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1.  Built environment and Property Crime in Seattle, 1998–2000: A Bayesian Analysis 
Environment & planning A  2010;42(6):1403-1420.
The past decade has seen a rapid growth in the use of a spatial perspective in studies of crime. In part this growth has been driven by the availability of georeferenced data, and the tools to analyze and visualize them: geographic information systems (GIS), spatial analysis, and spatial statistics. In this paper we use exploratory spatial data analysis (ESDA) tools and Bayesian models to help better understand the spatial patterning and predictors of property crime in Seattle, Washington for 1998–2000, including a focus on built environment variables. We present results for aggregate property crime data as well as models for specific property crime types: residential burglary, nonresidential burglary, theft, auto theft, and arson. ESDA confirms the presence of spatial clustering of property crime and we seek to explain these patterns using spatial Poisson models implemented in WinBUGS. Our results indicate that built environment variables were significant predictors of property crime, especially the presence of a highway on auto theft and burglary.
PMCID: PMC3984884
Property Crime; Exploratory Spatial Data Analysis; Bayesian Poisson Models; Seattle
2.  Using ZIP Code Business Patterns Data to Measure Alcohol Outlet Density 
Addictive behaviors  2011;36(7):777-780.
Some states maintain high-quality alcohol outlet databases but quality varies by state, making comprehensive comparative analysis across US communities difficult. This study assesses the adequacy of using ZIP Code Business Patterns (ZIP-BP) data on establishments as estimates of the number of alcohol outlets by ZIP code. Specifically we compare ZIP-BP alcohol outlet counts with high-quality data from state and local records surrounding 44 college campus communities across 10 states plus the District of Columbia. Results show that a composite measure is strongly correlated (R=0.89) with counts of alcohol outlets generated from official state records. Analyses based on Generalized Estimation Equation models show that community and contextual factors have little impact on the concordance between the two data sources. There are also minimal inter-state differences in the level of agreement. To validate the use of a convenient secondary data set (ZIP-BP) it is important to have a high correlation with the more complex, high quality and more costly data product (i.e., datasets based on the acquisition and geocoding of state and local records) and then to clearly demonstrate that the discrepancy between the two to be unrelated to relevant explanatory variables. Thus our overall findings support the adequacy of using a conveniently available data set (ZIP-BP data) to estimate alcohol outlet densities in ZIP code areas in future research.
PMCID: PMC3977340  PMID: 21411233
Alcohol Outlets Density; College Campuses; ZIP Code Business Patterns data; Generalized Estimation Equation Models
3.  Spatial Polygamy and Contextual Exposures (SPACEs): Promoting Activity Space Approaches in Research on Place and Health 
The American behavioral scientist  2013;57(8):1057-1081.
Exposure science has developed rapidly and there is an increasing call for greater precision in the measurement of individual exposures across space and time. Social science interest in an individual’s environmental exposure, broadly conceived, has arguably been quite limited conceptually and methodologically. Indeed, we appear to lag behind our exposure science colleagues in our theories, data, and methods. In this paper we discuss a framework based on the concept of spatial polygamy to demonstrate the need to collect new forms of data on human spatial behavior and contextual exposures across time and space. Adopting new data and methods will be essential if we want to better understand social inequality in terms of exposure to health risks and access to health resources. We discuss the opportunities and challenges focusing on the potential seemingly offered by focusing on human mobility, and specifically the utilization of activity space concepts and data. A goal of the paper is to spatialize social and health science concepts and research practice vis-a-vis the complexity of exposure. The paper concludes with some recommendations for future research focusing on theoretical and conceptual development, promoting research on new types of places and human movement, the dynamic nature of contexts, and on training. “When we elect wittingly or unwittingly, to work within a level … we tend to discern or construct – whichever emphasis you prefer – only those kinds of systems whose elements are confined to that level.”Otis Dudley Duncan (1961, p. 141). “…despite the new ranges created by improved transportation, local government units have tended to remain medieval in size.”Torsten Hägerstrand (1970, p.18) “A detective investigating a crime needs both tools and understanding. If he has no fingerprint powder, he will fail to find fingerprints on most surfaces. If he does not understand where the criminal is likely to have put his fingers, he will not look in the right places. Equally, the analyst of data needs both tools and understanding.”John Tukey (1977, p.1) “When we observe the environment, we necessarily do so on only a limited number of scales.”Simon Levin (1992, p. 1945) There is a desperate need to develop methods with the same precision for an individual’s environmental exposure as we have for an individual’s genome … even a partial, targeted understanding of exposure can provide substantial advantages.”Christopher Wild (2005, p.1848)
PMCID: PMC3975622
4.  A non-bacterial transcription factor inhibits bacterial transcription by a multipronged mechanism 
RNA Biology  2013;10(4):495-501.
The process of transcription initiation is the major target for regulation of gene expression in bacteria and is performed by a multi-subunit RNA polymerase enzyme (RNAp). A complex network of regulatory elements controls the activity of the RNAp to fine-tune transcriptional output. Thus, RNAp is a nexus for controlling bacterial gene expression at the transcription level. Many bacteriophages, viruses that infect bacteria, encode transcription factors that specifically target and modulate the activity of the host RNAp and, thereby, facilitate the acquisition of the host bacteria by the phage. Here, we describe the modus operandi of a T7 bacteriophage-encoded small protein called Gp2 and define Gp2 as a non-bacterial regulator of bacterial transcription.
PMCID: PMC3710356  PMID: 23558648
Gp2; RNA polymerase; T7 inhibition; bacterial transcription regulation; bacteriophage; σ factor
5.  Investigation of Genetic Variants, Birthweight and Hypothalamic-Pituitary-Adrenal Axis Function Suggests a Genetic Variant in the SERPINA6 Gene Is Associated with Corticosteroid Binding Globulin in the Western Australia Pregnancy Cohort (Raine) Study 
PLoS ONE  2014;9(4):e92957.
The hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents.
Morning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method.
The penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons.
Our study suggests that genetic variation in the SERPINA6 gene may be associated with altered CBG levels during adolescence. Replication of these findings is required.
PMCID: PMC3972221  PMID: 24691024
6.  Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite 
PLoS Pathogens  2013;9(12):e1003809.
Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome - lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3+ structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival.
Author Summary
Toxoplasma gondii resides in a parasitophorous vacuole that excludes transmembrane proteins required for recruitment of endosomes and lysosomes and thus, does not follow the path of classical lysosomal degradation. However, the non-fusogenic nature of the vacuole can be reverted when autophagy, a pathway to lysosomal degradation, is upregulated through the immune system or pharmacologically. Maintenance of the non-fusogenic nature of the vacuole is central to parasite survival. Thus, in addition to preventing degradation through a classical lysosomal pathway, T. gondii may also deploy strategies to prevent constitutive levels of autophagy from targeting the pathogen and causing its lysosomal degradation. We report that T. gondii accomplishes this task by causing EGFR activation in host cells. In cells that were not subjected to immune or pharmacologic upregulation of autophagy, blockade of EGFR resulted in parasite encasing by structures that expressed the autophagy protein LC3, vacuole-lysosomal fusion and autophagy protein-dependent killing of the parasite. Moreover, EGFR signaling also impaired targeting of the parasite by LC3+ structures in cells treated with stimulators of autophagy. Studies with T. gondii deficient in EGF domain containing-micronemal proteins (EGF-MICs) and recombinant EGF-MICs support the concept that these parasite adhesins contribute to EGFR activation.
PMCID: PMC3868508  PMID: 24367261
7.  Insight into the HIV-1 Vif SOCS-box–ElonginBC interaction 
Open Biology  2013;3(11):130100.
The HIV-1 viral infectivity factor (Vif) neutralizes cell-encoded antiviral APOBEC3 proteins by recruiting a cellular ElonginB (EloB)/ElonginC (EloC)/Cullin5-containing ubiquitin ligase complex, resulting in APOBEC3 ubiquitination and proteolysis. The suppressors-of-cytokine-signalling-like domain (SOCS-box) of HIV-1 Vif is essential for E3 ligase engagement, and contains a BC box as well as an unusual proline-rich motif. Here, we report the NMR solution structure of the Vif SOCS–ElonginBC (EloBC) complex. In contrast to SOCS-boxes described in other proteins, the HIV-1 Vif SOCS-box contains only one α-helical domain followed by a β-sheet fold. The SOCS-box of Vif binds primarily to EloC by hydrophobic interactions. The functionally essential proline-rich motif mediates a direct but weak interaction with residues 101–104 of EloB, inducing a conformational change from an unstructured state to a structured state. The structure of the complex and biophysical studies provide detailed insight into the function of Vif's proline-rich motif and reveal novel dynamic information on the Vif–EloBC interaction.
PMCID: PMC3843819  PMID: 24225024
HIV-1 viral infectivity factor; SOCS-box domain; ElonginBC; NMR; solution structure
8.  Risk factors associated with slide positivity among febrile patients in a conflict zone of north-eastern Myanmar along the China-Myanmar border 
Malaria Journal  2013;12:361.
Malaria within the Greater Mekong sub-region is extremely heterogeneous. While China and Thailand have been relatively successful in controlling malaria, Myanmar continues to see high prevalence. Coupled with the recent emergence of artemisinin-resistant malaria along the Thai-Myanmar border, this makes Myanmar an important focus of malaria within the overall region. However, accurate epidemiological data from Myanmar have been lacking, in part because of ongoing and emerging conflicts between the government and various ethnic groups. Here the results are reported from a risk analysis of malaria slide positivity in a conflict zone along the China-Myanmar border.
Surveys were conducted in 13 clinics and hospitals around Laiza City, Myanmar between April 2011 and October 2012. Demographic, occupational and educational information, as well as malaria infection history, were collected. Logistic models were used to assess risk factors for slide positivity.
Age patterns in Plasmodium vivax infections were younger than those with Plasmodium falciparum. Furthermore, males were more likely than females to have falciparum infections. Patients who reported having been infected with malaria during the previous year were much more likely to have a current vivax infection. During the second year of the study, falciparum infections among soldiers increased signficiantly.
These results fill some knowledge gaps with regard to risk factors associated with malaria slide positivity in this conflict region of north-eastern Myanmar. Since epidemiological studies in this region have been rare or non-existent, studies such as the current are crucial for understanding the dynamic nature of malaria in this extremely heterogeneous epidemiological landscape.
PMCID: PMC3852943  PMID: 24112638
Plasmodium falciparum; Plasmodium vivax; The Greater Mekong Subregion; Myanmar; China; Border malaria
9.  Feasibility of Using Global Positioning Systems (GPS) with Diverse Urban Adults: Before and After Data on Perceived Acceptability, Barriers, and Ease of Use 
Global positioning systems (GPS) have emerged as a research tool to better understand environmental influences on physical activity. This study examined the feasibility of using GPS in terms of perceived acceptability, barriers, and ease of use in a racially/ethnically diverse sample of lower socioeconomic position (SEP).
Data were from two pilot studies involving a total of 170 African American, Hispanic, and White urban adults with a mean (standard deviation) age of 47.8 (±13.1) years. Participants wore a GPS for up to seven days. They answered questions about GPS acceptability, barriers (wear-related concerns), and ease of use, before and after wearing the GPS.
We found high ratings of GPS acceptability and ease of use and low levels of wear-related concerns, which were maintained after data collection. While most were comfortable with their movements being tracked, older participants (p<0.05) and African Americans (p<0.05) reported lower comfort levels. Participants who were younger, with higher education, and low incomes were more likely to indicate that the GPS made the study more interesting (p<0.05). Participants described technical and wear-related problems, but few concerns related to safety, loss, or appearance.
Use of GPS was feasible in this racially/ethnically diverse, lower SEP sample.
PMCID: PMC3397153  PMID: 21952361
Global positioning system; Environment; Physical activity; Feasibility; Perceptions
11.  Engineering online and in-person social networks to sustain physical activity: application of a conceptual model 
BMC Public Health  2013;13:753.
High rates of physical inactivity compromise the health status of populations globally. Social networks have been shown to influence physical activity (PA), but little is known about how best to engineer social networks to sustain PA. To improve procedures for building networks that shape PA as a normative behavior, there is a need for more specific hypotheses about how social variables influence PA. There is also a need to integrate concepts from network science with ecological concepts that often guide the design of in-person and electronically-mediated interventions. Therefore, this paper: (1) proposes a conceptual model that integrates principles from network science and ecology across in-person and electronically-mediated intervention modes; and (2) illustrates the application of this model to the design and evaluation of a social network intervention for PA.
A conceptual model for engineering social networks was developed based on a scoping literature review of modifiable social influences on PA. The model guided the design of a cluster randomized controlled trial in which 308 sedentary adults were randomly assigned to three groups: WalkLink+: prompted and provided feedback on participants’ online and in-person social-network interactions to expand networks for PA, plus provided evidence-based online walking program and weekly walking tips; WalkLink: evidence-based online walking program and weekly tips only; Minimal Treatment Control: weekly tips only. The effects of these treatment conditions were assessed at baseline, post-program, and 6-month follow-up. The primary outcome was accelerometer-measured PA. Secondary outcomes included objectively-measured aerobic fitness, body mass index, waist circumference, blood pressure, and neighborhood walkability; and self-reported measures of the physical environment, social network environment, and social network interactions. The differential effects of the three treatment conditions on primary and secondary outcomes will be analyzed using general linear modeling (GLM), or generalized linear modeling if the assumptions for GLM cannot be met.
Results will contribute to greater understanding of how to conceptualize and implement social networks to support long-term PA. Establishing social networks for PA across multiple life settings could contribute to cultural norms that sustain active living.
Trial registration NCT01142804
PMCID: PMC3844372  PMID: 23945138
Social networks; Social environment; Social support; Built environment; Walking; Exercise; Accelerometers; Social media; Internet; Sustainability
12.  White Infant Mortality in Appalachian States, 1976-1980 and 1996-2000: Changing Patterns and Persistent Disparities 
Appalachian counties have historically had elevated infant mortality rates. Changes in infant mortality disparities over time in Appalachia are not well-understood. This study explores spatial inequalities in white infant mortality rates over time in the 13 Appalachian states, comparing counties in Appalachia with non-Appalachian counties.
Data are analyzed for 1,100 counties in 13 Appalachian states that include 420 counties designated as Appalachian by the Appalachian Regional Commission. Area Resource File data for 1976-1980 and 1996-2000 provide county- and city-level infant mortality rates, poverty rates, rural-urban continuum codes, and numbers of physicians per 1,000 residents. Multiple regression analyses evaluate whether Appalachian counties are significantly associated with elevated white infant mortality in each time period, accounting for covariates.
White infant mortality rates decreased substantially in all sub-regions over the last 2 decades; however, disparities in infant mortality did not diminish in Appalachian counties compared to non-Appalachian counties. After accounting for poverty, rural/urban status, and health care resources, Appalachian counties were significantly associated with comparatively higher infant mortality during the late 1970s but not in the late 1990s. At the more recent time point, higher poverty rates, residence in more rural areas, and lower physician density were associated with greater infant mortality risk.
Appalachian counties continue to experience relatively elevated infant mortality rates. Poverty and rurality remain important dimensions of health service need in Appalachia.
PMCID: PMC3733175  PMID: 22458318
Appalachia; disparity; infant mortality; rural
13.  Prenatal Endotoxemia and Placental Drug Transport in The Mouse: Placental Size-Specific Effects 
PLoS ONE  2013;8(6):e65728.
Lipopolysaccharide (LPS) in high doses inhibits placental multidrug resistance P-glycoprotein (P-gp - Abcb1a/b) and breast cancer resistance protein (BCRP - Abcg2). This potentially impairs fetal protection against harmful factors in the maternal circulation. However, it is unknown whether LPS exposure, at doses that mimic sub-lethal clinical infection, alters placental multidrug resistance. We hypothesized that sub-lethal (fetal) LPS exposure reduces placental P-gp activity. Acute LPS (n = 19;150 µg/kg; ip) or vehicle (n = 19) were given to C57BL/6 mice at E15.5 and E17.5. Placentas and fetal-units were collected 4 and 24 h following injection. Chronic LPS (n = 6; 5 µg/kg/day; ip) or vehicle (n = 5) were administered from E11.5–15.5 and tissues were collected 4 h after final treatment. P-gp activity was assessed by [3H]digoxin accumulation. Placental Abcb1a/b, Abcg2, interleukin-6 (Il-6), Tnf-α, Il-10 and toll-like receptor-4 (Tlr-4) mRNA were measured by qPCR. Maternal plasma IL-6 was determined. At E15.5, maternal IL-6 was elevated 4 h after single (p<0.001) and chronic (p<0.05) LPS, but levels had returned to baseline by 24 h. Placental Il-6 mRNA was also increased after acute and chronic LPS treatments (p<0.05), whereas Abcb1a/b and Abcg2 mRNA were unaffected. However, fetal [3H]digoxin accumulation was increased (p<0.05) 4 h after acute LPS, and maternal [3H]digoxin myocardial accumulation was increased (p<0.05) in mice exposed to chronic LPS treatments. There was a negative correlation between fetal [3H]digoxin accumulation and placental size (p<0.0001). Acute and chronic sub-lethal LPS exposure resulted in a robust inflammatory response in the maternal systemic circulation and placenta. Acute infection decreased placental P-gp activity in a time- and gestational age-dependent manner. Chronic LPS decreased P-gp activity in the maternal myocardium and there was a trend for fetuses with smaller placentas to accumulate more P-gp substrate than their larger counterparts. Collectively, we demonstrate that acute sub-lethal LPS exposure during pregnancy impairs fetal protection against potentially harmful xenobiotics in the maternal circulation.
PMCID: PMC3677882  PMID: 23762418
14.  Using quantile regression to examine the effects of inequality across the mortality distribution in the U.S. counties 
Social science & medicine (1982)  2012;74(12):1900-1910.
The U.S. has experienced a resurgence of income inequality in the past decades. The evidence regarding the mortality implications of this phenomenon has been mixed. This study employs a rarely used method in mortality research, quantile regression (QR), to provide insight into the ongoing debate of whether income inequality is a determinant of mortality and to investigate the varying relationship between inequality and mortality throughout the mortality distribution. Analyzing a U.S. dataset where the five-year (1998–2002) average mortality rates were combined with other county-level covariates, we found that the association between inequality and mortality was not constant throughout the mortality distribution and the impact of inequality on mortality steadily increased until the 80th percentile. When accounting for all potential confounders, inequality was significantly and positively related to mortality; however, this inequality–mortality relationship did not hold across the mortality distribution. A series of Wald tests confirmed this varying inequality–mortality relationship, especially between the lower and upper tails. The large variation in the estimated coefficients of the Gini index suggested that inequality had the greatest influence on those counties with a mortality rate of roughly 9.95 deaths per 1000 population (80th percentile) compared to any other counties. Furthermore, our results suggest that the traditional analytic methods that focus on mean or median value of the dependent variable can be, at most, applied to a narrow 20 percent of observations. This study demonstrates the value of QR. Our findings provide some insight as to why the existing evidence for the inequality–mortality relationship is mixed and suggest that analytical issues may play a role in clarifying whether inequality is a robust determinant of population health.
PMCID: PMC3568764  PMID: 22497847
Quantile regression; Income inequality; Mortality; County; USA
15.  Structures of the Compact Helical Core Domains of Feline Calicivirus and Murine Norovirus VPg Proteins 
Journal of Virology  2013;87(10):5318-5330.
We report the solution structures of the VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV), which have been determined by nuclear magnetic resonance spectroscopy. In both cases, the core of the protein adopts a compact helical structure flanked by flexible N and C termini. Remarkably, while the core of FCV VPg contains a well-defined three-helix bundle, the MNV VPg core has just the first two of these secondary structure elements. In both cases, the VPg cores are stabilized by networks of hydrophobic and salt bridge interactions. The Tyr residue in VPg that is nucleotidylated by the viral NS7 polymerase (Y24 in FCV, Y26 in MNV) occurs in a conserved position within the first helix of the core. Intriguingly, given its structure, VPg would appear to be unable to bind to the viral polymerase so as to place this Tyr in the active site without a major conformation change to VPg or the polymerase. However, mutations that destabilized the VPg core either had no effect on or reduced both the ability of the protein to be nucleotidylated and virus infectivity and did not reveal a clear structure-activity relationship. The precise role of the calicivirus VPg core in virus replication remains to be determined, but knowledge of its structure will facilitate future investigations.
PMCID: PMC3648151  PMID: 23487472
16.  Understanding the non-stationary associations between distrust of the health care system, health conditions, and self-rated health in the elderly: A geographically weighted regression approach 
Health & place  2012;18(3):576-585.
The goals of this study are to explore whether health condition is an antecedent extraneous factor for the relationship between health care system distrust and self-rated health among the elderly, and to investigate if the associations among these variables are place-specific. We used logistic geographically weighted regression to analyze data on an elderly sample residents in the Philadelphia metropolitan area. We found that the health conditions of the elderly account for the association between high distrust and poor/fair self-rated health and that the distrust/self-rated health relationship varied spatially. This finding suggests that a place-centered perspective can inform distrust/self-rated health research.
PMCID: PMC3319514  PMID: 22321903
self-rated health; health care system distrust; elderly; geographically weighted regression; Philadelphia metropolitan area
17.  Crystallization and initial crystallographic analysis of AafA: the major adhesive subunit of the enteroaggregative Escherichia coli AAF/II pilus 
The Enteroaggregative Escherichia coli AAF/II pilus plays an important role in the attachment to and invasion of the host during the initial stages of colonization. Here, the major adhesive subunit of AAF/II has been crystallized at pH 3.4 and diffraction data have been collected to 2.1 Å resolution.
AafA is the major adhesive pilin subunit of the aggregative adherence fimbriae (AAF) from enteroaggregative Escherichia coli, which play an important role by attaching to the host cells during the initial phase of bacterial colonization and invasion. AafA has been crystallized at pH 3.4 and diffraction data have been collected to 2.1 Å resolution. Molecular replacement was unsuccessful and selenomethionine-substituted protein and heavy-atom derivatives are being prepared for phasing.
PMCID: PMC3080148  PMID: 21505239
AafA; enteroaggregative Escherichia coli; pilin subunit; fimbriae
18.  Effects of Sertraline and Fluoxetine on P-Glycoprotein at Barrier Sites: In Vivo and In Vitro Approaches 
PLoS ONE  2013;8(2):e56525.
Background and Purpose
Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.
Experimental Approach
The P-gp substrate, tritiated digoxin ([3H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.
Key Results
In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [3H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.
Conclusions and Implications
Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.
PMCID: PMC3585317  PMID: 23468867
19.  What has geography got to do with it? Using GWR to explore place-specific associations with prenatal care utilization 
GeoJournal  2012;77(3):331-341.
We use a geographically weighted regression (GWR) approach to examine how the relationships between a set of predictors and prenatal care vary across the continental US. At its most fundamental, GWR is an exploratory technique that can facilitate the identification of areas with low prenatal care utilization and help better understand which predictors are associated with prenatal care at specific locations. Our work complements existing prenatal care research in providing an ecological, place-sensitive analysis. We found that the percent of the population who was uninsured was positively associated with the percent of women receiving late or no prenatal care in the global model. The GWR map not only confirmed, but also demonstrated the spatial varying association. Additionally, we found that the number of Ob-Gyn doctors per 100,000 females of childbearing age in a county was associated with the percentage of women receiving late or no prenatal care, and that a higher value of female disadvantage is associated with higher percentages of late or no prenatal care. GWR offers a more nuanced examination of prenatal care and provides empirical evidence in support of locally tailored health policy formation and program implementation, which may improve program effectiveness.
PMCID: PMC3569028  PMID: 23408146
Geographically weighted regression; Spatial non-stationarity; Local modeling; Prenatal care
20.  Crystallization and initial crystallographic analysis of the Streptococcus parasanguinis FW213 Fap1-­NRα adhesive domain at pH 5.0 
The adhesin fimbriae-associated protein 1 (Fap1) is a surface protein of Streptococcus parasanguinis FW213 and plays a major role in the formation of dental plaque in humans. Here, the adhesive domain Fap1-NRα, which is activated by acidic pH, has been crystallized at pH 5.0 and diffraction data have been collected to 3.0 Å resolution.
The adhesin fimbriae-associated protein 1 (Fap1) is a surface protein of Streptococcus parasanguinis FW213 and plays a major role in the formation of dental plaque in humans. Increased adherence is highly correlated to a reduction in pH and acid activation has been mapped to a subdomain: Fap1-NRα. Here, Fap1-NRα has been crystallized at pH 5.0 and diffraction data have been collected to 3.0 Å resolution. The crystals belonged to space group P41212 or P43212, with unit-cell parameters a = b = 122.0, c = 117.8 Å. It was not possible to conclusively determine the number of molecules in the asymmetric unit and heavy-atom derivatives are now being prepared.
PMCID: PMC3034626  PMID: 21301104
fimbriae-associated protein 1; Streptococcus parasanguinis FW213; adhesive domain; dental plaque
22.  Structural insight into the role of Streptococcus parasanguinis Fap1 within oral biofilm formation 
The fimbriae-associated protein 1 (Fap1) is a major adhesin of Streptococcus parasanguinis, a primary colonizer of the oral cavity that plays an important role in the formation of dental plaque. Fap1 is an extracellular adhesive surface fibre belonging to the serine-rich repeat protein (SRRP) family, which plays a central role in the pathogenesis of streptococci and staphylococci. The N-terminal adhesive region of Fap1 (Fap1-NR) is composed of two domains (Fap1-NRα and Fap1-NRβ) and is projected away from the bacterial surface via the extensive serine-rich repeat region, for adhesion to the salivary pellicle. The adhesive properties of Fap1 are modulated through a pH switch in which a reduction in pH results in a rearrangement between the Fap1-NRα and Fap1-NRβ domains, which assists in the survival of S. parasanguinis in acidic environments. We have solved the structure of Fap1-NRα at pH 5.0 to 3.0 Ǻ resolution and reveal how subtle rearrangements of the 3-helix bundle combined with a change in electrostatic potential mediates ‘opening’ and activation of the adhesive region. Further, we show that pH-dependent changes are critical for biofilm formation and present an atomic model for the inter-Fap1-NR interactions which have been assigned an important role in the biofilm formation.
PMCID: PMC3518267  PMID: 22166217
23.  Individual Health Care System Distrust and Neighborhood Social Environment: How Are They Jointly Associated with Self-rated Health? 
Americans’ distrust in the health care system has increased in the past decades; however, little research has explored the impact of distrust on self-rated health and even less is known about whether neighborhood social environment plays a role in understanding the relationship between distrust and self-rated health. This study fills these gaps by investigating both the direct and moderating associations of neighborhood social environment with self-rated health. Our analysis is based on the 2008 Philadelphia Health Management Corporation’s household survey and neighborhood-level data. Findings from multilevel logistic regression show that after controlling for individual- and neighborhood-level covariates, distrust is directly and adversely related to self-rated health, and that neighborhood social affluence and stability are directly and negatively associated with the odds of reporting poor/fair health. Neighborhood disadvantage and crime rates are not directly related to self-rated health, but increase the odds of having poor/fair health via distrust. Overall, our results suggest that macro-level actions can alter individual’s perception of residential environment and lead to improved health. To improve the public health in an urban setting, rebuilding confidence in the health care system is integral, and the policies that help establish safe and cohesive neighborhoods may reduce the adverse effect of distrust on self-rated health.
PMCID: PMC3191206  PMID: 21455831
Health care system distrust; Self-rated health; Neighborhood social environment; Multilevel modeling; Philadelphia
24.  Activity Space Environment and Dietary and Physical Activity Behaviors: A Pilot Study 
Health & place  2011;17(5):1150-1161.
This study examined relationships among individual demographics, environmental features (e.g., fast food outlet density, park land use) of residential neighborhoods and activity spaces, and obesity-related behaviors (diet, physical activity). Participants’ movement was tracked for seven days using global positioning systems (GPS). Two activity space measures (one standard deviation ellipse, daily path area) were derived from the GPS data. Activity spaces were generally larger than residential neighborhoods; environmental features of residential neighborhoods and activity spaces were weakly associated; and some activity space environmental features were related to dietary behaviors. Activity spaces may provide new insights into environmental influences on obesity-related behaviors.
PMCID: PMC3224849  PMID: 21696995
Global positioning system; Activity space; Neighborhood; Diet; Physical activity; Environment
25.  Pro-Inflammatory Cytokine Regulation of P-glycoprotein in the Developing Blood-Brain Barrier 
PLoS ONE  2012;7(8):e43022.
Placental P-glycoprotein (P-gp) acts to protect the developing fetus from exogenous compounds. This protection declines with advancing gestation leaving the fetus and fetal brain vulnerable to these compounds and potential teratogens in maternal circulation. This vulnerability may be more pronounced in pregnancies complicated by infection, which is common during pregnancy. Pro-inflammatory cytokines (released during infection) have been shown to be potent inhibitors of P-gp, but nothing is known regarding their effects at the developing blood-brain barrier (BBB). We hypothesized that P-gp function and expression in endothelial cells of the developing BBB will be inhibited by pro-inflammatory cytokines. We have derived brain endothelial cell (BEC) cultures from various stages of development of the guinea pig: gestational day (GD) 50, 65 (term ∼68 days) and postnatal day (PND) 14. Once these cultures reached confluence, BECs were treated with various doses (100–104 pg/mL) of pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6) or tumor necrosis factor- α (TNF-α). P-gp function or abcb1 mRNA (encodes P-gp) expression was assessed following treatment. Incubation of GD50 BECs with IL-1β, IL-6 or TNF-α resulted in no change in P-gp function. GD65 BECs displayed a dose-dependent decrease in function with all cytokines tested; maximal effects at 42%, 65% and 34% with IL-1β, IL-6 and TNF-α treatment, respectively (P<0.01). Inhibition of P-gp function by IL-1β, IL-6 and TNF-α was even greater in PND14 BECs; maximal effects at 36% (P<0.01), 84% (P<0.05) and 55% (P<0.01), respectively. Cytokine-induced reductions in P-gp function were associated with decreased abcb1 mRNA expression. These data suggest that BBB P-gp function is increasingly responsive to the inhibitory effects of pro-inflammatory cytokines, with increasing developmental age. Thus, women who experience infection and take prescription medication during pregnancy may expose the developing fetal brain to greater amounts of exogenous compounds – many of which are considered potentially teratogenic.
PMCID: PMC3433182  PMID: 22973436

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