL.1 are under construction. An update on developments in photoreceptor cell-directed expression of virally delivered genes will be presented.« less

Large scale RNAi screen in Tribolium reveals novel target genes for pest control and the proteasome as prime target.

PubMed

Ulrich, Julia; Dao, Van Anh; Majumdar, Upalparna; Schmitt-Engel, Christian; Schwirz, Jonas; Schultheis, Dorothea; Ströhlein, Nadi; Troelenberg, Nicole; Grossmann, Daniela; Richter, Tobias; Dönitz, Jürgen; Gerischer, Lizzy; Leboulle, Gérard; Vilcinskas, Andreas; Stanke, Mario; Bucher, Gregor

2015-09-03

Insect pest control is challenged by insecticide resistance and negative impact on ecology and health. One promising pest specific alternative is the generation of transgenic plants, which express double stranded RNAs targeting essential genes of a pest species. Upon feeding, the dsRNA induces gene silencing in the pest resulting in its death. However, the identification of efficient RNAi target genes remains a major challenge as genomic tools and breeding capacity is limited in most pest insects impeding whole-animal-high-throughput-screening. We use the red flour beetle Tribolium castaneum as a screening platform in order to identify the most efficient RNAi target genes. From about 5,000 randomly screened genes of the iBeetle RNAi screen we identify 11 novel and highly efficient RNAi targets. Our data allowed us to determine GO term combinations that are predictive for efficient RNAi target genes with proteasomal genes being most predictive. Finally, we show that RNAi target genes do not appear to act synergistically and that protein sequence conservation does not correlate with the number of potential off target sites. Our results will aid the identification of RNAi target genes in many pest species by providing a manageable number of excellent candidate genes to be tested and the proteasome as prime target. Further, the identified GO term combinations will help to identify efficient target genes from organ specific transcriptomes. Our off target analysis is relevant for the sequence selection used in transgenic plants.

Genotoxic chemical carcinogens target inducible genes in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamilton, J.W.; McCaffrey, J.; Caron, R.M.

1994-12-31

Our laboratory is interested in whether carcinogen-induced DNA damage is distributed nonrandomly in the genome - that is, {open_quotes}targeted{close_quotes} to specific genes or gene regions in vivo. As an indirect measure of whether targeting occurs at the gene level, we have examined whether carcinogens differentially alter the expression of individual genes. We have compared the effects of model genotoxic carcinogens that principally induce either strand breaks, simple alkylations, bulky lesions, or DNA cross-links on the expression of several constitutive and inducible genes in a simple in vivo system, the chick embryo. Each agent was examined for its effects on genemore » expression over a 24 hour period corresponding to the period of maximal DNA damage and repair induced by each compound. The doses used in these studies represented the maximum doses that caused no overt toxicity over a 96 hour period but that induced significant levels of DNA damage. Our results demonstrate that inducible genes are targeted by chemical carcinogens. We hypothesize that such effects may be a result of DNA damage specifically altering DNA-protein interactions within the promoters of inducible genes.« less

Poor neighborhoods: safe playgrounds.

PubMed

Powell, Elizabeth C; Ambardekar, Erin J; Sheehan, Karen M

2005-09-01

Although unstructured physical play is helpful to child development and physical activity is important to obesity prevention, up-to-date information about playgrounds and playground hazards in urban areas is limited. Local data are needed to identify problems and target interventions. The aim of this study was to describe the hazards in playgrounds located in low-income (median dollars 28,728-38,915) and very low-income (median dollars 18,266-18,955) Chicago neighborhoods. Using a standardized on-site survey (National Program for Playground Safety), two investigators reviewed seventy-eight public playgrounds for hazards related to playground design, safe surfaces, supervision, and equipment design and maintenance. The design of 56 playgrounds (72%) posed no hazards. One playground lacked protection from motor vehicles, and 21 had minor flaws. One playground had an asphalt surface; all others had protective surfaces, usually wood chips. The chips were too thin in many places, and in 15 playgrounds (19%), at least one concrete footing was exposed. Trash was a common surface hazard (68%). Although most equipment was safe (swings of soft materials and appropriate platform barriers), many pieces needed repairs. Equipment maintenance hazards included gaps (44%) and missing (38%) or broken parts (35%). In 13 of 39 playgrounds (33%) where children were observed playing, one or more were unsupervised. Playgrounds in very low-income neighborhoods more often had trash in the fall zone and exposed footings (P<.01 for each); there were no differences between low and very low-income neighborhoods in playground design or equipment maintenance. We conclude that playgrounds in low-income Chicago neighborhoods are of good design and have appropriate surfaces. Needed improvements include attention to wood chip depth, the removal of trash from the fall zone, and equipment repairs. Greater adult supervision is warranted.

Perceptions of prominent neighborhood individuals regarding neighborhood factors and intimate partner violence.

PubMed

Yonas, Michael; Akers, Aletha Y; Burke, Jessica G; Chang, Judy C; Thomas, Alicia L; Thomas, Aletha L; O'Campo, Patricia

2011-04-01

Research addressing the impact of neighborhood factors on intimate partner violence (IPV) often lacks discussion of how and why such factors impact IPV. In order to address this gap, 16 prominent neighborhood individuals (PNI) from 4 low-income urban neighborhoods were asked to share through in-depth interviews their insights and perceptions of IPV as an issue in their neighborhoods, and the relationship between social and structural neighborhood-level factors and IPV. PNIs most often associated IPV with only physical violence. Several did not feel IPV was a significant issue in their neighborhood, confirming a lack of awareness and underreporting of IPV. However, other PNIs were able to speak of the relationship between IPV and neighborhood factors, including lack of opportunities for employment, vacant housing, trash management, lack of community awareness, and social capacity to act to address IPV. Results provide unique insights regarding the mechanisms linking neighborhood factors to IPV outcomes. These results contribute to a deeper understanding of contextual influences upon IPV, the development of tailored quantitative research and to the design of local multi-level public health IPV intervention and prevention efforts.

Improving Mental Health Through the Regeneration of Deprived Neighborhoods: A Natural Experiment.

PubMed

White, James; Greene, Giles; Farewell, Daniel; Dunstan, Frank; Rodgers, Sarah; Lyons, Ronan A; Humphreys, Ioan; John, Ann; Webster, Chris; Phillips, Ceri J; Fone, David

2017-08-15

Neighborhood-level interventions provide an opportunity to better understand the impact of neighborhoods on health. In 2001, the Welsh Government, United Kingdom, funded Communities First, a program of neighborhood regeneration delivered to the 100 most deprived of the 881 electoral wards in Wales. In this study, we examined the association between neighborhood regeneration and mental health. Information on regeneration activities in 35 intervention areas (n = 4,197 subjects) and 75 control areas (n = 6,695 subjects) was linked to data on mental health from a cohort study with assessments made in 2001 (before regeneration) and 2008 (after regeneration). Propensity score matching was used to estimate the change in mental health in intervention neighborhoods versus control neighborhoods. Baseline differences between intervention and control areas were of similar magnitude as produced by paired randomization of neighborhoods. Regeneration was associated with an improvement in the mental health of residents in intervention areas compared with control neighborhoods (β = 1.54, 95% confidence interval: 0.50, 2.59), suggesting a reduction in socioeconomic inequalities in mental health. There was a dose-response relationship between length of residence in regeneration neighborhoods and improvements in mental health (P-trend = 0.05). These results show that targeted regeneration of deprived neighborhoods can improve mental health. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Screening for microsatellite instability target genes in colorectal cancers

PubMed Central

Vilkki, S; Launonen, V; Karhu, A; Sistonen, P; Vastrik, I; Aaltonen, L

2002-01-01

Background: Defects in the DNA repair system lead to genetic instability because replication errors are not corrected. This type of genetic instability is a key event in the malignant progression of HNPCC and a subset of sporadic colon cancers and mutation rates are particularly high at short repetitive sequences. Somatic deletions of coding mononucleotide repeats have been detected, for example, in the TGFßRII and BAX genes, and recently many novel target genes for microsatellite instability (MSI) have been proposed. Novel target genes are likely to be discovered in the future. More data should be created on background mutation rates in MSI tumours to evaluate mutation rates observed in the candidate target genes. Methods: Mutation rates in 14 neutral intronic repeats were evaluated in MSI tumours. Bioinformatic searches combined with keywords related to cancer and tumour suppressor or CRC related gene homology were used to find new candidate MSI target genes. By comparison of mutation frequencies observed in intronic mononucleotide repeats versus exonic coding repeats of potential MSI target genes, the significance of the exonic mutations was estimated. Results: As expected, the length of an intronic mononucleotide repeat correlated positively with the number of slippages for both G/C and A/T repeats (p=0.0020 and p=0.0012, respectively). BRCA1, CtBP1, and Rb1 associated CtIP and other candidates were found in a bioinformatic search combined with keywords related to cancer. Sequencing showed a significantly increased mutation rate in the exonic A9 repeat of CtIP (25/109=22.9%) as compared with similar intronic repeats (p≤0.001). Conclusions: We propose a new candidate MSI target gene CtIP to be evaluated in further studies. PMID:12414815

CRISPR/Cas9-mediated gene targeting in Arabidopsis using sequential transformation.

PubMed

Miki, Daisuke; Zhang, Wenxin; Zeng, Wenjie; Feng, Zhengyan; Zhu, Jian-Kang

2018-05-17

Homologous recombination-based gene targeting is a powerful tool for precise genome modification and has been widely used in organisms ranging from yeast to higher organisms such as Drosophila and mouse. However, gene targeting in higher plants, including the most widely used model plant Arabidopsis thaliana, remains challenging. Here we report a sequential transformation method for gene targeting in Arabidopsis. We find that parental lines expressing the bacterial endonuclease Cas9 from the egg cell- and early embryo-specific DD45 gene promoter can improve the frequency of single-guide RNA-targeted gene knock-ins and sequence replacements via homologous recombination at several endogenous sites in the Arabidopsis genome. These heritable gene targeting can be identified by regular PCR. Our approach enables routine and fine manipulation of the Arabidopsis genome.

Identification of neuronal target genes for CCAAT/Enhancer Binding Proteins

PubMed Central

Kfoury, N.; Kapatos, G.

2009-01-01

CCAAT/Enhancer Binding Proteins (C/EBPs) play pivotal roles in development and plasticity of the nervous system. Identification of the physiological targets of C/EBPs (C/EBP target genes) should therefore provide insight into the underlying biology of these processes. We used unbiased genome-wide mapping to identify 115 C/EBPβ target genes in PC12 cells that include transcription factors, neurotransmitter receptors, ion channels, protein kinases and synaptic vesicle proteins. C/EBPβ binding sites were located primarily within introns, suggesting novel regulatory functions, and were associated with binding sites for other developmentally important transcription factors. Experiments using dominant negatives showed C/EBPβ to repress transcription of a subset of target genes. Target genes in rat brain were subsequently found to preferentially bind C/EBPα, β and δ. Analysis of the hippocampal transcriptome of C/EBPβ knockout mice revealed dysregulation of a high percentage of transcripts identified as C/EBP target genes. These results support the hypothesis that C/EBPs play non-redundant roles in the brain. PMID:19103292

Targeted gene therapy and cell reprogramming in Fanconi anemia

PubMed Central

Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

2014-01-01

Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. PMID:24859981

Demarcation of local neighborhoods to study relations between contextual factors and health

PubMed Central

2010-01-01

Background Several studies have highlighted the importance of collective social factors for population health. One of the major challenges is an adequate definition of the spatial units of analysis which present properties potentially related to the target outcomes. Political and administrative divisions of urban areas are the most commonly used definition, although they suffer limitations in their ability to fully express the neighborhoods as social and spatial units. Objective This study presents a proposal for defining the boundaries of local neighborhoods in Rio de Janeiro city. Local neighborhoods are constructed by means of aggregation of contiguous census tracts which are homogeneous regarding socioeconomic indicators. Methodology Local neighborhoods were created using the SKATER method (TerraView software). Criteria used for socioeconomic homogeneity were based on four census tract indicators (income, education, persons per household, and percentage of population in the 0-4-year age bracket) considering a minimum population of 5,000 people living in each local neighborhood. The process took into account the geographic boundaries between administrative neighborhoods (a political-administrative division larger than a local neighborhood, but smaller than a borough) and natural geographic barriers. Results The original 8,145 census tracts were collapsed into 794 local neighborhoods, distributed along 158 administrative neighborhoods. Local neighborhoods contained a mean of 10 census tracts, and there were an average of five local neighborhoods per administrative neighborhood. The local neighborhood units demarcated in this study are less socioeconomically heterogeneous than the administrative neighborhoods and provide a means for decreasing the well-known statistical variability of indicators based on census tracts. The local neighborhoods were able to distinguish between different areas within administrative neighborhoods, particularly in relation to squatter

Demarcation of local neighborhoods to study relations between contextual factors and health.

PubMed

Santos, Simone M; Chor, Dora; Werneck, Guilherme Loureiro

2010-06-29

Several studies have highlighted the importance of collective social factors for population health. One of the major challenges is an adequate definition of the spatial units of analysis which present properties potentially related to the target outcomes. Political and administrative divisions of urban areas are the most commonly used definition, although they suffer limitations in their ability to fully express the neighborhoods as social and spatial units. This study presents a proposal for defining the boundaries of local neighborhoods in Rio de Janeiro city. Local neighborhoods are constructed by means of aggregation of contiguous census tracts which are homogeneous regarding socioeconomic indicators. Local neighborhoods were created using the SKATER method (TerraView software). Criteria used for socioeconomic homogeneity were based on four census tract indicators (income, education, persons per household, and percentage of population in the 0-4-year age bracket) considering a minimum population of 5,000 people living in each local neighborhood. The process took into account the geographic boundaries between administrative neighborhoods (a political-administrative division larger than a local neighborhood, but smaller than a borough) and natural geographic barriers. The original 8,145 census tracts were collapsed into 794 local neighborhoods, distributed along 158 administrative neighborhoods. Local neighborhoods contained a mean of 10 census tracts, and there were an average of five local neighborhoods per administrative neighborhood.The local neighborhood units demarcated in this study are less socioeconomically heterogeneous than the administrative neighborhoods and provide a means for decreasing the well-known statistical variability of indicators based on census tracts. The local neighborhoods were able to distinguish between different areas within administrative neighborhoods, particularly in relation to squatter settlements. Although the literature on

The Effect of Neighborhood Recorded Crime on Fear: Does Neighborhood Social Context Matter?

PubMed

Pearson, Amber L; Breetzke, Gregory; Ivory, Vivienne

2015-09-01

A number of individual and neighborhood-level factors may influence the relationship between recorded crime in one's neighborhood and fear of crime. Understanding these factors may assist in reducing fear, which has been associated with poorer physical and mental health. The aim of this study was to evaluate whether the effect of recorded crime rates on fear differs based on the neighborhood social context (social fragmentation) using hierarchical regression modelling, with separate analyses by crime type. Recorded crimes (2008-2010) and national (New Zealand) survey data were used. Higher crime in a neighborhood was associated with higher fear of crime, with only small effect size differences in feelings of fear by recorded type of crime. However, when stratified, the associations between violent and drug/alcohol crimes and fear of crime were larger for those living in highly fragmented neighborhoods compared with less fragmented neighborhoods. Efforts to alleviate fear of crime should focus on the broader neighborhood social context in which these feelings are espoused.

Framing ethnic variations in alcohol outcomes from biological pathways to neighborhood context.

PubMed

Chartier, Karen G; Scott, Denise M; Wall, Tamara L; Covault, Jonathan; Karriker-Jaffe, Katherine J; Mills, Britain A; Luczak, Susan E; Caetano, Raul; Arroyo, Judith A

2014-03-01

Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. Those discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene × stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts. These factors and their interrelationships are complex, requiring a multilevel perspective. The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. Copyright © 2014 by the Research Society on Alcoholism.

[A mini-review of targeting gene-virotherapy of cancer].

PubMed

Liu, Xin-Yuan; Gu, Jin-Fa

2006-10-01

New progress has been made on the project "targeting gene-virotherapy of cancer" proposed by us, which is "targeting dual gene-virotherapy of cancer". By the use of two genes, all the xenograft tumors in nude mice could be completely eliminated. The researches have been published in international journals, such as Hepatology and Cancer Research (a highlight paper). In this study, a further superior strategy--"double targeting virus-dual gene therapy" was introduced. This strategy was specialized by the use of tumor specific promoter to control the tumor specific suppressor gene, such as alpha-fetoprotein (AFP), which controls hepatoma specific suppressor gene LFIRE or HCCS1. In addition, a second tumor specific promoter, such as hTERT or survivin was used to control E1A or E1B in the construct, as hTERT-E1A-AFP-E1B-HCCS1 or LFIRE, a double tumor specific promoter controlling hepatoma specific LFIRE or HCCS1 gene. By the combined use of this construct with a very strong antitumor construct, such as hTERT-E1A-AFP-E1B-IL-24, a strategy with both excellent tumor killing effect and excellent safety with very little damage to normal cells was obtained. Therefore, double targeting virus-dual gene therapy might be one of the most potential strategies for cancer treatment. Furthermore, a new type of interferon was also introduced, which might be an ideal antitumor drug.

PSAT: A web tool to compare genomic neighborhoods of multiple prokaryotic genomes

PubMed Central

Fong, Christine; Rohmer, Laurence; Radey, Matthew; Wasnick, Michael; Brittnacher, Mitchell J

2008-01-01

Background The conservation of gene order among prokaryotic genomes can provide valuable insight into gene function, protein interactions, or events by which genomes have evolved. Although some tools are available for visualizing and comparing the order of genes between genomes of study, few support an efficient and organized analysis between large numbers of genomes. The Prokaryotic Sequence homology Analysis Tool (PSAT) is a web tool for comparing gene neighborhoods among multiple prokaryotic genomes. Results PSAT utilizes a database that is preloaded with gene annotation, BLAST hit results, and gene-clustering scores designed to help identify regions of conserved gene order. Researchers use the PSAT web interface to find a gene of interest in a reference genome and efficiently retrieve the sequence homologs found in other bacterial genomes. The tool generates a graphic of the genomic neighborhood surrounding the selected gene and the corresponding regions for its homologs in each comparison genome. Homologs in each region are color coded to assist users with analyzing gene order among various genomes. In contrast to common comparative analysis methods that filter sequence homolog data based on alignment score cutoffs, PSAT leverages gene context information for homologs, including those with weak alignment scores, enabling a more sensitive analysis. Features for constraining or ordering results are designed to help researchers browse results from large numbers of comparison genomes in an organized manner. PSAT has been demonstrated to be useful for helping to identify gene orthologs and potential functional gene clusters, and detecting genome modifications that may result in loss of function. Conclusion PSAT allows researchers to investigate the order of genes within local genomic neighborhoods of multiple genomes. A PSAT web server for public use is available for performing analyses on a growing set of reference genomes through any web browser with no client

Towards β-globin gene-targeting with integrase-defective lentiviral vectors.

PubMed

Inanlou, Davoud Nouri; Yakhchali, Bagher; Khanahmad, Hossein; Gardaneh, Mossa; Movassagh, Hesam; Cohan, Reza Ahangari; Ardestani, Mehdi Shafiee; Mahdian, Reza; Zeinali, Sirous

2010-11-01

We have developed an integrase-defective lentiviral (LV) vector in combination with a gene-targeting approach for gene therapy of β-thalassemia. The β-globin gene-targeting construct has two homologous stems including sequence upstream and downstream of the β-globin gene, a β-globin gene positioned between hygromycin and neomycin resistant genes and a herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene. Utilization of integrase-defective LV as a vector for the β-globin gene increased the number of selected clones relative to non-viral methods. This method represents an important step toward the ultimate goal of a clinical gene therapy for β-thalassemia.

Targeted gene therapy and cell reprogramming in Fanconi anemia.

PubMed

Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

2014-06-01

Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity.

PubMed

Zhao, Qing-Qing; Hu, Yu-Lan; Zhou, Yang; Li, Ni; Han, Min; Tang, Gu-Ping; Qiu, Feng; Tabata, Yasuhiko; Gao, Jian-Qing

2012-01-01

The success of gene transfection is largely dependent on the development of a vehicle or vector that can efficiently deliver a gene to cells with minimal toxicity. A liver cancer-targeted specific peptide (FQHPSF sequence) was successfully synthesized and linked with chitosan-linked polyethylenimine (CP) to form a new targeted gene delivery vector called CPT (CP/peptide). The structure of CPT was confirmed by (1)H nuclear magnetic resonance spectroscopy and ultraviolet spectrophotometry. The particle size of CPT/ DNA complexes was measured using laser diffraction spectrometry and the cytotoxicity of the copolymer was evaluated by methylthiazol tetrazolium method. The transfection efficiency evaluation of the CP copolymer was performed using luciferase activity assay. Cellular internalization of the CP/DNA complex was observed under confocal laser scanning microscopy. The targeting specificity of the polymer coupled to peptide was measured by competitive inhibition transfection study. The liver targeting specificity of the CPT copolymer in vivo was demonstrated by combining the copolymer with a therapeutic gene, interleukin-12, and assessed by its abilities in suppressing the growth of ascites tumor in mouse model. The results showed that the liver cancer-targeted specific peptide was successfully synthesized and linked with CP to form a new targeted gene delivery vector called CPT. The composition of CPT was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa), CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer. The synthesized CPT copolymer was proven to be an effective liver cancer-targeted vector for therapeutic gene

Specific genetic modifications of domestic animals by gene targeting and animal cloning

PubMed Central

Wang, Bin; Zhou, Jiangfeng

2003-01-01

The technology of gene targeting through homologous recombination has been extremely useful for elucidating gene functions in mice. The application of this technology was thought impossible in the large livestock species until the successful creation of the first mammalian clone "Dolly" the sheep. The combination of the technologies for gene targeting of somatic cells with those of animal cloning made it possible to introduce specific genetic mutations into domestic animals. In this review, the principles of gene targeting in somatic cells and the challenges of nuclear transfer using gene-targeted cells are discussed. The relevance of gene targeting in domestic animals for applications in bio-medicine and agriculture are also examined. PMID:14614774

Orthographic and Phonological Neighborhood Databases across Multiple Languages.

PubMed

Marian, Viorica

2017-01-01

The increased globalization of science and technology and the growing number of bilinguals and multilinguals in the world have made research with multiple languages a mainstay for scholars who study human function and especially those who focus on language, cognition, and the brain. Such research can benefit from large-scale databases and online resources that describe and measure lexical, phonological, orthographic, and semantic information. The present paper discusses currently-available resources and underscores the need for tools that enable measurements both within and across multiple languages. A general review of language databases is followed by a targeted introduction to databases of orthographic and phonological neighborhoods. A specific focus on CLEARPOND illustrates how databases can be used to assess and compare neighborhood information across languages, to develop research materials, and to provide insight into broad questions about language. As an example of how using large-scale databases can answer questions about language, a closer look at neighborhood effects on lexical access reveals that not only orthographic, but also phonological neighborhoods can influence visual lexical access both within and across languages. We conclude that capitalizing upon large-scale linguistic databases can advance, refine, and accelerate scientific discoveries about the human linguistic capacity.

A comparison of Agrobacterium-mediated transformation and protoplast-mediated transformation with CRISPR-Cas9 and bipartite gene targeting substrates, as effective gene targeting tools for Aspergillus carbonarius.

PubMed

Weyda, István; Yang, Lei; Vang, Jesper; Ahring, Birgitte K; Lübeck, Mette; Lübeck, Peter S

2017-04-01

In recent years, versatile genetic tools have been developed and applied to a number of filamentous fungi of industrial importance. However, the existing techniques have limitations when it comes to achieve the desired genetic modifications, especially for efficient gene targeting. In this study, we used Aspergillus carbonarius as a host strain due to its potential as a cell factory, and compared three gene targeting techniques by disrupting the ayg1 gene involved in the biosynthesis of conidial pigment in A. carbonarius. The absence of the ayg1 gene leads to phenotypic change in conidia color, which facilitated the analysis on the gene targeting frequency. The examined transformation techniques included Agrobacterium-mediated transformation (AMT) and protoplast-mediated transformation (PMT). Furthermore, the PMT for the disruption of the ayg1 gene was carried out with bipartite gene targeting fragments and the recently adapted CRISPR-Cas9 system. All three techniques were successful in generating Δayg1 mutants, but showed different efficiencies. The most efficient method for gene targeting was AMT, but further it was shown to be dependent on the choice of Agrobacterium strain. However, there are different advantages and disadvantages of all three gene targeting methods which are discussed, in order to facilitate future approaches for fungal strain improvements. Copyright © 2017 Elsevier B.V. All rights reserved.

Neighborhoods as a Power Factor.

ERIC Educational Resources Information Center

Woody, Bette; And Others

1980-01-01

Examines Washington, DC, Advisory Neighborhood Commissions (ANC) as an illustration of neighborhood involvement in city revitalization and maintenance. Considers (1) hypotheses about neighborhood roles and participation in public issue raising; (2) ANC structure, participation, and decision roles; and (3) likely roles neighborhood governments can…

Cancer gene therapy with targeted adenoviruses.

PubMed

Bachtarzi, Houria; Stevenson, Mark; Fisher, Kerry

2008-11-01

Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. This manuscript aims to provide an overview of the techniques currently under development for improving adenovirus delivery to malignant cells in vivo. Primary research articles reporting improvements in adenoviral gene delivery are described. Strategies include genetic modification of viral coat proteins, non-genetic modifications including polymer encapsulation approaches and pharmacological interventions. Reprogramming adenovirus tropism in vitro has been convincingly demonstrated using a range of genetic and physical strategies. These studies have provided new insights into our understanding of virology and the field is progressing. However, there are still some limitations that need special consideration before adenovirus-targeted cancer gene therapy emerges as a routine treatment in the clinical setting.

Differential Sensitivity of Target Genes to Translational Repression by miR-17~92

PubMed Central

Jin, Hyun Yong; Oda, Hiroyo; Chen, Pengda; Kang, Seung Goo; Valentine, Elizabeth; Liao, Lujian; Zhang, Yaoyang; Gonzalez-Martin, Alicia; Shepherd, Jovan; Head, Steven R.; Kim, Pyeung-Hyeun; Fu, Guo; Liu, Wen-Hsien; Han, Jiahuai

2017-01-01

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. PMID:28241004

Do observed or perceived characteristics of the neighborhood environment mediate associations between neighborhood poverty and cumulative biological risk?

PubMed Central

Schulz, Amy J.; Mentz, Graciela; Lachance, Laurie; Zenk, Shannon N.; Johnson, Jonetta; Stokes, Carmen; Mandell, Rebecca

2013-01-01

Objective To examine contributions of observed and perceived neighborhood characteristics in explaining associations between neighborhood poverty and cumulative biological risk (CBR) in an urban community. Methods Multilevel regression analyses were conducted using cross-sectional data from a probability sample survey (n=919), and observational and census data. Dependent variable: CBR. Independent variables: Neighborhood disorder, deterioration and characteristics; perceived neighborhood social environment, physical environment, and neighborhood environment. Covariates: Neighborhood and individual demographics, health-related behaviors. Results Observed and perceived indicators of neighborhood conditions were significantly associated with CBR, after accounting for both neighborhood and individual level socioeconomic indicators. Observed and perceived neighborhood environmental conditions mediated associations between neighborhood poverty and CBR. Conclusions Findings were consistent with the hypothesis that neighborhood conditions associated with economic divestment mediate associations between neighborhood poverty and CBR. PMID:24100238

Does neighborhood social cohesion modify the relationship between neighborhood social norms and smoking behaviors in Mexico?

PubMed

Lozano, Paula; Fleischer, Nancy L; Moore, Spencer; Shigematsu, Luz Myriam Reynales; Santillán, Edna Arillo; Thrasher, James F

2016-07-01

The aim of this study was to examine the separate and combined relationships of neighborhood social norms and neighborhood social cohesion with smoking behavior in a cohort of adult Mexican smokers. Neighborhood anti-smoking norms were measured as the proportion of residents in each neighborhood who believed that society disapproves of smoking. Perceived social cohesion was measured using a 5-item cohesion scale and aggregated to the neighborhood level. Higher neighborhood anti-smoking norms were associated with less successful quitting. Neighborhood social cohesion modified the relationship between neighborhood social norms and two smoking behaviors: smoking intensity and quit attempts. Residents of neighborhoods with weaker anti-smoking norms and higher social cohesion had lower smoking intensity and more quit attempts than residents living in other areas. Social cohesion may help buffer smoking behavior in areas with weak social norms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeted gene deletion of miRNAs in mice by TALEN system.

PubMed

Takada, Shuji; Sato, Tempei; Ito, Yoshiaki; Yamashita, Satoshi; Kato, Tomoko; Kawasumi, Miyuri; Kanai-Azuma, Masami; Igarashi, Arisa; Kato, Tomomi; Tamano, Moe; Asahara, Hiroshi

2013-01-01

Mice are among the most valuable model animal species with an enormous amount of heritage in genetic modification studies. However, targeting genes in mice is sometimes difficult, especially for small genes, such as microRNAs (miRNAs) and targeting genes in repeat sequences. Here we optimized the application of TALEN system for mice and successfully obtained gene targeting technique in mice for intergenic region and series of microRNAs. Microinjection of synthesized RNA of TALEN targeting each gene in one cell stage of embryo was carried out and injected oocytes were transferred into pseudopregnant ICR female mice, producing a high success rate of the targeted deletion of miRNA genes. In our condition, TALEN RNA without poly(A) tail worked better than that of with poly(A) tail. This mutated allele in miRNA was transmitted to the next generation, suggesting the successful germ line transmission of this targeting method. Consistent with our notion of miRNAs maturation mechanism, in homozygous mutant mice of miR-10a, the non- mutated strand of miRNAs expression was completely diminished. This method will lead us to expand and accelerate our genetic research using mice in a high throughput way.

Outdoor play among children in relation to neighborhood characteristics: a cross-sectional neighborhood observation study.

PubMed

Aarts, Marie-Jeanne; de Vries, Sanne I; van Oers, Hans Am; Schuit, Albertine J

2012-08-17

Although environmental characteristics as perceived by parents are known to be related to children's outdoor play behavior, less is known about the relation between independently measured neighborhood characteristics and outdoor play among children. The purpose of this study was to identify quantitative as well as qualitative neighborhood characteristics related to outdoor play by means of neighborhood observations. Questionnaires including questions on outdoor play behavior of the child were distributed among 3,651 parents of primary school children (aged 4-12 years). Furthermore, neighborhood observations were conducted in 33 Dutch neighborhoods to map neighborhood characteristics such as buildings, formal outdoor play facilities, public space, street pattern, traffic safety, social neighborhood characteristics, and general impression. Data of the questionnaires and the neighborhood observations were coupled via postal code of the respondents. Multilevel GEE analyses were performed to quantify the correlation between outdoor play and independently measured neighborhood characteristics. Parental education was negatively associated with outdoor play among children. Neither the presence nor the overall quality of formal outdoor play facilities were (positively) related to outdoor play among children in this study. Rather, informal play areas such as the presence of sidewalks were related to children's outdoor play. Also, traffic safety was an important characteristic associated with outdoor play. This study showed that, apart from individual factors such as parental education level, certain modifiable characteristics in the neighborhood environment (as measured by neighborhood observations) were associated with outdoor play among boys and girls of different age groups in The Netherlands. Local policy makers from different sectors can use these research findings in creating more activity-friendly neighborhoods for children.

Outdoor play among children in relation to neighborhood characteristics: a cross-sectional neighborhood observation study

PubMed Central

2012-01-01

Background Although environmental characteristics as perceived by parents are known to be related to children’s outdoor play behavior, less is known about the relation between independently measured neighborhood characteristics and outdoor play among children. The purpose of this study was to identify quantitative as well as qualitative neighborhood characteristics related to outdoor play by means of neighborhood observations. Methods Questionnaires including questions on outdoor play behavior of the child were distributed among 3,651 parents of primary school children (aged 4–12 years). Furthermore, neighborhood observations were conducted in 33 Dutch neighborhoods to map neighborhood characteristics such as buildings, formal outdoor play facilities, public space, street pattern, traffic safety, social neighborhood characteristics, and general impression. Data of the questionnaires and the neighborhood observations were coupled via postal code of the respondents. Multilevel GEE analyses were performed to quantify the correlation between outdoor play and independently measured neighborhood characteristics. Results Parental education was negatively associated with outdoor play among children. Neither the presence nor the overall quality of formal outdoor play facilities were (positively) related to outdoor play among children in this study. Rather, informal play areas such as the presence of sidewalks were related to children’s outdoor play. Also, traffic safety was an important characteristic associated with outdoor play. Conclusions This study showed that, apart from individual factors such as parental education level, certain modifiable characteristics in the neighborhood environment (as measured by neighborhood observations) were associated with outdoor play among boys and girls of different age groups in The Netherlands. Local policy makers from different sectors can use these research findings in creating more activity-friendly neighborhoods for

Promoting Active Urban Aging: A Measurement Approach to Neighborhood Walkability for Older Adults

PubMed Central

Weiss, Rachael L.; Maantay, Juliana A.; Fahs, Marianne

2011-01-01

Understanding the role of the built environment on physical activity behavior among older adults is an important public health goal, but evaluating these relationships remains complicated due to the difficulty of measuring specific attributes of the environment. As a result, there is conflicting evidence regarding the association between perceived and objectively measured walkability and physical activity among urban-dwelling older adults. This suggests that both actual environmental features and perceptions of these attributes influence walking behavior. The purpose of this pilot project is to create an Objective Walkability Index (OWI) by census block using a Geographic Information System (GIS) and supplement the results with resident perceptions thus more accurately characterizing the context of walkability. Computerized Neighborhood Environment Tracking (ComNET) was used to systematically assess environmental risks impacting activity patterns of older adults in two New York City neighborhoods. In addition, the Senior Center Evaluation of the Neighborhood Environment (SCENE) survey was administered to older adults attending two senior centers located within the target neighborhoods. The results indicate that there is substantial variation in OWI score both between and within the neighborhoods suggesting that residence in some communities may increase the risk of inactivity among older adults. Also, low walkability census blocks were clustered within each neighborhood providing an opportunity for targeted investigation into localized threats to walkability. A lack of consensus regarding the association between the built environment and physical activity among older adults is a consequence of the problems inherent in measuring these determinants. Further empirical evidence evaluating the complex relationships between the built environment and physical activity is an essential step towards creating active communities. PMID:21874149

Neighborhood socioeconomic deprivation, perceived neighborhood factors, and cortisol responses to induced stress among healthy adults.

PubMed

Barrington, Wendy E; Stafford, Mai; Hamer, Mark; Beresford, Shirley A A; Koepsell, Thomas; Steptoe, Andrew

2014-05-01

Associations between measures of neighborhood socioeconomic deprivation and health have been identified, yet work is needed to uncover explanatory mechanisms. One hypothesized pathway is through stress, yet the few studies that have evaluated associations between characteristics of deprived neighborhoods and biomarkers of stress are mixed. This study evaluated whether objectively measured neighborhood socioeconomic deprivation and individual perceived neighborhood characteristics (i.e. social control and fear of crime) impacted cortisol responses to an induced stressor among older healthy adults. Data from Heart Scan, a sub-study of the Whitehall II cohort, were used to generate multilevel piecewise growth-curve models of cortisol trajectories after a laboratory stressor accounting for neighborhood and demographic characteristics. Neighborhood socioeconomic deprivation was significantly associated with individual perceptions of social control and fear of crime in the neighborhood while an association with blunted cortisol reactivity was only evidence among women. Social control was significantly associated with greater cortisol reactivity and mediation between neighborhood socioeconomic deprivation and cortisol reactivity was suggested among women. These findings support a gender-dependent role of neighborhood in stress process models of health. Published by Elsevier Ltd.

RNA-guided genome editing for target gene mutations in wheat.

PubMed

Upadhyay, Santosh Kumar; Kumar, Jitesh; Alok, Anshu; Tuli, Rakesh

2013-12-09

The clustered, regularly interspaced, short palindromic repeats (CRISPR) and CRISPR-associated protein (Cas) system has been used as an efficient tool for genome editing. We report the application of CRISPR-Cas-mediated genome editing to wheat (Triticum aestivum), the most important food crop plant with a very large and complex genome. The mutations were targeted in the inositol oxygenase (inox) and phytoene desaturase (pds) genes using cell suspension culture of wheat and in the pds gene in leaves of Nicotiana benthamiana. The expression of chimeric guide RNAs (cgRNA) targeting single and multiple sites resulted in indel mutations in all the tested samples. The expression of Cas9 or sgRNA alone did not cause any mutation. The expression of duplex cgRNA with Cas9 targeting two sites in the same gene resulted in deletion of DNA fragment between the targeted sequences. Multiplexing the cgRNA could target two genes at one time. Target specificity analysis of cgRNA showed that mismatches at the 3' end of the target site abolished the cleavage activity completely. The mismatches at the 5' end reduced cleavage, suggesting that the off target effects can be abolished in vivo by selecting target sites with unique sequences at 3' end. This approach provides a powerful method for genome engineering in plants.

Eliminating Tuberculosis One Neighborhood at a Time

PubMed Central

Griffith, David E.; McGaha, Paul K.; Wolfgang, Melanie; Robinson, Celia B.; Clark, Patricia A.; Hassell, Willis L.; Robison, Valerie A.; Walker, Kerfoot P.; Wallace, Charles

2014-01-01

Objectives. We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. Methods. In 1996, we mapped reported TB cases (1985–1995) and positive tuberculin skin test (TST) reactors (1993–1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. Results. Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. Conclusions. Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States. PMID:24899457

Eliminating Tuberculosis One Neighborhood at a Time

PubMed Central

Griffith, David E.; McGaha, Paul K.; Wolfgang, Melanie; Robinson, Celia B.; Clark, Patricia A.; Hassell, Willis L.; Robison, Valerie A.; Walker, Kerfoot P.; Wallace, Charles

2013-01-01

Objectives. We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. Methods. In 1996, we mapped reported TB cases (1985–1995) and positive tuberculin skin test (TST) reactors (1993–1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. Results. Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. Conclusions. Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States. PMID:23078465

Adolescent Physical Activity: Moderation of Individual Factors by Neighborhood Environment.

PubMed

D'Angelo, Heather; Fowler, Stephanie L; Nebeling, Linda C; Oh, April Y

2017-06-01

Less than a third of U.S. adolescents meet federal physical activity (PA) guidelines. Understanding correlates of PA at multiple levels of the Social Ecological Model could improve PA interventions among youth. This study examines (1) associations between factors across the Social Ecological Model including psychosocial factors, perceived neighborhood physical and social environment characteristics, and adolescent moderate to vigorous PA (MVPA) and (2) whether perceived neighborhood characteristics moderate associations between psychosocial factors and MVPA. A national sample of adolescents (aged 12-17 years) in the 2014 Family Life, Activity, Sun, Health, and Eating Study was used to examine associations between psychosocial characteristics, perceived neighborhood social and physical characteristics, and self-reported weekly minutes of MVPA. Analyses were conducted in 2015. Interaction terms between psychosocial and neighborhood variables were added to multiple linear regression models to examine moderation hypotheses. Significant two-way interactions revealed that neighborhoods with features perceived as supportive of PA strengthened several psychosocial-MVPA associations. The positive associations between MVPA and friend norms, friend support, and attitudes were strengthened for adolescents living in neighborhoods with high versus low PA resource availability (all p<0.05). Furthermore, the association between controlled and autonomous motivation and MVPA was strengthened under conditions of shops/stores near (versus distant from) adolescents' homes (p<0.05). The association between some psychosocial factors and adolescent MVPA may be environment dependent. Neighborhood physical and social environments supportive of PA are important to consider when developing targeted PA interventions and may strengthen the association between psychosocial-level factors and adolescent MVPA. Copyright © 2017 American Journal of Preventive Medicine. All rights reserved.

Connecting Schools to Neighborhood Revitalization: The Case of the Maple Heights Neighborhood Association

ERIC Educational Resources Information Center

Pesch, Lawrence P.

2014-01-01

This case study focuses on the way a neighborhood association connects schools to broad change in an urban neighborhood of a large Midwestern city. The first section provides a review of the literature on community involvement in school and neighborhood reform. It reviews the historical origins of the current school-community relationship, the…

Synthesis of galactosyl compounds for targeted gene delivery.

PubMed

Ren, T; Zhang, G; Liu, D

2001-11-01

Cell-specific DNA delivery offers a great potential for targeted gene therapy. Toward this end, we have synthesized a series of compounds carrying galactose residues as a targeting ligand for asialoglycoprotein receptors of hepatocytes and primary amine groups as a functional domain for DNA binding. Biological activity of these galactosyl compounds in DNA delivery was evaluated in HepG2 and BL-6 cells and compared with respect to the number of galactose residues as well as primary amine groups in each molecule. Transfection experiments using a firefly luciferase gene as a reporter revealed that compounds with multivalent binding properties were more active in DNA delivery. An optimal transfection activity in HepG2 cells requires seven primary amine groups and a minimum of two galactose residues in each molecule. The transfection activity of compounds carrying multi-galactose residues can be inhibited by asialofetuin, a natural substrate for asialoglycoprotein receptors of hepatocytes, suggesting that gene transfer by these galactosyl compounds is asialoglycoprotein receptor-mediated. These results provide direct evidence in support of our new strategy for the use of small and synthetic compounds for cell specific and targeted gene delivery.

Genomic identification of direct target genes of LEAFY

PubMed Central

William, Dilusha A.; Su, Yanhui; Smith, Michael R.; Lu, Meina; Baldwin, Don A.; Wagner, Doris

2004-01-01

The switch from vegetative to reproductive development in plants necessitates a switch in the developmental program of the descendents of the stem cells in the shoot apical meristem. Genetic and molecular investigations have demonstrated that the plant-specific transcription factor and meristem identity regulator LEAFY (LFY) controls this developmental transition by inducing expression of a second transcription factor, APETALA1, and by regulating the expression of additional, as yet unknown, genes. Here we show that the additional LFY targets include the APETALA1-related factor, CAULI-FLOWER, as well as three transcription factors and two putative signal transduction pathway components. These genes are up-regulated by LFY even when protein synthesis is inhibited and, hence, appear to be direct targets of LFY. Supporting this conclusion, cis-regulatory regions upstream of these genes are bound by LFY in vivo. The newly identified LFY targets likely initiate the transcriptional changes that are required for the switch from vegetative to reproductive development in Arabidopsis. PMID:14736918

Identification of HMX1 target genes: A predictive promoter model approach

PubMed Central

Boulling, Arnaud; Wicht, Linda

2013-01-01

Purpose A homozygous mutation in the H6 family homeobox 1 (HMX1) gene is responsible for a new oculoauricular defect leading to eye and auricular developmental abnormalities as well as early retinal degeneration (MIM 612109). However, the HMX1 pathway remains poorly understood, and in the first approach to better understand the pathway’s function, we sought to identify the target genes. Methods We developed a predictive promoter model (PPM) approach using a comparative transcriptomic analysis in the retina at P15 of a mouse model lacking functional Hmx1 (dmbo mouse) and its respective wild-type. This PPM was based on the hypothesis that HMX1 binding site (HMX1-BS) clusters should be more represented in promoters of HMX1 target genes. The most differentially expressed genes in the microarray experiment that contained HMX1-BS clusters were used to generate the PPM, which was then statistically validated. Finally, we developed two genome-wide target prediction methods: one that focused on conserving PPM features in human and mouse and one that was based on the co-occurrence of HMX1-BS pairs fitting the PPM, in human or in mouse, independently. Results The PPM construction revealed that sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein) (Sgcg), teashirt zinc finger homeobox 2 (Tshz2), and solute carrier family 6 (neurotransmitter transporter, glycine) (Slc6a9) genes represented Hmx1 targets in the mouse retina at P15. Moreover, the genome-wide target prediction revealed that mouse genes belonging to the retinal axon guidance pathway were targeted by Hmx1. Expression of these three genes was experimentally validated using a quantitative reverse transcription PCR approach. The inhibitory activity of Hmx1 on Sgcg, as well as protein tyrosine phosphatase, receptor type, O (Ptpro) and Sema3f, two targets identified by the PPM, were validated with luciferase assay. Conclusions Gene expression analysis between wild-type and dmbo mice allowed us to develop a PPM

Applications of CRISPR/Cas9 technology for targeted mutagenesis, gene replacement and stacking of genes in higher plants.

PubMed

Luo, Ming; Gilbert, Brian; Ayliffe, Michael

2016-07-01

Mutagenesis continues to play an essential role for understanding plant gene function and, in some instances, provides an opportunity for plant improvement. The development of gene editing technologies such as TALENs and zinc fingers has revolutionised the targeted mutation specificity that can now be achieved. The CRISPR/Cas9 system is the most recent addition to gene editing technologies and arguably the simplest requiring only two components; a small guide RNA molecule (sgRNA) and Cas9 endonuclease protein which complex to recognise and cleave a specific 20 bp target site present in a genome. Target specificity is determined by complementary base pairing between the sgRNA and target site sequence enabling highly specific, targeted mutation to be readily engineered. Upon target site cleavage, error-prone endogenous repair mechanisms produce small insertion/deletions at the target site usually resulting in loss of gene function. CRISPR/Cas9 gene editing has been rapidly adopted in plants and successfully undertaken in numerous species including major crop species. Its applications are not restricted to mutagenesis and target site cleavage can be exploited to promote sequence insertion or replacement by recombination. The multiple applications of this technology in plants are described.

Hypoxia regulates alternative splicing of HIF and non-HIF target genes.

PubMed

Sena, Johnny A; Wang, Liyi; Heasley, Lynn E; Hu, Cheng-Jun

2014-09-01

Hypoxia is a common characteristic of many solid tumors. The hypoxic microenvironment stabilizes hypoxia-inducible transcription factor 1α (HIF1α) and 2α (HIF2α/EPAS1) to activate gene transcription, which promotes tumor cell survival. The majority of human genes are alternatively spliced, producing RNA isoforms that code for functionally distinct proteins. Thus, an effective hypoxia response requires increased HIF target gene expression as well as proper RNA splicing of these HIF-dependent transcripts. However, it is unclear if and how hypoxia regulates RNA splicing of HIF targets. This study determined the effects of hypoxia on alternative splicing (AS) of HIF and non-HIF target genes in hepatocellular carcinoma cells and characterized the role of HIF in regulating AS of HIF-induced genes. The results indicate that hypoxia generally promotes exon inclusion for hypoxia-induced, but reduces exon inclusion for hypoxia-reduced genes. Mechanistically, HIF activity, but not hypoxia per se is found to be necessary and sufficient to increase exon inclusion of several HIF targets, including pyruvate dehydrogenase kinase 1 (PDK1). PDK1 splicing reporters confirm that transcriptional activation by HIF is sufficient to increase exon inclusion of PDK1 splicing reporter. In contrast, transcriptional activation of a PDK1 minigene by other transcription factors in the absence of endogenous HIF target gene activation fails to alter PDK1 RNA splicing. This study demonstrates a novel function of HIF in regulating RNA splicing of HIF target genes. ©2014 American Association for Cancer Research.

Identification of Homeotic Target Genes in Drosophila Melanogaster Including Nervy, a Proto-Oncogene Homologue

PubMed Central

Feinstein, P. G.; Kornfeld, K.; Hogness, D. S.; Mann, R. S.

1995-01-01

In Drosophila, the specific morphological characteristics of each segment are determined by the homeotic genes that regulate the expression of downstream target genes. We used a subtractive hybridization procedure to isolate activated target genes of the homeotic gene Ultrabithorax (Ubx). In addition, we constructed a set of mutant genotypes that measures the regulatory contribution of individual homeotic genes to a complex target gene expression pattern. Using these mutants, we demonstrate that homeotic genes can regulate target gene expression at the start of gastrulation, suggesting a previously unknown role for the homeotic genes at this early stage. We also show that, in abdominal segments, the levels of expression for two target genes increase in response to high levels of Ubx, demonstrating that the normal down-regulation of Ubx in these segments is functional. Finally, the DNA sequence of cDNAs for one of these genes predicts a protein that is similar to a human proto-oncogene involved in acute myeloid leukemias. These results illustrate potentially general rules about the homeotic control of target gene expression and suggest that subtractive hybridization can be used to isolate interesting homeotic target genes. PMID:7498738

Multifunctional Nucleus-targeting Nanoparticles with Ultra-high Gene Transfection Efficiency for In Vivo Gene Therapy

PubMed Central

Li, Ling; Li, Xia; Wu, Yuzhe; Song, Linjiang; Yang, Xi; He, Tao; Wang, Ning; Yang, Suleixin; Zeng, Yan; Wu, Qinjie; Qian, Zhiyong; Wei, Yuquan; Gong, Changyang

2017-01-01

Cancer stem cell-like cells (CSCL) are responsible for tumor recurrence associated with conventional therapy (e.g. surgery, radiation, and chemotherapy). Here, we developed a novel multifunctional nucleus-targeting nanoparticle-based gene delivery system which is capable of targeting and eradicating CSCL. These nanoparticles can facilitate efficient endosomal escape and spontaneously penetrate into nucleus without additional nuclear localization signal. They also induced extremely high gene transfection efficiency (>95%) even in culture medium containing 30% serum, which significantly surpassed that of some commercial transfection reagents, such as Lipofectamine 2000 and Lipofectamine 3000 etc. Especially, when loaded with the TRAIL gene, this system mediated remarkable depletion of CSCL. Upon systemic administration, the nanoparticles accumulated in tumor sites while sparing the non-cancer tissues and significantly inhibited the growth of tumors with no evident systemic toxicity. Taken together, our results suggest that these novel multifunctional, nucleus-targeting nanoparticles are a very promising in vivo gene delivery system capable of targeting CSCL and represent a new treatment candidate for improving the survival of cancer patients. PMID:28529641

Neighborhood Differences in Post-Stroke Mortality

PubMed Central

Osypuk, Theresa L.; Ehntholt, Amy; Moon, J. Robin; Gilsanz, Paola; Glymour, M. Maria

2017-01-01

Background Post-stroke mortality is higher among residents of disadvantaged neighborhoods, but it is not known whether neighborhood inequalities are specific to stroke survival or similar to mortality patterns in the general population. We hypothesized that neighborhood disadvantage would predict higher post-stroke mortality and neighborhood effects would be relatively larger for stroke patients than for individuals with no history of stroke. Methods and Results Health and Retirement Study participants aged 50+ without stroke at baseline (n=15,560) were followed up to 12 years for incident stroke (1,715 events over 159,286 person-years) and mortality (5,325 deaths). Baseline neighborhood characteristics included objective measures based on census tracts (family income, poverty, deprivation, residential stability, and percent white, black or foreign-born) and self-reported neighborhood social ties. Using Cox proportional hazard models, we compared neighborhood mortality effects for people with versus without a history of stroke. Most neighborhood variables predicted mortality for both stroke patients and the general population in demographic-adjusted models. Neighborhood percent white predicted lower mortality for stroke survivors (HR=0.75 for neighborhoods in highest 25th percentile vs. below, 95 % CI: 0.62, 0.91) more strongly than for stroke-free adults (HR=0.92 (0.83, 1.02); p=0.04 for stroke-by-neighborhood interaction). No other neighborhood characteristic had different effects for people with versus without stroke. Neighborhood-mortality associations emerged within three months after stroke, when associations were often stronger than among stroke-free individuals. Conclusions Neighborhood characteristics predict post-stroke mortality, but most effects are similar for individuals without stroke. Eliminating disparities in stroke survival may require addressing pathways that are not specific to traditional post-stroke care. PMID:28228449

Targeted gene flow and rapid adaptation in an endangered marsupial.

PubMed

Kelly, Ella; Phillips, Ben L

2018-06-13

Targeted gene flow is an emerging conservation strategy. It involves translocating individuals with favorable genes to areas where they will have a conservation benefit. The applications for targeted gene flow are wide-ranging, but include pre-adapting natives to the arrival of invasive species. The endangered carnivorous marsupial, the northern quoll, has declined rapidly since the introduction of the cane toad, which fatally poisons quolls that attack them. There are, however, a few remaining toad-invaded quoll populations in which the quolls survive because they know not to eat cane toads. It is this "toad-smart" behavior that we hope to promote through targeted gene flow. For targeted gene flow to be feasible, however, toad-smarts must have a genetic basis. To assess this, we used a common garden experiment and found offspring from toad-exposed populations were substantially less likely to eat toads than those with toad-naïve parents. Hybrid offspring showed similar responses to quolls with two toad-exposed parents, indicating the trait may be dominant. Together, these results suggest a heritable trait and rapid adaptive response in small number of toad-impacted populations. Although questions remain about outbreeding depression, our results are encouraging for targeted gene flow: suggesting it should be possible to introduce toad-smart behavior into soon to be impacted quoll populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Interactions between neighborhood characteristics and individual functional status in relation to disability among Québec urbanites.

PubMed

Philibert, Mathieu D; Pampalon, Robert; Hamel, Denis; Daniel, Mark

2013-10-01

Disability is conceived as a person-context interaction. Neighborhoods are among the contexts potentially influencing disability. It is thus expected that neighborhood characteristics will be associated with disability prevalence and that such associations will be moderated by individual-level functional status. Empirical research targeting the influences of features of urban environments is relatively rare. To evaluate the presence of contextual differences in disability prevalence and to assess the moderating role of individual functional status on the association between neighborhood characteristics and disability prevalence. Multi-level analyses of individual-level data obtained from the Canadian Community Health Survey and neighborhood-level data derived from the Canada census. A contextual component was observed in the variability of disability prevalence. Significant neighborhood-level differences in disability were found across levels of social deprivation. Evidence of person-place interaction was equivocal. The contextual component of the variability in disability prevalence offers potential for targeting interventions to neighborhoods. The pathway by which social structure is associated with disability prevalence requires further research. Analyses of particular functional limitations may enhance our understanding of the mechanisms by which socioenvironmental factors affect disability. Publicly available survey data on disability in the general Canadian population, while useful, has limitations with respect to estimating socioenvironmental correlates of disability and potential person-place interactions. Copyright © 2013 Elsevier Inc. All rights reserved.

Deprivation and suicide mortality across 424 neighborhoods in Seoul, South Korea: a Bayesian spatial analysis.

PubMed

Yoon, Tae-Ho; Noh, Maengseok; Han, Junhee; Jung-Choi, Kyunghee; Khang, Young-Ho

2015-12-01

A neighborhood-level analysis of mortality from suicide would be informative in developing targeted approaches to reducing suicide. This study aims to examine the association of community characteristics with suicide in the 424 neighborhoods of Seoul, South Korea. Neighborhood-level mortality and population data (2005-2011) were obtained to calculate age-standardized suicide rates. Eight community characteristics and their associated deprivation index were employed as determinants of suicide rates. The Bayesian hierarchical model with mixed effects for neighborhoods was used to fit age-standardized suicide rates and other covariates with consideration of spatial correlations. Suicide rates for 424 neighborhoods were between 7.32 and 71.09 per 100,000. Ninety-nine percent of 424 neighborhoods recorded greater suicide rates than the Organization for Economic Cooperation and Development member countries' average. A stepwise relationship between area deprivation and suicide was found. Neighborhood-level indicators for lack of social support (residents living alone and the divorced or separated) and socioeconomic disadvantages (low educational attainment) were positively associated with suicide mortality after controlling for other covariates. Finding from this study could be used to identify priority areas and to develop community-based programs for preventing suicide in Seoul, South Korea.

Independent Associations and Interactions of Perceived Neighborhood and Psychosocial Constructs on Adults' Physical Activity.

PubMed

Dwyer, Laura A; Patel, Minal; Nebeling, Linda C; Oh, April Y

2018-05-01

Neighborhood and psychosocial variables are related to physical activity (PA), yet interactions between these factors in predicting PA are infrequently studied. This analysis examines the independent associations and interactions between self-reported neighborhood and psychosocial variables in relation to moderate to vigorous PA (MVPA) among adults from a US panel sample. In adjusted models, neighborhood social capital was positively associated with meeting MVPA guidelines. Fewer barriers, greater self-efficacy, and greater autonomous motivation also corresponded with greater odds of meeting MVPA guidelines. An interaction between social capital and autonomous motivation showed that social capital was only associated with MVPA when autonomous motivation was high. Participants who reported both high autonomous motivation and high social capital were most likely to meet MVPA guidelines. Neighborhood social capital, barriers, self-efficacy, and autonomous motivation may be important correlates in promoting adults' PA. Future directions include using objective neighborhood and PA data in similar analyses and investigating associations of neighborhood and psychosocial variables with multiple PA activities. Intervention research to promote PA should also examine whether effects of interventions targeting psychosocial constructs are moderated by features of an individual's neighborhood or whether perceived social capital can be addressed in interventions in conjunction with psychosocial variables.

Phonological neighborhood and word frequency effects in the stuttered disfluencies of children who stutter.

PubMed

Anderson, Julie D

2007-02-01

The purpose of this study was to examine (a) the role of neighborhood density (number of words that are phonologically similar to a target word) and frequency variables on the stuttering-like disfluencies of preschool children who stutter, and (b) whether these variables have an effect on the type of stuttering-like disfluency produced. A 500+ word speech sample was obtained from each participant (N = 15). Each stuttered word was randomly paired with the firstly produced word that closely matched it in grammatical class, familiarity, and number of syllables/phonemes. Frequency, neighborhood density, and neighborhood frequency values were obtained for the stuttered and fluent words from an online database. Findings revealed that stuttered words were lower in frequency and neighborhood frequency than fluent words. Words containing part-word repetitions and sound prolongations were also lower in frequency and/or neighborhood frequency than fluent words, but these frequency variables did not have an effect on single-syllable word repetitions. Neighborhood density failed to influence the susceptibility of words to stuttering, as well as the type of stuttering-like disfluency produced. In general, findings suggest that neighborhood and frequency variables not only influence the fluency with which words are produced in speech, but also have an impact on the type of stuttering-like disfluency produced.

Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit Neighborhood Health Study.

PubMed

Meyers, J L; Cerdá, M; Galea, S; Keyes, K M; Aiello, A E; Uddin, M; Wildman, D E; Koenen, K C

2013-08-13

Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene-environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 × 10(-7)) genetic variants from a recent meta-analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ~3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene-environment interaction, for smoking

Direct and indirect effects of neighborhood characteristics on the perpetration of dating violence across adolescence.

PubMed

Chang, Ling-Yin; Foshee, Vangie A; Reyes, Heathe Luz McNaughton; Ennett, Susan T; Halpern, Carolyn T

2015-03-01

Neighborhood context plays a role in the development of adolescent health risk behaviors, but few studies have investigated the influence of neighborhoods on the perpetration of dating violence. This longitudinal study examined the direct effects of risky neighborhood structural and physical characteristics on trajectories of the perpetration of dating violence, tested whether collective efficacy mediated these relationships, and determined if the effects varied by the sex of the adolescent. Adolescent data are from a multi-wave longitudinal study from grades 8 to 12; neighborhood data were collected from parents' interviews and U.S. Census data. Multilevel growth curve models were conducted with 3,218 students; the sample was 50% male, 41% White, 50% Black, and 9% other race/ethnicity. In models examining risky neighborhood variables one at a time, and controlling for potential individual-level confounders, the sex of the adolescent interacted with economic disadvantage, residential instability, and physical disorder; these risky neighborhood characteristics increased risk for girls' but not boys' perpetrating of dating violence. In full models with all of the risky neighborhood variables, the sex of the adolescent continued to interact with neighborhood economic disadvantage; living in economically disadvantaged neighborhoods increased girls' but not boys' risk for dating violence across all ages. No other risky neighborhood effects were found for boys or girls. Collective efficacy did not mediate the relationships between other neighborhood characteristics and the outcome. These findings suggest that dating violence prevention strategies for girls should consider the contexts in which they live rather than only targeting changes in their individual characteristics.

Does the social environment moderate associations of the built environment with Latinas' objectively-measured neighborhood outdoor physical activity?

PubMed

Perez, L G; Carlson, J; Slymen, D J; Patrick, K; Kerr, J; Godbole, S; Elder, J P; Ayala, G X; Arredondo, E M

2016-12-01

Favorable perceptions of the built and social neighborhood environment may promote outdoor physical activity (PA). However, little is known about their independent and interactive effects on neighborhood-specific outdoor PA. We examined associations of perceived built and social neighborhood environment factors, and their interactions, with objectively-measured neighborhood outdoor moderate-to-vigorous physical activity (MVPA) among a sample of Latina women in San Diego, CA. Analyses included baseline data collected in 2011-2013 from 86 Latinas with ≥ 2 days of combined accelerometer and global positioning system data and complete survey measures. We examined objective neighborhood outdoor MVPA within 500-meter home buffers. Generalized linear mixed models examined associations of 3 perceived built (e.g., sidewalk maintenance) and 3 social environmental (e.g., safety from crime) factors with engaging in any daily neighborhood outdoor MVPA. Models tested interactions between the built and social environmental factors. Although the perceived neighborhood environmental factors were not significantly related to daily neighborhood outdoor MVPA, we found 2 significant interactions: perceived sidewalk maintenance x safety from crime ( p  = 0.05) and neighborhood aesthetics x neighborhood social cohesion ( p  = 0.03). Sidewalk maintenance was positively related to daily neighborhood outdoor MVPA only among Latinas that reported low levels of safety from crime. Neighborhood aesthetics was positively related to daily neighborhood outdoor MVPA only among Latinas with high neighborhood social cohesion. Findings suggest several built and social environmental factors interact to influence Latinas' neighborhood outdoor MVPA. Interventions are needed targeting both built and social neighborhood environmental factors favorable to outdoor PA in the neighborhood.

Fe3O4 Nanoparticles in Targeted Drug/Gene Delivery Systems

PubMed Central

Shen, Lazhen; Li, Bei; Qiao, Yongsheng

2018-01-01

Fe3O4 nanoparticles (NPs), the most traditional magnetic nanoparticles, have received a great deal of attention in the biomedical field, especially for targeted drug/gene delivery systems, due to their outstanding magnetism, biocompatibility, lower toxicity, biodegradability, and other features. Naked Fe3O4 NPs are easy to aggregate and oxidize, and thus are often made with various coatings to realize superior properties for targeted drug/gene delivery. In this review, we first list the three commonly utilized synthesis methods of Fe3O4 NPs, and their advantages and disadvantages. In the second part, we describe coating materials that exhibit noticeable features that allow functionalization of Fe3O4 NPs and summarize their methods of drug targeting/gene delivery. Then our efforts will be devoted to the research status and progress of several different functionalized Fe3O4 NP delivery systems loaded with chemotherapeutic agents, and we present targeted gene transitive carriers in detail. In the following section, we illuminate the most effective treatment systems of the combined drug and gene therapy. Finally, we propose opportunities and challenges of the clinical transformation of Fe3O4 NPs targeting drug/gene delivery systems. PMID:29473914

Who Moves to Mixed-Income Neighborhoods?*

PubMed Central

McKinnish, Terra; White, T. Kirk

2011-01-01

This paper uses confidential Census data, specifically the 1990 and 2000 Census Long Form data, to study the income dispersion of recent cohorts of migrants to mixed-income neighborhoods. We investigate whether neighborhoods with high levels of income dispersion attract economically diverse in-migrants. If recent in-migrants to mixed-income neighborhoods exhibit high levels of income dispersion, this is consistent with stable mixed-income neighborhoods. If, however, mixed-income neighborhoods are comprised of homogenous low-income (high-income) cohorts of long-term residents combined with homogenous high-income (low-income) cohorts of recent arrivals, this is consistent with neighborhood transition. Our results indicate that neighborhoods with high levels of income dispersion do in fact attract a much more heterogeneous set of in-migrants, particularly from the tails of the income distribution. Our results also suggest that the residents of mixed-income neighborhoods may be less heterogeneous with respect to lifetime income. PMID:21479114

Bacteriophages and medical oncology: targeted gene therapy of cancer.

PubMed

Bakhshinejad, Babak; Karimi, Marzieh; Sadeghizadeh, Majid

2014-08-01

Targeted gene therapy of cancer is of paramount importance in medical oncology. Bacteriophages, viruses that specifically infect bacterial cells, offer a variety of potential applications in biomedicine. Their genetic flexibility to go under a variety of surface modifications serves as a basis for phage display methodology. These surface manipulations allow bacteriophages to be exploited for targeted delivery of therapeutic genes. Moreover, the excellent safety profile of these viruses paves the way for their potential use as cancer gene therapy platforms. The merge of phage display and combinatorial technology has led to the emergence of phage libraries turning phage display into a high throughput technology. Random peptide libraries, as one of the most frequently used phage libraries, provide a rich source of clinically useful peptide ligands. Peptides are known as a promising category of pharmaceutical agents in medical oncology that present advantages such as inexpensive synthesis, efficient tissue penetration and the lack of immunogenicity. Phage peptide libraries can be screened, through biopanning, against various targets including cancer cells and tissues that results in obtaining cancer-homing ligands. Cancer-specific peptides isolated from phage libraries show huge promise to be utilized for targeting of various gene therapy vectors towards malignant cells. Beyond doubt, bacteriophages will play a more impressive role in the future of medical oncology.

A targeted resequencing gene panel for focal epilepsy.

PubMed

Hildebrand, Michael S; Myers, Candace T; Carvill, Gemma L; Regan, Brigid M; Damiano, John A; Mullen, Saul A; Newton, Mark R; Nair, Umesh; Gazina, Elena V; Milligan, Carol J; Reid, Christopher A; Petrou, Steven; Scheffer, Ingrid E; Berkovic, Samuel F; Mefford, Heather C

2016-04-26

We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases. We searched for both germline and somatic mutations in 251 patients with unsolved sporadic or familial focal epilepsy and identified 11 novel or very rare missense variants in 5 different genes: CHRNA4, GRIN2B, KCNT1, PCDH19, and SCN1A. Of these, 2 were predicted to be pathogenic or likely pathogenic, explaining ∼0.8% of the cohort, and 8 were of uncertain significance based on available data. We have developed and validated a targeted resequencing panel for focal epilepsies, the most important clinical class of epilepsies, accounting for about 60% of all cases. Our application of MIP technology is an innovative approach that will be advantageous in the clinical setting because it is highly sensitive, efficient, and cost-effective for screening large patient cohorts. Our findings indicate that mutations in known genes likely explain only a small proportion of focal epilepsy cases. This is not surprising given the established clinical and genetic heterogeneity of these disorders and underscores the importance of further gene discovery studies in this complex syndrome. © 2016 American Academy of Neurology.

Alcohol and Cigarette Advertising on Billboards: Targeting with Social Cues.

ERIC Educational Resources Information Center

Schooler, Caroline; Basil, Michael D.

A study examined whether billboard advertising of tobacco and alcohol products is differentially targeted toward White, Black, Asian, and Hispanic neighborhoods. The study analyzed 901 billboards in neighborhood commercial districts in San Francisco, California, giving particular attention to tobacco and alcohol billboards. Neighborhood census…

A system for the measurement of gene targeting efficiency in human cell lines using an antibiotic resistance-GFP fusion gene.

PubMed

Konishi, Yuko; Karnan, Sivasundaram; Takahashi, Miyuki; Ota, Akinobu; Damdindorj, Lkhagvasuren; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2012-09-01

Gene targeting in a broad range of human somatic cell lines has been hampered by inefficient homologous recombination. To improve this technology and facilitate its widespread application, it is critical to first have a robust and efficient research system for measuring gene targeting efficiency. Here, using a fusion gene consisting of hygromycin B phosphotransferase and 3'-truncated enhanced GFP (HygR-5' EGFP) as a reporter gene, we created a molecular system monitoring the ratio of homologous to random integration (H/R ratio) of targeting vectors into the genome. Cell clones transduced with a reporter vector containing HygR-5' EGFP were efficiently established from two human somatic cell lines. Established HygR-5' EGFP reporter clones retained their capacity to monitor gene targeting efficiency for a longer duration than a conventional reporter system using an unfused 5' EGFP gene. With the HygR-5' EGFP reporter system, we reproduced previous findings of gene targeting frequency being up-regulated by the use of an adeno-associated viral (AAV) backbone, a promoter-trap system, or a longer homology arm in a targeting vector, suggesting that this system accurately monitors H/R ratio. Thus, our HygR-5' EGFP reporter system will assist in the development of an efficient AAV-based gene targeting technology.

Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

PubMed

Weß, Ludger; Schnieders, Frank

2017-12-01

Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

How neighborhood structural and institutional features can shape neighborhood social connectedness: a multilevel study of adolescent perceptions.

PubMed

Lenzi, Michela; Vieno, Alessio; Santinello, Massimo; Perkins, Douglas D

2013-06-01

According to the norms and collective efficacy model, the levels of social connectedness within a local community are a function of neighborhood structural characteristics, such as socioeconomic status and ethnic composition. The current work aims to determine whether neighborhood structural and institutional features (neighborhood wealth, percentage of immigrants, population density, opportunities for activities and meeting places) have an impact on different components of neighborhood social connectedness (intergenerational closure, trust and reciprocity, neighborhood-based friendship and personal relationships with neighbors). The study involved a representative sample of 389 early and middle adolescents aged 11-15 years old, coming from 31 Italian neighborhoods. Using hierarchical linear modeling, our findings showed that high population density, ethnic diversity, and physical and social disorder might represent obstacles for the creation of social ties within the neighborhood. On the contrary, the presence of opportunities for activities and meeting places in the neighborhood was associated with higher levels of social connectedness among residents.

Trajectories of Neighborhood Attainment after Prison

PubMed Central

Lee, Keun Bok; Harding, David J.; Morenoff, Jeffrey D.

2018-01-01

A potentially important but understudied aspect of prisoner reentry is the neighborhood environments experienced by formerly incarcerated people. We know that many formerly incarcerated people return to very disadvantaged neighborhood environments and that returning to disadvantaged neighborhoods after prison increases the risk of recidivism and reduces employment. Yet very little is known about the social, economic, and institutional processes that sort formerly incarcerated people into different neighborhoods after release or their trajectories of neighborhood attainment over time. Motivated by a conceptualization of prisoner reentry and reintegration as a process that unfolds over time, we examine trajectories of neighborhood environments after release. Motivated by the literatures on neighborhood attainment, social capital, and the role of criminal justice institutions in structuring the lives of former prisoners, we examine sources of variation in neighborhood attainment. We use administrative data from the Michigan Department of Corrections on formerly incarcerated people paroled in 2003 and followed for two years after release. Descriptive results from a latent class trajectory model show that most white and black formerly incarcerated people experience flat trajectories, with little upward or downward residential mobility over time. Findings from multi-level growth curve models suggest that institutional factors are particularly important for the neighborhood attainment of whites, while human capital and social ties are particularly important for blacks. Among both blacks and whites, pre-prison and first post-prison neighborhood conditions exhibit a strong association with post-prison neighborhood attainment, although these associations are larger for blacks than whites. PMID:28705357

Predicting essential genes for identifying potential drug targets in Aspergillus fumigatus.

PubMed

Lu, Yao; Deng, Jingyuan; Rhodes, Judith C; Lu, Hui; Lu, Long Jason

2014-06-01

Aspergillus fumigatus (Af) is a ubiquitous and opportunistic pathogen capable of causing acute, invasive pulmonary disease in susceptible hosts. Despite current therapeutic options, mortality associated with invasive Af infections remains unacceptably high, increasing 357% since 1980. Therefore, there is an urgent need for the development of novel therapeutic strategies, including more efficacious drugs acting on new targets. Thus, as noted in a recent review, "the identification of essential genes in fungi represents a crucial step in the development of new antifungal drugs". Expanding the target space by rapidly identifying new essential genes has thus been described as "the most important task of genomics-based target validation". In previous research, we were the first to show that essential gene annotation can be reliably transferred between distantly related four Prokaryotic species. In this study, we extend our machine learning approach to the much more complex Eukaryotic fungal species. A compendium of essential genes is predicted in Af by transferring known essential gene annotations from another filamentous fungus Neurospora crassa. This approach predicts essential genes by integrating diverse types of intrinsic and context-dependent genomic features encoded in microbial genomes. The predicted essential datasets contained 1674 genes. We validated our results by comparing our predictions with known essential genes in Af, comparing our predictions with those predicted by homology mapping, and conducting conditional expressed alleles. We applied several layers of filters and selected a set of potential drug targets from the predicted essential genes. Finally, we have conducted wet lab knockout experiments to verify our predictions, which further validates the accuracy and wide applicability of the machine learning approach. The approach presented here significantly extended our ability to predict essential genes beyond orthologs and made it possible to

Nonprofit Housing and Neighborhood Spillovers

ERIC Educational Resources Information Center

Ellen, Ingrid Gould; Voicu, Ioan

2006-01-01

Nonprofit organizations play a critical role in U.S. housing policy, a role typically justified by the claim that their housing investments produce significant neighbor-hood spillover benefits. However, little work has actually been done to measure these impacts on neighborhoods. This paper compares the neighborhood spillover effects of…

Seamless Genome Editing in Rice via Gene Targeting and Precise Marker Elimination.

PubMed

Nishizawa-Yokoi, Ayako; Saika, Hiroaki; Toki, Seiichi

2016-01-01

Positive-negative selection using hygromycin phosphotransferase (hpt) and diphtheria toxin A-fragment (DT-A) as positive and negative selection markers, respectively, allows enrichment of cells harboring target genes modified via gene targeting (GT). We have developed a successful GT system employing positive-negative selection and subsequent precise marker excision via the piggyBac transposon derived from the cabbage looper moth to introduce desired modifications into target genes in the rice genome. This approach could be applied to the precision genome editing of almost all endogenous genes throughout the genome, at least in rice.

Understanding Associations Between Neighborhood Socioeconomic Status and Negative Consequences of Drinking: a Moderated Mediation Analysis.

PubMed

Karriker-Jaffe, Katherine J; Liu, HuiGuo; Kaplan, Lauren M

2016-05-01

We explored how neighborhood socioeconomic status (SES) is related to negative consequences of drinking to explain why racial/ethnic minority group members are more at risk than Whites for adverse alcohol outcomes. We tested direct and indirect effects of neighborhood SES on alcohol problems and examined differences by gender and race. We used data from the 2000 and 2005 National Alcohol Surveys (N = 7912 drinkers aged 18 and older; 49 % female) linked with data from the 2000 Decennial Census in multivariate path models adjusting for individual demographics. In the full sample, neighborhood disadvantage had a significant direct path to increased negative consequences, with no indirect paths through depression, positive affect or pro-drinking attitudes. Neighborhood affluence had significant indirect paths to increased negative consequences through greater pro-drinking attitudes and increased heavy drinking. Subgroup analyses showed the indirect path from affluence to consequences held for White men, with no effects of neighborhood disadvantage. For racial/ethnic minority men, significant indirect paths emerged from both neighborhood disadvantage and affluence to increased consequences through greater pro-drinking attitudes and more heavy drinking. For minority women, there was an indirect effect of neighborhood affluence through reduced depression to fewer drinking consequences. There were limited neighborhood effects on alcohol outcomes for White women. Interventions targeting pro-drinking attitudes in both affluent and disadvantaged areas may help reduce alcohol-related problems among men. Initiatives to improve neighborhood conditions could enhance mental health of minority women and reduce alcohol-related health disparities.

Perceived School and Neighborhood Safety, Neighborhood Violence and Academic Achievement in Urban School Children

PubMed Central

AJ, Milam; CDM, Furr-Holden; PJ, Leaf

2010-01-01

Community and school violence continue to be a major public health problem, especially among urban children and adolescents. Little research has focused on the effect of school safety and neighborhood violence on academic performance. This study examines the effect of the school and neighborhood climate on academic achievement among a population of 3rd-5th grade students in an urban public school system. Community and school safety were assessed using the School Climate Survey, an annual city-wide assessment of student’s perception of school and community safety. Community violence was measured using the Neighborhood Inventory for Environmental Typology, an objective observational assessment of neighborhood characteristics. Academic achievement was measured using the Maryland State Assessment (MSA), a standardized exam given to all Maryland 3rd-8th graders. School Climate Data and MSA data were aggregated by school and grade. Objective assessments of neighborhood environment and students’ self-reported school and neighborhood safety were both strongly associated with academic performance. Increasing neighborhood violence was associated with statistically significant decreases from 4.2%-8.7% in math and reading achievement; increasing perceived safety was associated with significant increases in achievement from 16%-22%. These preliminary findings highlight the adverse impact of perceived safety and community violence exposure on primary school children’s academic performance. PMID:21197388

Neighborhood adversity, child health, and the role for community development.

PubMed

Jutte, Douglas P; Miller, Jennifer L; Erickson, David J

2015-03-01

Despite medical advances, childhood health and well-being have not been broadly achieved due to rising chronic diseases and conditions related to child poverty. Family and neighborhood living conditions can have lasting consequences for health, with community adversity affecting health outcomes in significant part through stress response and increased allostatic load. Exposure to this "toxic stress" influences gene expression and brain development with direct and indirect negative consequences for health. Ensuring healthy child development requires improving conditions in distressed, high-poverty neighborhoods by reducing children's exposure to neighborhood stressors and supporting good family and caregiver functioning. The community development industry invests more than $200 billion annually in low-income neighborhoods, with the goal of improving living conditions for residents. The most impactful investments have transformed neighborhoods by integrating across sectors to address both the built environment and the social and service environment. By addressing many facets of the social determinants of health at once, these efforts suggest substantial results for children, but health outcomes generally have not been considered or evaluated. Increased partnership between the health sector and community development can bring health outcomes explicitly into focus for community development investments, help optimize intervention strategies for health, and provide natural experiments to build the evidence base for holistic interventions for disadvantaged children. The problems and potential solutions are beyond the scope of practicing pediatricians, but the community development sector stands ready to engage in shared efforts to improve the health and development of our most at-risk children. Copyright © 2015 by the American Academy of Pediatrics.

Targeted systemic gene therapy and molecular imaging of cancer contribution of the vascular-targeted AAVP vector.

PubMed

Hajitou, Amin

2010-01-01

Gene therapy and molecular-genetic imaging have faced a major problem: the lack of an efficient systemic gene delivery vector. Unquestionably, eukaryotic viruses have been the vectors of choice for gene delivery to mammalian cells; however, they have had limited success in systemic gene therapy. This is mainly due to undesired uptake by the liver and reticuloendothelial system, broad tropism for mammalian cells causing toxicity, and their immunogenicity. On the other hand, prokaryotic viruses such as bacteriophage (phage) have no tropism for mammalian cells, but can be engineered to deliver genes to these cells. However, phage-based vectors have inherently been considered poor vectors for mammalian cells. We have reported a new generation of vascular-targeted systemic hybrid prokaryotic-eukaryotic vectors as chimeras between an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV/phage; AAVP). In this hybrid vector, the targeted bacteriophage serves as a shuttle to deliver the AAV transgene cassette inserted in an intergenomic region of the phage DNA genome. As a proof of concept, we assessed the in vivo efficacy of vector in animal models of cancer by displaying on the phage capsid the cyclic Arg-Gly-Asp (RGD-4C) ligand that binds to alphav integrin receptors specifically expressed on the angiogenic blood vessels of tumors. The ligand-directed vector was able to specifically deliver imaging and therapeutic transgenes to tumors in mice, rats, and dogs while sparing the normal organs. This chapter reviews some gene transfer strategies and the potential of the vascular-targeted AAVP vector for enhancing the effectiveness of existing systemic gene delivery and genetic-imaging technologies. Copyright (c) 2010 Elsevier Inc. All rights reserved.

STAT3 Target Genes Relevant to Human Cancers

PubMed Central

Carpenter, Richard L.; Lo, Hui-Wen

2014-01-01

Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and pathology of many diseases, including cancers. These efforts have uncovered an array of genes that can be positively and negatively regulated by STAT3, alone and in cooperation with other transcription factors. Through regulating gene expression, STAT3 has been demonstrated to play a pivotal role in many cellular processes including oncogenesis, tumor growth and progression, and stemness. Interestingly, recent studies suggest that STAT3 may behave as a tumor suppressor by activating expression of genes known to inhibit tumorigenesis. Additional evidence suggested that STAT3 may elicit opposing effects depending on cellular context and tumor types. These mixed results signify the need for a deeper understanding of STAT3, including its upstream regulators, parallel transcription co-regulators, and downstream target genes. To help facilitate fulfilling this unmet need, this review will be primarily focused on STAT3 downstream target genes that have been validated to associate with tumorigenesis and/or malignant biology of human cancers. PMID:24743777

Phonological Neighborhood and Word Frequency Effects in the Stuttered Disfluencies of Children Who Stutter

PubMed Central

Anderson, Julie D.

2008-01-01

Purpose The purpose of this study was to examine (a) the role of neighborhood density (number of words that are phonologically similar to a target word) and frequency variables on the stuttering-like disfluencies of preschool children who stutter, and (b) whether these variables have an effect on the type of stuttering-like disfluency produced. Method A 500+ word speech sample was obtained from each participant (N = 15). Each stuttered word was randomly paired with the firstly produced word that closely matched it in grammatical class, familiarity, and number of syllables/phonemes. Frequency, neighborhood density, and neighborhood frequency values were obtained for the stuttered and fluent words from an online database. Results Findings revealed that stuttered words were lower in frequency and neighborhood frequency than fluent words. Words containing part-word repetitions and sound prolongations were also lower in frequency and/or neighborhood frequency than fluent words, but these frequency variables did not have an effect on single-syllable word repetitions. Neighborhood density failed to influence the susceptibility of words to stuttering, as well as the type of stuttering-like disfluency produced. Conclusions In general, findings suggest that neighborhood and frequency variables not only influence the fluency with which words are produced in speech, but also have an impact on the type of stuttering-like disfluency produced. PMID:17344561

How Does the Neighborhood "Come through the Door?" Concentrated Disadvantage, Residential Instability, and the Home Environment for Preschoolers.

PubMed

May, Emily M; Azar, Sandra T; Matthews, Stephen A

2018-03-01

Living in a disadvantaged neighborhood is associated with heightened risk for poor school readiness and health outcomes in early childhood, and the home environment is thought to be a primary mechanism by which neighborhood context impacts preschoolers. This study examined the effects of neighborhood concentrated disadvantage and neighborhood residential instability on the home physical environment and home learning environment for preschoolers in economically disadvantaged families (N = 187). Using structural equation modeling, mothers' perceived neighborhood disorder and depressive symptoms were examined as mechanisms by which neighborhood context "comes through the door." Mothers' neighborhood social embeddedness was also explored as a protective factor. Results showed that concentrated disadvantage was negatively associated with the quality of the home physical environment, and residential instability was negatively associated with the quality of the home learning environment. Concentrated disadvantage had an indirect effect on the home learning environment through mothers' perceived neighborhood disorder and depressive symptoms. The effects of concentrated disadvantage on the home environment were buffered by mothers' neighborhood social embeddedness. Study findings advance understanding of socioeconomic- and place-based disparities in developmental outcomes and identify potential targets for interventions aimed at lessening effects of neighborhood disadvantage on families with young children. © Society for Community Research and Action 2018.

Outdoor tobacco advertising in six Boston neighborhoods. Evaluating youth exposure.

PubMed

Pucci, L G; Joseph, H M; Siegel, M

1998-08-01

The Food and Drug Administration (FDA), in its 1996 regulations to restrict certain forms of cigarette advertising likely to appeal to adolescents, prohibited outdoor tobacco advertising within 1,000 feet of schools and playgrounds. No published studies have determined the density of outdoor tobacco advertising within the FDA's prescribed 1,000-foot buffer zone around schools. To determine the prevalence, type, and proximity to public schools of all stationary, outdoor tobacco advertising in six Boston neighborhoods. A cross-sectional field survey conducted in six Boston neighborhoods with varying ethnic, cultural, and socioeconomic characteristics. The main outcome measure was advertising density within buffer zones around public schools. Youth in the six neighborhoods are heavily exposed to stationary, outdoor cigarette advertising. This exposure is intense in areas close to public schools, and more intense in neighborhoods with more children, with significant Black and Hispanic/Latino populations, and with low socioeconomic status. Advertising strategies employed by the tobacco industry are in line with accepted professional marketing practice that targets adolescents for other products. Given the pervasive nature of the outdoor tobacco advertising we observed in the present study, it appears that the only way to protect youth from exposure is by eliminating it from the community.

Magnetic nanoparticles for targeted therapeutic gene delivery and magnetic-inducing heating on hepatoma

NASA Astrophysics Data System (ADS)

Yuan, Chenyan; An, Yanli; Zhang, Jia; Li, Hongbo; Zhang, Hao; Wang, Ling; Zhang, Dongsheng

2014-08-01

Gene therapy holds great promise for treating cancers, but their clinical applications are being hampered due to uncontrolled gene delivery and expression. To develop a targeted, safe and efficient tumor therapy system, we constructed a tissue-specific suicide gene delivery system by using magnetic nanoparticles (MNPs) as carriers for the combination of gene therapy and hyperthermia on hepatoma. The suicide gene was hepatoma-targeted and hypoxia-enhanced, and the MNPs possessed the ability to elevate temperature to the effective range for tumor hyperthermia as imposed on an alternating magnetic field (AMF). The tumoricidal effects of targeted gene therapy associated with hyperthermia were evaluated in vitro and in vivo. The experiment demonstrated that hyperthermia combined with a targeted gene therapy system proffer an effective tool for tumor therapy with high selectivity and the synergistic effect of hepatoma suppression.

Neighborhood cohesion, neighborhood disorder, and cardiometabolic risk.

PubMed

Robinette, Jennifer W; Charles, Susan T; Gruenewald, Tara L

2018-02-01

Perceptions of neighborhood disorder (trash, vandalism) and cohesion (neighbors trust one another) are related to residents' health. Affective and behavioral factors have been identified, but often in studies using geographically select samples. We use a nationally representative sample (n = 9032) of United States older adults from the Health and Retirement Study to examine cardiometabolic risk in relation to perceptions of neighborhood cohesion and disorder. Lower cohesion is significantly related to greater cardiometabolic risk in 2006/2008 and predicts greater risk four years later (2010/2012). The longitudinal relation is partially accounted for by anxiety and physical activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Who Gentrifies Low-Income Neighborhoods?

PubMed

McKinnish, Terra; Walsh, Randall; White, T Kirk

2010-03-01

This paper uses confidential Census data, specifically the 1990 and 2000 Census Long Form data, to study demographic processes in neighborhoods that gentrified during the 1990's. In contrast to previous studies, the analysis is conducted at the more refined census-tract level, with a narrower definition of gentrification and more closely matched comparison neighborhoods. Furthermore, our access to individual-level data with census tract identifiers allows us to separately identify recent in-migrants and long-term residents. Our results indicate that, on average, the demographic flows associated with the gentrification of urban neighborhoods during the 1990's are not consistent with displacement and harm to minority households. In fact, taken as a whole, our results suggest that gentrification of predominantly black neighborhoods creates neighborhoods that are attractive to middle-class black households.

Neighborhood-Specific and General Social Support: Which Buffers the Effect of Neighborhood Disorder on Depression?

ERIC Educational Resources Information Center

Kim, Joongbaeck; Ross, Catherine E.

2009-01-01

Is neighborhood-specific social support the most effective type of social support for buffering the effect of neighborhood disorder on depression? Matching theory suggests that it is. The authors extend the research on neighborhood disorder and adult depression by showing that individuals who have higher levels of both general and…

Urbanism, Neighborhood Context, and Social Networks.

PubMed

Cornwell, Erin York; Behler, Rachel L

2015-09-01

Theories of urbanism suggest that the urban context erodes individuals' strong social ties with friends and family. Recent research has narrowed focus to the neighborhood context, emphasizing how localized structural disadvantage affects community-level cohesion and social capital. In this paper, we argue that neighborhood context also shapes social ties with friends and family- particularly for community-dwelling seniors. We hypothesize that neighborhood disadvantage, residential instability, and disorder restrict residents' abilities to cultivate close relationships with neighbors and non-neighbor friends and family. Using data from the National Social Life, Health, and Aging Project (NSHAP), we find that older adults who live in disadvantaged neighborhoods have smaller social networks. Neighborhood disadvantage is also associated with less close network ties and less frequent interaction - but only among men. Furthermore, residents of disordered neighborhoods have smaller networks and weaker ties. We urge scholars to pay greater attention to how neighborhood context contributes to disparities in network-based access to resources.

Urbanism, Neighborhood Context, and Social Networks

PubMed Central

Cornwell, Erin York; Behler, Rachel L.

2017-01-01

Theories of urbanism suggest that the urban context erodes individuals’ strong social ties with friends and family. Recent research has narrowed focus to the neighborhood context, emphasizing how localized structural disadvantage affects community-level cohesion and social capital. In this paper, we argue that neighborhood context also shapes social ties with friends and family– particularly for community-dwelling seniors. We hypothesize that neighborhood disadvantage, residential instability, and disorder restrict residents’ abilities to cultivate close relationships with neighbors and non-neighbor friends and family. Using data from the National Social Life, Health, and Aging Project (NSHAP), we find that older adults who live in disadvantaged neighborhoods have smaller social networks. Neighborhood disadvantage is also associated with less close network ties and less frequent interaction – but only among men. Furthermore, residents of disordered neighborhoods have smaller networks and weaker ties. We urge scholars to pay greater attention to how neighborhood context contributes to disparities in network-based access to resources. PMID:28819338

Neighborhood Disorder, Social Support, and Outcomes Among Violence-Exposed African American Women.

PubMed

Pickover, Alison M; Bhimji, Jabeene; Sun, Shufang; Evans, Anna; Allbaugh, Lucy J; Dunn, Sarah E; Kaslow, Nadine J

2018-06-01

Intimate partner violence (IPV) against women, particularly those living in poverty who have multiple marginalized identities, is a significant public health issue. IPV is associated with numerous mental health concerns including depression, hopelessness, and suicidal behavior. The present study examined the ecological determinants of these mental health outcomes in a high-risk sample of 67 low-income, African American women survivors of IPV. Based on an ecological framework that conceptualizes individuals as nested in multiple, interactive systems, we examined, longitudinally, the main and interactive effects of self-reported neighborhood disorder and social support from family members and friends on participants' mental health (i.e., self-reported depressive symptoms, hopelessness, and suicide intent). In multiple regression analyses, neighborhood disorder interacted with social support from family members to predict depressive symptoms and hopelessness over time. Neighborhood disorder also interacted with social support from friends to predict hopelessness and suicide intent over time. High levels of social support buffered against the dangerous effects of neighborhood disorder on depressive symptoms, hopelessness, and suicide intent; at low levels of social support, there was no significant association between neighborhood disorder and those mental health outcomes. Neighborhood disorder and social support did not yield significant main effects. These findings underscore the importance of interventions that target individuals, families, and communities (e.g., community empowerment programs). Group interventions may also be important for low-income, African American women survivors of IPV, as they can help survivors establish and strengthen relationships and social support.

Perceived neighborhood social cohesion and stroke.

PubMed

Kim, Eric S; Park, Nansook; Peterson, Christopher

2013-11-01

Research in the last three decades has shown that negative neighborhood factors such as neighborhood violence, noise, traffic, litter, low neighborhood socioeconomic status, and poor air quality increase the risk of poor health. Fewer studies have examined the potential protective effect that neighborhood factors can have on health, particularly stroke. We examined whether higher perceived neighborhood social cohesion was associated with lower stroke incidence after adjusting for traditional risk and psychological factors that have been linked with stroke risk. Prospective data from the Health and Retirement Study--a nationally representative panel study of American adults over the age of 50--were used. Analyses were conducted on a subset of 6740 adults who were stroke-free at baseline. Analyses adjusted for chronic illnesses and relevant sociodemographic, behavioral, and psychosocial factors. Over a four-year follow-up, higher perceived neighborhood social cohesion was associated with a lower risk of stroke. Each standard deviation increase in perceived neighborhood social cohesion was associated with a multivariate-adjusted odds ratio (O.R.) of 0.85 for stroke incidence (95% CI, 0.75-0.97, p < 0.05). The effect of perceived neighborhood social cohesion remained significant after adjusting for a comprehensive set of risk factors. Therefore, perceived neighborhood social cohesion plays an important role in protecting against stroke. Copyright © 2013 Elsevier Ltd. All rights reserved.

AGeNNT: annotation of enzyme families by means of refined neighborhood networks.

PubMed

Kandlinger, Florian; Plach, Maximilian G; Merkl, Rainer

2017-05-25

Large enzyme families may contain functionally diverse members that give rise to clusters in a sequence similarity network (SSN). In prokaryotes, the genome neighborhood of a gene-product is indicative of its function and thus, a genome neighborhood network (GNN) deduced for an SSN provides strong clues to the specific function of enzymes constituting the different clusters. The Enzyme Function Initiative ( http://enzymefunction.org/ ) offers services that compute SSNs and GNNs. We have implemented AGeNNT that utilizes these services, albeit with datasets purged with respect to unspecific protein functions and overrepresented species. AGeNNT generates refined GNNs (rGNNs) that consist of cluster-nodes representing the sequences under study and Pfam-nodes representing enzyme functions encoded in the respective neighborhoods. For cluster-nodes, AGeNNT summarizes the phylogenetic relationships of the contributing species and a statistic indicates how unique nodes and GNs are within this rGNN. Pfam-nodes are annotated with additional features like GO terms describing protein function. For edges, the coverage is given, which is the relative number of neighborhoods containing the considered enzyme function (Pfam-node). AGeNNT is available at https://github.com/kandlinf/agennt . An rGNN is easier to interpret than a conventional GNN, which commonly contains proteins without enzymatic function and overly specific neighborhoods due to phylogenetic bias. The implemented filter routines and the statistic allow the user to identify those neighborhoods that are most indicative of a specific metabolic capacity. Thus, AGeNNT facilitates to distinguish and annotate functionally different members of enzyme families.

How residential mobility and school choice challenge assumptions of neighborhood place-based interventions.

PubMed

Silver, Diana; Weitzman, Beth C; Mijanovich, Tod; Holleman, Martha

2012-01-01

Explore the importance of residential mobility and use of services outside neighborhoods when interventions targeting low-income families are planned and implemented. Analysis of cross-sectional telephone household survey data on childhood mobility and school enrollment in four large distressed cities. Baltimore, Maryland; Detroit, Michigan; Philadelphia, Pennsylvania; and Richmond, Virginia. Total of 1723 teens aged 10 to 18 years and their parents. Continuous self-report of the number of years parents lived in the neighborhood of residence and city; self-report of whether the child attends school in their neighborhood; and categorical self report of parents' marital status, mother's education, parent race, family income, child's age, and child's sex. Chi-square and multivariate logistic regression. In this sample, 85.2% of teens reported living in the city where they were born. However, only 44.4% of black teens lived in neighborhoods where they were born, compared with 59.2% of white teens. Although 50.3% of black teens attended schools outside of their current neighborhoods, only 31.4% of whites did. Residential mobility was more common among black than white children (odds ratio = 1.82; p < .001), and black teens had 43% lesser odds of attending school in their home communities. Mobility among low-income and minority families challenges some assumptions of neighborhood interventions premised on years of exposure to enriched services and changes in the built environment.

Impact of a Neighborhood-Based Curriculum on the Helpfulness of Pediatric Residents' Anticipatory Guidance to Impoverished Families.

PubMed

Real, Francis J; Beck, Andrew F; Spaulding, Jeanne R; Sucharew, Heidi; Klein, Melissa D

2016-11-01

Introduction Neighborhood location has been shown to impact childhood health and well-being. It follows that neighborhood context-the risks and assets present within a patient's neighborhood-may be an important consideration during provision of primary care. Pediatric residents often serve as the primary care physicians for high risk populations though are often unfamiliar with local neighborhoods. As such, education interventions that deepen residents' understanding of a patient's neighborhood context may allow for targeted care provision. A neighborhood-based curriculum was therefore created to improve residents' familiarity with local neighborhoods. Methods The neighborhood-based curriculum utilized a shared interactive presentation to address the topics of housing, nutrition, safe play, pharmacies, and transportation. Education modules included introduction to readily available on-line resources. A pre-post survey assessed resident self-perceived competence on the curricular topics of interest. Caregivers were interviewed in the post-curriculum period to rate the helpfulness of resident-administered advice. Results Following the curriculum, residents reported improved competence on the topics of safe play and transportation (p < 0.05). When addressed in the clinical setting, the large majority of families felt that residents' advice on curricular topics was helpful; however, individual curricular topics were not consistently addressed during clinical encounters. Discussion A neighborhood-based education curriculum can be effective in teaching pediatric residents about the social determinants of health and local neighborhood resources. As research increasingly demonstrates the impact of neighborhood on health, we expect further educational focus on neighborhood as a means from which to educate residents who often care for an impoverished population.

Neighborhood socioeconomic disadvantage and 30-day rehospitalization: a retrospective cohort study.

PubMed

Kind, Amy J H; Jencks, Steve; Brock, Jane; Yu, Menggang; Bartels, Christie; Ehlenbach, William; Greenberg, Caprice; Smith, Maureen

2014-12-02

Measures of socioeconomic disadvantage may enable improved targeting of programs to prevent rehospitalizations, but obtaining such information directly from patients can be difficult. Measures of U.S. neighborhood socioeconomic disadvantage are more readily available but are rarely used clinically. To evaluate the association between neighborhood socioeconomic disadvantage at the census block group level, as measured by the Singh validated area deprivation index (ADI), and 30-day rehospitalization. Retrospective cohort study. United States. Random 5% national sample of Medicare patients discharged with congestive heart failure, pneumonia, or myocardial infarction between 2004 and 2009 (n = 255,744). Medicare data were linked to 2000 census data to construct an ADI for each patient's census block group, which were then sorted into percentiles by increasing ADI. Relationships between neighborhood ADI grouping and 30-day rehospitalization were evaluated using multivariate logistic regression models, controlling for patient sociodemographic characteristics, comorbid conditions and severity, and index hospital characteristics. The 30-day rehospitalization rate did not vary significantly across the least disadvantaged 85% of neighborhoods, which had an average rehospitalization rate of 21%. However, within the most disadvantaged 15% of neighborhoods, rehospitalization rates increased from 22% to 27% with worsening ADI. This relationship persisted after full adjustment, with the most disadvantaged neighborhoods having a rehospitalization risk (adjusted risk ratio, 1.09 [95% CI, 1.05 to 1.12]) similar to that of chronic pulmonary disease (adjusted risk ratio, 1.06 [CI, 1.04 to 1.08]) and greater than that of uncomplicated diabetes (adjusted risk ratio, 0.95 [CI, 0.94 to 0.97]). No direct markers of care quality or access. Residence within a disadvantaged U.S. neighborhood is a rehospitalization predictor of magnitude similar to chronic pulmonary disease. Measures of

The neighborhoods they live in: the effects of neighborhood residence on child and adolescent outcomes.

PubMed

Leventhal, T; Brooks-Gunn, J

2000-03-01

This article provides a comprehensive review of research on the effects of neighborhood residence on child and adolescent well-being. The first section reviews key methodological issues. The following section considers links between neighborhood characteristics and child outcomes and suggests the importance of high socioeconomic status (SES) for achievement and low SES and residential instability for behavioral/emotional outcomes. The third section identifies 3 pathways (institutional resources, relationships, and norms/collective efficacy) through which neighborhoods might influence development, and which represent an extension of models identified by C. Jencks and S. Mayer (1990) and R. J. Sampson (1992). The models provide a theoretical base for studying neighborhood mechanisms and specify different levels (individual, family, school, peer, community) at which processes may operate. Implications for an emerging developmental framework for research on neighborhoods are discussed.

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

NASA Astrophysics Data System (ADS)

Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

2015-03-01

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing

The influence of HOPE VI neighborhood revitalization on neighborhood-based physical activity: A mixed-methods approach.

PubMed

Dulin-Keita, Akilah; Clay, Olivio; Whittaker, Shannon; Hannon, Lonnie; Adams, Ingrid K; Rogers, Michelle; Gans, Kim

2015-08-01

This study uses a mixed methods approach to 1) identify surrounding residents' perceived expectations for Housing Opportunities for People Everywhere (HOPE VI) policy on physical activity outcomes and to 2) quantitatively examine the odds of neighborhood-based physical activity pre-/post-HOPE VI in a low socioeconomic status, predominantly African American community in Birmingham, Alabama. To address aim one, we used group concept mapping which is a structured approach for data collection and analyses that produces pictures/maps of ideas. Fifty-eight residents developed statements about potential influences of HOPE VI on neighborhood-based physical activity. In the quantitative study, we examined whether these potential influences increased the odds of neighborhood walking/jogging. We computed block entry logistic regression models with a larger cohort of residents at baseline (n = 184) and six-months (n = 142, 77% retention; n = 120 for all informative variables). We examined perceived neighborhood disorder (perceived neighborhood disorder scale), walkability and aesthetics (Neighborhood Environment Walkability Scale) and HOPE VI-related community safety and safety for physical activity as predictors. During concept mapping, residents generated statements that clustered into three distinct concepts, "Increased Leisure Physical Activity," "Safe Play Areas," and "Generating Health Promoting Resources." The quantitative analyses indicated that changes in neighborhood walkability increased the odds of neighborhood-based physical activity (p = 0.04). When HOPE VI-related safety for physical activity was entered into the model, it was associated with increased odds of physical activity (p = 0.04). Walkability was no longer statistically significant. These results suggest that housing policies that create walkable neighborhoods and that improve perceptions of safety for physical activity may increase neighborhood-based physical activity. However, the longer

Effect of neighborhood stigma on economic transactions

PubMed Central

Besbris, Max; Faber, Jacob William; Rich, Peter; Sharkey, Patrick

2015-01-01

The hypothesis of neighborhood stigma predicts that individuals who reside in areas known for high crime, poverty, disorder, and/or racial isolation embody the negative characteristics attributed to their communities and experience suspicion and mistrust in their interactions with strangers. This article provides an experimental test of whether neighborhood stigma affects individuals in one domain of social life: economic transactions. To evaluate the neighborhood stigma hypothesis, this study adopts an audit design in a locally organized, online classified market, using advertisements for used iPhones and randomly manipulating the neighborhood of the seller. The primary outcome under study is the number of responses generated by sellers from disadvantaged relative to advantaged neighborhoods. Advertisements from disadvantaged neighborhoods received significantly fewer responses than advertisements from advantaged neighborhoods. Results provide robust evidence that individuals from disadvantaged neighborhoods bear a stigma that influences their prospects in economic exchanges. The stigma is greater for advertisements originating from disadvantaged neighborhoods where the majority of residents are black. This evidence reveals that residence in a disadvantaged neighborhood not only affects individuals through mechanisms involving economic resources, institutional quality, and social networks but also affects residents through the perceptions of others. PMID:25848041

Neurobiology of autism gene products: towards pathogenesis and drug targets.

PubMed

Kleijer, Kristel T E; Schmeisser, Michael J; Krueger, Dilja D; Boeckers, Tobias M; Scheiffele, Peter; Bourgeron, Thomas; Brose, Nils; Burbach, J Peter H

2014-03-01

The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets. The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms. Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions. The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity. ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

A Longitudinal Analysis of the Influence of the Neighborhood Environment on Recreational Walking within the Neighborhood: Results from RESIDE

PubMed Central

Knuiman, Matthew; Divitini, Mark; Foster, Sarah; Hooper, Paula; Boruff, Bryan; Bull, Fiona; Giles-Corti, Billie

2017-01-01

Background: There is limited longitudinal evidence confirming the role of neighborhood environment attributes in encouraging people to walk more or if active people simply choose to live in activity-friendly neighborhoods. Natural experiments of policy changes to create more walkable communities provide stronger evidence for a causal effect of neighborhood environments on residents’ walking. Objectives: We aimed to investigate longitudinal associations between objective and perceived neighborhood environment measures and neighborhood recreational walking. Methods: We analyzed longitudinal data collected over 8 yr (four surveys) from the RESIDential Environments (RESIDE) Study (Perth, Australia, 2003–2012). At each time point, participants reported the frequency and total minutes of recreational walking/week within their neighborhood and neighborhood environment perceptions. Objective measures of the neighborhood environment were generated using a Geographic Information System (GIS). Results: Local recreational walking was influenced by objectively measured access to a medium-/large-size park, beach access, and higher street connectivity, which was reduced when adjusted for neighborhood perceptions. In adjusted models, positive perceptions of access to a park and beach, higher street connectivity, neighborhood esthetics, and safety from crime were independent determinants of increased neighborhood recreational walking. Local recreational walking increased by 9 min/wk (12% increase in frequency) for each additional perceived neighborhood attribute present. Conclusions: Our findings provide urban planners and policy makers with stronger causal evidence of the positive impact of well-connected neighborhoods and access to local parks of varying sizes on local residents’ recreational walking and health. https://doi.org/10.1289/EHP823 PMID:28728139

Single molecule targeted sequencing for cancer gene mutation detection.

PubMed

Gao, Yan; Deng, Liwei; Yan, Qin; Gao, Yongqian; Wu, Zengding; Cai, Jinsen; Ji, Daorui; Li, Gailing; Wu, Ping; Jin, Huan; Zhao, Luyang; Liu, Song; Ge, Liangjin; Deem, Michael W; He, Jiankui

2016-05-19

With the rapid decline in cost of sequencing, it is now affordable to examine multiple genes in a single disease-targeted clinical test using next generation sequencing. Current targeted sequencing methods require a separate step of targeted capture enrichment during sample preparation before sequencing. Although there are fast sample preparation methods available in market, the library preparation process is still relatively complicated for physicians to use routinely. Here, we introduced an amplification-free Single Molecule Targeted Sequencing (SMTS) technology, which combined targeted capture and sequencing in one step. We demonstrated that this technology can detect low-frequency mutations using artificially synthesized DNA sample. SMTS has several potential advantages, including simple sample preparation thus no biases and errors are introduced by PCR reaction. SMTS has the potential to be an easy and quick sequencing technology for clinical diagnosis such as cancer gene mutation detection, infectious disease detection, inherited condition screening and noninvasive prenatal diagnosis.

Gene replacements and insertions in rice by intron targeting using CRISPR-Cas9.

PubMed

Li, Jun; Meng, Xiangbing; Zong, Yuan; Chen, Kunling; Zhang, Huawei; Liu, Jinxing; Li, Jiayang; Gao, Caixia

2016-09-12

Sequence-specific nucleases have been exploited to create targeted gene knockouts in various plants(1), but replacing a fragment and even obtaining gene insertions at specific loci in plant genomes remain a serious challenge. Here, we report efficient intron-mediated site-specific gene replacement and insertion approaches that generate mutations using the non-homologous end joining (NHEJ) pathway using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system. Using a pair of single guide RNAs (sgRNAs) targeting adjacent introns and a donor DNA template including the same pair of sgRNA sites, we achieved gene replacements in the rice endogenous gene 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) at a frequency of 2.0%. We also obtained targeted gene insertions at a frequency of 2.2% using a sgRNA targeting one intron and a donor DNA template including the same sgRNA site. Rice plants harbouring the OsEPSPS gene with the intended substitutions were glyphosate-resistant. Furthermore, the site-specific gene replacements and insertions were faithfully transmitted to the next generation. These newly developed approaches can be generally used to replace targeted gene fragments and to insert exogenous DNA sequences into specific genomic sites in rice and other plants.

Who Gentrifies Low-Income Neighborhoods?*

PubMed Central

McKinnish, Terra; Walsh, Randall; White, T. Kirk

2009-01-01

This paper uses confidential Census data, specifically the 1990 and 2000 Census Long Form data, to study demographic processes in neighborhoods that gentrified during the 1990’s. In contrast to previous studies, the analysis is conducted at the more refined census-tract level, with a narrower definition of gentrification and more closely matched comparison neighborhoods. Furthermore, our access to individual-level data with census tract identifiers allows us to separately identify recent in-migrants and long-term residents. Our results indicate that, on average, the demographic flows associated with the gentrification of urban neighborhoods during the 1990’s are not consistent with displacement and harm to minority households. In fact, taken as a whole, our results suggest that gentrification of predominantly black neighborhoods creates neighborhoods that are attractive to middle-class black households. PMID:20161532

Production of Prnp-/- goats by gene targeting in adult fibroblasts.

PubMed

Zhu, Caihong; Li, Bei; Yu, Guohua; Chen, Jianquan; Yu, Huiqing; Chen, Juan; Xu, Xujun; Wu, Youbing; Zhang, Aimin; Cheng, Guoxiang

2009-04-01

Homozygous mice devoid of functional Prnp are resistant to scrapie and prion propagation, but heterozygous mice for Prnp disruption still suffer from prion disease and prion deposition. We have previously generated heterozygous cloned goats with one allele of Prnp functional disruption. To obtain goats with both alleles of Prnp be disrupted which would be resistant to scrapie completely, a second-round gene targeting was applied to disrupt the wild type allele of Prnp in the heterozygous goats. By second-round gene targeting, we successfully disrupted the wild type allele of Prnp in primary Prnp (+/-) goat skin fibroblasts and obtained a Prnp (-/-) cell line without Prnp expression. This is the first report on successful targeting modification in primary adult somatic cells of animals. These cells were used as nuclear donors for somatic cell cloning to produce Prnp (-/-) goats. A total of 57 morulae or blastocytes developed from the reconstructed embryos were transferred to 31 recipients, which produced 7 pregnancies at day 35. At 73 days of gestation, we obtained one cloned fetus with Prnp (-/-) genotype. Our research not only indicated that multiple genetic modifications could be accomplished by multi-round gene targeting in primary somatic cells, but also provided strong evidence that gene targeting in adult cells other than fetal cells could be applied to introduce precise genetic modifications in animals without destroying the embryos.

Understanding Associations between Neighborhood Socioeconomic Status and Negative Consequences of Drinking: A Moderated Mediation Analysis

PubMed Central

Karriker-Jaffe, Katherine J.; Liu, HuiGuo; Kaplan, Lauren M.

2016-01-01

Aims We explored how neighborhood socioeconomic status (SES) is related to negative consequences of drinking to explain why racial/ethnic minority group members are more at risk than Whites for adverse alcohol outcomes. We tested direct and indirect effects of neighborhood SES on alcohol problems and examined differences by gender and race. Methods We used data from the 2000 and 2005 National Alcohol Surveys (N=7,912 drinkers aged 18 and older; 49% female) linked with data from the 2000 Decennial Census in multivariate path models adjusting for individual demographics. Results In the full sample, neighborhood disadvantage had a significant direct path to increased negative consequences, with no indirect paths through depression, positive affect or pro-drinking attitudes. Neighborhood affluence had significant indirect paths to increased negative consequences through greater pro-drinking attitudes and increased heavy drinking. Sub-group analyses showed the indirect path from affluence to consequences held for White men, with no effects of neighborhood disadvantage. For racial/ethnic minority men, significant indirect paths emerged from both neighborhood disadvantage and affluence to increased consequences through greater pro-drinking attitudes and more heavy drinking. For minority women, there was an indirect effect of neighborhood affluence through reduced depression to fewer drinking consequences. There were limited neighborhood effects on alcohol outcomes for White women. Conclusions Interventions targeting pro-drinking attitudes in both affluent and disadvantaged areas may help reduce alcohol-related problems among men. Initiatives to improve neighborhood conditions could enhance mental health of minority women and reduce alcohol-related health disparities. PMID:26898509

The Neighborhood Energy Balance Equation: Does Neighborhood Food Retail Environment + Physical Activity Environment = Obesity? The CARDIA Study

PubMed Central

Boone-Heinonen, Janne; Diez-Roux, Ana V.; Goff, David C.; Loria, Catherine M.; Kiefe, Catarina I.; Popkin, Barry M.; Gordon-Larsen, Penny

2013-01-01

Background Recent obesity prevention initiatives focus on healthy neighborhood design, but most research examines neighborhood food retail and physical activity (PA) environments in isolation. We estimated joint, interactive, and cumulative impacts of neighborhood food retail and PA environment characteristics on body mass index (BMI) throughout early adulthood. Methods and Findings We used cohort data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study [n=4,092; Year 7 (24-42 years, 1992-1993) followed over 5 exams through Year 25 (2010-2011); 12,921 person-exam observations], with linked time-varying geographic information system-derived neighborhood environment measures. Using regression with fixed effects for individuals, we modeled time-lagged BMI as a function of food and PA resource density (counts per population) and neighborhood development intensity (a composite density score). We controlled for neighborhood poverty, individual-level sociodemographics, and BMI in the prior exam; and included significant interactions between neighborhood measures and by sex. Using model coefficients, we simulated BMI reductions in response to single and combined neighborhood improvements. Simulated increase in supermarket density (from 25th to 75th percentile) predicted inter-exam reduction in BMI of 0.09 kg/m2 [estimate (95% CI): -0.09 (-0.16, -0.02)]. Increasing commercial PA facility density predicted BMI reductions up to 0.22 kg/m2 in men, with variation across other neighborhood features [estimate (95% CI) range: -0.14 (-0.29, 0.01) to -0.22 (-0.37, -0.08)]. Simultaneous increases in supermarket and commercial PA facility density predicted inter-exam BMI reductions up to 0.31 kg/m2 in men [estimate (95% CI) range: -0.23 (-0.39, -0.06) to -0.31 (-0.47, -0.15)] but not women. Reduced fast food restaurant and convenience store density and increased public PA facility density and neighborhood development intensity did not predict reductions in BMI

Malt liquor marketing in inner cities: the role of neighborhood racial composition.

PubMed

McKee, Pat; Jones-Webb, Rhonda; Hannan, Peter; Pham, Lan

2011-01-01

In response to anecdotal reports that African American neighborhoods are targeted for high-alcohol malt liquor advertising, the authors observed alcohol ads on off-premise alcohol outlets, billboards, and transit structures in 10 U.S. cities over 3 years. Malt liquor ads were prevalent on storefronts, but rare on billboards. Using Poisson regression, the authors found that storefront malt liquor ads were more common in neighborhoods with higher percentages of African Americans, even after controlling for social and physical disorder. Results suggest that policymakers attempting to reduce malt liquor-related harms may do well to consider regulations that limit storefront advertising exposure.

Nearest neighbors by neighborhood counting.

PubMed

Wang, Hui

2006-06-01

Finding nearest neighbors is a general idea that underlies many artificial intelligence tasks, including machine learning, data mining, natural language understanding, and information retrieval. This idea is explicitly used in the k-nearest neighbors algorithm (kNN), a popular classification method. In this paper, this idea is adopted in the development of a general methodology, neighborhood counting, for devising similarity functions. We turn our focus from neighbors to neighborhoods, a region in the data space covering the data point in question. To measure the similarity between two data points, we consider all neighborhoods that cover both data points. We propose to use the number of such neighborhoods as a measure of similarity. Neighborhood can be defined for different types of data in different ways. Here, we consider one definition of neighborhood for multivariate data and derive a formula for such similarity, called neighborhood counting measure or NCM. NCM was tested experimentally in the framework of kNN. Experiments show that NCM is generally comparable to VDM and its variants, the state-of-the-art distance functions for multivariate data, and, at the same time, is consistently better for relatively large k values. Additionally, NCM consistently outperforms HEOM (a mixture of Euclidean and Hamming distances), the "standard" and most widely used distance function for multivariate data. NCM has a computational complexity in the same order as the standard Euclidean distance function and NCM is task independent and works for numerical and categorical data in a conceptually uniform way. The neighborhood counting methodology is proven sound for multivariate data experimentally. We hope it will work for other types of data.

Neighborhood Context and Immigrant Young Children's Development

ERIC Educational Resources Information Center

Leventhal, Tama; Shuey, Elizabeth A.

2014-01-01

This study explored how neighborhood social processes and resources, relevant to immigrant families and immigrant neighborhoods, contribute to young children's behavioral functioning and achievement across diverse racial/ethnic groups. Data were drawn from the Project on Human Development in Chicago Neighborhoods, a neighborhood-based,…

Identification of STAT target genes in adipocytes

PubMed Central

Zhao, Peng; Stephens, Jacqueline M.

2013-01-01

Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. Studies in the last two decades have identified the hormones and cytokines that activate specific STATs in adipocytes in vitro and in vivo. Five of the seven STAT family members are expressed in adipocyte (STATs 1, 3, 5A, 5B and 6). Many transcription factors, including STATs, have been shown to play an important role in adipose tissue development and function. This review will summarize the importance of adipocytes, indicate the cytokines and hormones that utilize the JAK-STAT signaling pathway in fat cells and focus on the identification of STAT target genes in mature adipocytes. To date, specific target genes have been identified for STATs, 1, 5A and 5B, but not for STATs 3 and 6. PMID:24058802

Bioinformatics approaches to predict target genes from transcription factor binding data.

PubMed

Essebier, Alexandra; Lamprecht, Marnie; Piper, Michael; Bodén, Mikael

2017-12-01

Transcription factors regulate gene expression and play an essential role in development by maintaining proliferative states, driving cellular differentiation and determining cell fate. Transcription factors are capable of regulating multiple genes over potentially long distances making target gene identification challenging. Currently available experimental approaches to detect distal interactions have multiple weaknesses that have motivated the development of computational approaches. Although an improvement over experimental approaches, existing computational approaches are still limited in their application, with different weaknesses depending on the approach. Here, we review computational approaches with a focus on data dependency, cell type specificity and usability. With the aim of identifying transcription factor target genes, we apply available approaches to typical transcription factor experimental datasets. We show that approaches are not always capable of annotating all transcription factor binding sites; binding sites should be treated disparately; and a combination of approaches can increase the biological relevance of the set of genes identified as targets. Copyright © 2017 Elsevier Inc. All rights reserved.

Cis-regulatory element based targeted gene finding: genome-wide identification of abscisic acid- and abiotic stress-responsive genes in Arabidopsis thaliana.

PubMed

Zhang, Weixiong; Ruan, Jianhua; Ho, Tuan-Hua David; You, Youngsook; Yu, Taotao; Quatrano, Ralph S

2005-07-15

A fundamental problem of computational genomics is identifying the genes that respond to certain endogenous cues and environmental stimuli. This problem can be referred to as targeted gene finding. Since gene regulation is mainly determined by the binding of transcription factors and cis-regulatory DNA sequences, most existing gene annotation methods, which exploit the conservation of open reading frames, are not effective in finding target genes. A viable approach to targeted gene finding is to exploit the cis-regulatory elements that are known to be responsible for the transcription of target genes. Given such cis-elements, putative target genes whose promoters contain the elements can be identified. As a case study, we apply the above approach to predict the genes in model plant Arabidopsis thaliana which are inducible by a phytohormone, abscisic acid (ABA), and abiotic stress, such as drought, cold and salinity. We first construct and analyze two ABA specific cis-elements, ABA-responsive element (ABRE) and its coupling element (CE), in A.thaliana, based on their conservation in rice and other cereal plants. We then use the ABRE-CE module to identify putative ABA-responsive genes in A.thaliana. Based on RT-PCR verification and the results from literature, this method has an accuracy rate of 67.5% for the top 40 predictions. The cis-element based targeted gene finding approach is expected to be widely applicable since a large number of cis-elements in many species are available.

Obesogenic Neighborhood Environments, Child and Parent Obesity

PubMed Central

Saelens, Brian E.; Sallis, James F.; Frank, Lawrence D.; Couch, Sarah C.; Zhou, Chuan; Colburn, Trina; Cain, Kelli L.; Chapman, James; Glanz, Karen

2012-01-01

Background Identifying neighborhood environment attributes related to childhood obesity can inform environmental changes for obesity prevention. Purpose To evaluate child and parent weight status across neighborhoods in King County/Seattle and San Diego County differing in GIS-defined physical activity environment (PAE) and nutrition environment (NE) characteristics. Methods Neighborhoods were selected to represent high (favorable) versus low (unfavorable) on the two measures, forming four neighborhood types (low on both measures, low PAE/high NE, high PAE/low NE, and high on both measures). Weight and height of children aged 6–11 years and one parent (n=730) from selected neighborhoods were assessed in 2007–2009. Differences in child and parent overweight and obesity by neighborhood type were examined, adjusting for neighborhood-, family-, and individual-level demographics. Results Children from neighborhoods high on both environment measures were less likely to be obese (7.7% vs 15.9% OR=0.44, p=0.02) and marginally less likely to be overweight (23.7% vs 31.7%; OR=0.67, p=0.08) than children from neighborhoods low on both measures. In models adjusted for parent weight status and demographic factors, neighborhood environment type remained related to child obesity (high vs low on both measures; OR=0.41, p<0.03). Parents in neighborhoods high on both measures (versus low on both) were marginally less likely to be obese (20.1% vs 27.7%; OR=0.66; p=0.08), although parent overweight did not differ on this variable. The lower odds of parent obesity in neighborhoods with environments supportive of physical activity and healthy eating remained in models adjusted for demographics (high vs low on the environment measures; OR=0.57, p=0.053). Conclusions Findings support the proposed GIS-based definitions of obesogenic neighborhoods for children and parents that consider both physical activity and nutrition environment features. PMID:22516504

Xander: employing a novel method for efficient gene-targeted metagenomic assembly

DOE PAGES

Wang, Qiong; Fish, Jordan A.; Gilman, Mariah; ...

2015-08-05

Here, metagenomics can provide important insight into microbial communities. However, assembling metagenomic datasets has proven to be computationally challenging. Current methods often assemble only fragmented partial genes. We present a novel method for targeting assembly of specific protein-coding genes. This method combines a de Bruijn graph, as used in standard assembly approaches, and a protein profile hidden Markov model (HMM) for the gene of interest, as used in standard annotation approaches. These are used to create a novel combined weighted assembly graph. Xander performs both assembly and annotation concomitantly using information incorporated in this graph. We demonstrate the utility ofmore » this approach by assembling contigs for one phylogenetic marker gene and for two functional marker genes, first on Human Microbiome Project (HMP)-defined community Illumina data and then on 21 rhizosphere soil metagenomic datasets from three different crops totaling over 800 Gbp of unassembled data. We compared our method to a recently published bulk metagenome assembly method and a recently published gene-targeted assembler and found our method produced more, longer, and higher quality gene sequences. In conclusion, xander combines gene assignment with the rapid assembly of full-length or near full-length functional genes from metagenomic data without requiring bulk assembly or post-processing to find genes of interest. HMMs used for assembly can be tailored to the targeted genes, allowing flexibility to improve annotation over generic annotation pipelines.« less

Xander: employing a novel method for efficient gene-targeted metagenomic assembly.

PubMed

Wang, Qiong; Fish, Jordan A; Gilman, Mariah; Sun, Yanni; Brown, C Titus; Tiedje, James M; Cole, James R

2015-01-01

Metagenomics can provide important insight into microbial communities. However, assembling metagenomic datasets has proven to be computationally challenging. Current methods often assemble only fragmented partial genes. We present a novel method for targeting assembly of specific protein-coding genes. This method combines a de Bruijn graph, as used in standard assembly approaches, and a protein profile hidden Markov model (HMM) for the gene of interest, as used in standard annotation approaches. These are used to create a novel combined weighted assembly graph. Xander performs both assembly and annotation concomitantly using information incorporated in this graph. We demonstrate the utility of this approach by assembling contigs for one phylogenetic marker gene and for two functional marker genes, first on Human Microbiome Project (HMP)-defined community Illumina data and then on 21 rhizosphere soil metagenomic datasets from three different crops totaling over 800 Gbp of unassembled data. We compared our method to a recently published bulk metagenome assembly method and a recently published gene-targeted assembler and found our method produced more, longer, and higher quality gene sequences. Xander combines gene assignment with the rapid assembly of full-length or near full-length functional genes from metagenomic data without requiring bulk assembly or post-processing to find genes of interest. HMMs used for assembly can be tailored to the targeted genes, allowing flexibility to improve annotation over generic annotation pipelines. This method is implemented as open source software and is available at https://github.com/rdpstaff/Xander_assembler.

Children's physical activity and parents' perception of the neighborhood environment: neighborhood impact on kids study.

PubMed

Tappe, Karyn A; Glanz, Karen; Sallis, James F; Zhou, Chuan; Saelens, Brian E

2013-03-27

Physical activity is important to children's physical health and well-being. Many factors contribute to children's physical activity, and the built environment has garnered considerable interest recently, as many young children spend much of their time in and around their immediate neighborhood. Few studies have identified correlates of children's activity in specific locations. This study examined associations between parent report of their home neighborhood environment and children's overall and location-specific physical activity. Parents and children ages 6 to 11 (n=724), living in neighborhoods identified through objective built environment factors as high or low in physical activity environments, were recruited from Seattle and San Diego metropolitan areas, 2007-2009. Parents completed a survey about their child's activity and perceptions of home neighborhood environmental attributes. Children wore an accelerometer for 7 days. Multivariate regression models explored perceived environment correlates of parent-reported child's recreational physical activity in their neighborhood, in parks, and in general, as well as accelerometry-based moderate-to-vigorous activity (MVPA) minutes. Parent-reported proximity to play areas correlated positively with both accelerometery MVPA and parent-reported total child physical activity. Lower street connectivity and higher neighborhood aesthetics correlated with higher reported child activity in the neighborhood, while reported safety from crime and walk and cycle facilities correlated positively with reported child activity in public recreation spaces. Different aspects of parent's perceptions of the neighborhood environment appear to correlate with different aspects of children's activity. However, prioritizing closer proximity to safe play areas may best improve children's physical activity and, in turn, reduce their risk of obesity and associated chronic diseases.

Collateral Consequences of Violence in Disadvantaged Neighborhoods

ERIC Educational Resources Information Center

Harding, David J.

2009-01-01

Using data from Add Health, this study investigates the role of neighborhood violence in mediating the effects of neighborhood disadvantage on high school graduation and teenage pregnancy. Results show that neighborhood violence is a strong predictor of both outcomes, net of individual, family, community and school controls. Neighborhood violence…

Gene silencing in Tribolium castaneum as a tool for the targeted identification of candidate RNAi targets in crop pests.

PubMed

Knorr, Eileen; Fishilevich, Elane; Tenbusch, Linda; Frey, Meghan L F; Rangasamy, Murugesan; Billion, Andre; Worden, Sarah E; Gandra, Premchand; Arora, Kanika; Lo, Wendy; Schulenberg, Greg; Valverde-Garcia, Pablo; Vilcinskas, Andreas; Narva, Kenneth E

2018-02-01

RNAi shows potential as an agricultural technology for insect control, yet, a relatively low number of robust lethal RNAi targets have been demonstrated to control insects of agricultural interest. In the current study, a selection of lethal RNAi target genes from the iBeetle (Tribolium castaneum) screen were used to demonstrate efficacy of orthologous targets in the economically important coleopteran pests Diabrotica virgifera virgifera and Meligethes aeneus. Transcript orthologs of 50 selected genes were analyzed in D. v. virgifera diet-based RNAi bioassays; 21 of these RNAi targets showed mortality and 36 showed growth inhibition. Low dose injection- and diet-based dsRNA assays in T. castaneum and D. v. virgifera, respectively, enabled the identification of the four highly potent RNAi target genes: Rop, dre4, ncm, and RpII140. Maize was genetically engineered to express dsRNA directed against these prioritized candidate target genes. T 0 plants expressing Rop, dre4, or RpII140 RNA hairpins showed protection from D. v. virgifera larval feeding damage. dsRNA targeting Rop, dre4, ncm, and RpII140 in M. aeneus also caused high levels of mortality both by injection and feeding. In summary, high throughput systems for model organisms can be successfully used to identify potent RNA targets for difficult-to-work with agricultural insect pests.

Impact of Urban Neighborhood Disadvantage on Late Stage Breast Cancer Diagnosis in Virginia.

PubMed

DeGuzman, Pam Baker; Cohn, Wendy F; Camacho, Fabian; Edwards, Brandy L; Sturz, Vanessa N; Schroen, Anneke T

2017-04-01

Research suggests that residents of inner-city urban neighborhoods have higher rates of late stage cancer diagnosis. Identifying urban neighborhoods with high rates of both concentrated disadvantage and late stage cancer diagnosis may assist health care providers to target screening interventions to reduce disparities. The purposes of this study were to (1) create an index to evaluate concentrated disadvantage (CD) using non-racial measures of poverty, (2) determine the impact of neighborhood CD on late stage breast cancer diagnosis in US cities, and (3) to understand the role of obesity on this relationship. We used census block group- (CBG) level poverty indicators from five Virginia cities to develop the index. Breast cancer cases of women aged 18-65 who lived in the five cities were identified from the 2000-2012 Virginia Cancer Registry. A logistic regression model with random intercept was used to evaluate the impact of disadvantage on late stage breast cancer diagnosis. CBG-level maps were developed to geographically identify neighborhoods with both high rates of CD and late breast cancer staging. Over 900 CBGs and 6000 breast cases were included. Global fit of the concentrated disadvantage model was acceptable. The effect of disadvantage on late stage was significant (OR = 1.0083, p = 0.032). Inner-city poverty impacts risk of late stage breast cancer diagnosis. Area-level obesity is highly correlated with neighborhood poverty (ρ = 0.74, p < 0.0001) but the mediating direct and indirect effects are non-significant. Intervening in these high poverty neighborhoods may help combat disparities in late stage diagnosis for urban poor and for minorities living in these underserved neighborhoods, but more study is needed to understanding the complex relationship between concentrated neighborhood poverty, obesity, and late stage diagnosis.

Cumulative Effects of Neighborhood Social Adversity and Personal Crime Victimization on Adolescent Psychotic Experiences

PubMed Central

Newbury, Joanne; Arseneault, Louise; Caspi, Avshalom; Moffitt, Terrie E; Odgers, Candice L

2018-01-01

targeted towards victimized youth living in urban and socially adverse neighborhoods. PMID:28535284

Cumulative Effects of Neighborhood Social Adversity and Personal Crime Victimization on Adolescent Psychotic Experiences.

PubMed

Newbury, Joanne; Arseneault, Louise; Caspi, Avshalom; Moffitt, Terrie E; Odgers, Candice L; Fisher, Helen L

2018-02-15

Little is known about the impact of urbanicity, adverse neighborhood conditions and violent crime victimization on the emergence of adolescent psychotic experiences. Participants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins who were interviewed about adolescent psychotic experiences at age 18. Urbanicity, neighborhood characteristics, and personal victimization by violent crime were measured during childhood and adolescence via geocoded census data, surveys of over 5000 immediate neighbors of the E-Risk participants, and interviews with participants themselves. Adolescents raised in urban vs rural neighborhoods were significantly more likely to have psychotic experiences (OR = 1.67, 95% CI = 1.21-2.30, P = .002). This association remained significant after considering potential confounders including family socioeconomic status, family psychiatric history, and adolescent substance problems (OR = 1.43, 95% CI = 1.01-2.03, P = .042), but became nonsignificant after considering adverse social conditions in urban neighborhoods such as low social cohesion and high neighborhood disorder (OR = 1.35, 95% CI = 0.94-1.92, P = .102). The combined association of adverse neighborhood social conditions and personal crime victimization with adolescent psychotic experiences (adjusted OR = 4.86, 95% CI = 3.28-7.20, P < .001) was substantially greater than for either exposure alone, highlighting a potential interaction between neighborhood conditions and crime victimization (interaction contrast ratio = 1.81, 95% CI = -0.03 to 3.65) that was significant at the P = .054 level. Cumulative effects of adverse neighborhood social conditions and personal victimization by violent crime during upbringing partly explain why adolescents in urban settings are more likely to report psychotic experiences. Early intervention efforts for psychosis could be targeted towards victimized youth living in urban and socially

Generation of TALE nickase-mediated gene-targeted cows expressing human serum albumin in mammary glands.

PubMed

Luo, Yan; Wang, Yongsheng; Liu, Jun; Cui, Chenchen; Wu, Yongyan; Lan, Hui; Chen, Qi; Liu, Xu; Quan, Fusheng; Guo, Zekun; Zhang, Yong

2016-02-08

Targeting exogenous genes at milk protein loci via gene-targeting technology is an ideal strategy for producing large quantities of pharmaceutical proteins. Transcription-activator-like effector (TALE) nucleases (TALENs) are an efficient genome-editing tool. However, the off-target effects may lead to unintended gene mutations. In this study, we constructed TALENs and TALE nickases directed against exon 2 of the bovine β-lactoglobulin (BLG) locus. The nickases can induce a site-specific DNA single-strand break, without inducing double-strand break and nonhomologous end joining mediated gene mutation, and lower cell apoptosis rate than TALENs. After co-transfecting the bovine fetal fibroblasts with human serum albumin (HSA) gene-targeting vector and TALE nickase expression vectors, approximately 4.8% (40/835) of the cell clones contained HSA at BLG locus. Unexpectedly, one homozygous gene-targeted cell clone (1/835, 0.1%) was obtained by targeting both alleles of BLG in a single round of transfection. The recombinant protein mimicking the endogenous BLG was highly expressed and correctly folded in the mammary glands of the targeted cows, and the expression level of HSA was significantly increased in the homozygous targeted cows. Results suggested that the combination of TALE nickase-mediated gene targeting and somatic cell nuclear transfer is a feasible and safe approach in producing gene-targeted livestock.

From genes to milk: genomic organization and epigenetic regulation of the mammary transcriptome.

PubMed

Lemay, Danielle G; Pollard, Katherine S; Martin, William F; Freeman Zadrowski, Courtneay; Hernandez, Joseph; Korf, Ian; German, J Bruce; Rijnkels, Monique

2013-01-01

Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival.

Neighborhood Concentrated Disadvantage and Dating Violence among Urban Adolescents: The Mediating Role of Neighborhood Social Processes.

PubMed

Garthe, Rachel C; Gorman-Smith, Deborah; Gregory, Joshua; E Schoeny, Michael

2018-06-01

The link between relationship violence and aspects of neighborhood concentrated disadvantage (e.g., percent of unemployed adults, percent of families below poverty level), has been established. However, the literature examining neighborhood social processes, including informal social control and social cohesion, in relation to adolescent dating violence has shown mixed results with a limited theoretical foundation and methodology. Using a social disorganization theoretical framework, this study examined the mediating role of these neighborhood social processes in the relation between concentrated disadvantage and adolescent dating violence within an urban context. Participants included 605 adult residents in 30 census tracts and 203 adolescents from neighborhoods on the West and South sides of Chicago. Neighborhood-level concentrated disadvantage was measured via Census data, adult residents reported on neighborhood social processes, and youth reported on dating violence. Informal social control was negatively associated with dating violence, and social cohesion was positively associated with dating violence. A multilevel mediation model showed that concentrated disadvantage was related to higher levels of dating violence via lower levels of informal social control. These results extend social disorganization theory to dating violence within an urban context, while also highlighting the important role of neighborhood processes on relationship violence. Implications for research and intervention programming are discussed. © Society for Community Research and Action 2018.

Development and Deployment of the Computer Assisted Neighborhood Visual Assessment System (CANVAS) to Measure Health-Related Neighborhood Conditions

PubMed Central

Bader, Michael D. M.; Mooney, Stephen J.; Lee, Yeon Jin; Sheehan, Daniel; Neckerman, Kathryn M.; Rundle, Andrew G.; Teitler, Julien O.

2014-01-01

Public health research has shown that neighborhood conditions are associated with health behaviors and outcomes. Systematic neighborhood audits have helped researchers measure neighborhood conditions that they deem theoretically relevant but not available in existing administrative data. Systematic audits, however, are expensive to conduct and rarely comparable across geographic regions. We describe the development of an online application, the Computer Assisted Neighborhood Visual Assessment System (CANVAS), that uses Google Street View to conduct virtual audits of neighborhood environments. We use this system to assess the inter-rater reliability of 187 items related to walkability and physical disorder on a national sample of 150 street segments in the United States. We find that many items are reliably measured across auditors using CANVAS and that agreement between auditors appears to be uncorrelated with neighborhood demographic characteristics. Based on our results we conclude that Google Street View and CANVAS offer opportunities to develop greater comparability across neighborhood audit studies. PMID:25545769

Self-focusing therapeutic gene delivery with intelligent gene vector swarms: intra-swarm signalling through receptor transgene expression in targeted cells.

PubMed

Tolmachov, Oleg E

2015-01-01

Gene delivery in vivo that is tightly focused on the intended target cells is essential to maximize the benefits of gene therapy and to reduce unwanted side-effects. Cell surface markers are immediately available for probing by therapeutic gene vectors and are often used to direct gene transfer with these vectors to specific target cell populations. However, it is not unusual for the choice of available extra-cellular markers to be too scarce to provide a reliable definition of the desired therapeutically relevant set of target cells. Therefore, interrogation of intra-cellular determinants of cell-specificity, such as tissue-specific transcription factors, can be vital in order to provide detailed cell-guiding information to gene vector particles. An important improvement in cell-specific gene delivery can be achieved through auto-buildup in vector homing efficiency using intelligent 'self-focusing' of swarms of vector particles on target cells. Vector self-focusing was previously suggested to rely on the release of diffusible chemo-attractants after a successful target-specific hit by 'scout' vector particles. I hypothesize that intelligent self-focusing behaviour of swarms of cell-targeted therapeutic gene vectors can be accomplished without the employment of difficult-to-use diffusible chemo-attractants, instead relying on the intra-swarm signalling through cells expressing a non-diffusible extra-cellular receptor for the gene vectors. In the proposed model, cell-guiding information is gathered by the 'scout' gene vector particles, which: (1) attach to a variety of cells via a weakly binding (low affinity) receptor; (2) successfully facilitate gene transfer into these cells; (3) query intra-cellular determinants of cell-specificity with their transgene expression control elements and (4) direct the cell-specific biosynthesis of a vector-encoded strongly binding (high affinity) cell-surface receptor. Free members of the vector swarm loaded with therapeutic cargo

EBF factors drive expression of multiple classes of target genes governing neuronal development.

PubMed

Green, Yangsook S; Vetter, Monica L

2011-04-30

Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

Neighborhood Influences on Perceived Social Support Among Parents: Findings from the Project on Human Development in Chicago Neighborhoods

PubMed Central

Tendulkar, Shalini A.; Koenen, Karestan C.; Dunn, Erin C.; Buka, Stephen; Subramanian, S. V.

2012-01-01

Background Social support is frequently linked to positive parenting behavior. Similarly, studies increasingly show a link between neighborhood residential environment and positive parenting behavior. However, less is known about how the residential environment influences parental social support. To address this gap, we examine the relationship between neighborhood concentrated disadvantage and collective efficacy and the level and change in parental caregiver perceptions of non-familial social support. Methodology/Principal Findings The data for this study came from three data sources, the Project on Human Development in Chicago Neighborhoods (PHDCN) Study's Longitudinal Cohort Survey of caregivers and their offspring, a Community Survey of adult residents in these same neighborhoods and the 1990 Census. Social support is measured at Wave 1 and Wave 3 and neighborhood characteristics are measured at Wave 1. Multilevel linear regression models are fit. The results show that neighborhood collective efficacy is a significant (ß = .04; SE = .02; p = .03), predictor of the positive change in perceived social support over a 7 year period, however, not of the level of social support, adjusting for key compositional variables and neighborhood concentrated disadvantage. In contrast concentrated neighborhood disadvantage is not a significant predictor of either the level or change in social support. Conclusion Our finding suggests that neighborhood collective efficacy may be important for inducing the perception of support from friends in parental caregivers over time. PMID:22493683

Neighborhood influences on perceived social support among parents: findings from the project on human development in Chicago neighborhoods.

PubMed

Tendulkar, Shalini A; Koenen, Karestan C; Dunn, Erin C; Buka, Stephen; Subramanian, S V

2012-01-01

Social support is frequently linked to positive parenting behavior. Similarly, studies increasingly show a link between neighborhood residential environment and positive parenting behavior. However, less is known about how the residential environment influences parental social support. To address this gap, we examine the relationship between neighborhood concentrated disadvantage and collective efficacy and the level and change in parental caregiver perceptions of non-familial social support. The data for this study came from three data sources, the Project on Human Development in Chicago Neighborhoods (PHDCN) Study's Longitudinal Cohort Survey of caregivers and their offspring, a Community Survey of adult residents in these same neighborhoods and the 1990 Census. Social support is measured at Wave 1 and Wave 3 and neighborhood characteristics are measured at Wave 1. Multilevel linear regression models are fit. The results show that neighborhood collective efficacy is a significant (ß = .04; SE = .02; p = .03), predictor of the positive change in perceived social support over a 7 year period, however, not of the level of social support, adjusting for key compositional variables and neighborhood concentrated disadvantage. In contrast concentrated neighborhood disadvantage is not a significant predictor of either the level or change in social support. Our finding suggests that neighborhood collective efficacy may be important for inducing the perception of support from friends in parental caregivers over time.

Schools, Neighborhood Risk Factors, and Crime

ERIC Educational Resources Information Center

Willits, Dale; Broidy, Lisa; Denman, Kristine

2013-01-01

Prior research has identified a link between schools (particularly high schools) and neighborhood crime rates. However, it remains unclear whether the relationship between schools and crime is a reflection of other criminogenic dynamics at the neighborhood level or whether schools influence neighborhood crime patterns independently of other…

Multi-kilobase homozygous targeted gene replacement in human induced pluripotent stem cells.

PubMed

Byrne, Susan M; Ortiz, Luis; Mali, Prashant; Aach, John; Church, George M

2015-02-18

Sequence-specific nucleases such as TALEN and the CRISPR/Cas9 system have so far been used to disrupt, correct or insert transgenes at precise locations in mammalian genomes. We demonstrate efficient 'knock-in' targeted replacement of multi-kilobase genes in human induced pluripotent stem cells (iPSC). Using a model system replacing endogenous human genes with their mouse counterpart, we performed a comprehensive study of targeting vector design parameters for homologous recombination. A 2.7 kilobase (kb) homozygous gene replacement was achieved in up to 11% of iPSC without selection. The optimal homology arm length was around 2 kb, with homology length being especially critical on the arm not adjacent to the cut site. Homologous sequence inside the cut sites was detrimental to targeting efficiency, consistent with a synthesis-dependent strand annealing (SDSA) mechanism. Using two nuclease sites, we observed a high degree of gene excisions and inversions, which sometimes occurred more frequently than indel mutations. While homozygous deletions of 86 kb were achieved with up to 8% frequency, deletion frequencies were not solely a function of nuclease activity and deletion size. Our results analyzing the optimal parameters for targeting vector design will inform future gene targeting efforts involving multi-kilobase gene segments, particularly in human iPSC. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Modularly assembled designer TAL effector nucleases for targeted gene knockout and gene replacement in eukaryotes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, T; Huang, S; Zhao, XF

Recent studies indicate that the DNA recognition domain of transcription activator-like (TAL) effectors can be combined with the nuclease domain of FokI restriction enzyme to produce TAL effector nucleases (TALENs) that, in pairs, bind adjacent DNA target sites and produce double-strand breaks between the target sequences, stimulating non-homologous end-joining and homologous recombination. Here, we exploit the four prevalent TAL repeats and their DNA recognition cipher to develop a 'modular assembly' method for rapid production of designer TALENs (dTALENs) that recognize unique DNA sequence up to 23 bases in any gene. We have used this approach to engineer 10 dTALENs tomore » target specific loci in native yeast chromosomal genes. All dTALENs produced high rates of site-specific gene disruptions and created strains with expected mutant phenotypes. Moreover, dTALENs stimulated high rates (up to 34%) of gene replacement by homologous recombination. Finally, dTALENs caused no detectable cytotoxicity and minimal levels of undesired genetic mutations in the treated yeast strains. These studies expand the realm of verified TALEN activity from cultured human cells to an intact eukaryotic organism and suggest that low-cost, highly dependable dTALENs can assume a significant role for gene modifications of value in human and animal health, agriculture and industry.« less

Inheritable Silencing of Endogenous Genes by Hit-and-Run Targeted Epigenetic Editing.

PubMed

Amabile, Angelo; Migliara, Alessandro; Capasso, Paola; Biffi, Mauro; Cittaro, Davide; Naldini, Luigi; Lombardo, Angelo

2016-09-22

Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. Here, we repurpose the endogenous retroviruses' silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. This was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo DNA methylation, thus ensuring long-term memory of the repressive epigenetic state. Silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted DNA demethylation. We demonstrate the portability of this technology by multiplex gene silencing, adopting different DNA binding platforms and interrogating thousands of genomic loci in different cell types, including primary T lymphocytes. Targeted epigenome editing might have broad application in research and medicine. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Assessment of Neighborhood Context in a Nationally Representative Study

PubMed Central

Cagney, Kathleen A.

2014-01-01

Objectives. This paper introduces new measures of neighborhood context that are included in the second wave of the National Social Life, Health, and Aging Project (NSHAP). We describe the use of field interviewer ratings of respondents’ neighborhood conditions, as well as the adaptation of existing measures for the assessment of neighborhood social context among urban and nonurban older adults. Method. We construct scales of neighborhood problems, neighborhood social cohesion, neighborhood social ties, and perceived neighborhood danger, and assess their reliability and validity. We then calculate descriptive statistics for measures of neighborhood context across respondent age, gender, and racial/ethnic background, and across low-, moderate-, and high-density residential blocks. Results. We find that older women report greater neighborhood cohesion and more neighborhood ties than older men, but women also perceive more neighborhood danger. Black and Hispanic older adults reside in neighborhoods with more problems, lower cohesion, fewer social ties, and greater perceived danger. Neighborhood characteristics also vary across residential densities. Neighborhood problems and perceived danger increase with block-level density, but neighborhood social cohesion and social ties were lowest among residents of moderate-density blocks. Discussion. The inclusion of neighborhood context measures in the second wave of NSHAP provides a unique opportunity to explore associations among neighborhood context, social connectedness, and indicators of health and function among older adults. We discuss limitations of the measures and provide recommendations for their use. PMID:24875376

Neighborhood Incivilities, Perceived Neighborhood Safety, and Walking to School Among Urban-Dwelling Children

PubMed Central

Rossen, Lauren M.; Pollack, Keshia M.; Curriero, Frank C.; Shields, Timothy M.; Smart, Mieka J.; Furr-Holden, C. Debra M.; Cooley-Strickland, Michele

2011-01-01

Background Walking to school is an important source of physical activity among children. There is a paucity of research exploring environmental determinants of walking to school among children in urban areas. Methods A cross-sectional secondary analysis of baseline data (2007) from 365 children in the “Multiple Opportunities to Reach Excellence” (MORE) Study (8 to 13 years; Mean 9.60 years, SD 1.04). Children and caregivers were asked about walking to school and perceived safety. Objective measures of the environment were obtained using a validated environmental neighborhood assessment. Results Over half (55.83%) of children reported walking to school most of the time. High levels of neighborhood incivilities were associated with lower levels of perceived safety (OR: 0.39, 95% CI: 0.21 to 0.72). Living on a block above the median in incivilities was associated with a 353% increase in odds of walking to school (OR: 3.53; 95% CI: 1.68 to 7.39). Conclusions Children residing in neighborhoods high in incivilities are more likely to walk to school, in spite of lower levels of perceived safety. As a high proportion of children residing in disadvantaged neighborhoods walk to school, efforts should be directed at minimizing exposure to neighborhood hazards by ensuring safe routes to and from school. PMID:21415453

Fast Food and Neighborhood Stroke Risk

PubMed Central

Morgenstern, Lewis B.; Escobar, James D.; Sánchez, Brisa N.; Hughes, Rebecca; Zuniga, Belinda G.; Garcia, Nelda; Lisabeth, Lynda D.

2009-01-01

Objective To investigate the association between the number of fast food restaurants and ischemic stroke in neighborhoods. Methods This work was a pre-specified part of the Brain Attack in Corpus Christi (BASIC) project. Ischemic stroke cases were prospectively ascertained in Nueces County, Texas. Home addresses were geocoded and used to establish the census tract for each stroke case. Census tracts were used as proxies for neighborhoods (n=64). Using a standard definition, fast food restaurants were identified from a commercial list. Poisson regression was used to study the association between the number of fast food restaurants in the neighborhood, using a 1-mile buffer around each census tract, and the risk of stroke in the neighborhood. Models were adjusted for demographics and neighborhood socioeconomic status (SES). Results There were 1,247 completed ischemic strokes from January 2000 through June 2003 and 262 fast food restaurants. The median number of fast food restaurants per census tract including buffer was 22 (IQR 12–33). Adjusting for neighborhood demographics and SES, the association of fast food restaurants with stroke was significant (p=0.02). The association suggested that the risk of stroke in a neighborhood increased by 1% for every fast food restaurant (RR 1.01 95% CI: 1.00–1.01). The relative risk of stroke comparing neighborhoods in the 75th to the 25th percentile of the distribution of fast food restaurants was 1.13 (95% CI: 1.02–1.25). Interpretation Controlling for demographic and SES factors, there was a significant association between fast food restaurants and stroke risk in neighborhoods in this community-based study. PMID:19743456

Negative Life Events Vary by Neighborhood and Mediate the Relation between Neighborhood Context and Psychological Well-Being

PubMed Central

King, Katherine; Ogle, Christin

2014-01-01

Researchers have speculated that negative life events are more common in troubled neighborhoods, amplifying adverse effects on health. Using a clustered representative sample of Chicago residents (2001–03; n = 3,105) from the Chicago Community Adult Health Survey, we provide the first documentation that negative life events are highly geographically clustered compared to health outcomes. Associations between neighborhood context and negative life events were also found to vary by event type. We then demonstrate the power of a contextualized approach by testing path models in which life events mediate the relation between neighborhood characteristics and health outcomes, including self-rated health, anxiety, and depression. The indirect paths between neighborhood conditions and health through negative life event exposure are highly significant and large compared to the direct paths from neighborhood conditions to health. Our results indicate that neighborhood conditions can have acute as well as chronic effects on health, and that negative life events are a powerful mechanism by which context may influence health. PMID:24714115

Negative life events vary by neighborhood and mediate the relation between neighborhood context and psychological well-being.

PubMed

King, Katherine; Ogle, Christin

2014-01-01

Researchers have speculated that negative life events are more common in troubled neighborhoods, amplifying adverse effects on health. Using a clustered representative sample of Chicago residents (2001-03; n = 3,105) from the Chicago Community Adult Health Survey, we provide the first documentation that negative life events are highly geographically clustered compared to health outcomes. Associations between neighborhood context and negative life events were also found to vary by event type. We then demonstrate the power of a contextualized approach by testing path models in which life events mediate the relation between neighborhood characteristics and health outcomes, including self-rated health, anxiety, and depression. The indirect paths between neighborhood conditions and health through negative life event exposure are highly significant and large compared to the direct paths from neighborhood conditions to health. Our results indicate that neighborhood conditions can have acute as well as chronic effects on health, and that negative life events are a powerful mechanism by which context may influence health.

Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

PubMed Central

Mumbach, Maxwell R; Satpathy, Ansuman T; Boyle, Evan A; Dai, Chao; Gowen, Benjamin G; Cho, Seung Woo; Nguyen, Michelle L; Rubin, Adam J; Granja, Jeffrey M; Kazane, Katelynn R; Wei, Yuning; Nguyen, Trieu; Greenside, Peyton G; Corces, M Ryan; Tycko, Josh; Simeonov, Dimitre R; Suliman, Nabeela; Li, Rui; Xu, Jin; Flynn, Ryan A; Kundaje, Anshul; Khavari, Paul A; Marson, Alexander; Corn, Jacob E; Quertermous, Thomas; Greenleaf, William J; Chang, Howard Y

2018-01-01

The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer–promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases. PMID:28945252

Neighborhood Racial Isolation, Disorder and Obesity

ERIC Educational Resources Information Center

Chang, Virginia W.; Hillier, Amy E.; Mehta, Neil K.

2009-01-01

Recent research suggests that racial residential segregation may be detrimental to health. This study investigates the influence of neighborhood racial isolation on obesity and considers the role of neighborhood disorder as a mediator in this relationship. For the city of Philadelphia, we find that residence in a neighborhood with high black…

Neighborhood Variation in Gang Member Concentrations

ERIC Educational Resources Information Center

Katz, Charles M.; Schnebly, Stephen M.

2011-01-01

This study examines the relationship between neighborhood structure, violent crime, and concentrations of gang members at the neighborhood level. We rely on official police gang list data, police crime data, and two waves of decennial census data characterizing the socioeconomic and demographic conditions of 93 neighborhoods in Mesa, Arizona.…

Mining, identification and function analysis of microRNAs and target genes in peanut (Arachis hypogaea L.).

PubMed

Zhang, Tingting; Hu, Shuhao; Yan, Caixia; Li, Chunjuan; Zhao, Xiaobo; Wan, Shubo; Shan, Shihua

2017-02-01

In the present investigation, a total of 60 conserved peanut (Arachis hypogaea L.) microRNA (miRNA) sequences, belonging to 16 families, were identified using bioinformatics methods. There were 392 target gene sequences, identified from 58 miRNAs with Target-align software and BLASTx analyses. Gene Ontology (GO) functional analysis suggested that these target genes were involved in mediating peanut growth and development, signal transduction and stress resistance. There were 55 miRNA sequences, verified employing a poly (A) tailing test, with a success rate of up to 91.67%. Twenty peanut target gene sequences were randomly selected, and the 5' rapid amplification of the cDNA ends (5'-RACE) method were used to validate the cleavage sites of these target genes. Of these, 14 (70%) peanut miRNA targets were verified by means of gel electrophoresis, cloning and sequencing. Furthermore, functional analysis and homologous sequence retrieval were conducted for target gene sequences, and 26 target genes were chosen as the objects for stress resistance experimental study. Real-time fluorescence quantitative PCR (qRT-PCR) technology was applied to measure the expression level of resistance-associated miRNAs and their target genes in peanut exposed to Aspergillus flavus (A. flavus) infection and drought stress, respectively. In consequence, 5 groups of miRNAs & targets were found accorded with the mode of miRNA negatively controlling the expression of target genes. This study, preliminarily determined the biological functions of some resistance-associated miRNAs and their target genes in peanut. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast

DTIC Science & Technology

2004-05-01

AD Award Number: DAMD17-03-1-0232 TITLE: A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast PRINCIPAL INVESTIGATOR...Approach to Identify Novel Breast DAMD17-03-1-0232 Cancer Gene Targets in Yeast 6. A UTHOR(S) Craig Bennett, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S...Unlimited 13. ABSTRACT (Maximum 200 Words) We are using the yeast Saccharomyces cerevisiae to identify new cancer gene targets that interact with the

Tuning Gene Activity by Inducible and Targeted Regulation of Gene Expression in Minimal Bacterial Cells.

PubMed

Mariscal, Ana M; Kakizawa, Shigeyuki; Hsu, Jonathan Y; Tanaka, Kazuki; González-González, Luis; Broto, Alicia; Querol, Enrique; Lluch-Senar, Maria; Piñero-Lambea, Carlos; Sun, Lijie; Weyman, Philip D; Wise, Kim S; Merryman, Chuck; Tse, Gavin; Moore, Adam J; Hutchison, Clyde A; Smith, Hamilton O; Tomita, Masaru; Venter, J Craig; Glass, John I; Piñol, Jaume; Suzuki, Yo

2018-05-22

Functional genomics studies in minimal mycoplasma cells enable unobstructed access to some of the most fundamental processes in biology. Conventional transposon bombardment and gene knockout approaches often fail to reveal functions of genes that are essential for viability, where lethality precludes phenotypic characterization. Conditional inactivation of genes is effective for characterizing functions central to cell growth and division, but tools are limited for this purpose in mycoplasmas. Here we demonstrate systems for inducible repression of gene expression based on clustered regularly interspaced short palindromic repeats-mediated interference (CRISPRi) in Mycoplasma pneumoniae and synthetic Mycoplasma mycoides, two organisms with reduced genomes actively used in systems biology studies. In the synthetic cell, we also demonstrate inducible gene expression for the first time. Time-course data suggest rapid kinetics and reversible engagement of CRISPRi. Targeting of six selected endogenous genes with this system results in lowered transcript levels or reduced growth rates that agree with lack or shortage of data in previous transposon bombardment studies, and now produces actual cells to analyze. The ksgA gene encodes a methylase that modifies 16S rRNA, rendering it vulnerable to inhibition by the antibiotic kasugamycin. Targeting the ksgA gene with CRISPRi removes the lethal effect of kasugamycin and enables cell growth, thereby establishing specific and effective gene modulation with our system. The facile methods for conditional gene activation and inactivation in mycoplasmas open the door to systematic dissection of genetic programs at the core of cellular life.

Identification and consequences of miRNA-target interactions--beyond repression of gene expression.

PubMed

Hausser, Jean; Zavolan, Mihaela

2014-09-01

Comparative genomics analyses and high-throughput experimental studies indicate that a microRNA (miRNA) binds to hundreds of sites across the transcriptome. Although the knockout of components of the miRNA biogenesis pathway has profound phenotypic consequences, most predicted miRNA targets undergo small changes at the mRNA and protein levels when the expression of the miRNA is perturbed. Alternatively, miRNAs can establish thresholds in and increase the coherence of the expression of their target genes, as well as reduce the cell-to-cell variability in target gene expression. Here, we review the recent progress in identifying miRNA targets and the emerging paradigms of how miRNAs shape the dynamics of target gene expression.

Gene Therapy Targeting Glaucoma: Where Are We?

PubMed Central

Liu, Xuyang; Rasmussen, Carol A.; Gabelt, B’Ann T.; Brandt, Curtis R.; Kaufman, Paul L.

2010-01-01

In a chronic disease such as glaucoma, a therapy that provides a long lasting local effect, with minimal systemic side effects, while circumventing the issue of patient compliance, is very attractive. The field of gene therapy is growing rapidly and ocular applications are expanding. Our understanding of the molecular pathogenesis of glaucoma is leading to greater specificity in ocular tissue targeting. Improvements in gene delivery techniques, refinement of vector construction methods, and development of better animal models combine to bring this potential therapy closer to reality. PMID:19539835

Case Study: LSNA, Logan Square Neighborhood Association. Strong Neighborhoods, Strong Schools. The Indicators Project on Education Organizing.

ERIC Educational Resources Information Center

Blanc, Suzanne; Brown, Joanna; Nevarez-La Torre, Aida; Brown, Chris

This report describes Chicago's Logan Square Neighborhood Association (LSNA), which has long worked to mobilize neighborhood residents to maintain and improve the quality of community life and bring additional resources and services into the neighborhood. LSNA prioritizes the needs of low- and moderate-income residents. LSNA works to make schools…

Identification of downstream metastasis-associated target genes regulated by LSD1 in colon cancer cells.

PubMed

Chen, Jiang; Ding, Jie; Wang, Ziwei; Zhu, Jian; Wang, Xuejian; Du, Jiyi

2017-03-21

This study aims to identify downstream target genes regulated by lysine-specific demethylase 1 (LSD1) in colon cancer cells and investigate the molecular mechanisms of LSD1 influencing invasion and metastasis of colon cancer. We obtained the expression changes of downstream target genes regulated by small-interfering RNA-LSD1 and LSD1-overexpression via gene expression profiling in two human colon cancer cell lines. An Affymetrix Human Transcriptome Array 2.0 was used to identify differentially expressed genes (DEGs). We screened out LSD1-target gene associated with proliferation, metastasis, and invasion from DEGs via Gene Ontology and Pathway Studio. Subsequently, four key genes (CABYR, FOXF2, TLE4, and CDH1) were computationally predicted as metastasis-related LSD1-target genes. ChIp-PCR was applied after RT-PCR and Western blot validations to detect the occupancy of LSD1-target gene promoter-bound LSD1. A total of 3633 DEGs were significantly upregulated, and 4642 DEGs were downregulated in LSD1-silenced SW620 cells. A total of 4047 DEGs and 4240 DEGs were upregulated and downregulated in LSD1-overexpressed HT-29 cells, respectively. RT-PCR and Western blot validated the microarray analysis results. ChIP assay results demonstrated that LSD1 might be negative regulators for target genes CABYR and CDH1. The expression level of LSD1 is negatively correlated with mono- and dimethylation of histone H3 lysine4(H3K4) at LSD1- target gene promoter region. No significant mono-methylation and dimethylation of H3 lysine9 methylation was detected at the promoter region of CABYR and CDH1. LSD1- depletion contributed to the upregulation of CABYR and CDH1 through enhancing the dimethylation of H3K4 at the LSD1-target genes promoter. LSD1- overexpression mediated the downregulation of CABYR and CDH1expression through decreasing the mono- and dimethylation of H3K4 at LSD1-target gene promoter in colon cancer cells. CABYR and CDH1 might be potential LSD1-target genes in colon

Targeted Gene Deletion in Cordyceps militaris Using the Split-Marker Approach.

PubMed

Lou, HaiWei; Ye, ZhiWei; Yun, Fan; Lin, JunFang; Guo, LiQiong; Chen, BaiXiong; Mu, ZhiXian

2018-05-01

The macrofungus Cordyceps militaris contains many kinds of bioactive ingredients that are regulated by functional genes, but the functions of many genes in C. militaris are still unknown. In this study, to improve the frequency of homologous integration, a genetic transformation system based on a split-marker approach was developed for the first time in C. militaris to knock out a gene encoding a terpenoid synthase (Tns). The linear and split-marker deletion cassettes were constructed and introduced into C. militaris protoplasts by PEG-mediated transformation. The transformation of split-marker fragments resulted in a higher efficiency of targeted gene disruption than the transformation of linear deletion cassettes did. The color phenotype of the Tns gene deletion mutants was different from that of wild-type C. militaris. Moreover, a PEG-mediated protoplast transformation system was established, and stable genetic transformants were obtained. This method of targeted gene deletion represents an important tool for investigating the role of C. militaris genes.

Neighborhoods Matter: The Role of Universities in the School Reform Neighborhood Development Movement

ERIC Educational Resources Information Center

Taylor, Henry Louis; McGlynn, Linda; Luter, D. Gavin

2013-01-01

Where you find distressed neighborhoods, you will also find poorly performing public schools. Yet many contemporary school reform efforts ignore neighborhood-level factors that undeniably impact school performance. The purpose of this study is to use a case study approach with social institutional and urban school reform regime frameworks to…

Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors

PubMed Central

Shao, Longjiang; Tekedereli, Ibrahim; Wang, Jianghua; Yuca, Erkan; Tsang, Susan; Sood, Anil; Lopez-Berestein, Gabriel; Ozpolat, Bulent; Ittmann, Michael

2012-01-01

Purpose The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer (PCa) tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in PCa cells. The junction of theTMPRSS2 and ERG derived portions of the fusion mRNA constitutes a cancer specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low toxicity treatment for PCa. Experimental Design We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (Type III or Type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of PCa cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms. Results The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed. Conclusions Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with PCa. PMID:23052253

Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors.

PubMed

Shao, Longjiang; Tekedereli, Ibrahim; Wang, Jianghua; Yuca, Erkan; Tsang, Susan; Sood, Anil; Lopez-Berestein, Gabriel; Ozpolat, Bulent; Ittmann, Michael

2012-12-15

The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer. We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms. The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed. Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer. ©2012 AACR.

Neighborhood Disadvantage and Physical Function: The Contributions of Neighborhood-Level Perceptions of Safety From Crime and Walking for Recreation.

PubMed

Loh, Venurs H Y; Rachele, Jerome N; Brown, Wendy J; Ghani, Fatima; Turrell, Gavin

2018-04-20

Residents of more socioeconomically disadvantaged neighborhoods are more likely to report poorer physical function, although the reasons for this remain unknown. It is possible that neighborhood-level perceptions of safety from crime contribute to this relationship through its association with walking for recreation. Data were obtained from the fourth wave (collected in 2013) of the HABITAT (How Areas in Brisbane Influence HealTh and AcTivity) multilevel longitudinal study of middle- to older-aged adults (46-74 y) residing in 200 neighborhoods in Brisbane, Australia. The data were analyzed separately for men (n = 2190) and women (n = 2977) using multilevel models. Residents of the most disadvantaged neighborhoods had poorer physical function, perceived their neighborhoods to be less safe from crime, and do less walking for recreation. These factors accounted for differences in physical function between disadvantaged and advantaged neighborhoods (24% for men and 25% for women). This study highlights the importance of contextual characteristics, through their associations with behaviors, that can have in explaining the relationship between neighborhood disadvantage and physical function. Interventions aimed at improving neighborhood safety integrated with supportive environments for physical activity may have positive impact on physical function among all socioeconomic groups.

ASSOCIATIONS BETWEEN HOUSEHOLD AND NEIGHBORHOOD INCOME AND ANXIETY SYMPTOMS IN YOUNG ADOLESCENTS

PubMed Central

Vine, Michaela; Vander Stoep, Ann; Bell, Janice; Rhew, Isaac C.; Gudmundsen, Gretchen; McCauley, Elizabeth

2013-01-01

Background A better understanding of the role of both family- and neighborhood-level socioeconomic characteristics in the development of anxiety disorders is important for identifying salient target populations for intervention efforts. Little research has examined the question of whether associations between anxiety and socioeconomic status (SES) differ depending upon the level at which SES is measured or way in which anxiety manifests. We studied associations between both household- and neighborhood-level income and four different manifestations of anxiety in a community sample of young adolescents. Methods We conducted a cross-sectional analysis of data on 498 subjects aged 11–13 from a cohort study of Seattle-area middle school students. Generalized estimating equations were used to examine the association between both annual household income and neighborhood median income and each of four anxiety subscale scores from the multidimensional anxiety scale for children (MASC): physical symptoms, harm avoidance, social anxiety, and separation/panic anxiety. Results A negative association was found between household income and scores on two of the four MASC subscales—physical symptoms and separation/panic anxiety. In contrast, at equivalent levels of household income, adolescents living in higher income neighborhoods reported higher physical and harm avoidance symptom scores. Conclusion The role that SES plays in the development of childhood anxiety appears to be complex and to differ depending on the specific type of anxiety that is manifest and whether income is evaluated at the household or neighborhood level. PMID:22581412

Neighborhood disorder, peer network health, and substance use among young urban adolescents.

PubMed

Mason, Michael J; Light, John M; Mennis, Jeremy; Rusby, Julie C; Westling, Erika; Crewe, Stephanie; Zaharakis, Nikola; Way, Thomas; Flay, Brian R

2017-09-01

The current study investigated the moderating effect of peer networks on neighborhood disorder's association with substance use in a sample of primarily African American urban adolescents. A convenience sample of 248 adolescents was recruited from urban health care settings and followed for two years, assessing psychological, social, and geographic risk and protective characteristics. A subset of 106 substance using participants were used for the analyses. A moderation model was tested to determine if the influence of neighborhood disorder (percent vacant housing, assault index, percent single parent headed households, percent home owner occupied, percent below poverty line) on substance use was moderated by peer network health (sum of peer risk and protective behaviors). Evidence for hypothesized peer network moderation was supported. A latent growth model found that peer network health is most strongly associated with lower baseline substance use for young adolescents residing in more disordered neighborhoods. Over the course of two years (ages approximately 14-16) this protective effect declines, and the decline is stronger for more disordered neighborhoods. Understanding the longitudinal moderating effects of peer networks within high-risk urban settings is important to the development and testing of contextually sensitive peer-based interventions. suggest that targeting the potential protective qualities of peer networks may be a promising approach for interventions seeking to reduce substance use, particularly among younger urban adolescents living in high-risk neighborhoods. Copyright © 2017 Elsevier B.V. All rights reserved.

Conduct Disorder and Neighborhood Effects.

PubMed

Jennings, Wesley G; Perez, Nicholas M; Reingle Gonzalez, Jennifer M

2018-05-07

There has been a considerable amount of scholarly attention to the relationship between neighborhood effects and conduct disorder, particularly in recent years. Having said this, it has been nearly two decades since a comprehensive synthesis of this literature has been conducted. Relying on a detailed and comprehensive search strategy and inclusion criteria, this article offers a systematic and interdisciplinary review of 47 empirical studies that have examined neighborhood effects and conduct disorder. Described results suggest that there are generally robust linkages between adverse neighborhood factors and conduct disorder and externalizing behavior problems, as 67 of the 93 (72.04%) effect sizes derived from these studies yielded statistically significant neighborhood effects. The review also identifies salient mediating and moderating influences. It discusses study limitations and directions for future research as well.

The associations between objectively-determined and self-reported urban form characteristics and neighborhood-based walking in adults.

PubMed

Jack, Elizabeth; McCormack, Gavin R

2014-06-04

destination mix was positively associated with participation, HW x physical barriers and MW x pedestrian infrastructure were positively associated with minutes, and HW x safety from crime was negatively associated with minutes, of transportation walking. Neither neighborhood type nor its interactions with perceived measures of walkability were associated with recreational walking, although perceived aesthetics was associated with participation (OR = 1.18, p < .05). Objectively-determined and self-reported built characteristics are associated with neighborhood-based transportation walking. The objectively-determined built environment might moderate associations between perceptions of walkability and neighborhood-based transportation walking. Interventions that target perceptions in addition to modifications to the neighborhood built environment could result in increases in physical activity among adults.

Neighborhood Ethnic Density as an Explanation for the Academic Achievement of Ethnic Minority Youth Placed in Neighborhood Disadvantage

ERIC Educational Resources Information Center

Madyun, Na'im; Lee, Moosung

2010-01-01

The underachievement of ethnic minority youth from disadvantaged neighborhoods is a pervasive educational issue this nation is facing. Based on an ecological perspective, we examined the contextual effects of neighborhood ethnic density and neighborhood disadvantage on the academic achievement of Hmong immigrant youths. Utilizing hierarchical…

MicroRNA expression, target genes, and signaling pathways in infants with a ventricular septal defect.

PubMed

Chai, Hui; Yan, Zhaoyuan; Huang, Ke; Jiang, Yuanqing; Zhang, Lin

2018-02-01

This study aimed to systematically investigate the relationship between miRNA expression and the occurrence of ventricular septal defect (VSD), and characterize the miRNA target genes and pathways that can lead to VSD. The miRNAs that were differentially expressed in blood samples from VSD and normal infants were screened and validated by implementing miRNA microarrays and qRT-PCR. The target genes regulated by differentially expressed miRNAs were predicted using three target gene databases. The functions and signaling pathways of the target genes were enriched using the GO database and KEGG database, respectively. The transcription and protein expression of specific target genes in critical pathways were compared in the VSD and normal control groups using qRT-PCR and western blotting, respectively. Compared with the normal control group, the VSD group had 22 differentially expressed miRNAs; 19 were downregulated and three were upregulated. The 10,677 predicted target genes participated in many biological functions related to cardiac development and morphogenesis. Four target genes (mGLUR, Gq, PLC, and PKC) were involved in the PKC pathway and four (ECM, FAK, PI3 K, and PDK1) were involved in the PI3 K-Akt pathway. The transcription and protein expression of these eight target genes were significantly upregulated in the VSD group. The 22 miRNAs that were dysregulated in the VSD group were mainly downregulated, which may result in the dysregulation of several key genes and biological functions related to cardiac development. These effects could also be exerted via the upregulation of eight specific target genes, the subsequent over-activation of the PKC and PI3 K-Akt pathways, and the eventual abnormal cardiac development and VSD.

Geometrical tile design for complex neighborhoods.

PubMed

Czeizler, Eugen; Kari, Lila

2009-01-01

Recent research has showed that tile systems are one of the most suitable theoretical frameworks for the spatial study and modeling of self-assembly processes, such as the formation of DNA and protein oligomeric structures. A Wang tile is a unit square, with glues on its edges, attaching to other tiles and forming larger and larger structures. Although quite intuitive, the idea of glues placed on the edges of a tile is not always natural for simulating the interactions occurring in some real systems. For example, when considering protein self-assembly, the shape of a protein is the main determinant of its functions and its interactions with other proteins. Our goal is to use geometric tiles, i.e., square tiles with geometrical protrusions on their edges, for simulating tiled paths (zippers) with complex neighborhoods, by ribbons of geometric tiles with simple, local neighborhoods. This paper is a step toward solving the general case of an arbitrary neighborhood, by proposing geometric tile designs that solve the case of a "tall" von Neumann neighborhood, the case of the f-shaped neighborhood, and the case of a 3 x 5 "filled" rectangular neighborhood. The techniques can be combined and generalized to solve the problem in the case of any neighborhood, centered at the tile of reference, and included in a 3 x (2k + 1) rectangle.

Geometrical Tile Design for Complex Neighborhoods

PubMed Central

Czeizler, Eugen; Kari, Lila

2009-01-01

Recent research has showed that tile systems are one of the most suitable theoretical frameworks for the spatial study and modeling of self-assembly processes, such as the formation of DNA and protein oligomeric structures. A Wang tile is a unit square, with glues on its edges, attaching to other tiles and forming larger and larger structures. Although quite intuitive, the idea of glues placed on the edges of a tile is not always natural for simulating the interactions occurring in some real systems. For example, when considering protein self-assembly, the shape of a protein is the main determinant of its functions and its interactions with other proteins. Our goal is to use geometric tiles, i.e., square tiles with geometrical protrusions on their edges, for simulating tiled paths (zippers) with complex neighborhoods, by ribbons of geometric tiles with simple, local neighborhoods. This paper is a step toward solving the general case of an arbitrary neighborhood, by proposing geometric tile designs that solve the case of a “tall” von Neumann neighborhood, the case of the f-shaped neighborhood, and the case of a 3 × 5 “filled” rectangular neighborhood. The techniques can be combined and generalized to solve the problem in the case of any neighborhood, centered at the tile of reference, and included in a 3 × (2k + 1) rectangle. PMID:19956398

Children’s physical activity and parents’ perception of the neighborhood environment: neighborhood impact on kids study

PubMed Central

2013-01-01

Background Physical activity is important to children’s physical health and well-being. Many factors contribute to children’s physical activity, and the built environment has garnered considerable interest recently, as many young children spend much of their time in and around their immediate neighborhood. Few studies have identified correlates of children’s activity in specific locations. This study examined associations between parent report of their home neighborhood environment and children’s overall and location-specific physical activity. Methods Parents and children ages 6 to 11 (n=724), living in neighborhoods identified through objective built environment factors as high or low in physical activity environments, were recruited from Seattle and San Diego metropolitan areas, 2007–2009. Parents completed a survey about their child’s activity and perceptions of home neighborhood environmental attributes. Children wore an accelerometer for 7 days. Multivariate regression models explored perceived environment correlates of parent-reported child’s recreational physical activity in their neighborhood, in parks, and in general, as well as accelerometry-based moderate-to-vigorous activity (MVPA) minutes. Results Parent-reported proximity to play areas correlated positively with both accelerometery MVPA and parent-reported total child physical activity. Lower street connectivity and higher neighborhood aesthetics correlated with higher reported child activity in the neighborhood, while reported safety from crime and walk and cycle facilities correlated positively with reported child activity in public recreation spaces. Conclusions Different aspects of parent’s perceptions of the neighborhood environment appear to correlate with different aspects of children’s activity. However, prioritizing closer proximity to safe play areas may best improve children’s physical activity and, in turn, reduce their risk of obesity and associated chronic diseases

Identification of apoptosis-related PLZF target genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernardo, Maria Victoria; Yelo, Estefania; Gimeno, Lourdes

2007-07-27

The PLZF gene encodes a BTB/POZ-zinc finger-type transcription factor, involved in physiological development, proliferation, differentiation, and apoptosis. In this paper, we investigate proliferation, survival, and gene expression regulation in stable clones from the human haematopoietic K562, DG75, and Jurkat cell lines with inducible expression of PLZF. In Jurkat cells, but not in K562 and DG75 cells, PLZF induced growth suppression and apoptosis in a cell density-dependent manner. Deletion of the BTB/POZ domain of PLZF abrogated growth suppression and apoptosis. PLZF was expressed with a nuclear speckled pattern distinctively in the full-length PLZF-expressing Jurkat clones, suggesting that the nuclear speckled localizationmore » is required for PLZF-induced apoptosis. By microarray analysis, we identified that the apoptosis-inducer TP53INP1, ID1, and ID3 genes were upregulated, and the apoptosis-inhibitor TERT gene was downregulated. The identification of apoptosis-related PLZF target genes may have biological and clinical relevance in cancer typified by altered PLZF expression.« less

Pre-end-stage renal disease care not associated with dialysis facility neighborhood poverty in the United States.

PubMed

Plantinga, Laura C; Kim, Min; Goetz, Margarethe; Kleinbaum, David G; McClellan, William; Patzer, Rachel E

2014-01-01

Receipt of nephrology care prior to end-stage renal disease (ESRD) is a strong predictor of decreased mortality and morbidity, and neighborhood poverty may influence access to care. Our objective was to examine whether neighborhood poverty is associated with lack of pre-ESRD care at dialysis facilities. In a multi-level ecological study using geospatially linked 2007-2010 Dialysis Facility Report and 2006-2010 American Community Survey data, we examined whether high neighborhood poverty (≥20% of households in census tract living below poverty) was associated with dialysis facility-level lack of pre-ESRD care (percentage of patients with no nephrology care prior to dialysis start) in mixed-effects models, adjusting for facility and neighborhood confounders and allowing for neighborhood and regional random effects. Among the 5,184 facilities examined, 1,778 (34.3%) were located in a high-poverty area. Lack of pre-ESRD care was similar in poverty areas (30.8%) and other neighborhoods (29.6%). With adjustment, the absolute increase in percentage of patients at a facility with no pre-ESRD care associated with facility location in a poverty area versus other neighborhood was only 0.08% (95% CI -1.32, 1.47; p = 0.9). Potential effect modification by race and income inequality was detected. Despite previously reported detrimental effects of neighborhood poverty on health, facility neighborhood poverty was not associated with receipt of pre-ESRD care, suggesting no need to target interventions to increase access to pre-ESRD care at facilities in poorer geographic areas.

Pre-end-stage renal disease care not associated with dialysis facility neighborhood poverty in the United States

PubMed Central

Plantinga, Laura C.; Kim, Min; Goetz, Margarethe; Kleinbaum, David G.; McClellan, William; Patzer, Rachel E.

2014-01-01

Background Receipt of nephrology care prior to end-stage renal disease (ESRD) is a strong predictor of decreased mortality and morbidity, and neighborhood poverty may influence access to care. Our objective was to examine whether neighborhood poverty is associated with lack of pre-ESRD care at dialysis facilities. Methods In a multi-level ecological study using geospatially linked 2007-2010 Dialysis Facility Report and 2006-2010 American Community Survey data, we examined whether high neighborhood poverty (≥20% of households in census tract living below poverty) was associated with dialysis facility-level lack of pre-ESRD care (percentage of patients with no nephrology care prior to dialysis start) in mixed-effects models, adjusting for facility and neighborhood confounders and allowing for neighborhood and regional random effects. Results Among the 5184 facilities examined, 1778 (34.3%) were located in a high poverty area. Lack of pre-ESRD care was similar in poverty areas (30.8%) and other neighborhoods (29.6%). With adjustment, the absolute increase in percentage of patients at a facility with no pre-ESRD care associated with facility location in a poverty area vs. other neighborhood was only 0.08% (95% CI: -1.32%, 1.47%; P=0.9). Potential effect modification by race and income inequality was detected. Conclusion Despite previously reported detrimental effects of neighborhood poverty on health, facility neighborhood poverty was not associated with receipt of pre-ESRD care, suggesting no need to target interventions to increase access to pre-ESRD care at facilities in poorer geographic areas. PMID:24434854

Neighborhood context and youth cardiovascular health behaviors.

PubMed

Lee, Rebecca E; Cubbin, Catherine

2002-03-01

This study sought to determine the relationships between race/ethnicity, socioeconomic status (SES), and cardiovascular health behaviors among youths and whether neighborhood characteristics are associated with such behaviors independently of individual characteristics. Linear models determined the effects of individual and neighborhood characteristics (SES, social disorganization, racial/ethnic minority concentration, urbanization) on dietary habits, physical activity, and smoking among 8165 youths aged 12 to 21 years. Low SES was associated with poorer dietary habits, less physical activity, and higher odds of smoking. After adjustment for SES, Black race was associated with poorer dietary habits and lower odds of smoking. Hispanic ethnicity was associated with healthier dietary habits, lower levels of physical activity, and lower odds of smoking than non-Hispanic ethnicity. Low neighborhood SES and high neighborhood social disorganization were independently associated with poorer dietary habits, while high neighborhood Hispanic concentration and urbanicity were associated with healthier dietary habits. Neighborhood characteristics were not associated with physical activity or smoking. Changes in neighborhood social structures and policies that reduce social inequalities may enhance cardiovascular health behaviors.

Neighborhood contexts and the mediating role of neighborhood social cohesion on health and psychological distress among Hispanic and non-Hispanic residents.

PubMed

Rios, Rebeca; Aiken, Leona S; Zautra, Alex J

2012-02-01

Neighborhood social cohesion (NSC) may contribute to understanding how neighborhood contexts influence the physical and mental health of residents. We examined the relation of NSC to self-rated mental and physical health and evaluated the mediating role of NSC on relations between neighborhood socioeconomic status, ethnic composition, and health. A sample of 3,098 Hispanic and non-Hispanic residents within 597 census tracts in metropolitan Phoenix, Arizona rated their health, psychological distress, and their perceptions of NSC. Census tract estimates provided neighborhood contextual measures. Neighborhood social cohesion was significantly related to better physical and mental health. Both individually rated NSC and neighborhood-level NSC mediated relations between neighborhood contexts and health outcomes. Substantive findings were consistent across Hispanic and non-Hispanic residents. The findings have implications for improving ethnic and socioeconomic disparities in physical and mental health through attention to social cohesion among neighborhood residents.

Hazardous Waste Sites, Stress, and Neighborhood Quality in USA.

ERIC Educational Resources Information Center

Greenberg, Michael; And Others

1994-01-01

Reports the results of a survey from seven neighborhoods adjacent to hazardous waste sites. The survey asked residents to rate their neighborhoods, compare the quality of their present neighborhoods to the quality of their previous neighborhoods, and report on stresses associated with their neighborhood. (LZ)

Optimization of Applications with Non-blocking Neighborhood Collectives via Multisends on the Blue Gene/P Supercomputer.

PubMed

Kumar, Sameer; Heidelberger, Philip; Chen, Dong; Hines, Michael

2010-04-19

We explore the multisend interface as a data mover interface to optimize applications with neighborhood collective communication operations. One of the limitations of the current MPI 2.1 standard is that the vector collective calls require counts and displacements (zero and nonzero bytes) to be specified for all the processors in the communicator. Further, all the collective calls in MPI 2.1 are blocking and do not permit overlap of communication with computation. We present the record replay persistent optimization to the multisend interface that minimizes the processor overhead of initiating the collective. We present four different case studies with the multisend API on Blue Gene/P (i) 3D-FFT, (ii) 4D nearest neighbor exchange as used in Quantum Chromodynamics, (iii) NAMD and (iv) neural network simulator NEURON. Performance results show 1.9× speedup with 32(3) 3D-FFTs, 1.9× speedup for 4D nearest neighbor exchange with the 2(4) problem, 1.6× speedup in NAMD and almost 3× speedup in NEURON with 256K cells and 1k connections/cell.

The impact of neighborhood walkability on walking: does it differ across adult life stage and does neighborhood buffer size matter?

PubMed

Villanueva, Karen; Knuiman, Matthew; Nathan, Andrea; Giles-Corti, Billie; Christian, Hayley; Foster, Sarah; Bull, Fiona

2014-01-01

We explored the impact of neighborhood walkability on young adults, early-middle adults, middle-aged adults, and older adults' walking across different neighborhood buffers. Participants completed the Western Australian Health and Wellbeing Surveillance System Survey (2003-2009) and were allocated a neighborhood walkability score at 200m, 400m, 800m, and 1600m around their home. We found little difference in strength of associations across neighborhood size buffers for all life stages. We conclude that neighborhood walkability supports more walking regardless of adult life stage and is relevant for small (e.g., 200m) and larger (e.g., 1600m) neighborhood buffers. © 2013 The Authors. Published by Elsevier Ltd All rights reserved.

Formative research for a healthy diet intervention among inner-city adolescents: the importance of family, school and neighborhood environment.

PubMed

Dodson, Jennifer L; Hsiao, Ya-Chun; Kasat-Shors, Madhuri; Murray, Laura; Nguyen, Nga Kim; Richards, Adam K; Gittelsohn, Joel

2009-01-01

To understand influences on diet among low-income African-American adolescents in East Baltimore. Formative research was conducted for a food store-centered healthy diet intervention targeted to inner-city youth. Family, school and neighborhood influences on eating habits and health concepts were explored. Family structure, economic resources and past experiences influence what food means to adolescents. Healthy food in school and local stores is limited. Terminology to categorize foods was identified, including the term "home foods". Suggested adolescent nutritional interventions include promotion of home-based eating, improving availability of healthy foods in school and neighborhood stores, and targeted educational materials.

From Genes to Milk: Genomic Organization and Epigenetic Regulation of the Mammary Transcriptome

PubMed Central

Lemay, Danielle G.; Pollard, Katherine S.; Martin, William F.; Freeman Zadrowski, Courtneay; Hernandez, Joseph; Korf, Ian; German, J. Bruce; Rijnkels, Monique

2013-01-01

Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival

Associations Between Family Support, Family Intimacy, and Neighborhood Violence and Physical Activity in Urban Adolescent Girls

PubMed Central

Kuo, JoAnn; Voorhees, Carolyn C.; Haythornthwaite, Jennifer A.; Young, Deborah Rohm

2007-01-01

We examined the association between various dimensions of the family environment, including family intimacy and involvement in activities, family support for physical activity, and neighborhood violence (perceived and objective) and physical activity among urban, predominantly African American, ninth-grade girls in Balti-more, Md. Greater family intimacy (P = .05) and support (P = .01), but not neighborhood violence, was associated with physical activity. Family factors, including family intimacy and support, are potential targets in physical activity interventions for urban high-school girls. PMID:17138926

Trends in maternal and infant health in poor urban neighborhoods: good news from the 1990s, but challenges remain.

PubMed

Howell, Embry M; Pettit, Kathryn L S; Kingsley, G Thomas

2005-01-01

During the 1990s, numerous public policy changes occurred that may have affected the health of mothers and infants in low-income neighborhoods. This article examines trends in key maternal and child health indicators to determine whether disparities between high-poverty neighborhoods and other neighborhoods have declined. Using neighborhood-level vital statistics and U.S. Census data, we categorized "neighborhoods" (Census tracts) as being high poverty (greater than 30% of population below the federal poverty level in 1990) or not. We compared trends in four key indicators--births to teenagers, late prenatal care, low birth-weight; and infant mortality--over the 1990s among high-poverty and other neighborhoods in Cuyahoga County, Ohio; Denver, Colorado; Marion County, Indiana; and Oakland, California. In all four metropolitan areas, trends in high-poverty neighborhoods were more favorable than in other neighborhoods. The most consistently positive trend was the reduction in the rate of teen births. The metropolitan areas with the most intensive programs to improve maternal and child health--Cuyahoga County and Oakland-saw the most consistent improvement across all indicators. Still, great disparities between high-poverty and other neighborhoods remain, and only Oakland shows promise of achieving some of the Healthy People 2010 maternal and child health goals in its high-poverty neighborhoods. While there has been a reduction in maternal and infant health disparities between high-poverty and other neighborhoods, much work remains to eliminate disparities and achieve the 2010 goals. Small area data are useful in isolating the neighborhoods that should be targeted. Experience from the 1990s suggests that a combination of several intensive interventions can be effective at reducing disparities.

Human microRNA target analysis and gene ontology clustering by GOmir, a novel stand-alone application

PubMed Central

Roubelakis, Maria G; Zotos, Pantelis; Papachristoudis, Georgios; Michalopoulos, Ioannis; Pappa, Kalliopi I; Anagnou, Nicholas P; Kossida, Sophia

2009-01-01

Background microRNAs (miRNAs) are single-stranded RNA molecules of about 20–23 nucleotides length found in a wide variety of organisms. miRNAs regulate gene expression, by interacting with target mRNAs at specific sites in order to induce cleavage of the message or inhibit translation. Predicting or verifying mRNA targets of specific miRNAs is a difficult process of great importance. Results GOmir is a novel stand-alone application consisting of two separate tools: JTarget and TAGGO. JTarget integrates miRNA target prediction and functional analysis by combining the predicted target genes from TargetScan, miRanda, RNAhybrid and PicTar computational tools as well as the experimentally supported targets from TarBase and also providing a full gene description and functional analysis for each target gene. On the other hand, TAGGO application is designed to automatically group gene ontology annotations, taking advantage of the Gene Ontology (GO), in order to extract the main attributes of sets of proteins. GOmir represents a new tool incorporating two separate Java applications integrated into one stand-alone Java application. Conclusion GOmir (by using up to five different databases) introduces miRNA predicted targets accompanied by (a) full gene description, (b) functional analysis and (c) detailed gene ontology clustering. Additionally, a reverse search initiated by a potential target can also be conducted. GOmir can freely be downloaded BRFAA. PMID:19534746

Human microRNA target analysis and gene ontology clustering by GOmir, a novel stand-alone application.

PubMed

Roubelakis, Maria G; Zotos, Pantelis; Papachristoudis, Georgios; Michalopoulos, Ioannis; Pappa, Kalliopi I; Anagnou, Nicholas P; Kossida, Sophia

2009-06-16

microRNAs (miRNAs) are single-stranded RNA molecules of about 20-23 nucleotides length found in a wide variety of organisms. miRNAs regulate gene expression, by interacting with target mRNAs at specific sites in order to induce cleavage of the message or inhibit translation. Predicting or verifying mRNA targets of specific miRNAs is a difficult process of great importance. GOmir is a novel stand-alone application consisting of two separate tools: JTarget and TAGGO. JTarget integrates miRNA target prediction and functional analysis by combining the predicted target genes from TargetScan, miRanda, RNAhybrid and PicTar computational tools as well as the experimentally supported targets from TarBase and also providing a full gene description and functional analysis for each target gene. On the other hand, TAGGO application is designed to automatically group gene ontology annotations, taking advantage of the Gene Ontology (GO), in order to extract the main attributes of sets of proteins. GOmir represents a new tool incorporating two separate Java applications integrated into one stand-alone Java application. GOmir (by using up to five different databases) introduces miRNA predicted targets accompanied by (a) full gene description, (b) functional analysis and (c) detailed gene ontology clustering. Additionally, a reverse search initiated by a potential target can also be conducted. GOmir can freely be downloaded BRFAA.

Neighborhood Factors and Dating Violence Among Youth

PubMed Central

Johnson, Renee M.; Parker, Elizabeth M.; Rinehart, Jenny; Nail, Jennifer; Rothman, Emily F.

2015-01-01

Context The purpose of this review is to summarize the empirical research on neighborhood-level factors and dating violence among adolescents and emerging adults to guide future research and practice. Evidence acquisition In 2015, 20 articles were identified through a search of the literature using PubMed. Eligible articles included those that: (1) had been published in a peer-reviewed journal since 2005; (2) reported a measure of association between at least one neighborhood-level factor and dating violence; and (3) had a study population of youth aged <26 years. We abstracted information about the studies, including measurement of dating violence and neighborhood factors, and measures of effect. Evidence synthesis Results were summarized into three categories based on the aspect of neighborhood which was the focus of the work: demographic and structural characteristics (n=11), neighborhood disorder (n=12), and social disorganization (n=8). There was some evidence to suggest that neighborhood disadvantage is associated with dating violence, but very little evidence to suggest that residence characteristics (e.g., racial heterogeneity) are associated with dating violence. Results do suggest that perceived neighborhood disorder is associated with physical dating violence perpetration, but do not suggest that it is associated with physical dating violence victimization. Social control and community connectedness are both associated with dating violence, but findings on collective efficacy are mixed. Conclusions Existing research suggests that neighborhood factors may be associated with dating violence. However, there is a limited body of research on the neighborhood context of dating violence and more rigorous research is needed. PMID:26296444

The Influence of Lexical Status and Neighborhood Density on Children's Nonword Repetition

ERIC Educational Resources Information Center

Metsala, Jamie L.; Chisholm, Gina M.

2010-01-01

This study examined effects of lexical status and neighborhood density of constituent syllables on children's nonword repetition and interactions with nonword length. Lexical status of the target syllable impacted repetition accuracy for the longest nonwords. In addition, children made more errors that changed a nonword syllable to a word syllable…

Targeted Mutagenesis of Duplicated Genes in Soybean with Zinc-Finger Nucleases1[W][OA

PubMed Central

Curtin, Shaun J.; Zhang, Feng; Sander, Jeffry D.; Haun, William J.; Starker, Colby; Baltes, Nicholas J.; Reyon, Deepak; Dahlborg, Elizabeth J.; Goodwin, Mathew J.; Coffman, Andrew P.; Dobbs, Drena; Joung, J. Keith; Voytas, Daniel F.; Stupar, Robert M.

2011-01-01

We performed targeted mutagenesis of a transgene and nine endogenous soybean (Glycine max) genes using zinc-finger nucleases (ZFNs). A suite of ZFNs were engineered by the recently described context-dependent assembly platform—a rapid, open-source method for generating zinc-finger arrays. Specific ZFNs targeting DICER-LIKE (DCL) genes and other genes involved in RNA silencing were cloned into a vector under an estrogen-inducible promoter. A hairy-root transformation system was employed to investigate the efficiency of ZFN mutagenesis at each target locus. Transgenic roots exhibited somatic mutations localized at the ZFN target sites for seven out of nine targeted genes. We next introduced a ZFN into soybean via whole-plant transformation and generated independent mutations in the paralogous genes DCL4a and DCL4b. The dcl4b mutation showed efficient heritable transmission of the ZFN-induced mutation in the subsequent generation. These findings indicate that ZFN-based mutagenesis provides an efficient method for making mutations in duplicate genes that are otherwise difficult to study due to redundancy. We also developed a publicly accessible Web-based tool to identify sites suitable for engineering context-dependent assembly ZFNs in the soybean genome. PMID:21464476

Normal Collagen and Bone Production by Gene-targeted Human Osteogenesis Imperfecta iPSCs

PubMed Central

Deyle, David R; Khan, Iram F; Ren, Gaoying; Wang, Pei-Rong; Kho, Jordan; Schwarze, Ulrike; Russell, David W

2012-01-01

Osteogenesis imperfecta (OI) is caused by dominant mutations in the type I collagen genes. In principle, the skeletal abnormalities of OI could be treated by transplantation of patient-specific, bone-forming cells that no longer express the mutant gene. Here, we develop this approach by isolating mesenchymal cells from OI patients, inactivating their mutant collagen genes by adeno-associated virus (AAV)-mediated gene targeting, and deriving induced pluripotent stem cells (iPSCs) that were expanded and differentiated into mesenchymal stem cells (iMSCs). Gene-targeted iMSCs produced normal collagen and formed bone in vivo, but were less senescent and proliferated more than bone-derived MSCs. To generate iPSCs that would be more appropriate for clinical use, the reprogramming and selectable marker transgenes were removed by Cre recombinase. These results demonstrate that the combination of gene targeting and iPSC derivation can be used to produce potentially therapeutic cells from patients with genetic disease. PMID:22031238

The past and presence of gene targeting: from chemicals and DNA via proteins to RNA.

PubMed

Geel, T M; Ruiters, M H J; Cool, R H; Halby, L; Voshart, D C; Andrade Ruiz, L; Niezen-Koning, K E; Arimondo, P B; Rots, M G

2018-06-05

The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene-targeting efforts exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given location in order to inactivate a gene or to correct mutations. We here describe an example towards correcting a genetic mutation underlying Pompe's disease using a nucleotide-fused nuclease (TFO-MunI). In addition to the promise of gene correction, scientists soon realized that genes could be inactivated or even re-activated without inducing potentially harmful DNA damage by targeting transcriptional modulators to a particular gene. However, it proved difficult to fuse protein effector domains to the first generation of programmable DNA-binding agents. The engineering of gene-targeting proteins (zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs)) circumvented this problem. The disadvantage of protein-based gene targeting is that a fusion protein needs to be engineered for every locus. The recent introduction of CRISPR/Cas offers a flexible approach to target a (fusion) protein to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Author(s).

Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines.

PubMed

Gulec, Cagri; Coban, Neslihan; Ozsait-Selcuk, Bilge; Sirma-Ekmekci, Sema; Yildirim, Ozlem; Erginel-Unaltuna, Nihan

2017-04-01

ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

Perceived School and Neighborhood Safety, Neighborhood Violence and Academic Achievement in Urban School Children

ERIC Educational Resources Information Center

Milam, A. J.; Furr-Holden, C. D. M.; Leaf, P. J.

2010-01-01

Community and school violence continue to be a major public health problem, especially among urban children and adolescents. Little research has focused on the effect of school safety and neighborhood violence on academic performance. This study examines the effect of the school and neighborhood climate on academic achievement among a population…

Effect of a large gaming neighborhood and a strategy adaptation neighborhood for bolstering network reciprocity in a prisoner's dilemma game

NASA Astrophysics Data System (ADS)

Ogasawara, Takashi; Tanimoto, Jun; Fukuda, Eriko; Hagishima, Aya; Ikegaya, Naoki

2014-12-01

In 2 × 2 prisoner's dilemma (PD) games, network reciprocity is one mechanism for adding social viscosity, leading to a cooperative equilibrium. In this paper, we explain how gaming neighborhoods and strategy-adaptation neighborhoods affect network reciprocity independently in spatial PD games. We explore an appropriate range of strategy adaptation neighborhoods as opposed to the conventional method of making the gaming and strategy adaptation neighborhoods coincide to enhance the level of cooperation. In cases of expanding gaming neighborhoods, network reciprocity falls to a low level relative to the conventional setting. In the discussion below, which is based on the results of our simulation, we explore how these enhancements come about. Essentially, varying the range of the neighborhoods influences how cooperative clusters form and expand in the evolutionary process.

The Power of Place: Social Network Characteristics, Perceived Neighborhood Features, and Psychological Distress Among African Americans in the Historic Hill District in Pittsburgh, Pennsylvania.

PubMed

Flórez, Karen R; Ghosh-Dastidar, Madhumita Bonnie; Beckman, Robin; de la Haye, Kayla; Duru, Obidiugwu Kenrik; Abraído-Lanza, Ana F; Dubowitz, Tamara

2016-09-01

African American neighborhoods have been historically targeted for urban renewal projects, which impact social composition and resident's health. The Hill District in Pittsburgh, PA is such a neighborhood. This research sought to investigate the extent to which social networks and perceived neighborhood social cohesion and safety were associated with psychological distress among residents in an African American neighborhood undergoing urban renewal, before the implementation of major neighborhood changes. Findings revealed a modest, significant inverse association between social network size and psychological distress (β = -0.006, p < .01), even after controlling for age, employment, education, and income. Perceived neighborhood safety predicted decreased psychological distress (β = -1.438, p < .01), but not social cohesion, which is consistent with past research. Findings suggest that social networks protect against psychological distress, but neighborhood perceptions are also paramount. © Society for Community Research and Action 2016.

Poor, Rural Neighborhoods and Early School Achievement.

ERIC Educational Resources Information Center

Bickel, Robert; Smith, Cynthia; Eagle, Teresa Hardman

A study sought to identify the existence of neighborhood effects on school achievement that are independent of social class and family background among students from poor, rural neighborhoods. Ethnographic material yielded a concept of rural West Virginia neighborhoods in which residents expect their encounters to be friendly, informal, almost…

Neighborhood age structure and cognitive function in a nationally-representative sample of older adults in the U.S.

PubMed

Friedman, Esther M; Shih, Regina A; Slaughter, Mary E; Weden, Margaret M; Cagney, Kathleen A

2017-02-01

Recent evidence suggests that living in a neighborhood with a greater percentage of older adults is associated with better individual health, including lower depression, better self-rated health, and a decreased risk of overall mortality. However, much of the work to date suffers from four limitations. First, none of the U.S.-based studies examine the association at the national level. Second, no studies have examined three important hypothesized mechanisms - neighborhood socioeconomic status and neighborhood social and physical characteristics - which are significantly correlated with both neighborhood age structure and health. Third, no U.S. study has longitudinally examined cognitive health trajectories. We build on this literature by examining nine years of nationally-representative data from the Health and Retirement Study (2002-2010) on men and women aged 51 and over linked with Census data to examine the relationship between the percentage of adults 65 and older in a neighborhood and individual cognitive health trajectories. Our results indicate that living in a neighborhood with a greater percentage of older adults is related to better individual cognition at baseline but we did not find any significant association with cognitive decline. We also explored potential mediators including neighborhood socioeconomic status, perceived neighborhood cohesion and perceived neighborhood physical disorder. We did not find evidence that neighborhood socioeconomic status explains this relationship; however, there is suggestive evidence that perceived cohesion and disorder may explain some of the association between age structure and cognition. Although more work is needed to identify the precise mechanisms, this work may suggest a potential contextual target for public health interventions to prevent cognitive impairment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neighborhood Age Structure and Cognitive Function in a Nationally-Representative Sample of Older Adults in the U.S

PubMed Central

Friedman, Esther M.; Shih, Regina A.; Slaughter, Mary E.; Weden, Margaret M.; Cagney, Kathleen A.

2017-01-01

Recent evidence suggests that living in a neighborhood with a greater percentage of older adults is associated with better individual health, including lower depression, better self-rated health, and a decreased risk of overall mortality. However, much of the work to date suffers from four limitations. First, none of the U.S.-based studies examine the association at the national level. Second, no studies have examined three important hypothesized mechanisms - neighborhood socioeconomic status and neighborhood social and physical characteristics - which are significantly correlated with both neighborhood age structure and health. Third, no U.S. study has longitudinally examined cognitive health trajectories. We build on this literature by examining nine years of nationally-representative data from the Health and Retirement Study (2002–2010) on men and women aged 51 and over linked with Census data to examine the relationship between the percentage of adults 65 and older in a neighborhood and individual cognitive health trajectories. Our results indicate that living in a neighborhood with a greater percentage of older adults is related to better individual cognition at baseline but we did not find any significant association with cognitive decline. We also explored potential mediators including neighborhood socioeconomic status, perceived neighborhood cohesion and perceived neighborhood physical disorder. We did not find evidence that neighborhood socioeconomic status explains this relationship; however, there is suggestive evidence that perceived cohesion and disorder may explain some of the association between age structure and cognition. Although more work is needed to identify the precise mechanisms, this work may suggest a potential contextual target for public health interventions to prevent cognitive impairment. PMID:28033564

The price of access: capitalization of neighborhood contextual factors

PubMed Central

2013-01-01

Background Studies of neighborhood context on health behavior have not considered that the health benefits of context may be ‘capitalized’ into, or included in, higher housing values. This study examines the associations of better neighborhood context with neighborhood housing values. Methods We use the third wave of Add Health (2000-2001) to estimate the association of neighborhood contextual variables and housing values first across then within income types. This is a census block group-level analysis. Results We find that neighborhood context, especially access to fruit and vegetable outlets, is capitalized into, or associated with, higher housing values. Fast food and convenience store access are associated with lower housing values. Capitalization differs by income quartile of the neighborhood. Even those in the poorest neighborhoods value access to fresh fruits and vegetables, and those in the wealthier neighborhoods value activity resources. All neighborhood incomes types place negative value on fast food access and convenience store access. Conclusions Access to health-related contextual attributes is capitalized into higher housing prices. Access to fresh fruits and vegetables is valued in neighborhoods of all income levels. Modeling these associations by neighborhood income levels helps explain the mixed results in the literature on the built environment in terms of linking health outcomes to access. PMID:23927010

Targeted Antiangiogenesis Gene Therapy Using Targeted Cationic Microbubbles Conjugated with CD105 Antibody Compared with Untargeted Cationic and Neutral Microbubbles

PubMed Central

Zhou, Yu; Gu, Haitao; Xu, Yan; Li, Fan; Kuang, Shaojing; Wang, Zhigang; Zhou, Xiyuan; Ma, Huafeng; Li, Pan; Zheng, Yuanyi; Ran, Haitao; Jian, Jia; Zhao, Yajing; Song, Weixiang; Wang, Qiushi; Wang, Dong

2015-01-01

Objective This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB). Methods CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume. Results CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 μg, 18.21±1.22 μg, and 0.48±0.04 μg per 5×108 microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble

Targeted antiangiogenesis gene therapy using targeted cationic microbubbles conjugated with CD105 antibody compared with untargeted cationic and neutral microbubbles.

PubMed

Zhou, Yu; Gu, Haitao; Xu, Yan; Li, Fan; Kuang, Shaojing; Wang, Zhigang; Zhou, Xiyuan; Ma, Huafeng; Li, Pan; Zheng, Yuanyi; Ran, Haitao; Jian, Jia; Zhao, Yajing; Song, Weixiang; Wang, Qiushi; Wang, Dong

2015-01-01

This study aimed to develop targeted cationic microbubbles conjugated with a CD105 antibody (CMB105) for use in targeted vascular endothelial cell gene therapy and ultrasound imaging. We compared the results with untargeted cationic microbubbles (CMB) and neutral microbubbles (NMB). CMB105 were prepared and compared with untargeted CMB and NMB. First, the microbubbles were characterized in terms of size, zeta-potential, antibody binding ability and plasmid DNA loading capacity. A tumor model of subcutaneous breast cancer in nude mice was used for our experiments. The ability of different types of microbubbles to target HUVECs in vitro and tumor neovascularization in vivo was measured. The endostatin gene was selected for its outstanding antiangiogenesis effect. For in vitro experiments, the transfection efficiency and cell cycle were analyzed using flow cytometry, and the transcription and expression of endostatin were measured by qPCR and Western blotting, respectively. Vascular tube cavity formation and tumor cell invasion were used to evaluate the antiangiogenesis gene therapy efficiency in vitro. Tumors were exposed to ultrasound irradiation with different types of microbubbles, and the gene therapy effects were investigated by detecting apoptosis induction and changes in tumor volume. CMB105 and CMB differed significantly from NMB in terms of zeta-potential, and the DNA loading capacities were 16.76±1.75 μg, 18.21±1.22 μg, and 0.48±0.04 μg per 5×10(8) microbubbles, respectively. The charge coupling of plasmid DNA to CMB105 was not affected by the presence of the CD105 antibody. Both CMB105 and CMB could target to HUVECs in vitro, whereas only CMB105 could target to tumor neovascularization in vivo. In in vitro experiments, the transfection efficiency of CMB105 was 24.7-fold higher than the transfection efficiency of NMB and 1.47-fold higher than the transfection efficiency of CMB (P<0.05). With ultrasound-targeted microbubble destruction (UTMD

Examining differences in types and location of recruitment venues for young males and females from urban neighborhoods: findings from a multi-site HIV prevention study.

PubMed

Chutuape, Kate S; Ziff, Mauri; Auerswald, Colette; Castillo, Marné; McFadden, Antionette; Ellen, Jonathan

2009-01-01

Finding and accessing members of youth subpopulations, such as young men who have sex with men (YMSM) of color or young females of color, for behavioral or disease surveillance or study recruitment, pose particular challenges. Venue-based sampling strategies--which hinge on where individuals congregate or "hang out" rather than where they live--appear to be effective alternatives. Methods used to identify venues focus on engaging members of social networks to learn where targeted populations congregate. However, it is not always clear if and how these methods differ according to gender, whether the youth accessed at a venue are actually from neighborhoods in which the venues are found, and whether the location of venues relative to neighborhoods of residence is different for young men and young women. This study illustrates the gender differences in venue type and venue location where eligible youth study participants from high-risk neighborhoods could be accessed for HIV research across 15 research sites (sites). The findings indicate that the study's method led to identifying venues where one quarter or more of the youth were eligible study participants and from the high-risk neighborhoods. Sites targeting young women of color had a higher proportion of eligible study participants who were also from the high-risk neighborhoods than sites targeting YMSM. Clubs were most commonly identified by sites targeting YMSM as recruitment venues, whereas neighborhood-based service or commercial centers were more common venues for young women of color. This study reveals how venue-based recruitment strategies can be tailored and resources maximized by understanding the key differences in the types of venues preferred by males and females and by recognizing that female-preferred venues are more likely to be closer to home.

New developments in demographic targeting--the implications of 1991.

PubMed

Humby, C R

1989-01-01

This paper examines benefits that systems such as ACORN, a demographic marketing system that classifies neighborhoods, offer today and monitors some of the trends. It then considers the impact of the 1992 UK census and gives a view of what marketeers can expect in the next 5 years. Neighborhood classifications represent a summary of the consumption patterns of a set of neighbors. If we could reach individuals based on the current life stage the gains to be had would be as great again as that offered by the neighborhood classifications themselves. The greatest weakness of all the neighborhood-based systems is their inability to target at life stage or age.

Child, family, and neighborhood associations with parent and peer interactive play during early childhood.

PubMed

Kenney, Mary Kay

2012-04-01

To examine national patterns of peer and parent interactive play opportunities that enhance early learning/socialization. Bivariate and multivariable analyses of cross-sectional data on 22,797 children aged 1-5 years from the National Survey of Children's Health 2007 were performed to determine the child, family, and neighborhood factors associated with four parent-initiated activities. Outcomes measures included time (days/week) children spent: participating in peer play; being read to; sung to/told stories; and taken on family outings. Covariates included race/ethnicity, poverty, TV watching, childcare, child and maternal physical and mental health, family factors (structure, size, language, stress, education), and neighborhood factors (amenities, support, physical condition, safety). According to adjusted regression models, minority children from lower income, non-English-speaking households with limited education, poorer maternal health and greater parenting stress were read to/told stories less than children without these characteristics, while neighborhood factors exerted less influence. In contrast, significant reductions in days/week of peer play were associated with unsupportive neighborhoods and those with the poorest physical conditions and limited amenities. Likewise, reductions in outings were associated with fewer neighborhood amenities. The findings of this study indicate that a variety of child, family, and neighborhood factors are associated with parent-initiated behaviors such as reading, storytelling, peer interactive play, and family outings. Appropriate evidence-based home visiting interventions targeting child health, parenting skills, early childhood education, and social services in at-risk communities would appear to be appropriate vehicles for addressing such parent-initiated play activities that have the potential to enhance development.

Missed opportunities: racial and neighborhood socioeconomic disparities in emergency colorectal cancer diagnosis and surgery.

PubMed

Pruitt, Sandi L; Davidson, Nicholas O; Gupta, Samir; Yan, Yan; Schootman, Mario

2014-12-09

Disparities by race and neighborhood socioeconomic status exist for many colorectal cancer (CRC) outcomes, including screening use and mortality. We used population-based data to determine if disparities also exist for emergency CRC diagnosis and surgery. We examined two emergency CRC outcomes using 1992-2005 population-based U.S. SEER-Medicare data. Among CRC patients aged ≥66 years, we examined racial (African American vs. white) and neighborhood poverty disparities in two emergency outcomes defined as: 1) newly diagnosed CRC or 2) CRC surgery associated with: obstruction, perforation, or emergency inpatient admission. Multilevel logistic regression (patients nested in census tracts) analyses adjusted for sociodemographic, tumor, and clinical covariates. Of 83,330 CRC patients, 29.1% were diagnosed emergently. Of 55,046 undergoing surgery, 26.0% had emergency surgery. For both outcomes, race and neighborhood poverty disparities were evident. A significant race by poverty interaction (p < .001) was noted: poverty rate was associated with both outcomes among African Americans, but not whites. Compared to whites in low poverty (<10%) neighborhoods, African Americans in high poverty (≥20%) neighborhoods had increased odds of emergency diagnosis (AOR: 1.50, 95% CI: 1.38-1.63) and surgery (AOR: 1.63, 95% CI: 1.47-1.81). Emergency CRC outcomes are associated with high poverty residence among African Americans in this population-based study, potentially contributing to observed disparities in CRC morbidity and mortality. Targeted efforts to increase CRC screening among African Americans living in high poverty neighborhoods could reduce preventable disparities.

Identification of target genes of synovial sarcoma-associated fusion oncoprotein using human pluripotent stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayakawa, Kazuo; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya

2013-03-22

Highlights: ► We tried to identify targets of synovial sarcoma (SS)-associated SYT–SSX fusion gene. ► We established pluripotent stem cell (PSC) lines with inducible SYT–SSX gene. ► SYT–SSX responsive genes were identified by the induction of SYT–SSX in PSC. ► SS-related genes were selected from database by in silico analyses. ► 51 genes were finally identified among SS-related genes as targets of SYT–SSX in PSC. -- Abstract: Synovial sarcoma (SS) is a malignant soft tissue tumor harboring chromosomal translocation t(X; 18)(p11.2; q11.2), which produces SS-specific fusion gene, SYT–SSX. Although precise function of SYT–SSX remains to be investigated, accumulating evidences suggestmore » its role in gene regulation via epigenetic mechanisms, and the product of SYT–SSX target genes may serve as biomarkers of SS. Lack of knowledge about the cell-of-origin of SS, however, has placed obstacle in the way of target identification. Here we report a novel approach to identify SYT–SSX2 target genes using human pluripotent stem cells (hPSCs) containing a doxycycline-inducible SYT–SSX2 gene. SYT–SSX2 was efficiently induced both at mRNA and protein levels within three hours after doxycycline administration, while no morphological change of hPSCs was observed until 24 h. Serial microarray analyses identified genes of which the expression level changed more than twofold within 24 h. Surprisingly, the majority (297/312, 95.2%) were up-regulated genes and a result inconsistent with the current concept of SYT–SSX as a transcriptional repressor. Comparing these genes with SS-related genes which were selected by a series of in silico analyses, 49 and 2 genes were finally identified as candidates of up- and down-regulated target of SYT–SSX, respectively. Association of these genes with SYT–SSX in SS cells was confirmed by knockdown experiments. Expression profiles of SS-related genes in hPSCs and human mesenchymal stem cells (hMSCs) were

Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection.

PubMed

Saito, Shinta; Ura, Kiyoe; Kodama, Miho; Adachi, Noritaka

2015-06-30

Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene-targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon-trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non-homologous integration of exon-trap vectors. Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy.

Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting.

PubMed

Gerlai, R; Williams, S P; Cairns, B; Van Bruggen, N; Moran, P; Shih, A; Caras, I; Sauer, H; Phillips, H S; Winslow, J W

1998-11-01

Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins--cell-adhesion molecules--and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location

Neighborhood education inequality and drinking behavior.

PubMed

Lê, Félice; Ahern, Jennifer; Galea, Sandro

2010-11-01

The neighborhood distribution of education (education inequality) may influence substance use among neighborhood residents. Using data from the New York Social Environment Study (conducted in 2005; n=4000), we examined the associations of neighborhood education inequality (measured using Gini coefficients of education) with alcohol use prevalence and levels of alcohol consumption among alcohol users. Analyses were adjusted for neighborhood education level, income level and income inequality, as well as for individual demographic and socioeconomic characteristics and history of drinking prior to residence in the current neighborhood. Neighborhood social norms about drinking were examined as a possible mediator. In adjusted generalized estimating equation regression models, one-standard-deviation-higher education inequality was associated with 1.18 times higher odds of alcohol use (logistic regression odds ratio=1.18, 95% confidence interval 1.08-1.30) but 0.79 times lower average daily alcohol consumption among alcohol users (Poisson regression relative rate=0.79, 95% confidence interval 0.68-0.92). The results tended to differ in magnitude depending on respondents' individual educational levels. There was no evidence that these associations were mediated by social drinking norms, although norms did vary with education inequality. Our results provide further evidence of a relation between education inequality and drinking behavior while illustrating the importance of considering different drinking outcomes and heterogeneity between neighborhood subgroups. Future research could fruitfully consider other potential mechanisms, such as alcohol availability or the role of stress; research that considers multiple mechanisms and their combined effects may be most informative. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Building Strengths in the Neighborhood

ERIC Educational Resources Information Center

Quigley, Richard

2005-01-01

This article features Woodland Hills's Neighborhood Youth Services. The Neighborhood Youth Services (NYS) program is a community-based program created by Woodland Hills, a residential program for troubled adolescents in Duluth, Minnesota. Principles for building respectful adult and peer relationships developed in the treatment environment were…

Social Norms and the Consumption of Fruits and Vegetables across New York City Neighborhoods.

PubMed

Li, Yan; Zhang, Donglan; Pagán, José A

2016-04-01

Consumption of fruits and vegetables is associated with a lower risk of developing many chronic health conditions such as diabetes and cardiovascular disease. While five or more servings of fruits and vegetables per day are recommended, only 50 % of New York City (NYC) residents consume two or more servings per day. In addition, there is wide variation in dietary behaviors across different neighborhoods in NYC. Using a validated agent-based model and data from 34 NYC neighborhoods, we simulate how a mass media and nutrition education campaign strengthening positive social norms about food consumption may potentially increase the proportion of the population who consume two or more servings of fruits and vegetables per day in NYC. We found that the proposed intervention results in substantial increases in daily fruit and vegetable consumption, but the campaign may be less effective in neighborhoods with relatively low education levels or a relatively high proportion of male residents. A well-designed, validated agent-based model has the potential to provide insights on the impact of an intervention targeting social norms before it is implemented and shed light on the important neighborhood factors that may affect the efficacy of the intervention.

Targeted gene disruption in Koji mold Aspergillus oryzae.

PubMed

Maruyama, Jun-Ichi; Kitamoto, Katsuhiko

2011-01-01

Filamentous fungi have received attentions as hosts for heterologous protein production because of their high secretion capability and eukaryotic post-translational modifications. One of the safest hosts for heterologous protein production is Koji mold Aspergillus oryzae since it has been used in the production of Japanese fermented foods for over 1,000 years. The production levels of proteins from higher eukaryotes are much lower than those of homologous (fungal) proteins. Bottlenecks in the heterologous protein production are suggested to be proteolytic degradation of the produced protein in the medium and the secretory pathway. For construction of excellent host strains, many genes causing the bottlenecks should be disrupted rapidly and efficiently. We developed a marker recycling system with the highly efficient gene-targeting background in A. oryzae. By employing this technique, we performed multiple gene disruption of the ten protease genes. The decuple protease gene disruptant showed fourfold production level of a heterologous protein compared with the wild-type strain.

Retinoschisislike alterations in the mouse eye caused by gene targeting of the Norrie disease gene.

PubMed

Ruether, K; van de Pol, D; Jaissle, G; Berger, W; Tornow, R P; Zrenner, E

1997-03-01

To investigate the retinal function and morphology of mice carrying a replacement mutation in exon 2 of the Norrie disease gene. Recently, Norrie disease mutant mice have been generated using gene targeting technology. The mutation removes the 56 N-terminal amino acids of the Norrie gene product. Ganzfeld electroretinograms (ERGs) were obtained in five animals hemizygous or homozygous for the mutant gene and in three female animals heterozygous for the mutant gene. As controls, three males carrying the wild-type gene were examined. Electroretinogram testing included rod a- and b-wave V-log I functions, oscillatory potentials, and cone responses. The fundus morphology has been visualized by scanning laser ophthalmoscopy. Rod and cone ERG responses and fundus morphology were not significantly different among female heterozygotes and wild-type mice. In contrast, the hemizygous mice displayed a severe loss of ERG b-wave, leading to a negatively shaped scotopic ERG and a marked reduction of oscillatory potentials. The a-wave was normal at low intensities, and only with brighter flashes was there a moderate amplitude loss. Cone amplitudes were barely recordable in the gene-targeted males. Ophthalmoscopy revealed snowflakelike vitreal changes, retinoschisis, and pigment epithelium irregularities in hemizygotes and homozygotes, but no changes in female heterozygotes. The negatively shaped scotopic ERG in male mice with a Norrie disease gene mutation probably was caused by retinoschisis. Pigment epithelial changes and degenerations of the outer retina are relatively mild. These findings may be a clue to the embryonal retinoschisislike pathogenesis of Norrie disease in humans or it may indicate a different expression of the Norrie disease gene defect in mice compared to that in humans.

MORE NEIGHBORHOOD RETAIL ASSOCIATED WITH LOWER OBESITY AMONG NEW YORK CITY PUBLIC HIGH SCHOOL STUDENTS

PubMed Central

Bader, Michael D. M.; Schwartz-Soicher, Ofira; Jack, Darby; Weiss, Christopher C.; Richards, Catherine A.; Quinn, James W.; Lovasi, Gina S.; Neckerman, Kathryn M.; Rundle, Andrew G.

2014-01-01

Policies target fast food outlets to curb adolescent obesity. We argue that researchers should examine the entire retail ecology of neighborhoods, not just fast food outlets. We examine the association between the neighborhood retail environment and obesity using Fitnessgram data collected from 94,348 New York City public high school students. In generalized hierarchical linear models, the number of fast food restaurants predicted lower odds of obesity for adolescents (OR:0.972 per establishment; CI:0.957--0.988). In a “placebo test” we found that banks – a measure of neighborhood retail ecology – also predicted lower obesity (OR:0.979 per bank; CI:0.962–0.994). Retail disinvestment might be associated with greater obesity; accordingly, public health research should study the influence of general retail disinvestment not just food-specific investment. PMID:23827943

More neighborhood retail associated with lower obesity among New York City public high school students.

PubMed

Bader, Michael D M; Schwartz-Soicher, Ofira; Jack, Darby; Weiss, Christopher C; Richards, Catherine A; Quinn, James W; Lovasi, Gina S; Neckerman, Kathryn M; Rundle, Andrew G

2013-09-01

Policies target fast food outlets to curb adolescent obesity. We argue that researchers should examine the entire retail ecology of neighborhoods, not just fast food outlets. We examine the association between the neighborhood retail environment and obesity using Fitnessgram data collected from 94,348 New York City public high school students. In generalized hierarchical linear models, the number of fast food restaurants predicted lower odds of obesity for adolescents (OR:0.972 per establishment; CI:0.957-0.988). In a "placebo test" we found that banks--a measure of neighborhood retail ecology--also predicted lower obesity (OR:0.979 per bank; CI:0.962-0.994). Retail disinvestment might be associated with greater obesity; accordingly, public health research should study the influence of general retail disinvestment not just food-specific investment. © 2013 Elsevier Ltd. All rights reserved.

Neighborhood Poverty and Adolescent Development

ERIC Educational Resources Information Center

McBride Murry, Velma; Berkel, Cady; Gaylord-Harden, Noni K.; Copeland-Linder, Nikeea; Nation, Maury

2011-01-01

This article provides a comprehensive review of studies conducted over the past decade on the effects of neighborhood and poverty on adolescent normative and nonnormative development. Our review includes a summary of studies examining the associations between neighborhood poverty and adolescent identity development followed by a review of studies…

Neighborhood Influences on Emergency Medical Services Use for Acute Stroke: A Population-Based Cross-sectional Study.

PubMed

Meurer, William J; Levine, Deborah A; Kerber, Kevin A; Zahuranec, Darin B; Burke, James; Baek, Jonggyu; Sánchez, Brisa; Smith, Melinda A; Morgenstern, Lewis B; Lisabeth, Lynda D

2016-03-01

Delay to hospital arrival limits acute stroke treatment. Use of emergency medical services (EMS) is key in ensuring timely stroke care. We aim to identify neighborhoods with low EMS use and to evaluate whether neighborhood-level factors are associated with EMS use. We conducted a secondary analysis of data from the Brain Attack Surveillance in Corpus Christi project, a population-based stroke surveillance study of ischemic stroke and intracerebral hemorrhage cases presenting to emergency departments in Nueces County, TX. The primary outcome was arrival by EMS. The primary exposures were neighborhood resident age, poverty, and violent crime. We estimated the association of neighborhood-level factors with EMS use, using hierarchic logistic regression, controlling for individual factors (stroke severity, ethnicity, and age). During 2000 to 2009 there were 4,004 identified strokes, with EMS use data available for 3,474. Nearly half (49%) of stroke cases arrived by EMS. Adjusted stroke EMS use was lower in neighborhoods with higher family income (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.75 to 0.97) and a larger percentage of older adults (OR 0.70; 95% CI 0.56 to 0.89). Individual factors associated with stroke EMS use included white race (OR 1.41; 95% CI 1.13 to 1.76) and older age (OR 1.36 per 10-year age increment; 95% CI 1.27 to 1.46). The proportion of neighborhood stroke cases arriving by EMS ranged from 17% to 71%. The fully adjusted model explained only 0.3% (95% CI 0% to 1.1%) of neighborhood EMS stroke use variance, indicating that individual factors are more strongly associated with stroke EMS use than neighborhood factors. Although some neighborhood-level factors were associated with EMS use, patient-level factors explained nearly all variability in stroke EMS use. In this community, strategies to increase EMS use should target individuals rather than specific neighborhoods. Copyright © 2015 American College of Emergency Physicians. Published by

The Neighborhood Environment: Perceived Fall Risk, Resources, and Strategies for Fall Prevention.

PubMed

Chippendale, Tracy; Boltz, Marie

2015-08-01

To explore the experience of older adults in their neighborhood in relation to perceived fall risk, fear of falling (FOF), and resources/strategies for fall prevention. Fourteen older adults, 65 years of age and older from 3 urban senior centers, participated in this qualitative study. The semistructured interview guidelines and background questionnaire were developed by the researchers based on the literature and an existing measure of walkability. Both tools were refined based on pilot interviews with seniors. Collaizzi's phenomenological method was used for data analysis. Five themes emerged from the data: (a) The built environment contributes to perceived fall risk and FOF, (b) personal strategies used to adapt to perceived neighborhood fall risks-behavioral approaches, (c) resources for physical activity and safety, (d) barriers to physical activity and exercise, and (e) neighborhood features as a motivator. Urban-dwelling seniors perceive that neighborhood features contribute to or mitigate fall risk and FOF. Behavioral strategies are used by seniors to prevent outdoor falls. The findings can help clinicians develop targeted fall prevention interventions for well elders and help urban planners to design and retrofit urban environments to reduce fall risk. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

NEIGHBORHOOD IMMIGRATION AND NATIVE OUT-MIGRATION

PubMed Central

Crowder, Kyle; Hall, Matthew; Tolnay, Stewart E.

2011-01-01

This study combines data from the Panel Study of Income Dynamics with data from four censuses to examine the effects of foreign-born populations in the immediate neighborhood of residence and surrounding neighborhoods on the residential mobility decisions of native-born black and white householders. We find that the likelihood of out-mobility for native householders is significantly and positively associated with the relative size of, and increases in, the immigrant population in the neighborhood. Consistent with theoretical arguments related to the distance dependence of mobility, large concentrations of immigrants in surrounding areas reduce native out-mobility, presumably by reducing the attractiveness of the most likely mobility destinations. A sizable share of local immigration effects can be explained by the mobility-related characteristics of native-born individuals living in immigrant-populated areas, but the racial composition of the neighborhood (for native whites) and local housing market conditions (for native blacks) also are important mediating factors. The implications of these patterns for processes of neighborhood change and broader patterns of residential segregation are discussed. PMID:21731082

Crispr-mediated Gene Targeting of Human Induced Pluripotent Stem Cells.

PubMed

Byrne, Susan M; Church, George M

2015-01-01

CRISPR/Cas9 nuclease systems can create double-stranded DNA breaks at specific sequences to efficiently and precisely disrupt, excise, mutate, insert, or replace genes. However, human embryonic stem or induced pluripotent stem cells (iPSCs) are more difficult to transfect and less resilient to DNA damage than immortalized tumor cell lines. Here, we describe an optimized protocol for genome engineering of human iPSCs using a simple transient transfection of plasmids and/or single-stranded oligonucleotides. With this protocol, we achieve transfection efficiencies greater than 60%, with gene disruption efficiencies from 1-25% and gene insertion/replacement efficiencies from 0.5-10% without any further selection or enrichment steps. We also describe how to design and assess optimal sgRNA target sites and donor targeting vectors; cloning individual iPSC by single cell FACS sorting, and genotyping successfully edited cells.

Complex network theory for the identification and assessment of candidate protein targets.

PubMed

McGarry, Ken; McDonald, Sharon

2018-06-01

In this work we use complex network theory to provide a statistical model of the connectivity patterns of human proteins and their interaction partners. Our intention is to identify important proteins that may be predisposed to be potential candidates as drug targets for therapeutic interventions. Target proteins usually have more interaction partners than non-target proteins, but there are no hard-and-fast rules for defining the actual number of interactions. We devise a statistical measure for identifying hub proteins, we score our target proteins with gene ontology annotations. The important druggable protein targets are likely to have similar biological functions that can be assessed for their potential therapeutic value. Our system provides a statistical analysis of the local and distant neighborhood protein interactions of the potential targets using complex network measures. This approach builds a more accurate model of drug-to-target activity and therefore the likely impact on treating diseases. We integrate high quality protein interaction data from the HINT database and disease associated proteins from the DrugTarget database. Other sources include biological knowledge from Gene Ontology and drug information from DrugBank. The problem is a very challenging one since the data is highly imbalanced between target proteins and the more numerous nontargets. We use undersampling on the training data and build Random Forest classifier models which are used to identify previously unclassified target proteins. We validate and corroborate these findings from the available literature. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hypoxia-inducible tumour-specific promoters as a dual-targeting transcriptional regulation system for cancer gene therapy

PubMed Central

Javan, Bita; Shahbazi, Majid

2017-01-01

Transcriptional targeting is the best approach for specific gene therapy. Hypoxia is a common feature of the tumour microenvironment. Therefore, targeting gene expression in hypoxic cells by placing transgene under the control of a hypoxia-responsive promoter can be a good strategy for cancer-specific gene therapy. The hypoxia-inducible gene expression system has been investigated more in suicide gene therapy and it can also be of great help in knocking down cancer gene therapy with siRNAs. However, this system needs to be optimised to have maximum efficacy with minimum side effects in normal tissues. The combination of tissue-/tumour-specific promoters with HRE core sequences has been found to enhance the specificity and efficacy of this system. In this review, hypoxia-inducible gene expression system as well as gene therapy strategies targeting tumour hypoxia will be discussed. This review will also focus on hypoxia-inducible tumour-specific promoters as a dual-targeting transcriptional regulation systems developed for cancer-specific gene therapy. PMID:28798809

Pathways from neighborhood poverty to depression among older adults

PubMed Central

Joshi, Spruha; Mooney, Stephen J.; Rundle, Andrew G.; Quinn, James W.; Beard, John R.; Cerdá, Magdalena

2017-01-01

The pathways through which neighborhood poverty can affect resident depression are still unknown. We investigated mechanisms through which neighborhood poverty may influence depression among older adults. Participants were drawn from the New York City Neighborhood and Mental Health in the Elderly Study II, a 3-wave study of adults aged 65–75 (n=3,497) at baseline. Neighborhood poverty and homicide were associated with depressive symptoms at follow-up waves (RR:1.20, 95%CI: 1.05, 1.36; RR: 1.09, 95%CI: 1.02, 1.17, respectively). Homicide accounted for 30% of the effect of neighborhood poverty on depressive symptoms. Neighborhood exposure to violence may be a key mechanism through which neighborhood poverty influences depression among older adults. PMID:28049071

Housing, Neighborhoods, and Children's Health

ERIC Educational Resources Information Center

Ellen, Ingrid Gould; Glied, Sherry

2015-01-01

In theory, improving low-income families' housing and neighborhoods could also improve their children's health, through any number of mechanisms. For example, less exposure to environmental toxins could prevent diseases such as asthma; a safer, less violent neighborhood could improve health by reducing the chances of injury and death, and by…

Neighborhood crime and transit station access mode choice - phase III of neighborhood crime and travel behavior.

DOT National Transportation Integrated Search

2015-08-01

This report provides the findings from the third phase of a three-part study about the influences of neighborhood crimes on travel : mode choice. While previous phases found evidence that high levels of neighborhood crime discourage people from choos...

Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation

PubMed Central

Qian, Jiang; Esumi, Noriko; Chen, Yangjian; Wang, Qingliang; Chowers, Itay; Zack, Donald J.

2005-01-01

Identification of tissue-specific gene regulatory networks can yield insights into the molecular basis of a tissue's development, function and pathology. Here, we present a computational approach designed to identify potential regulatory target genes of photoreceptor cell-specific transcription factors (TFs). The approach is based on the hypothesis that genes related to the retina in terms of expression, disease and/or function are more likely to be the targets of retina-specific TFs than other genes. A list of genes that are preferentially expressed in retina was obtained by integrating expressed sequence tag, SAGE and microarray datasets. The regulatory targets of retina-specific TFs are enriched in this set of retina-related genes. A Bayesian approach was employed to integrate information about binding site location relative to a gene's transcription start site. Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted. To experimentally assess the validity of the bioinformatic predictions, mobility shift, transient transfection and chromatin immunoprecipitation assays were performed with five predicted CRX targets, and the results were suggestive of CRX regulation in 5/5, 3/5 and 4/5 cases, respectively. Together, these experiments strongly suggest that RP1, GUCY2D, ABCA4 are novel targets of CRX. PMID:15967807

Active Transportation in Adult Survivors of Childhood Cancer and Neighborhood Controls

PubMed Central

Slater, Megan E.; Kelly, Aaron S.; Sadak, Karim T.; Ross, Julie A.

2015-01-01

Purpose Childhood cancer survivors (CCS) are at high risk of treatment-related late effects, including cardiovascular disease and diabetes, which can be exacerbated by inadequate physical activity (PA). Previous PA interventions targeting CCS have focused on the domain of leisure-time/recreational PA. Active transportation, another domain of PA, has not been described in CCS. Therefore, this study aimed to identify active transportation behaviors, barriers, and correlates in adult CCS. Methods We recruited 158 adult CCS and 153 controls matched on age, sex, and neighborhood for a survey regarding active transportation behaviors and perceptions. Linear and logistic regression models accounting for correlation among matched participants were used. Results Adult CCS engaged in similar levels of active transportation as controls (2.72 vs. 2.32 hours/week, P=0.40) despite perceiving greater health-related barriers (1.88 vs. 1.65 (measured on four-point Likert scale), P=0.01). Marital/relationship status (odds ratio (OR)=0.30, 95% confidence interval (CI)=0.11–0.81), planning/psychosocial barriers (OR=0.15, 95% CI=0.04–0.53), and perceived neighborhood walkability (OR=2.55, 95% CI=1.14–5.66) were correlates of active transportation among adult CCS, while objective neighborhood walkability (OR=1.03, 95% CI=1.01–1.05) was a correlate among controls. Conclusions Results suggest adult CCS and controls utilize active transportation at approximately equal levels. Factors other than health, including perceived neighborhood walkability, appear to influence active transportation behaviors to a greater degree in adult CCS. Implications for Cancer Survivors Interventions might consider promoting active transportation as a way to incorporate more PA into the daily lives of adult CCS. Such interventions will not be widely successful, however, without existing or improved neighborhood walkability/bikeability. PMID:25809159

Active transportation in adult survivors of childhood cancer and neighborhood controls.

PubMed

Slater, Megan E; Kelly, Aaron S; Sadak, Karim T; Ross, Julie A

2016-02-01

Childhood cancer survivors (CCS) are at high risk of treatment-related late effects, including cardiovascular disease and diabetes, which can be exacerbated by inadequate physical activity (PA). Previous PA interventions targeting CCS have focused on the domain of leisure-time/recreational PA. Active transportation, another domain of PA, has not been described in CCS. Therefore, this study aimed to identify active transportation behaviors, barriers, and correlates in adult CCS. We recruited 158 adult CCS and 153 controls matched on age, sex, and neighborhood for a survey regarding active transportation behaviors and perceptions. Linear and logistic regression models accounting for correlation among matched participants were used. Adult CCS engaged in similar levels of active transportation as controls (2.72 vs. 2.32 h/week, P = 0.40) despite perceiving greater health-related barriers (1.88 vs. 1.65 (measured on four-point Likert scale), P = 0.01). Marital/relationship status (odds ratio (OR) = 0.30, 95 % confidence interval (CI) = 0.11-0.81), planning/psychosocial barriers (OR = 0.15, 95 % CI = 0.04-0.53), and perceived neighborhood walkability (OR = 2.55, 95 % CI = 1.14-5.66) were correlates of active transportation among adult CCS, while objective neighborhood walkability (OR = 1.03, 95 % CI = 1.01-1.05) was a correlate among controls. Results suggest adult CCS and controls utilize active transportation at approximately equal levels. Factors other than health, including perceived neighborhood walkability, are related to active transportation behaviors to a greater degree in adult CCS. Interventions might consider promoting active transportation as a way to incorporate more PA into the daily lives of adult CCS. Such interventions will not be likely successful, however, without existing or improved neighborhood walkability/bikeability.

Ultrasound-Mediated Vascular Gene Transfection by Cavitation of Endothelial-Targeted Cationic Microbubbles

PubMed Central

Xie, Aris; Belcik, Todd; Qi, Yue; Morgan, Terry K.; Champaneri, Shivam A.; Taylor, Sarah; Davidson, Brian P.; Zhao, Yan; Klibanov, Alexander L.; Kuliszewski, Michael A.; Leong-Poi, Howard; Ammi, Azzdine; Lindner, Jonathan R.

2013-01-01

OBJECTIVES Ultrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection. BACKGROUND Contrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound. METHODS Cationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)–stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging. RESULTS Charge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm2). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1–targeted microbubbles and by ultrasound molecular imaging of P-selectin–targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin–targeted microbubbles but was associated with

Folic-Acid-Targeted Self-Assembling Supramolecular Carrier for Gene Delivery.

PubMed

Liao, Rongqiang; Yi, Shouhui; Liu, Manshuo; Jin, Wenling; Yang, Bo

2015-07-27

A targeting gene carrier for cancer-specific delivery was successfully developed through a "multilayer bricks-mortar" strategy. The gene carrier was composed of adamantane-functionalized folic acid (FA-AD), an adamantane-functionalized poly(ethylene glycol) derivative (PEG-AD), and β-cyclodextrin-grafted low-molecular-weight branched polyethylenimine (PEI-CD). Carriers produced by two different self-assembly schemes, involving either precomplexation of the PEI-CD with the FA-AD and PEG-AD before pDNA condensation (Method A) or pDNA condensation with the PEI-CD prior to addition of the FA-AD and PEG-AD to engage host-guest complexation (Method B) were investigated for their ability to compact pDNA into nanoparticles. Cell viability studies show that the material produced by the Method A assembly scheme has lower cytotoxicity than branched PEI 25 kDa (PEI-25KD) and that the transfection efficiency is maintained. These findings suggest that the gene carrier, based on multivalent host-guest interactions, could be an effective, targeted, and low-toxicity carrier for delivering nucleic acid to target cells. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Promoting walking in older adults: Perceived neighborhood walkability influences the effectiveness of motivational messages.

PubMed

Notthoff, Nanna; Carstensen, Laura L

2017-06-01

Positively framed messages seem to promote walking in older adults better than negatively framed messages. This study targeted elderly people in communities unfavorable to walking. Walking was measured with pedometers during baseline (1 week) and intervention (4 weeks). Participants ( n = 74) were informed about either the benefits of walking or the negative consequences of not walking. Perceived neighborhood walkability was assessed with a modified version of the Neighborhood Walkability Scale. When perceived walkability was high, positively framed messages were more effective than negatively framed messages in promoting walking; when perceived walkability was low, negatively framed messages were comparably effective to positively framed messages.

Promoting walking in older adults: Perceived neighborhood walkability influences the effectiveness of motivational messages

PubMed Central

Notthoff, Nanna; Carstensen, Laura L.

2015-01-01

Positively-framed messages seem to promote walking in older adults better than negatively-framed messages. This study targeted elderly people in communities unfavorable to walking. Walking was measured with pedometers during baseline (one week) and intervention (four weeks). Participants (n = 74) were either informed about the benefits of walking or the negative consequences of not walking. Perceived neighborhood walkability was assessed with a modified version of the Neighborhood Walkability Scale. When perceived walkability was high positively-framed messages were more effective than negatively-framed messages in promoting walking; when perceived walkability was low negatively-framed messages were comparably effective to positively-framed messages. PMID:26604128

Neighborhoods and Parenting: Assessing the Influence of Neighborhood Quality on the Parental Monitoring of Youth

ERIC Educational Resources Information Center

Zuberi, Anita

2016-01-01

The present study examines the relationship between neighborhood quality and parental monitoring of youth aged 10 to 18 (N = 1,630) from the Child Development Supplement of the Panel Study of Income Dynamics. Multiple measures of the neighborhood, including parents' perceptions of quality, structure (i.e., poverty and affluence), and social…

Neighborhood Economic Enterprises: An Analysis, Survey, and Guide to Resources in Starting Up Neighborhood Enterprises.

ERIC Educational Resources Information Center

Kotler, Neil G.

This pamphlet provides information on the history of and current trends toward neighborhood economic enterprises and provides guidance for setting up such enterprises. A bibliography of books, articles, and newsletters that have information on how to start and sustain neighborhood businesses and cooperatives is provided. Also included is a list of…

Engineering liposomal nanoparticles for targeted gene therapy.

PubMed

Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

2017-08-01

Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

Pathways from neighborhood poverty to depression among older adults.

PubMed

Joshi, Spruha; Mooney, Stephen J; Rundle, Andrew G; Quinn, James W; Beard, John R; Cerdá, Magdalena

2017-01-01

The pathways through which neighborhood poverty can affect resident depression are still unknown. We investigated mechanisms through which neighborhood poverty may influence depression among older adults. Participants were drawn from the New York City Neighborhood and Mental Health in the Elderly Study II, a 3-wave study of adults aged 65-75 (n=3,497) at baseline. Neighborhood poverty and homicide were associated with depressive symptoms at follow-up waves (RR:1.20, 95%CI: 1.05, 1.36; RR: 1.09, 95%CI: 1.02, 1.17, respectively). Homicide accounted for 30% of the effect of neighborhood poverty on depressive symptoms. Neighborhood exposure to violence may be a key mechanism through which neighborhood poverty influences depression among older adults. Copyright © 2016 Elsevier Ltd. All rights reserved.

CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection.

PubMed

Kim, Heon Seok; Lee, Kyungjin; Bae, Sangsu; Park, Jeongbin; Lee, Chong-Kyo; Kim, Meehyein; Kim, Eunji; Kim, Minju; Kim, Seokjoong; Kim, Chonsaeng; Kim, Jin-Soo

2017-06-23

Several groups have used genome-wide libraries of lentiviruses encoding small guide RNAs (sgRNAs) for genetic screens. In most cases, sgRNA expression cassettes are integrated into cells by using lentiviruses, and target genes are statistically estimated by the readout of sgRNA sequences after targeted sequencing. We present a new virus-free method for human gene knockout screens using a genome-wide library of CRISPR/Cas9 sgRNAs based on plasmids and target gene identification via whole-genome sequencing (WGS) confirmation of authentic mutations rather than statistical estimation through targeted amplicon sequencing. We used 30,840 pairs of individually synthesized oligonucleotides to construct the genome-scale sgRNA library, collectively targeting 10,280 human genes ( i.e. three sgRNAs per gene). These plasmid libraries were co-transfected with a Cas9-expression plasmid into human cells, which were then treated with cytotoxic drugs or viruses. Only cells lacking key factors essential for cytotoxic drug metabolism or viral infection were able to survive. Genomic DNA isolated from cells that survived these challenges was subjected to WGS to directly identify CRISPR/Cas9-mediated causal mutations essential for cell survival. With this approach, we were able to identify known and novel genes essential for viral infection in human cells. We propose that genome-wide sgRNA screens based on plasmids coupled with WGS are powerful tools for forward genetics studies and drug target discovery. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Drug2Gene: an exhaustive resource to explore effectively the drug-target relation network.

PubMed

Roider, Helge G; Pavlova, Nadia; Kirov, Ivaylo; Slavov, Stoyan; Slavov, Todor; Uzunov, Zlatyo; Weiss, Bertram

2014-03-11

Information about drug-target relations is at the heart of drug discovery. There are now dozens of databases providing drug-target interaction data with varying scope, and focus. Therefore, and due to the large chemical space, the overlap of the different data sets is surprisingly small. As searching through these sources manually is cumbersome, time-consuming and error-prone, integrating all the data is highly desirable. Despite a few attempts, integration has been hampered by the diversity of descriptions of compounds, and by the fact that the reported activity values, coming from different data sets, are not always directly comparable due to usage of different metrics or data formats. We have built Drug2Gene, a knowledge base, which combines the compound/drug-gene/protein information from 19 publicly available databases. A key feature is our rigorous unification and standardization process which makes the data truly comparable on a large scale, allowing for the first time effective data mining in such a large knowledge corpus. As of version 3.2, Drug2Gene contains 4,372,290 unified relations between compounds and their targets most of which include reported bioactivity data. We extend this set with putative (i.e. homology-inferred) relations where sufficient sequence homology between proteins suggests they may bind to similar compounds. Drug2Gene provides powerful search functionalities, very flexible export procedures, and a user-friendly web interface. Drug2Gene v3.2 has become a mature and comprehensive knowledge base providing unified, standardized drug-target related information gathered from publicly available data sources. It can be used to integrate proprietary data sets with publicly available data sets. Its main goal is to be a 'one-stop shop' to identify tool compounds targeting a given gene product or for finding all known targets of a drug. Drug2Gene with its integrated data set of public compound-target relations is freely accessible without

Dual CRISPR-Cas9 Cleavage Mediated Gene Excision and Targeted Integration in Yarrowia lipolytica.

PubMed

Gao, Difeng; Smith, Spencer; Spagnuolo, Michael; Rodriguez, Gabriel; Blenner, Mark

2018-05-29

CRISPR-Cas9 technology has been successfully applied in Yarrowia lipolytica for targeted genomic editing including gene disruption and integration; however, disruptions by existing methods typically result from small frameshift mutations caused by indels within the coding region, which usually resulted in unnatural protein. In this study, a dual cleavage strategy directed by paired sgRNAs is developed for gene knockout. This method allows fast and robust gene excision, demonstrated on six genes of interest. The targeted regions for excision vary in length from 0.3 kb up to 3.5 kb and contain both non-coding and coding regions. The majority of the gene excisions are repaired by perfect nonhomologous end-joining without indel. Based on this dual cleavage system, two targeted markerless integration methods are developed by providing repair templates. While both strategies are effective, homology mediated end joining (HMEJ) based method are twice as efficient as homology recombination (HR) based method. In both cases, dual cleavage leads to similar or improved gene integration efficiencies compared to gene excision without integration. This dual cleavage strategy will be useful for not only generating more predictable and robust gene knockout, but also for efficient targeted markerless integration, and simultaneous knockout and integration in Y. lipolytica. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes.

PubMed

Lee, Wonsik; Do, Truc; Zhang, Ge; Kahne, Daniel; Meredith, Timothy C; Walker, Suzanne

2018-06-08

Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here, we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain nonessential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway. Guided by this hypothesis, we have identified antibiotic/counterselectable markers to accelerate reverse engineering of two increasingly antibiotic-resistant pathogens, Staphylococcus aureus and Acinetobacter baumannii. For S. aureus, we used wall teichoic acid biosynthesis inhibitors to select for the absence of tarO and for A. baumannii, we used colistin to select for the absence of lpxC. We have obtained desired gene deletions, gene fusions, and promoter swaps in a single plating step with perfect efficiency. Our method can also be adapted to generate markerless deletions of genes using FLP recombinase. The tools described here will accelerate research on two important pathogens, and the concept we outline can be readily adapted to any organism for which a suitable target pathway can be identified.

Living environment matters: relationships between neighborhood characteristics and health of the residents in a Dutch municipality.

PubMed

Putrik, Polina; de Vries, Nanne K; Mujakovic, Suhreta; van Amelsvoort, Ludovic; Kant, Ijmert; Kunst, Anton E; van Oers, Hans; Jansen, Maria

2015-02-01

Characteristics of an individual alone cannot exhaustively explain all the causes of poor health, and neighborhood of residence have been suggested to be one of the factors that contribute to health. However, knowledge about aspects of the neighborhood that are most important to health is limited. The main objective of this study was to explore associations between certain features of neighborhood environment and self-rated health and depressive symptoms in Maastricht (The Netherlands). A large amount of routinely collected neighborhood data were aggregated by means of factor analysis to 18 characteristics of neighborhood social and physical environment. Associations between these characteristics and self-rated health and presence of depressive symptoms were further explored in multilevel logistic regression models adjusted for individual demographic and socio-economic factors. The study sample consisted of 9,879 residents (mean age 55 years, 48 % male). Residents of unsafe communities were less likely to report good health (OR 0.88 95 % CI 0.80-0.97) and depressive symptoms (OR 0.81 95 % CI 0.69-0.97), and less cohesive environment was related to worse self-rated health (OR 0.81 95 % CI 0.72-0.92). Residents of neighborhoods with more car traffic nuisance and more disturbance from railway noise reported worse mental health (OR 0.79 95 % CI 0.68-0.92 and 0.85 95 % CI 0.73-0.99, respectively). We did not observe any association between health and quality of parking and shopping facilities, facilities for public or private transport, neighborhood aesthetics, green space, industrial nuisance, sewerage, neighbor nuisance or satisfaction with police performance. Our findings can be used to support development of integrated health policies targeting broader determinants of health. Improving safety, social cohesion and decreasing traffic nuisance in disadvantaged neighborhoods might be a promising way to improve the health of residents and reduce health inequalities.

Space, race, and poverty: Spatial inequalities in walkable neighborhood amenities?

PubMed Central

Aldstadt, Jared; Whalen, John; White, Kellee; Castro, Marcia C.; Williams, David R.

2017-01-01

BACKGROUND Multiple and varied benefits have been suggested for increased neighborhood walkability. However, spatial inequalities in neighborhood walkability likely exist and may be attributable, in part, to residential segregation. OBJECTIVE Utilizing a spatial demographic perspective, we evaluated potential spatial inequalities in walkable neighborhood amenities across census tracts in Boston, MA (US). METHODS The independent variables included minority racial/ethnic population percentages and percent of families in poverty. Walkable neighborhood amenities were assessed with a composite measure. Spatial autocorrelation in key study variables were first calculated with the Global Moran’s I statistic. Then, Spearman correlations between neighborhood socio-demographic characteristics and walkable neighborhood amenities were calculated as well as Spearman correlations accounting for spatial autocorrelation. We fit ordinary least squares (OLS) regression and spatial autoregressive models, when appropriate, as a final step. RESULTS Significant positive spatial autocorrelation was found in neighborhood socio-demographic characteristics (e.g. census tract percent Black), but not walkable neighborhood amenities or in the OLS regression residuals. Spearman correlations between neighborhood socio-demographic characteristics and walkable neighborhood amenities were not statistically significant, nor were neighborhood socio-demographic characteristics significantly associated with walkable neighborhood amenities in OLS regression models. CONCLUSIONS Our results suggest that there is residential segregation in Boston and that spatial inequalities do not necessarily show up using a composite measure. COMMENTS Future research in other geographic areas (including international contexts) and using different definitions of neighborhoods (including small-area definitions) should evaluate if spatial inequalities are found using composite measures but also should use measures of

A review of neighborhood effects and early child development: How, where, and for whom, do neighborhoods matter?

PubMed

Minh, Anita; Muhajarine, Nazeem; Janus, Magdalena; Brownell, Marni; Guhn, Martin

2017-07-01

This paper describes a scoping review of 42 studies of neighborhood effects on developmental health for children ages 0-6, published between 2009 and 2014. It focuses on three themes: (1) theoretical mechanisms that drive early childhood development, i.e. how neighborhoods matter for early childhood development; (2) dependence of such mechanisms on place-based characteristics i.e. where neighborhood effects occur; (3) dependence of such mechanisms on child characteristics, i.e. for whom is development most affected. Given that ecological systems theories postulate diverse mechanisms via which neighborhood characteristics affect early child development, we specifically examine evidence on mediation and/or moderation effects. We conclude by discussing future challenges, and proposing recommendations for analyses that utilize ecological longitudinal population-based databases. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Neighborhood-level LGBT hate crimes and current illicit drug use among sexual minority youth

PubMed Central

Duncan, Dustin T.; Hatzenbuehler, Mark L.; Johnson, Renee M.

2014-01-01

Objective To investigate whether past-30 day illicit drug use among sexual minority youth was more common in neighborhoods with a greater prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT, or sexual minority) individuals. Methods We used a population-based survey of public school youth in Boston, Massachusetts, consisting of 1292 9th–12th grade students from the 2008 Boston Youth Survey Geospatial Dataset (sexual minority n = 108). Data on LGBT hate crimes involving assaults or assaults and battery between 2005 and 2008 were obtained from the Boston Police Department and linked to youths’ residential address. Youth reported past-30 day use of marijuana and other illicit drugs. Wilcoxon–Mann–Whitney tests and corresponding p-values were computed to assess differences in substance use by neighborhood-level LGBT assault hate crime rate among sexual minority youth (n = 103). Results The LGBT assault hate crime rate in the neighborhoods of sexual minority youth who reported current marijuana use was 23.7 per 100,000, compared to 12.9 per 100,000 for sexual minority youth who reported no marijuana use (p = 0.04). No associations between LGBT assault hate crimes and marijuana use among heterosexual youth (p > 0.05) or between sexual minority marijuana use and overall neighborhood-level violent and property crimes (p > 0.05) were detected, providing evidence for result specificity. Conclusions We found a significantly greater prevalence of marijuana use among sexual minority youth in neighborhoods with a higher prevalence of LGBT assault hate crimes. These results suggest that neighborhood context (i.e., LGBT hate crimes) may contribute to sexual orientation disparities in marijuana use. PMID:24326203

Neighborhood-level LGBT hate crimes and current illicit drug use among sexual minority youth.

PubMed

Duncan, Dustin T; Hatzenbuehler, Mark L; Johnson, Renee M

2014-02-01

To investigate whether past-30 day illicit drug use among sexual minority youth was more common in neighborhoods with a greater prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT, or sexual minority) individuals. We used a population-based survey of public school youth in Boston, Massachusetts, consisting of 1292 9th-12th grade students from the 2008 Boston Youth Survey Geospatial Dataset (sexual minority n=108). Data on LGBT hate crimes involving assaults or assaults and battery between 2005 and 2008 were obtained from the Boston Police Department and linked to youths' residential address. Youth reported past-30 day use of marijuana and other illicit drugs. Wilcoxon-Mann-Whitney tests and corresponding p-values were computed to assess differences in substance use by neighborhood-level LGBT assault hate crime rate among sexual minority youth (n=103). The LGBT assault hate crime rate in the neighborhoods of sexual minority youth who reported current marijuana use was 23.7 per 100,000, compared to 12.9 per 100,000 for sexual minority youth who reported no marijuana use (p=0.04). No associations between LGBT assault hate crimes and marijuana use among heterosexual youth (p>0.05) or between sexual minority marijuana use and overall neighborhood-level violent and property crimes (p>0.05) were detected, providing evidence for result specificity. We found a significantly greater prevalence of marijuana use among sexual minority youth in neighborhoods with a higher prevalence of LGBT assault hate crimes. These results suggest that neighborhood context (i.e., LGBT hate crimes) may contribute to sexual orientation disparities in marijuana use. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Schizophrenia and subsequent neighborhood deprivation: revisiting the social drift hypothesis using population, twin and molecular genetic data.

PubMed

Sariaslan, A; Fazel, S; D'Onofrio, B M; Långström, N; Larsson, H; Bergen, S E; Kuja-Halkola, R; Lichtenstein, P

2016-05-03

Neighborhood influences in the etiology of schizophrenia have been emphasized in a number of systematic reviews, but causality remains uncertain. To test the social drift hypothesis, we used three complementary genetically informed Swedish cohorts. First, we used nationwide Swedish data on approximately 760 000 full- and half-sibling pairs born between 1951 and 1974 and quantitative genetic models to study genetic and environmental influences on the overlap between schizophrenia in young adulthood and subsequent residence in socioeconomically deprived neighborhoods. Schizophrenia diagnoses were ascertained using the National Patient Registry. Second, we tested the overlap between childhood psychotic experiences and neighborhood deprivation in early adulthood in the longitudinal Twin Study of Child and Adolescent Development (TCHAD; n=2960). Third, we investigated to what extent polygenic risk scores for schizophrenia predicted residence in deprived neighborhoods during late adulthood using the TwinGene sample (n=6796). Sibling data suggested that living in deprived neighborhoods was substantially heritable; 65% (95% confidence interval (95% CI): 60-71%) of the variance was attributed to genetic influences. Although the correlation between schizophrenia and neighborhood deprivation was moderate in magnitude (r=0.22; 95% CI: 0.20-0.24), it was entirely explained by genetic influences. We replicated these findings in the TCHAD sample. Moreover, the association between polygenic risk for schizophrenia and neighborhood deprivation was statistically significant (R(2)=0.15%, P=0.002). Our findings are primarily consistent with a genetic selection interpretation where genetic liability for schizophrenia also predicts subsequent residence in socioeconomically deprived neighborhoods. Previous studies may have overemphasized the relative importance of environmental influences in the social drift of schizophrenia patients. Clinical and policy interventions will therefore

Neighborhood characteristics and differential risk for depressive and anxiety disorders across racial/ethnic groups in the United States.

PubMed

Alegría, Margarita; Molina, Kristine M; Chen, Chih-Nan

2014-01-01

The prevalence of psychiatric disorders varies depending on the person's neighborhood context, their racial/ethnic group, and the specific diagnoses being examined. Less is known about specific neighborhood features that represent differential risk for depressive and anxiety disorders (DAD) across racial/ethnic groups in the United States. This study examines whether neighborhood etiologic factors are associated with DAD, above and beyond individual-level characteristics, and whether these associations are moderated by race/ethnicity. We utilized nationally representative data (N = 13,837) from the Collaborative Psychiatric Epidemiology Studies (CPES-Geocode file). Separate weighted multilevel logistic regression models were fitted for any past-year depressive and/or anxiety disorder, any depressive disorder only, and any anxiety disorder only. After adjusting for individual-level characteristics, African Americans living in a neighborhood with greater affluence and Afro-Caribbeans residing in more residentially unstable neighborhoods were at increased risk for any past-year depressive disorder as compared to their non-Latino white counterparts. Further, Latinos residing in neighborhoods with greater levels of Latino/immigrant concentration were at increased risk of any past-year anxiety disorder. Lastly, Asians living in neighborhoods with higher levels of economic disadvantage were at decreased risk of any past-year depressive and/or anxiety disorders compared to non-Latino whites, independent of individual-level factors. Differences across subethnic groups are also evident. Results suggest neighborhood characteristics operate differently on risk for DAD across racial/ethnic groups. Our findings have important implications for designing and targeting interventions to address DAD risk among racial/ethnic minorities. © 2013 Wiley Periodicals, Inc.

Neighborhood Characteristics and Differential Risk for Depressive and Anxiety Disorders Across Racial/Ethnic Groups in the United States

PubMed Central

Alegría, Margarita; Molina, Kristine M.; Chen, Chih-Nan

2017-01-01

Background Evidence consistently suggests that prevalence of psychiatric disorders varies depending on the person’s neighborhood context, their racial/ethnic group, and the specific diagnoses being examined. Yet, less is known about specific neighborhood features that represent differential risk for depressive and anxiety disorders (DAD) across racial/ethnic groups in the U.S. This study examines whether neighborhood etiologic factors are associated with DAD, above and beyond individual-level characteristics; and whether these associations are moderated by race/ethnicity. Methods We utilized nationally representative data (N= 13, 837) from the Collaborative Psychiatric Epidemiology Studies (CPES-Geocode file). Separate weighted multilevel logistic regression models were fitted for any past-year depressive and/or anxiety disorder, any depressive disorder only, and any anxiety disorder only. Results After adjusting for individual-level characteristics, African Americans living in a neighborhood with greater affluence and Black Caribbeans residing in more residentially unstable neighborhoods were at increased risk for any past-year depressive disorder as compared to their non-Latino white counterparts. Further, Latinos residing in neighborhoods with greater levels of Latino/immigrant concentration were at an increased risk of any past-year anxiety disorder. Lastly, Asians living in neighborhoods with higher levels of economic disadvantage were at a decreased risk of any past-year depressive and/or anxiety disorders compared to non-Latino whites, independent of individual-level factors. Conclusions Results suggest neighborhood characteristics operate differently on risk for DAD across racial/ethnic groups. Our findings have important implications for designing and targeting interventions to address mental health risk among racial/ethnic minorities. PMID:24123668

Effects of communities, neighborhoods and stores on retail pricing and promotion of beer.

PubMed

Harwood, Eileen M; Erickson, Darin J; Fabian, Lindsey E A; Jones-Webb, Rhonda; Slater, Sandy; Chaloupka, Frank J

2003-09-01

This study examines how communities, neighborhoods and stores influence retail pricing and promotion of beer. In the year 2000, trained field staff conducted observations in 2,024 retail alcohol stores in 160 communities throughout the contiguous United States. Based on a nationally representative sample of schools, we selected communities defined by the school's catchment area, or the vicinity from which the majority of students are drawn. We randomly selected off-sale alcohol retail establishments from a complete list of stores likely to sell tobacco or alcohol in the selected communities. Beer price and promotions are based on observations of Miller and Budweiser beer brands in the stores. Neighborhoods are defined by the store's census block. We used cross-sectional, hierarchical regression models and mixed methods procedures to analyze data. Community, neighborhood and store characteristics were related to beer price; however, only community and store characteristics were predictive of beer promotions. Overall, the pricing and promotion of beer vary systematically by some characteristics of communities, neighborhoods and stores, but not significantly by the number of young people populating a neighborhood. In addition, pricing and promotion of Budweiser and Miller beers, in particular, do not appear to target racial minority populations. Because of the significant effect of store characteristics, public health agencies and advocates might focus prevention efforts on collaborations with liquor control agencies to reduce variations in pricing and promotion of beer, which ultimately encourage risky drinking behaviors. Further studies are needed to examine the effects of pricing and promotion on alcohol-related social problems.

How to Find Lessons from the Public Health Literature: Example of a Scoping Study Protocol on the Neighborhood Environment

PubMed Central

Levasseur, Mélanie; Généreux, Mélissa; Desroches, Josiane; Carrier, Annie; Lacasse, Francis; Chabot, Éric; Abecia, Ana; Gosselin, Louise; Vanasse, Alain

2016-01-01

Background: As key determinants of many favorable health and quality of life outcomes, it is important to identify factors associated with mobility and social participation. Although several investigations have been carried out on mobility, social participation and neighborhood environment, there is no clear integration of these results. This paper presents a scoping study protocol that aims to provide a comprehensive understanding of how the physical and social neighborhood environment is associated with or influences mobility and social participation in older adults. Methods: The rigorous methodological framework for scoping studies is used to synthesize and disseminate current knowledge on the associations or influence of the neighborhood environment on mobility and social participation in aging. Nine databases from public health and other fields are searched with 51 predetermined keywords. Using content analysis, all data are exhaustively analyzed, organized, and synthesized independently by two research assistants. Discussion: A comprehensive synthesis of empirical studies provides decision-makers, clinicians and researchers with current knowledge and best practices regarding neighborhood environments with a view to enhancing mobility and social participation. Such a synthesis represents an original contribution and can ultimately support decisions and development of innovative interventions and clear guidelines for the creation of age-supportive environments. Improvements in public health and clinical interventions might be the new innovation needed to foster health and quality of life for aging population. Finally, the aspects of the associations or influence of the neighborhood environment on mobility and social participation not covered by previous research are identified. Conclusions: Among factors that impact mobility and social participation, the neighborhood environment is important since interventions targeting it may have a greater impact on an

Neighborhood disorder, psychological distress, and heavy drinking.

PubMed

Hill, Terrence D; Angel, Ronald J

2005-09-01

Studies show that residents of disadvantaged neighborhoods drink more heavily than residents of more affluent neighborhoods. However, explanations for this association are not well developed. Using data collected from a sample of low-income women with children from Boston, Chicago, and San Antonio, we explore the possibility that perceptions of neighborhood disorder encourage heavy drinking. Drawing on Conger's (Q. J. Stud. Alcohol 17 (1956) 296) tension reduction hypothesis, we propose that the stress of living in a neighborhood characterized by problems with drugs, crime, teen pregnancy, unemployment, idle youth, abandoned houses, and unresponsive police can be psychologically distressing and lead some people to consume alcohol as a means of palliative escape, to regulate feelings of anxiety and depression. In support of the tension reduction hypothesis, we find that the positive association between neighborhood disorder and heavy drinking is largely mediated by anxiety and depression.

Improved methods of AAV-mediated gene targeting for human cell lines using ribosome-skipping 2A peptide

PubMed Central

Karnan, Sivasundaram; Ota, Akinobu; Konishi, Yuko; Wahiduzzaman, Md; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2016-01-01

The adeno-associated virus (AAV)-based targeting vector has been one of the tools commonly used for genome modification in human cell lines. It allows for relatively efficient gene targeting associated with 1–4-log higher ratios of homologous-to-random integration of targeting vectors (H/R ratios) than plasmid-based targeting vectors, without actively introducing DNA double-strand breaks. In this study, we sought to improve the efficiency of AAV-mediated gene targeting by introducing a 2A-based promoter-trap system into targeting constructs. We generated three distinct AAV-based targeting vectors carrying 2A for promoter trapping, each targeting a GFP-based reporter module incorporated into the genome, PIGA exon 6 or PIGA intron 5. The absolute gene targeting efficiencies and H/R ratios attained using these vectors were assessed in multiple human cell lines and compared with those attained using targeting vectors carrying internal ribosome entry site (IRES) for promoter trapping. We found that the use of 2A for promoter trapping increased absolute gene targeting efficiencies by 3.4–28-fold and H/R ratios by 2–5-fold compared to values obtained with IRES. In CRISPR-Cas9-assisted gene targeting using plasmid-based targeting vectors, the use of 2A did not enhance the H/R ratios but did upregulate the absolute gene targeting efficiencies compared to the use of IRES. PMID:26657635

The Effect of Prime Duration in Masked Orthographic Priming Depends on Neighborhood Distribution

ERIC Educational Resources Information Center

Robert, Christelle; Mathey, Stephanie

2012-01-01

A lexical decision task was used with a masked priming procedure to investigate whether and to what extent neighborhood distribution influences the effect of prime duration in masked orthographic priming. French word targets had two higher frequency neighbors that were either distributed over two letter positions (e.g., "LOBE/robe-loge")…

Using Google Street View to audit neighborhood environments.

PubMed

Rundle, Andrew G; Bader, Michael D M; Richards, Catherine A; Neckerman, Kathryn M; Teitler, Julien O

2011-01-01

Research indicates that neighborhood environment characteristics such as physical disorder influence health and health behavior. In-person audit of neighborhood environments is costly and time-consuming. Google Street View may allow auditing of neighborhood environments more easily and at lower cost, but little is known about the feasibility of such data collection. To assess the feasibility of using Google Street View to audit neighborhood environments. This study compared neighborhood measurements coded in 2008 using Street View with neighborhood audit data collected in 2007. The sample included 37 block faces in high-walkability neighborhoods in New York City. Field audit and Street View data were collected for 143 items associated with seven neighborhood environment constructions: aesthetics, physical disorder, pedestrian safety, motorized traffic and parking, infrastructure for active travel, sidewalk amenities, and social and commercial activity. To measure concordance between field audit and Street View data, percentage agreement was used for categoric measures and Spearman rank-order correlations were used for continuous measures. The analyses, conducted in 2009, found high levels of concordance (≥80% agreement or ≥0.60 Spearman rank-order correlation) for 54.3% of the items. Measures of pedestrian safety, motorized traffic and parking, and infrastructure for active travel had relatively high levels of concordance, whereas measures of physical disorder had low levels. Features that are small or that typically exhibit temporal variability had lower levels of concordance. This exploratory study indicates that Google Street View can be used to audit neighborhood environments. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

The geography of recreational open space: influence of neighborhood racial composition and neighborhood poverty.

PubMed

Duncan, Dustin T; Kawachi, Ichiro; White, Kellee; Williams, David R

2013-08-01

The geography of recreational open space might be inequitable in terms of minority neighborhood racial/ethnic composition and neighborhood poverty, perhaps due in part to residential segregation. This study evaluated the association between minority neighborhood racial/ethnic composition, neighborhood poverty, and recreational open space in Boston, Massachusetts (US). Across Boston census tracts, we computed percent non-Hispanic Black, percent Hispanic, and percent families in poverty as well as recreational open space density. We evaluated spatial autocorrelation in study variables and in the ordinary least squares (OLS) regression residuals via the Global Moran's I. We then computed Spearman correlations between the census tract socio-demographic characteristics and recreational open space density, including correlations adjusted for spatial autocorrelation. After this, we computed OLS regressions or spatial regressions as appropriate. Significant positive spatial autocorrelation was found for neighborhood socio-demographic characteristics (all p value = 0.001). We found marginally significant positive spatial autocorrelation in recreational open space (Global Moran's I = 0.082; p value = 0.053). However, we found no spatial autocorrelation in the OLS regression residuals, which indicated that spatial models were not appropriate. There was a negative correlation between census tract percent non-Hispanic Black and recreational open space density (r S = -0.22; conventional p value = 0.005; spatially adjusted p value = 0.019) as well as a negative correlation between predominantly non-Hispanic Black census tracts (>60 % non-Hispanic Black in a census tract) and recreational open space density (r S = -0.23; conventional p value = 0.003; spatially adjusted p value = 0.007). In bivariate and multivariate OLS models, percent non-Hispanic Black in a census tract and predominantly Black census tracts were associated with

Id-1 gene and gene products as therapeutic targets for treatment of breast cancer and other types of carcinoma

DOEpatents

Desprez, Pierre-Yves; Campisi, Judith

2014-08-19

A method for treatment of breast cancer and other types of cancer. The method comprises targeting and modulating Id-1 gene expression, if any, for the Id-1 gene, or gene products in breast or other epithelial cancers in a patient by delivering products that modulate Id-1 gene expression. When expressed, Id-1 gene is a prognostic indicator that cancer cells are invasive and metastatic.

Neighborhood Energy/Economic Development project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1991-12-31

Energy costs impact low income communities more than anyone else. Low income residents pay a larger percentage of their incomes for energy costs. In addition, they generally have far less discretionary energy use to eliminate in response to increasing energy prices. Furthermore, with less discretionary income, home energy efficiency improvements are often too expensive. Small neighborhood businesses are in the same situation. Improved efficiency in the use of energy can improve this situation by reducing energy costs for residents and local businesses. More importantly, energy management programs can increase the demand for local goods and services and lead to themore » creation of new job training and employment opportunities. In this way, neighborhood based energy efficiency programs can support community economic development. The present project, undertaken with the support of the Urban Consortium Energy Task Force, was intended to serve as a demonstration of energy/economic programming at the neighborhood level. The San Francisco Neighborhood Energy/Economic Development (NEED) project was designed to be a visible demonstration of bringing the economic development benefits of energy management home to low-income community members who need it most. To begin, a Community Advisory Committee was established to guide the design of the programs to best meet needs of the community. Subsequently three neighborhood energy/economic development programs were developed: The small business energy assistance program; The youth training and weatherization program; and, The energy review of proposed housing development projects.« less

Neighborhood Effects on Health: Concentrated Advantage and Disadvantage

PubMed Central

Finch, Brian K.; Do, D. Phuong; Heron, Melonie; Bird, Chloe; Seeman, Teresa; Lurie, Nicole

2010-01-01

We investigate an alternative conceptualization of neighborhood context and its association with health. Using an index that measures a continuum of concentrated advantage and disadvantage, we examine whether the relationship between neighborhood conditions and health varies by socio-economic status. Using NHANES III data geo-coded to census tracts, we find that while largely uneducated neighborhoods are universally deleterious, individuals with more education benefit from living in highly educated neighborhoods to a greater degree than individuals with lower levels of education. PMID:20627796

Zinc-finger nuclease-mediated targeted insertion of reporter genes for quantitative imaging of gene expression in sea urchin embryos

PubMed Central

Ochiai, Hiroshi; Sakamoto, Naoaki; Fujita, Kazumasa; Nishikawa, Masatoshi; Suzuki, Ken-ichi; Matsuura, Shinya; Miyamoto, Tatsuo; Sakuma, Tetsushi; Shibata, Tatsuo; Yamamoto, Takashi

2012-01-01

To understand complex biological systems, such as the development of multicellular organisms, it is important to characterize the gene expression dynamics. However, there is currently no universal technique for targeted insertion of reporter genes and quantitative imaging in multicellular model systems. Recently, genome editing using zinc-finger nucleases (ZFNs) has been reported in several models. ZFNs consist of a zinc-finger DNA-binding array with the nuclease domain of the restriction enzyme FokI and facilitate targeted transgene insertion. In this study, we successfully inserted a GFP reporter cassette into the HpEts1 gene locus of the sea urchin, Hemicentrotus pulcherrimus. We achieved this insertion by injecting eggs with a pair of ZFNs for HpEts1 with a targeting donor construct that contained ∼1-kb homology arms and a 2A-histone H2B–GFP cassette. We increased the efficiency of the ZFN-mediated targeted transgene insertion by in situ linearization of the targeting donor construct and cointroduction of an mRNA for a dominant-negative form of HpLig4, which encodes the H. pulcherrimus homolog of DNA ligase IV required for error-prone nonhomologous end joining. We measured the fluorescence intensity of GFP at the single-cell level in living embryos during development and found that there was variation in HpEts1 expression among the primary mesenchyme cells. These findings demonstrate the feasibility of ZFN-mediated targeted transgene insertion to enable quantification of the expression levels of endogenous genes during development in living sea urchin embryos. PMID:22711830

Girls' self-efficacy in the context of neighborhood gender stratification.

PubMed

Soller, Brian; Jackson, Aubrey L

2018-05-01

Scholars have linked neighborhood characteristics to self-efficacy, but few have considered how gender factors into this association. We integrate literature on neighborhoods, gender stratification, and self-efficacy to examine the association between women's relative resources among neighborhood residents and adolescents' self-efficacy. We hypothesize that girls report more self-efficacy when they reside in neighborhoods where women have more socioeconomic resources relative to men. We test this hypothesis using data from the Project on Human Development in Chicago Neighborhoods and the 1990 Census. Results from multilevel regression models with gender-interacted effects indicate the neighborhood level of women's relative resources was not associated with boys' self-efficacy. However, girls reported higher self-efficacy when women's relative resources in their neighborhoods were greater. This association persisted after including potential individual- and neighborhood-level confounding variables. Our study underscores the importance of attending to gendered processes when understanding how neighborhoods impact youth. Copyright © 2018. Published by Elsevier Inc.

Applications of Gene Targeting Technology to Mental Retardation and Developmental Disability Research

ERIC Educational Resources Information Center

Pimenta, Aurea F.; Levitt, Pat

2005-01-01

The human and mouse genome projects elucidated the sequence and position map of innumerous genes expressed in the central nervous system (CNS), advancing our ability to manipulate these sequences and create models to investigate regulation of gene expression and function. In this article, we reviewed gene targeting methodologies with emphasis on…

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

PubMed

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-02-14

Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). The PAX8-target gene set was ranked 1/615 in the discovery (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10 -5 (including six with P<5 × 10 -8 ). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P GSEA =0.025) and IGROV1 (P GSEA =0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

PubMed Central

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-01-01

Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10−5 (including six with P<5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC. PMID:28103614

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

PubMed Central

van Dongen, Stijn; Haluck-Kangas, Ashley; Sarshad, Aishe A; Bartom, Elizabeth T; Kim, Kwang-Youn A; Scholtens, Denise M; Hafner, Markus; Zhao, Jonathan C; Murmann, Andrea E

2017-01-01

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells. PMID:29063830

Recognizing Spoken Words: The Neighborhood Activation Model

PubMed Central

Luce, Paul A.; Pisoni, David B.

2012-01-01

Objective A fundamental problem in the study of human spoken word recognition concerns the structural relations among the sound patterns of words in memory and the effects these relations have on spoken word recognition. In the present investigation, computational and experimental methods were employed to address a number of fundamental issues related to the representation and structural organization of spoken words in the mental lexicon and to lay the groundwork for a model of spoken word recognition. Design Using a computerized lexicon consisting of transcriptions of 20,000 words, similarity neighborhoods for each of the transcriptions were computed. Among the variables of interest in the computation of the similarity neighborhoods were: 1) the number of words occurring in a neighborhood, 2) the degree of phonetic similarity among the words, and 3) the frequencies of occurrence of the words in the language. The effects of these variables on auditory word recognition were examined in a series of behavioral experiments employing three experimental paradigms: perceptual identification of words in noise, auditory lexical decision, and auditory word naming. Results The results of each of these experiments demonstrated that the number and nature of words in a similarity neighborhood affect the speed and accuracy of word recognition. A neighborhood probability rule was developed that adequately predicted identification performance. This rule, based on Luce's (1959) choice rule, combines stimulus word intelligibility, neighborhood confusability, and frequency into a single expression. Based on this rule, a model of auditory word recognition, the neighborhood activation model, was proposed. This model describes the effects of similarity neighborhood structure on the process of discriminating among the acoustic-phonetic representations of words in memory. The results of these experiments have important implications for current conceptions of auditory word recognition in

Neighborhood Environment and Disparities in Health Care Access Among Urban Medicare Beneficiaries With Diabetes: A Retrospective Cohort Study.

PubMed

Ryvicker, Miriam; Sridharan, Sridevi

2018-01-01

Older adults' health is sensitive to variations in neighborhood environment, yet few studies have examined how neighborhood factors influence their health care access. This study examined whether neighborhood environmental factors help to explain racial and socioeconomic disparities in health care access and outcomes among urban older adults with diabetes. Data from 123 233 diabetic Medicare beneficiaries aged 65 years and older in New York City were geocoded to measures of neighborhood walkability, public transit access, and primary care supply. In 2008, 6.4% had no office-based "evaluation and management" (E&M) visits. Multilevel logistic regression indicated that this group had greater odds of preventable hospitalization in 2009 (odds ratio = 1.31; 95% confidence interval: 1.22-1.40). Nonwhites and low-income individuals had greater odds of a lapse in E&M visits and of preventable hospitalization. Neighborhood factors did not help to explain these disparities. Further research is needed on the mechanisms underlying these disparities and older adults' ability to navigate health care. Even in an insured population living in a provider-dense city, targeted interventions may be needed to overcome barriers to chronic illness care for older adults in the community.

Prediction of target genes for miR-140-5p in pulmonary arterial hypertension using bioinformatics methods.

PubMed

Li, Fangwei; Shi, Wenhua; Wan, Yixin; Wang, Qingting; Feng, Wei; Yan, Xin; Wang, Jian; Chai, Limin; Zhang, Qianqian; Li, Manxiang

2017-12-01

The expression of microRNA (miR)-140-5p is known to be reduced in both pulmonary arterial hypertension (PAH) patients and monocrotaline-induced PAH models in rat. Identification of target genes for miR-140-5p with bioinformatics analysis may reveal new pathways and connections in PAH. This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR-140-5p to provide theoretical evidences for further researches on role of miR-140-5p in PAH. Multiple downstream target genes and upstream transcription factors (TFs) of miR-140-5p were predicted in the analysis. Gene ontology (GO) enrichment analysis indicated that downstream target genes of miR-140-5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis found that downstream target genes were mainly located in Notch, TGF-beta, PI3K/Akt, and Hippo signaling pathway. According to TF-miRNA-mRNA network, the important downstream target genes of miR-140-5p were PPI, TGF-betaR1, smad4, JAG1, ADAM10, FGF9, PDGFRA, VEGFA, LAMC1, TLR4, and CREB. After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR-140-5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro .

Bringing Promise to Washington, DC. The DC Promise Neighborhood Initiative. Program on Neighborhoods and Youth Development

ERIC Educational Resources Information Center

Comey, Jennifer; Scott, Molly M.; Popkin, Susan J.; Falkenburger, Elsa

2012-01-01

The U.S. Department of Education's Promise Neighborhood Initiative (DCPNI) is one of the Obama administration's major antipoverty initiatives and a core strategy of the White House's Neighborhood Revitalization Initiative. It is intended to improve educational outcomes by creating a continuum of school readiness, academic services, and family and…

ARNetMiT R Package: association rules based gene co-expression networks of miRNA targets.

PubMed

Özgür Cingiz, M; Biricik, G; Diri, B

2017-03-31

miRNAs are key regulators that bind to target genes to suppress their gene expression level. The relations between miRNA-target genes enable users to derive co-expressed genes that may be involved in similar biological processes and functions in cells. We hypothesize that target genes of miRNAs are co-expressed, when they are regulated by multiple miRNAs. With the usage of these co-expressed genes, we can theoretically construct co-expression networks (GCNs) related to 152 diseases. In this study, we introduce ARNetMiT that utilize a hash based association rule algorithm in a novel way to infer the GCNs on miRNA-target genes data. We also present R package of ARNetMiT, which infers and visualizes GCNs of diseases that are selected by users. Our approach assumes miRNAs as transactions and target genes as their items. Support and confidence values are used to prune association rules on miRNA-target genes data to construct support based GCNs (sGCNs) along with support and confidence based GCNs (scGCNs). We use overlap analysis and the topological features for the performance analysis of GCNs. We also infer GCNs with popular GNI algorithms for comparison with the GCNs of ARNetMiT. Overlap analysis results show that ARNetMiT outperforms the compared GNI algorithms. We see that using high confidence values in scGCNs increase the ratio of the overlapped gene-gene interactions between the compared methods. According to the evaluation of the topological features of ARNetMiT based GCNs, the degrees of nodes have power-law distribution. The hub genes discovered by ARNetMiT based GCNs are consistent with the literature.

Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

PubMed

Tian, Zhiqiang; Wang, Huaizhi; Jia, Zhengcai; Shi, Jinglei; Tang, Jun; Mao, Liwei; Liu, Hongli; Deng, Yijing; He, Yangdong; Ruan, Zhihua; Li, Jintao; Wu, Yuzhang; Ni, Bing

2010-12-01

Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)β(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

Obesogenic and youth oriented restaurant marketing in public housing neighborhoods.

PubMed

Lee, Rebecca E; Heinrich, Katie M; Reese-Smith, Jacqueline Y; Regan, Gail R; Adamus-Leach, Heather J

2014-03-01

To compare restaurant marketing by restaurant and neighborhood type. All restaurants (61=fast food, FF; 72=table service, TS) within an 800-meter radius of 13 public housing developments (HD) and 4 comparison neighborhoods were audited using the Restaurant Assessment Tool©2010. HD neighborhoods were lower income and higher minority than comparison neighborhoods with similar density and street connectivity. Restaurants in HD neighborhoods had fewer healthy entrées than comparison neighborhoods. FF restaurants had cheaper beverages and more children's meals, supersize drinks, free prize with purchase, super-size items, special characters, and more items geared to driving than TS restaurants. Residents of lower socioeconomic neighborhoods may be differentially exposed to unhealthy food options.

Blood-Derived Smooth Muscle Cells as a Target for Gene Delivery

PubMed Central

Yang, Zhe; Shao, Hongwei; Tan, Yaohong; Eton, Darwin; Yu, Hong

2008-01-01

Objective To examine the feasibility of using blood-derived smooth muscle cells (BD-SMCs) as a target for to deliver therapeutic proteins. Materials and Methods Mononuclear cells (MNC) were isolated from peripheral blood. The outgrowth colonies from MNC culture were differentiated into BD-SMCs in media containing platelet-derived growth factor BB. Phenotypic characterization of BD-SMCs was assessed by immunocytochemistry. Cell proliferation, gene transfer efficiency with a retroviral vector, apoptosis, and the biological activity of the transduced gene product from the BD-SMCs were evaluated in vitro and in vivo in comparison with vascular derived SMC (VSMCs). Results BD-SMCs stained positive for SMC markers. No significant difference was observed between BD-SMCs and VSMCs in cell proliferation, migration, adhesiveness, and gene transfer efficiency. After BD-SMCs were transduced with a retroviral vector carrying the secreted alkaline phosphatase gene (SEAP), 174 ± 50 μg biologically active SEAP was produced per 106 cells over 24 hrs. After injecting 5×106 cells expressing SEAP intravenously into rabbits, SEAP concentration increased significantly in the circulation from 0.14 ± 0.04 μg/ml to 2.34 ± 0.16 μg/ml 3 days after cell injection (P<0.01, n=3). Circulating levels of SEAP decreased to 1.76 μg /ml one week later and remained at this level up to 8 weeks, then declined to pre-cell injection level at 12 weeks. VSMC in vivo gene expression data were equivalent. Conclusion BD-SMCs have similar characteristics to mature VSMCs, and can be used as a novel target for gene transfer to deliver a therapeutic protein. Clinical relevance Cell-based therapy strategies offer the potential to correct a wide spectrum of inherited and acquired human diseases. Translation to a clinical trial will require a detailed pre-clinical study to understand the characteristics of the isolated cells. BD-SMC are practical and effective targets for ex vivo genetic engineering. They are

Target mimics: an embedded layer of microRNA-involved gene regulatory networks in plants.

PubMed

Meng, Yijun; Shao, Chaogang; Wang, Huizhong; Jin, Yongfeng

2012-05-21

MicroRNAs (miRNAs) play an essential role in gene regulation in plants. At the same time, the expression of miRNA genes is also tightly controlled. Recently, a novel mechanism called "target mimicry" was discovered, providing another layer for modulating miRNA activities. However, except for the artificial target mimics manipulated for functional studies on certain miRNA genes, only one example, IPS1 (Induced by Phosphate Starvation 1)-miR399 was experimentally confirmed in planta. To date, few analyses for comprehensive identification of natural target mimics have been performed in plants. Thus, limited evidences are available to provide detailed information for interrogating the questionable issue whether target mimicry was widespread in planta, and implicated in certain biological processes. In this study, genome-wide computational prediction of endogenous miRNA mimics was performed in Arabidopsis and rice, and dozens of target mimics were identified. In contrast to a recent report, the densities of target mimic sites were found to be much higher within the untranslated regions (UTRs) when compared to those within the coding sequences (CDSs) in both plants. Some novel sequence characteristics were observed for the miRNAs that were potentially regulated by the target mimics. GO (Gene Ontology) term enrichment analysis revealed some functional insights into the predicted mimics. After degradome sequencing data-based identification of miRNA targets, the regulatory networks constituted by target mimics, miRNAs and their downstream targets were constructed, and some intriguing subnetworks were further exploited. These results together suggest that target mimicry may be widely implicated in regulating miRNA activities in planta, and we hope this study could expand the current understanding of miRNA-involved regulatory networks.

Ultrasound-mediated vascular gene transfection by cavitation of endothelial-targeted cationic microbubbles.

PubMed

Xie, Aris; Belcik, Todd; Qi, Yue; Morgan, Terry K; Champaneri, Shivam A; Taylor, Sarah; Davidson, Brian P; Zhao, Yan; Klibanov, Alexander L; Kuliszewski, Michael A; Leong-Poi, Howard; Ammi, Azzdine; Lindner, Jonathan R

2012-12-01

Ultrasound-mediated gene delivery can be amplified by acoustic disruption of microbubble carriers that undergo cavitation. We hypothesized that endothelial targeting of microbubbles bearing cDNA is feasible and, through optimizing proximity to the vessel wall, increases the efficacy of gene transfection. Contrast ultrasound-mediated gene delivery is a promising approach for site-specific gene therapy, although there are concerns with the reproducibility of this technique and the safety when using high-power ultrasound. Cationic lipid-shelled decafluorobutane microbubbles bearing a targeting moiety were prepared and compared with nontargeted microbubbles. Microbubble targeting efficiency to endothelial adhesion molecules (P-selectin or intercellular adhesion molecule [ICAM]-1) was tested using in vitro flow chamber studies, intravital microscopy of tumor necrosis factor-alpha (TNF-α)-stimulated murine cremaster muscle, and targeted contrast ultrasound imaging of P-selectin in a model of murine limb ischemia. Ultrasound-mediated transfection of luciferase reporter plasmid charge coupled to microbubbles in the post-ischemic hindlimb muscle was assessed by in vivo optical imaging. Charge coupling of cDNA to the microbubble surface was not influenced by the presence of targeting ligand, and did not alter the cavitation properties of cationic microbubbles. In flow chamber studies, surface conjugation of cDNA did not affect attachment of targeted microbubbles at microvascular shear stresses (0.6 and 1.5 dyne/cm(2)). Attachment in vivo was also not affected by cDNA according to intravital microscopy observations of venular adhesion of ICAM-1-targeted microbubbles and by ultrasound molecular imaging of P-selectin-targeted microbubbles in the post-ischemic hindlimb in mice. Transfection at the site of high acoustic pressures (1.0 and 1.8 MPa) was similar for control and P-selectin-targeted microbubbles but was associated with vascular rupture and hemorrhage. At 0.6 MPa

Integrated computational biology analysis to evaluate target genes for chronic myelogenous leukemia.

PubMed

Zheng, Yu; Wang, Yu-Ping; Cao, Hongbao; Chen, Qiusheng; Zhang, Xi

2018-06-05

Although hundreds of genes have been linked to chronic myelogenous leukemia (CML), many of the results lack reproducibility. In the present study, data across multiple modalities were integrated to evaluate 579 CML candidate genes, including literature‑based CML‑gene relation data, Gene Expression Omnibus RNA expression data and pathway‑based gene‑gene interaction data. The expression data included samples from 76 patients with CML and 73 healthy controls. For each target gene, four metrics were proposed and tested with case/control classification. The effectiveness of the four metrics presented was demonstrated by the high classification accuracy (94.63%; P<2x10‑4). Cross metric analysis suggested nine top candidate genes for CML: Epidermal growth factor receptor, tumor protein p53, catenin β 1, janus kinase 2, tumor necrosis factor, abelson murine leukemia viral oncogene homolog 1, vascular endothelial growth factor A, B‑cell lymphoma 2 and proto‑oncogene tyrosine‑protein kinase. In addition, 145 CML candidate pathways enriched with 485 out of 579 genes were identified (P<8.2x10‑11; q=0.005). In conclusion, weighted genetic networks generated using computational biology may be complementary to biological experiments for the evaluation of known or novel CML target genes.

New TFII-I family target genes involved in embryonic development.

PubMed

Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg

2009-09-04

Two members of the TFII-I family transcription factor genes, GTF2I and GTF2IRD1, are the prime candidates responsible for the craniofacial and cognitive abnormalities of Williams syndrome patients. We have previously generated mouse lines with targeted disruption of Gtf2i and Gtf2ird1. Microarray analysis revealed significant changes in the expression profile of mutant embryos. Here we described three unknown genes that were dramatically down-regulated in mutants. The 2410018M08Rik/Scand3 gene encodes a protein of unknown function with CHCH and hATC domains. Scand3 is down-regulated during mouse embryonic stem cell (ES) differentiation. 4933436H12Rik is a testis-specific gene, which encodes a protein with no known domains. It is expressed in mouse ES cells. 1110008P08Rik/Kbtbd7 encodes an adapter protein with BTB/POZ, BACK, and Kelch motifs, previously shown to recruit substrates to the enzymatic complexes of the histone modifying or E3 ubiquitin ligase activities. Based on its expression pattern Kbtbd7 may have a specific role in brain development and function. All three genes possess well-conserved TFII-I-binding consensus sites within proximal promoters. Therefore our analysis suggests that these genes can be direct targets of TFII-I proteins and their impaired expression, as a result of the GTF2I and GTF2IRD1 haploinsufficiency, could contribute to the etiology of Williams syndrome.

The association of individual and neighborhood social cohesion, stressors, and crime on smoking status among African-American women in southeastern US subsidized housing neighborhoods.

PubMed

Andrews, Jeannette O; Mueller, Martina; Newman, Susan D; Magwood, Gayenell; Ahluwalia, Jasjit S; White, Kellee; Tingen, Martha S

2014-12-01

The purpose of this study was to examine the associations between individual and neighborhood social contextual factors and smoking prevalence among African-American women in subsidized neighborhoods. We randomly sampled 663 adult women in 17 subsidized neighborhoods in two Southeastern US states. The smoking prevalence among participants was 37.6%, with an estimated neighborhood household prevalence ranging from 30 to 68%. Smokers were more likely to be older, have lower incomes, have lower BMI, and live with other smokers. Women with high social cohesion were less likely to smoke, although living in neighborhoods with higher social cohesion was not associated with smoking prevalence. Women with higher social cohesion were more likely to be older and had lived in the neighborhood longer. Women with high stress (related to violence and disorder) and who lived in neighborhoods with higher stress were more likely to smoke. Younger women were more likely to have higher stress than older women. There were no statistically significant associations with objective neighborhood crime data in any model. This is the first study to examine both individual and neighborhood social contextual correlates among African-American women in subsidized neighborhoods. This study extends findings about smoking behaviors and neighborhood social contexts in this high-risk, urban population. Future research is needed to explore age and residential stability differences and perceptions of social cohesion, neighborhood disorder, and perceived violence in subsidized housing. Further research is also warranted on African-American women, subsidized housing, smoking, social context, health disparities' effective strategies to address these individual and contextual factors to better inform future ecological-based multilevel prevention, and cessation intervention strategies.

Gene therapy to target ER stress in brain diseases.

PubMed

Valenzuela, Vicente; Martínez, Gabriela; Duran-Aniotz, Claudia; Hetz, Claudio

2016-10-01

Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context. This article is part of a Special Issue entitled SI:ER stress. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of semantic neighborhood density in abstract and concrete words.

PubMed

Reilly, Megan; Desai, Rutvik H

2017-12-01

Concrete and abstract words are thought to differ along several psycholinguistic variables, such as frequency and emotional content. Here, we consider another variable, semantic neighborhood density, which has received much less attention, likely because semantic neighborhoods of abstract words are difficult to measure. Using a corpus-based method that creates representations of words that emphasize featural information, the current investigation explores the relationship between neighborhood density and concreteness in a large set of English nouns. Two important observations emerge. First, semantic neighborhood density is higher for concrete than for abstract words, even when other variables are accounted for, especially for smaller neighborhood sizes. Second, the effects of semantic neighborhood density on behavior are different for concrete and abstract words. Lexical decision reaction times are fastest for words with sparse neighborhoods; however, this effect is stronger for concrete words than for abstract words. These results suggest that semantic neighborhood density plays a role in the cognitive and psycholinguistic differences between concrete and abstract words, and should be taken into account in studies involving lexical semantics. Furthermore, the pattern of results with the current feature-based neighborhood measure is very different from that with associatively defined neighborhoods, suggesting that these two methods should be treated as separate measures rather than two interchangeable measures of semantic neighborhoods. Copyright © 2017 Elsevier B.V. All rights reserved.

Changes in gene expression in PBMCs profiles of PPARα target genes in obese and non-obese individuals during fasting.

PubMed

Felicidade, Ingrid; Marcarini, Juliana Cristina; Carreira, Clísia Mara; Amarante, Marla Karine; Afman, Lydia A; Mantovani, Mário Sérgio; Ribeiro, Lúcia Regina

2015-01-01

The prevalence of obesity has risen dramatically and the World Health Organization estimates that 700 million people will be obese worldwide by 2015. Approximately, 50% of the Brazilian population above 20 years of age is overweight, and 16% is obese. This study aimed to evaluate the differences in the expression of PPARα target genes in human peripheral blood mononuclear cells (PBMCs) and free fatty acids (FFA) in obese and non-obese individuals after 24 h of fasting. We first presented evidence that Brazilian people exhibit expression changes in PPARα target genes in PBMCs under fasting conditions. Q-PCR was utilized to assess the mRNA expression levels of target genes. In both groups, the FFA concentrations increased significantly after 24 h of fasting. The basal FFA mean concentration was two-fold higher in the obese group compared with the non-obese group. After fasting, all genes evaluated in this study showed increased expression levels compared with basal expression in both groups. However, our results reveal no differences in gene expression between the obese and non-obese, more studies are necessary to precisely delineate the associated mechanisms, particularly those that include groups with different degrees of obesity and patients with diabetes mellitus type 2 because the expression of the main genes that are involved in β-oxidation and glucose level maintenance are affected by these factors. © 2014 S. Karger AG, Basel.

Neighborhood Disorder, Subjective Alienation, and Distress

ERIC Educational Resources Information Center

Ross, Catherine E.; Mirowsky, John

2009-01-01

Living in a threatening, noxious, and dangerous neighborhood may produce anxiety, anger, and depression because it is subjectively alienating. We hypothesize that neighborhood disorder represents ambient threat that elicits perceptions of powerlessness, normlessness, mistrust, and isolation. These perceptions in turn lead to anxious and angry…

Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma.

PubMed

Gu, De-Leung; Chen, Yen-Hsieh; Shih, Jou-Ho; Lin, Chi-Hung; Jou, Yuh-Shan; Chen, Chian-Feng

2013-12-21

High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

Identification of highly effective target genes for RNAi-mediated control of emerald ash borer, Agrilus planipennis.

PubMed

Rodrigues, Thais B; Duan, Jian J; Palli, Subba R; Rieske, Lynne K

2018-03-22

Recent study has shown that RNA interference (RNAi) is efficient in emerald ash borer (EAB), Agrilus planipennis, and that ingestion of double-stranded RNA (dsRNA) targeting specific genes causes gene silencing and mortality in neonates. Here, we report on the identification of highly effective target genes for RNAi-mediated control of EAB. We screened 13 candidate genes in neonate larvae and selected the most effective target genes for further investigation, including their effect on EAB adults and on a non-target organism, Tribolium castaneum. The two most efficient target genes selected, hsp (heat shock 70-kDa protein cognate 3) and shi (shibire), caused up to 90% mortality of larvae and adults. In EAB eggs, larvae, and adults, the hsp is expressed at higher levels when compared to that of shi. Ingestion of dsHSP and dsSHI caused mortality in both neonate larvae and adults. Administration of a mixture of both dsRNAs worked better than either dsRNA by itself. In contrast, injection of EAB.dsHSP and EAB.dsSHI did not cause mortality in T. castaneum. Thus, the two genes identified cause high mortality in the EAB with no apparent phenotype effects in a non-target organism, the red flour beetle, and could be used in RNAi-mediated control of this invasive pest.

Preserving Neighborhood Opportunity: Where Federal Housing Subsidies Expire

PubMed Central

Lens, Michael C.; Reina, Vincent

2017-01-01

Rent burdens are increasing in U.S. metropolitan areas while subsidies on privately owned, publicly subsidized rental units are expiring. As a result, some of the few remaining affordable units in opportunity neighborhoods are at risk of being converted to market rate. Policy makers face a decision about whether to devote their efforts and scarce resources toward developing new affordable housing, recapitalizing existing subsidized housing, and/or preserving properties with expiring subsidies. There are several reasons to preserve these subsidies, one being that properties may be located in neighborhoods with greater opportunity. In this article, we use several sources of data at the census tract level to learn how subsidy expirations affect neighborhood opportunity for low-income households. Our analysis presents several key findings. First, we find that units that left the project-based Section 8 program were – on average – in lower opportunity neighborhoods, but these neighborhoods were improving. In addition, properties due to expiry from the Section 8 program between 2011 and 2020 are in higher opportunity neighborhoods than any other subsidy program. On the contrary, new Low-Income Housing Tax Credit (LIHTC) units were developed in tracts similar to those where LIHTC units are currently active, which tend to be lower opportunity neighborhoods. PMID:28553063

Preserving Neighborhood Opportunity: Where Federal Housing Subsidies Expire.

PubMed

Lens, Michael C; Reina, Vincent

2016-01-01

Rent burdens are increasing in U.S. metropolitan areas while subsidies on privately owned, publicly subsidized rental units are expiring. As a result, some of the few remaining affordable units in opportunity neighborhoods are at risk of being converted to market rate. Policy makers face a decision about whether to devote their efforts and scarce resources toward developing new affordable housing, recapitalizing existing subsidized housing, and/or preserving properties with expiring subsidies. There are several reasons to preserve these subsidies, one being that properties may be located in neighborhoods with greater opportunity. In this article, we use several sources of data at the census tract level to learn how subsidy expirations affect neighborhood opportunity for low-income households. Our analysis presents several key findings. First, we find that units that left the project-based Section 8 program were - on average - in lower opportunity neighborhoods, but these neighborhoods were improving. In addition, properties due to expiry from the Section 8 program between 2011 and 2020 are in higher opportunity neighborhoods than any other subsidy program. On the contrary, new Low-Income Housing Tax Credit (LIHTC) units were developed in tracts similar to those where LIHTC units are currently active, which tend to be lower opportunity neighborhoods.

Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4 ▿ †

PubMed Central

Li, Pingxin; Yao, Hongjie; Zhang, Zhiqiang; Li, Ming; Luo, Yuan; Thompson, Paul R.; Gilmour, David S.; Wang, Yanming

2008-01-01

Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression. PMID:18505818

Advances in plant gene-targeted and functional markers: a review

PubMed Central

2013-01-01

Public genomic databases have provided new directions for molecular marker development and initiated a shift in the types of PCR-based techniques commonly used in plant science. Alongside commonly used arbitrarily amplified DNA markers, other methods have been developed. Targeted fingerprinting marker techniques are based on the well-established practices of arbitrarily amplified DNA methods, but employ novel methodological innovations such as the incorporation of gene or promoter elements in the primers. These markers provide good reproducibility and increased resolution by the concurrent incidence of dominant and co-dominant bands. Despite their promising features, these semi-random markers suffer from possible problems of collision and non-homology analogous to those found with randomly generated fingerprints. Transposable elements, present in abundance in plant genomes, may also be used to generate fingerprints. These markers provide increased genomic coverage by utilizing specific targeted sites and produce bands that mostly seem to be homologous. The biggest drawback with most of these techniques is that prior genomic information about retrotransposons is needed for primer design, prohibiting universal applications. Another class of recently developed methods exploits length polymorphism present in arrays of multi-copy gene families such as cytochrome P450 and β-tubulin genes to provide cross-species amplification and transferability. A specific class of marker makes use of common features of plant resistance genes to generate bands linked to a given phenotype, or to reveal genetic diversity. Conserved DNA-based strategies have limited genome coverage and may fail to reveal genetic diversity, while resistance genes may be under specific evolutionary selection. Markers may also be generated from functional and/or transcribed regions of the genome using different gene-targeting approaches coupled with the use of RNA information. Such techniques have the

Using GPS Data to Study Neighborhood Walkability and Physical Activity.

PubMed

Rundle, Andrew G; Sheehan, Daniel M; Quinn, James W; Bartley, Katherine; Eisenhower, Donna; Bader, Michael M D; Lovasi, Gina S; Neckerman, Kathryn M

2016-03-01

Urban form characteristics intended to support pedestrian activity, collectively referred to as neighborhood walkability, are thought to increase total physical activity. However, little is known about how neighborhood walkability influences utilization of neighborhood space by residents and their overall physical activity. Sociodemographic information and data on mobility and physical activity over 1-week periods measured by GPS loggers and accelerometers were collected from 803 residents of New York City between November 2010 and November 2011. Potentially accessible neighborhood areas were defined as land area within a 1-kilometer distance of the subject's home (radial buffer) and within a 1-kilometer journey on the street network from the home (network buffer). To define actual areas utilized by subjects, a minimum convex polygon was plotted around GPS waypoints falling within 1 kilometer of the home. A neighborhood walkability scale was calculated for each neighborhood area. Data were analyzed in 2014. Total residential neighborhood space utilized by subjects was significantly associated with street intersection density and was significantly negatively associated with residential density and subway stop density within 1 kilometer of the home. Walkability scale scores were significantly higher within utilized as compared with non-utilized neighborhood areas. Neighborhood walkability in the utilized neighborhood area was positively associated with total weekly physical activity (32% [95% CI=17%, 49%] more minutes of moderate-equivalent physical activity across the interquartile range of walkability). Neighborhood walkability is associated with neighborhood spaces utilized by residents and total weekly physical activity. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Engineering nucleases for gene targeting: safety and regulatory considerations.

PubMed

Pauwels, Katia; Podevin, Nancy; Breyer, Didier; Carroll, Dana; Herman, Philippe

2014-01-25

Nuclease-based gene targeting (NBGT) represents a significant breakthrough in targeted genome editing since it is applicable from single-celled protozoa to human, including several species of economic importance. Along with the fast progress in NBGT and the increasing availability of customized nucleases, more data are available about off-target effects associated with the use of this approach. We discuss how NBGT may offer a new perspective for genetic modification, we address some aspects crucial for a safety improvement of the corresponding techniques and we also briefly relate the use of NBGT applications and products to the regulatory oversight. Copyright © 2013 Elsevier B.V. All rights reserved.

PLGA/polymeric liposome for targeted drug and gene co-delivery.

PubMed

Wang, Hanjie; Zhao, Peiqi; Su, Wenya; Wang, Sheng; Liao, Zhenyu; Niu, Ruifang; Chang, Jin

2010-11-01

Chemotherapy is one of the most effective approaches to treat cancers in the clinic, but the problems, such as multidrug resistance (MDR), low bioavailability and toxicity, severely constrain the further application of chemotherapy. Our group recently reported that cationic PLGA/folate coated PEGlated polymeric liposome core-shell nanoparticles (PLGA/FPL NPs). It was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell for targeting co-delivery of drug and gene. Hydrophobic drugs can be incorporated into the core and the cationic shell of the drug-loaded nanoparticles can be used to bind DNA. The drug-loaded PLGA/FPL NPs/DNA complexes offer advantages to overcome these problems mentioned above, such as co-delivery of drugs and DNA to improving the chemosensitivity of cancer cells at a gene level, and targeting delivery of drug to the cancer tissue that enhance the bioavailability and reduce the toxicity. The experiment showed that nanoparticles have core-shell structure with nanosize, sustained drug release profile and good DNA-binding ability. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and genes to the same cells with high gene transfection and drug delivery efficiency. Our data suggest that the PLGA/FPL NPs may be a useful drug and gene co-delivery system. Copyright © 2010 Elsevier Ltd. All rights reserved.

Perceived Neighborhood Safety and Adolescent School Functioning

PubMed Central

Martin-Storey, Alexa; Crosnoe, Robert

2014-01-01

This study examined the association between adolescents’ perceptions of their neighborhoods’ safety and multiple elements of their functioning in school with data on 15 year olds from the NICHD Study of Early Child Care and Youth Development (n = 924). In general, perceived neighborhood safety was more strongly associated with aspects of schooling that were more psychosocial in nature (e.g., school attachment) than those that were more cognitive (e.g., test scores). Examination of neighborhood and family moderators of these associations revealed that perceived neighborhood safety was negatively associated with grades for youth from low-income families but was positively associated with school attachment for youth from such families when they lived in neighborhoods rated by observers as high in physical disorder. PMID:25045245

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

PubMed Central

Sun, Xingshen; Yan, Ziying; Yi, Yaling; Li, Ziyi; Lei, Diana; Rogers, Christopher S.; Chen, Juan; Zhang, Yulong; Welsh, Michael J.; Leno, Gregory H.; Engelhardt, John F.

2008-01-01

Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene–deficient model in the domestic ferret using recombinant adeno-associated virus–mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases. PMID:18324338

The LIM-homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rascle, Anne; Neumann, Tanja; Raschta, Anne-Sarah

2009-01-01

LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies, but their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. Microarray analysis using a tetracycline-inducible LMX1B expression system in HeLa cells revealed that a subset of NF-{kappa}B target genes, including IL-6 and IL-8, are upregulated in LMX1B-expressing cells. Inhibition of NF-{kappa}B activity by short interfering RNA-mediated knock-down of p65 impairs, while activation of NF-{kappa}B activity by TNF-{alpha} synergizes induction of NF-{kappa}B target genes by LMX1B. Chromatin immunoprecipitation demonstratedmore » that LMX1B binds to the proximal promoter of IL-6 and IL-8 in vivo, in the vicinity of the characterized {kappa}B site, and that LMX1B recruitment correlates with increased NF-{kappa}B DNA association. IL-6 promoter-reporter assays showed that the {kappa}B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of NF-{kappa}B target genes is affected in the kidney of Lmx1b{sup -/-} knock-out mice, thus supporting the biological relevance of our findings. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-{kappa}B target genes in cooperation with nuclear p50/p65 NF-{kappa}B.« less

PCAN: phenotype consensus analysis to support disease-gene association.

PubMed

Godard, Patrice; Page, Matthew

2016-12-07

Bridging genotype and phenotype is a fundamental biomedical challenge that underlies more effective target discovery and patient-tailored therapy. Approaches that can flexibly and intuitively, integrate known gene-phenotype associations in the context of molecular signaling networks are vital to effectively prioritize and biologically interpret genes underlying disease traits of interest. We describe Phenotype Consensus Analysis (PCAN); a method to assess the consensus semantic similarity of phenotypes in a candidate gene's signaling neighborhood. We demonstrate that significant phenotype consensus (p < 0.05) is observable for ~67% of 4,549 OMIM disease-gene associations, using a combination of high quality String interactions + Metabase pathways and use Joubert Syndrome to demonstrate the ease with which a significant result can be interrogated to highlight discriminatory traits linked to mechanistically related genes. We advocate phenotype consensus as an intuitive and versatile method to aid disease-gene association, which naturally lends itself to the mechanistic deconvolution of diverse phenotypes. We provide PCAN to the community as an R package ( http://bioconductor.org/packages/PCAN/ ) to allow flexible configuration, extension and standalone use or integration to supplement existing gene prioritization workflows.

Parental and Adolescent Perceptions of Neighborhood Safety Related to Adolescents’ Physical Activity in Their Neighborhood

PubMed Central

Esteban-Cornejo, Irene; Carlson, Jordan A.; Conway, Terry L.; Cain, Kelli L.; Saelens, Brian E.; Frank, Lawrence D.; Glanz, Karen; Roman, Caterina G.; Sallis, James F.

2017-01-01

Purpose The purpose of this study was to examine the association between adolescent and parental perceptions of neighborhood safety and adolescents’ physical activity in multiple locations and to investigate the moderating effect of sex within this association. Method This cross-sectional study was conducted with 928 adolescents aged 12 to 16 years old and 1 of their parents. Adolescents and parents reported their perceptions of neighborhood safety (traffic safety, pedestrian safety, crime safety, and stranger danger safety). Adolescents reported how often they were physically active in multiple locations (physical activity in the neighborhood, in parks, and for active transport). Mixed-effects linear regression models were used to investigate these associations while controlling for demographics and the Walkability Index. Results Parent-perceived crime safety was positively associated with adolescents’ physical activity in parks (B = .094, p = .024). Parent-perceived traffic safety was positively associated with adolescents’ reported physical activity in the neighborhood (B = .186, p = .014). Adolescents’ physical activity for active transport was positively associated with parent-perceived traffic safety (B = .179, p = .001), stranger danger safety (B = .110, p = .013), and crime safety (B = .077, p = .035). There were 2 interactions by sex on the relation between adolescent traffic safety perception and parent pedestrian safety perception in the neighborhood and adolescents’ physical activity in parks (i.e., statistically significant only for boys). Conclusions Parents’ perceptions of traffic, stranger danger, and crime safety were all related to adolescents’ active transportation. Multiple safety concerns may be motivating parents to restrict adolescent mobility by walking and bicycling. PMID:27030158

SPATIAL AND TEMPORAL DIMENSIONS OF NEIGHBORHOOD EFFECTS ON HIGH SCHOOL GRADUATION.

PubMed

Crowder, Kyle; South, Scott J

2011-01-30

Research into the effects of neighborhood characteristics on children's behavior has burgeoned in recent years, but these studies have generally adopted a limited conceptualization of the spatial and temporal dimensions of neighborhood effects. We use longitudinal data from the Panel Study of Income Dynamics and techniques of spatial data analysis to examine how both the socioeconomic characteristics of extralocal neighborhoods-neighborhoods surrounding the immediate neighborhood of residence-and the duration of exposure to disadvantaged neighborhoods throughout the childhood life course influence the likelihood of graduating from high school. Among blacks and whites, socioeconomic advantage in the immediate neighborhood increases the likelihood of completing high school, but among whites higher levels of socioeconomic advantage in extralocal neighborhoods decrease high school graduation rates. Extralocal neighborhood advantage suppresses the influence of advantage in the immediate neighborhood so that controlling for extralocal conditions provides stronger support for the neighborhood effects hypothesis than has previously been observed. Exposure to advantaged neighborhoods over the childhood life course exerts a stronger effect than point-in-time measures on high school graduation, and racial differences in exposure to advantaged neighbors over the childhood life course help to suppress a net black advantage in the likelihood of completing high school.

NEIGHBORHOOD NORMS AND SUBSTANCE USE AMONG TEENS

PubMed Central

Musick, Kelly; Seltzer, Judith A.; Schwartz, Christine R.

2008-01-01

This paper uses new data from the Los Angeles Family and Neighborhood Survey (L.A. FANS) to examine how neighborhood norms shape teenagers’ substance use. Specifically, it takes advantage of clustered data at the neighborhood level to relate adult neighbors’ attitudes and behavior with respect to smoking, drinking, and drugs, which we treat as norms, to teenagers’ own smoking, drinking, and drug use. We use hierarchical linear models to account for parents’ attitudes and behavior and other characteristics of individuals and families. We also investigate how the association between neighborhood norms and teen behavior depends on: (1) the strength of norms, as measured by consensus in neighbors’ attitudes and conformity in their behavior; (2) the willingness and ability of neighbors to enforce norms, for instance, by monitoring teens’ activities; and (3) the degree to which teens are exposed to their neighbors. We find little association between neighborhood norms and teen substance use, regardless of how we condition the relationship. We discuss possible theoretical and methodological explanations for this finding. PMID:18496598