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1.  MORE NEIGHBORHOOD RETAIL ASSOCIATED WITH LOWER OBESITY AMONG NEW YORK CITY PUBLIC HIGH SCHOOL STUDENTS 
Health & place  2013;23:104-110.
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.
doi:10.1016/j.healthplace.2013.05.005
PMCID: PMC4088344  PMID: 23827943
Adolescent obesity; New York City; fast food; retail ecology; neighborhoods
2.  Distribution of Non-AT1, Non-AT2 Binding of 125I-Sarcosine1, Isoleucine8 Angiotensin II in Neurolysin Knockout Mouse Brains 
PLoS ONE  2014;9(8):e105762.
The recent identification of a novel binding site for angiotensin (Ang) II as the peptidase neurolysin (E.C. 3.4.24.16) has implications for the renin-angiotensin system (RAS). This report describes the distribution of specific binding of 125I-Sarcosine1, Isoleucine8 Ang II (125I-SI Ang II) in neurolysin knockout mouse brains compared to wild-type mouse brains using quantitative receptor autoradiography. In the presence of p-chloromercuribenzoic acid (PCMB), which unmasks the novel binding site, widespread distribution of specific (3 µM Ang II displaceable) 125I-SI Ang II binding in 32 mouse brain regions was observed. Highest levels of binding >700 fmol/g initial wet weight were seen in hypothalamic, thalamic and septal regions, while the lowest level of binding <300 fmol/g initial wet weight was in the mediolateral medulla. 125I-SI Ang II binding was substantially higher by an average of 85% in wild-type mouse brains compared to neurolysin knockout brains, suggesting the presence of an additional non-AT1, non-AT2, non-neurolysin Ang II binding site in the mouse brain. Binding of 125I-SI Ang II to neurolysin in the presence of PCMB was highest in hypothalamic and ventral cortical brain regions, but broadly distributed across all regions surveyed. Non-AT1, non-AT2, non-neurolysin binding was also highest in the hypothalamus but had a different distribution than neurolysin. There was a significant reduction in AT2 receptor binding in the neurolysin knockout brain and a trend towards decreased AT1 receptor binding. In the neurolysin knockout brains, the size of the lateral ventricles was increased by 56% and the size of the mid forebrain (−2.72 to +1.48 relative to Bregma) was increased by 12%. These results confirm the identity of neurolysin as a novel Ang II binding site, suggesting that neurolysin may play a significant role in opposing the pathophysiological actions of the brain RAS and influencing brain morphology.
doi:10.1371/journal.pone.0105762
PMCID: PMC4141804  PMID: 25147932
3.  Neighborhood Walkability and Active Travel (Walking and Cycling) in New York City 
Urban planners have suggested that built environment characteristics can support active travel (walking and cycling) and reduce sedentary behavior. This study assessed whether engagement in active travel is associated with neighborhood walkability measured for zip codes in New York City. Data were analyzed on engagement in active travel and the frequency of walking or biking ten blocks or more in the past month, from 8,064 respondents to the New York City 2003 Community Health Survey (CHS). A neighborhood walkability scale that measures: residential, intersection, and subway stop density; land use mix; and the ratio of retail building floor area to retail land area was calculated for each zip code. Data were analyzed using zero-inflated negative binomial regression incorporating survey sample weights and adjusting for respondents’ sociodemographic characteristics. Overall, 44 % of respondents reported no episodes of active travel and among those who reported any episode, the mean number was 43.2 episodes per month. Comparing the 75th to the 25th percentile of zip code walkability, the odds ratio for reporting zero episodes of active travel was 0.71 (95 % CI 0.61, 0.83) and the exponentiated beta coefficient for the count of episodes of active travel was 1.13 (95 % CI 1.06, 1.21). Associations between lower walkability and reporting zero episodes of active travel were significantly stronger for non-Hispanic Whites as compared to non-Hispanic Blacks and to Hispanics and for those living in higher income zip codes. The results suggest that neighborhood walkability is associated with higher engagement in active travel.
doi:10.1007/s11524-012-9758-7
PMCID: PMC3732693  PMID: 22941058
Active travel; Neighborhood walkability; Urban health; Walking
4.  Overexpression of Adenosine A2A Receptors in Rats: Effects on Depression, Locomotion, and Anxiety 
Adenosine A2A receptors (A2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer’s disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer’s disease.
doi:10.3389/fpsyt.2014.00067
PMCID: PMC4055866  PMID: 24982640
adenosine A2A receptors; memory; anxiety; depression; stress; locomotion; dopamine
5.  Length of residence and social integration: The contingent effects of neighborhood poverty 
Health & place  2013;21:10.1016/j.healthplace.2013.02.002.
Given the well-established benefits of social integration for physical and mental health, studies have begun to explore how access to social ties and social support may be shaped by the residential context in which people live. As a critical health exposure, social integration may be one important mechanism by which places affect health. This paper brings together research on two previously studied contextual determinants of social integration. Specifically, we use multi-level data from the Chicago Community Adult Health Survey to investigate the relationships between an individual’s length of residence and measures of social integration. We then investigate the extent to which these relationships are moderated by neighborhood poverty. We find that the relationship between length of residence and some measures of social integration are stronger in poor neighborhoods than in more affluent ones.
doi:10.1016/j.healthplace.2013.02.002
PMCID: PMC3873868  PMID: 23501379
Residential stability; Social support; Neighborhood poverty; Urban policy
6.  Associations between Body Mass Index and Park Proximity, Size, Cleanliness and Recreational Facilities 
Purpose
To determine whether body mass index (BMI) is associated with proximity to neighborhood parks, the size of the parks, their cleanliness and the availability of recreational facilities in the parks.
Design
Cross-sectional.
Setting
New York City.
Subjects
13,102 adults (median age 45 years, 36% male) recruited from 2000–2002.
Measures
Anthropometric and socio-demographic data from study subjects were linked to Department of Parks & Recreation data on park space, cleanliness, and facilities. Neighborhood level socio-demographic and park proximity metrics were created for half-mile radius circular buffers around each subject’s residence. Proximity to park space was measured as the proportion of the subject’s neighborhood buffer area that was total park space, large park space (a park > 6 acres) and small park space (a park <=6 acres).
Analysis
Hierarchical linear models were used to determine whether neighborhood park metrics were associated with BMI.
Results
Higher proximity to large park space was significantly associated with lower BMI (beta = −1.69 95% CI = −2.76, −0.63). Across the population distribution of proximity to large park space, compared to subjects living in neighborhoods at the 10th percentile of the distribution, the covariate adjusted average BMI was estimated to be 0.35 kg/m2 lower for those living in neighborhoods at the 90th percentile. The proportion of neighborhood area that was small park space was not associated with BMI, nor was park cleanliness or the availability of recreational facilities.
Conclusions
Neighborhood proximity to large park spaces is modestly associated with lower BMI in a diverse urban population.
doi:10.4278/ajhp.110809-QUAN-304
PMCID: PMC3696994  PMID: 23448416
Obesity; Body mass index; park proximity; neighborhood
7.  Postnatal Growth Defects in Mice with Constitutive Depletion of Central Serotonin 
ACS Chemical Neuroscience  2012;4(1):171-181.
Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (−95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2–/– mouse line and VMAT2sert-cre mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2pet1-cre) in 5-HT raphe neurons leading to partial (−75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2sert-cre mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2sert-cre and Tph2–/– mice, but not in the VMAT2pet1-cre mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.
doi:10.1021/cn300165x
PMCID: PMC3547491  PMID: 23336056
Cerebral cortex; development; somatic growth; knockout mice; vesicular monoamine transporter; tryptophan hydroxylase; cux1
8.  Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats 
The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1–100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning.
doi:10.3389/fnmol.2014.00095
PMCID: PMC4249455  PMID: 25520616
cGMP; exploratory; hippocampus; LTP; LTD; metaplasticity; NPR-B; memory
9.  Individual- and School-Level Sociodemographic Predictors of Obesity Among New York City Public School Children 
American Journal of Epidemiology  2012;176(11):986-994.
To identify student- and school-level sociodemographic characteristics associated with overweight and obesity, the authors conducted cross-sectional analyses of data from 624,204 public school children (kindergarten through 12th grade) who took part in the 2007–2008 New York City Fitnessgram Program. The overall prevalence of obesity was 20.3%, and the prevalence of overweight was 17.6%. In multivariate models, the odds of being obese as compared with normal weight were higher for boys versus girls (odds ratio (OR) = 1.39, 95% confidence interval (CI): 1.36, 1.42), for black (OR = 1.11, 95% CI: 1.07, 1.15) and Hispanic (OR = 1.48, 95% CI: 1.43, 1.53) children as compared with white children, for children receiving reduced-price (OR = 1.17, 95% CI: 1.13, 1.21) or free (OR = 1.12, 95% CI: 1.09, 1.15) school lunches as compared with those paying full price, and for US-born students (OR = 1.54, 95% CI: 1.50, 1.58) as compared with foreign-born students. After adjustment for individual-level factors, obesity was associated with the percentage of students who were US-born (across interquartile range (75th percentile vs. 25th), OR = 1.10, 95% CI: 1.07, 1.14) and the percentage of students who received free or reduced-price lunches (across interquartile range, OR = 1.13, 95% CI: 1.10, 1.18). The authors conclude that individual sociodemographic characteristics and school-level sociodemographic composition are associated with obesity among New York City public school students.
doi:10.1093/aje/kws187
PMCID: PMC3626053  PMID: 23132672
child; obesity; overweight; physical fitness; schools
10.  Body Mass Index, Safety Hazards, and Neighborhood Attractiveness 
Background
Neighborhood attractiveness and safety may encourage physical activity and help individuals maintain a healthy weight. However, these neighborhood characteristics may not be equally relevant to health across all settings and population subgroups.
Purpose
To evaluate whether potentially attractive neighborhood features are associated with lower BMI, whether safety hazards are associated with higher BMI, and whether environment–environment interactions are present such that associations for a particular characteristic are stronger in an otherwise supportive environment.
Methods
Survey data and measured height and weight were collected from a convenience sample of 13,102 adult New York City (NYC) residents in 2000–2002; data analyses were completed 2008–2012. Built-environment measures based on municipal GIS data sources were constructed within 1-km network buffers to assess walkable urban form (density, land-use mix, transit access); attractiveness (sidewalk cafés, landmark buildings, street trees, street cleanliness); and safety (homicide rate, pedestrian–auto collision and fatality prevalence). Generalized linear models with cluster-robust SEs controlled for individual and area-based sociodemographic characteristics.
Results
The presence of sidewalk cafés, density of landmark buildings, and density of street trees were associated with lower BMI, whereas the proportion of streets rated as clean was associated with higher BMI. Interactions were observed for sidewalk cafés with neighborhood poverty and walkability, for street-tree density with walkability, and for street cleanliness with safety. Safety hazard indicators were not independently associated with BMI.
Conclusions
Potentially attractive community and natural features were associated with lower BMI among adults in NYC, and there was some evidence of effect modification.
doi:10.1016/j.amepre.2012.06.018
PMCID: PMC3593726  PMID: 22992355
11.  A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5 
The kinin B1 receptor is an inducible receptor not normally expressed but induced by inflammatory stimuli and plays a major role in neutrophil recruitment, particularly in response to the cytokine interleukin-1β (IL-1β). However, the exact mechanism involved in this response is unclear. The aim of this study was to dissect the molecular mechanism involved, in particular to determine whether specific ELR-CXCL chemokines (specific neutrophil chemoattractants) played a role. Using intravital microscopy, we demonstrated that IL-1 β induced leukocyte rolling, adherence and emigration in mesenteric venules of wild type (WT) mice, associated with an increase of B1 receptor mRNA expression, was substantially attenuated (>80%) in B1 receptor knockout mice (B1KO). This effect in B1KO mice was correlated with a selective down regulation of IL-1β-induced CXCL5 mRNA and protein expression compared to WT mice. Furthermore a selective neutralizing CXCL5 antibody caused profound suppression of leukocyte emigration in IL-1β treated WT mice. Finally, treatment of human endothelial cells with IL-1β enhanced mRNA expression of B1 receptor and the human CXCL5 homologues (hCXCL5 and hCXCL6). This response was suppressed by ~50% when cells were pretreated with the B1 receptor antagonist des-Arg9[Leu]8BK whilst treatment with des-Arg9-BK, the B1 receptor agonist, caused a concentration-dependent increase in hCXCL5 and hCXCL6 mRNA expression. This study unveils a pro-inflammatory pathway centred on kinin B1 receptor activation of CXCL5 leading to leukocyte trafficking, and highlights the B1 receptor as a potential target in the therapeutics of inflammatory disease.
PMCID: PMC3696729  PMID: 17878384
Neutrophils; Chemokines; Inflammation; Endothelials cells; cell trafficking
12.  Socio-economic status, neighborhood food environments and consumption of fruits and vegetables in New York City 
Public health nutrition  2013;16(7):1197-1205.
Objective
Recommendations for fruit and vegetable consumption are largely unmet. Lower socio-economic status (SES), neighborhood poverty and poor access to retail outlets selling healthy foods are thought to predict lower consumption. The objective of this study was to assess the inter-relationships between these risk factors as predictors of fruit and vegetable consumption.
Design
Cross-sectional multi-level analyses of data on fruit and vegetable consumption, socio-demographic characteristics, neighborhood poverty and access to healthy retail food outlets.
Setting
Survey data from the 2002 and 2004 New York City Community Health Survey linked by residential zip code to neighborhood data.
Subjects
15,634 adult survey respondents.
Results
Overall 9.9% of respondents reported eating ≥5 servings of fruits or vegetables in the day prior to the survey. Among women the odds of eating ≥5 servings increased with higher income and among men and women with higher educational attainment. Compared to women with less than a high school education, the OR was 1.12 (95% CI 0.82, 1.55) for high school graduates, 1.95 (95% CI 1.43, 2.66) for those with some college education and 2.13 (95% CI 1.56, 2.91) for college graduates. The association between education and fruit and vegetable consumption was significantly stronger for women living in lower verses higher poverty Zip codes (p for interaction <0.05). The density of healthy food outlets did not predict consumption of fruits or vegetables.
Conclusions
Higher SES is associated with higher consumption of produce, an association that, in women, is stronger for those residing in lower poverty neighborhoods.
doi:10.1017/S1368980012005642
PMCID: PMC3696996  PMID: 23388104
13.  Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations 
PLoS ONE  2013;8(6):e66048.
Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study.
doi:10.1371/journal.pone.0066048
PMCID: PMC3689787  PMID: 23805197
14.  Beneficial Effects of the Activation of the Angiotensin-(1–7) Mas Receptor in a Murine Model of Adriamycin-Induced Nephropathy 
PLoS ONE  2013;8(6):e66082.
Angiotensin-(1–7) [Ang-(1–7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas+/+) and Mas knockout (Mas−/−) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas+/+, but not in Mas−/− mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1–7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.
doi:10.1371/journal.pone.0066082
PMCID: PMC3676359  PMID: 23762470
15.  Rat Model for Dominant Dystrophic Epidermolysis Bullosa: Glycine Substitution Reduces Collagen VII Stability and Shows Gene-Dosage Effect 
PLoS ONE  2013;8(5):e64243.
Dystrophic epidermolysis bullosa, a severely disabling hereditary skin fragility disorder, is caused by mutations in the gene coding for collagen VII, a specialized adhesion component of the dermal-epidermal junction zone. Both recessive and dominant forms are known; the latter account for about 40% of cases. Patients with dominant dystrophic epidermolysis bullosa exhibit a spectrum of symptoms ranging from mild localized to generalized skin manifestations. Individuals with the same mutation can display substantial phenotypic variance, emphasizing the role of modifying genes in this disorder. The etiology of dystrophic epidermolysis bullosa has been known for around two decades; however, important pathogenetic questions such as involvement of modifier genes remain unanswered and a causative therapy has yet to be developed. Much of the failure to make progress in these areas is due to the lack of suitable animal models that capture all aspects of this complex monogenetic disorder. Here, we report the first rat model of dominant dystrophic epidermolysis bullosa. Affected rats carry a spontaneous glycine to aspartic acid substitution, p.G1867D, within the main structural domain of collagen VII. This confers dominant-negative interference of protein folding and decreases the stability of mutant collagen VII molecules and their polymers, the anchoring fibrils. The phenotype comprises fragile and blister-prone skin, scarring and nail dystrophy. The model recapitulates all signs of the human disease with complete penetrance. Homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene-dosage effect of mutated alleles in dystrophic epidermolysis bullosa. This novel viable and workable animal model for dominant dystrophic epidermolysis bullosa will be valuable for addressing molecular disease mechanisms, effects of modifying genes, and development of novel molecular therapies for patients with dominantly transmitted skin disease.
doi:10.1371/journal.pone.0064243
PMCID: PMC3662756  PMID: 23717576
16.  Overexpression of Full-Length Centrobin Rescues Limb Malformation but Not Male Fertility of the Hypodactylous (hd) Rats 
PLoS ONE  2013;8(4):e60859.
Rat hypodactyly (hd) mutation is characterized by abnormal spermatogenesis and sperm decapitation, limb malformation (missing digits II and III) and growth retardation. We have previously reported centrobin (centrosome BRCA2-interacting protein) truncation at the C-terminus in the hd mutant. Here, we report data from a transgenic rescue experiment carried out to determine a role of centrobin in pathogenesis of hd. The transgenic construct, consisting of full-length-coding cDNA linked to a ubiquitous strong promoter/enhancer combination, was inserted to chromosome 16 into a LINE repeat. No known gene is present in the vicinity of the insertion site. Transgenic centrobin was expressed in all tissues tested, including testis. Transgenic animals show normal body weight and limb morphology as well as average weight of testis and epididymis. Yet, abnormal spermatogenesis and sperm decapitation persisted in the transgenic animals. Western blotting showed the coexistence of full-length and truncated or partially degraded centrobin in sperm of the rescued transgenic animals. Immunocytochemistry showed a buildup of centrobin and ODF2 (outer dense fiber 2) at the sperm decapitation site in the hd mutant and rescued transgenic rats. Additional findings included bulge-like formations and thread-like focal dissociations along the sperm flagellum and the organization of multiple whorls of truncated sperm flagella in the epididymal lumen. We conclude that centrobin is essential for normal patterning of the limb autopod. Centrobin may be required for stabilizing the attachment of the sperm head to flagellum and for maintaining the structural integrity of the sperm flagellum. We postulate that the presence of truncated centrobin, coexisting with full-length centrobin, together with incorrect timing of transgenic centrobin expression may hamper the rescue of fertility in hd male rats.
doi:10.1371/journal.pone.0060859
PMCID: PMC3620055  PMID: 23577170
17.  CXCL5 limits macrophage foam cell formation in atherosclerosis 
The Journal of Clinical Investigation  2013;123(3):1343-1347.
The ELR+-CXCL chemokines have been described typically as potent chemoattractants and activators of neutrophils during the acute phase of inflammation. Their role in atherosclerosis, a chronic inflammatory vascular disease, has been largely unexplored. Using a mouse model of atherosclerosis, we found that CXCL5 expression was upregulated during disease progression, both locally and systemically, but was not associated with neutrophil infiltration. Unexpectedly, inhibition of CXCL5 was not beneficial but rather induced a significant macrophage foam cell accumulation in murine atherosclerotic plaques. Additionally, we demonstrated that CXCL5 modulated macrophage activation, increased expression of the cholesterol efflux regulatory protein ABCA1, and enhanced cholesterol efflux activity in macrophages. These findings reveal a protective role for CXCL5, in the context of atherosclerosis, centered on the regulation of macrophage foam cell formation.
doi:10.1172/JCI66580
PMCID: PMC3582141  PMID: 23376791
18.  The Angiotensin-Melatonin Axis 
Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies.
doi:10.1155/2013/521783
PMCID: PMC3556444  PMID: 23365722
19.  Laser Fusion of Mouse Embryonic Cells and Intra-Embryonic Fusion of Blastomeres without Affecting the Embryo Integrity 
PLoS ONE  2012;7(12):e50029.
Manipulation with early mammalian embryos is the one of the most important approach to study preimplantation development. Artificial cell fusion is a research tool for various biotechnological experiments. However, the existing methods have various disadvantages, first of them impossibility to fuse selected cells within multicellular structures like mammalian preimplantation embryos. In our experiments we have successfully used high repetition rate picosecond near infrared laser beam for fusion of pairs of oocytes and oocytes with blastomeres. Fused cells looked morphologically normal and keep their ability for further divisions in vitro. We also fused two or three blastomeres inside four-cell mouse embryos. The presence of one, two or three nuclei in different blastomeres of the same early preimplantation mouse embryo was confirmed under UV-light after staining of DNA with the vital dye Hoechst-33342. The most of established embryos demonstrated high viability and developed in vitro to the blastocyst stage. We demonstrated for the first time the use of laser beam for the fusion of various embryonic cells of different size and of two or three blastomeres inside of four-cell mouse embryos without affecting the embryo’s integrity and viability. These embryos with blastomeres of various ploidy maybe unique model for numerous purposes. Thus, we propose laser optical manipulation as a new tool for investigation of fundamental mechanisms of mammalian development.
doi:10.1371/journal.pone.0050029
PMCID: PMC3515590  PMID: 23227157
20.  Kinin B1 Receptor in Adipocytes Regulates Glucose Tolerance and Predisposition to Obesity 
PLoS ONE  2012;7(9):e44782.
Background
Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B1 receptor knockout mice (B1−/−) are leaner and exhibit improved insulin sensitivity.
Methodology/Principal Findings
Here we show that kinin B1 receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B1 receptors. In these cells, treatment with the B1 receptor agonist des-Arg9-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B1−/− mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B1 receptor was limited to cells of the adipose tissue (aP2-B1/B1−/−). Similarly to B1−/− mice, aP2-B1/B1−/− mice were leaner than wild type controls. However, exclusive expression of the kinin B1 receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B1−/− mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B1 receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B1/B1−/− when compared to B1−/− mice. When subjected to high fat diet, aP2-B1/B1−/− mice gained more weight than B1−/− littermates, becoming as obese as the wild types.
Conclusions/Significance
Thus, kinin B1 receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.
doi:10.1371/journal.pone.0044782
PMCID: PMC3443087  PMID: 23024762
21.  Creating and validating GIS measures of urban design for health research 
Studies relating urban design to health have been impeded by the unfeasibility of conducting field observations across large areas and the lack of validated objective measures of urban design. This study describes measures for five dimensions of urban design – imageability, enclosure, human scale, transparency, and complexity – created using public geographic information systems (GIS) data from the US Census and city and state government. GIS measures were validated for a sample of 588 New York City block faces using a well-documented field observation protocol. Correlations between GIS and observed measures ranged from 0.28 to 0.89. Results show valid urban design measures can be constructed from digital sources.
doi:10.1016/j.jenvp.2009.03.004
PMCID: PMC3433081  PMID: 22956856
GIS; Urban design; Methods development; Physical activity; Walking
22.  Blocking of bradykinin receptor B1 protects from focal closed head injury in mice by reducing axonal damage and astroglia activation 
The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.
doi:10.1038/jcbfm.2012.62
PMCID: PMC3434625  PMID: 22569191
astrocytes; β-APP; closed head injury; kinin receptors; R-715; TNF-α
23.  Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes 
PLoS ONE  2012;7(7):e40573.
The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.
doi:10.1371/journal.pone.0040573
PMCID: PMC3400662  PMID: 22829877
24.  Emergence and evolution of the renin–angiotensin–aldosterone system 
The renin–angiotensin–aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-012-0894-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00109-012-0894-z
PMCID: PMC3354321  PMID: 22527880
Evolution; Evolutionary medicine; Renin; Angiotensin; Aldosterone; Volume regulation; Salt; Hypertension; Cardiovascular diseases; RAAS
25.  Reconsidering Access: Park Facilities and Neighborhood Disamenities in New York City 
With increasing concern about rising rates of obesity, public health researchers have begun to examine the availability of parks and other spaces for physical activity, particularly in cities, to assess whether access to parks reduces the risk of obesity. Much of the research in this field has shown that proximity to parks may support increased physical activity in urban environments; however, as yet, there has been limited consideration of environmental impediments or disamenities that might influence individuals’ perceptions or usage of public recreation opportunities. Prior research suggests that neighborhood disamenities, for instance crime, pedestrian safety, and noxious land uses, might dissuade people from using parks or recreational facilities and vary by neighborhood composition. Motivated by such research, this study estimates the relationship between neighborhood compositional characteristics and measures of park facilities, controlling for variation in neighborhood disamenities, using geographic information systems (GIS) data for New York City parks and employing both kernel density estimation and distance measures. The central finding is that attention to neighborhood disamenities can appreciably alter the relationship between neighborhood composition and spatial access to parks. Policy efforts to enhance the recreational opportunities in urban areas should expand beyond a focus on availability to consider also the hazards and disincentives that may influence park usage.
doi:10.1007/s11524-011-9551-z
PMCID: PMC3079030  PMID: 21360245
Built environment; Parks; Spatial accessibility; GIS

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