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1.  Sex Differences in Motivational Responses to Dietary Fat in Syrian Hamsters 
Physiology & behavior  2015;147:102-116.
Women are more likely than men to exhibit motivational disorders (e.g., anhedonia and anxiety) with limited treatment options, and to overconsume high-fat “comfort foods” to improve motivational disruptions. Unfortunately, neurobiological underpinnings for sex differences in motivational disruptions and their responses to dietary fat are poorly understood. To help bridge these fundamental knowledge gaps, we assessed behavioral and neurobiological responses to dietary fat in a hamster model of female-biased motivational lability. Relative to social housing, social separation reduced hedonic drive in a new behavioral assay, the reward investigational preference (RIP) test. Fluoxetine or desipramine treatment for 21, but not 7, days improved RIP test performance. Pharmacologic specificity in this test was shown by non-responsiveness to diazepam, tracazolate, propranolol, or naltrexone. In the anxiety-related feeding/exploration conflict (AFEC) test, social separation worsened latency to eat highly palatable food under anxiogenic conditions, but not in home cages. Social separation also reduced weight gain, food intake, and adiposity while elevating energy expenditure, assessed by caloric efficiency and indirect calorimetry. Furthermore, chronic high-fat feeding improved anhedonic and anxious responses to separation, particularly in females. In the motivation-influencing nucleus accumbens, females, but not males, exhibited a separation-induced anxiety-related decrease in Creb1 mRNA levels and an anhedonia-related decrease in ΔFosb mRNA levels. Consistent with its antidepressant- and anxiolytic-like effects on behavior, high-fat feeding elevated accumbal Creb1 and ΔFosb mRNA levels in females only. Another accumbal reward marker, Tlr4 mRNA, was elevated in females by high-fat feeding. These results show that social separation of hamsters provides a novel model of sex-dependent comorbid anhedonia, anxiety, and anorexia, and implicate accumbal CREB, ΔFosB, and TLR4. Moreover, the results validate a new assay for chronic anti-depressant efficacy.
doi:10.1016/j.physbeh.2015.04.029
PMCID: PMC4456274  PMID: 25896879
anhedonia; anorexia; antidepressant; anxiety; anxiolytic
2.  Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development—Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus 
PLoS Genetics  2016;12(5):e1006000.
Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10−8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.
Author Summary
Gliomas are devastating malignant brain tumors that are very rarely curable. Despite extensive research to define pathways and genes involved in the development of disease, there is still an urgent need to improve therapy. Some dog breeds have a considerable elevated risk of glioma, making the dog a suitable model for locating genes potentially of importance also for development of human glioma. In this study we defined a genomic region strongly associated with glioma in dogs. We also showed that this genomic region had likely been under selection in the dog breeds with the highest risk of developing glioma. Sometimes selection for breed specific traits results in amplification of disease causing mutations together with the variant selected for. We located three candidate genes in the identified region: CAMKK2, P2RX7 and DENR. We performed further functional studies to evaluate the potential role of these genes in both canine and human glioma. By comparing normal and tumor tissue we could show that two of the genes—CAMKK2 and P2RX7, were affected at the level of gene expression and protein structure, respectively. We propose that further investigation of all three genes could be of interest with potential benefit to both dog and human.
doi:10.1371/journal.pgen.1006000
PMCID: PMC4865040  PMID: 27171399
3.  Early Developmental and Evolutionary Origins of Gene Body DNA Methylation Patterns in Mammalian Placentas 
PLoS Genetics  2015;11(8):e1005442.
Over the last 20-80 million years the mammalian placenta has taken on a variety of morphologies through both divergent and convergent evolution. Recently we have shown that the human placenta genome has a unique epigenetic pattern of large partially methylated domains (PMDs) and highly methylated domains (HMDs) with gene body DNA methylation positively correlating with level of gene expression. In order to determine the evolutionary conservation of DNA methylation patterns and transcriptional regulatory programs in the placenta, we performed a genome-wide methylome (MethylC-seq) analysis of human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas as well as opossum extraembryonic membrane. We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues. Higher relative gene body methylation was the conserved feature across all mammalian placentas, despite differences in PMD/HMDs and absolute methylation levels. Specifically, higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification was observed compared with the rest of the genome. As in human placenta, higher methylation is associated with higher gene expression and is predictive of genic location across species. Analysis of DNA methylation in oocytes and preimplantation embryos shows a conserved pattern of gene body methylation similar to the placenta. Intriguingly, mouse and cow oocytes and mouse early embryos have PMD/HMDs but their placentas do not, suggesting that PMD/HMDs are a feature of early preimplantation methylation patterns that become lost during placental development in some species and following implantation of the embryo.
Author Summary
The placenta is vital for the proper development of the fetus, not only facilitating the exchange of nutrients, oxygen, and waste between the mother and the fetus but also acting as an interface to the maternal immune system and regulating fetal growth by excreting hormones and growth factors. DNA methylation is important for both placental and embryonic development as loss of proteins involved in DNA methylation can result in placental dysmorphology and early embryonic death. The human placenta has a unique DNA methylation landscape characterized by alternating regions of low methylation, covering silent genes with tissue-specific developmental functions, and high methylation, covering active genes. In order to better understand the significance of this DNA methylation landscape in the human placenta, we performed a cross-species comparison of DNA methylation in mammalian placentas, oocytes, and early embryos from this and other studies. Although the levels and extent of hypomethylation differed between mammalian placentas, what we found to be highly conserved was relatively higher methylation levels over active genes. These same genes also had high methylation in the opossum extraembryonic membrane, a primitive placenta, as well as oocytes and early embryos, suggesting that high methylation over these genes predated placental mammals and is established very early in development.
doi:10.1371/journal.pgen.1005442
PMCID: PMC4524645  PMID: 26241857
4.  BMI1 Is Expressed in Canine Osteosarcoma and Contributes to Cell Growth and Chemotherapy Resistance 
PLoS ONE  2015;10(6):e0131006.
BMI1, a stem cell factor and member of the polycomb group of genes, has been shown to contribute to growth and chemoresistance of several human malignancies including primary osteosarcoma (OSA). Naturally occurring OSA in the dog represents a large animal model of human OSA, however the potential role of BMI1 in canine primary and metastatic OSA has not been examined. Immunohistochemical staining of canine primary and metastatic OSA tumors revealed strong nuclear expression of BMI1. An identical staining pattern was found in both primary and metastatic human OSA tissues. Canine OSA cell lines (Abrams, Moresco, and D17) expressed high levels of BMI1 compared with canine osteoblasts and knockdown or inhibition of BMI1 by siRNA or by small molecule BMI1-inhibitor PTC-209 demonstrated a role for BMI1 in canine OSA cell growth and resistance to carboplatin and doxorubicin chemotherapy. These findings suggest that inhibition of BMI1 in primary or metastatic OSA may improve response to chemotherapy and that the dog may serve as a large animal model to evaluate such therapy.
doi:10.1371/journal.pone.0131006
PMCID: PMC4482432  PMID: 26110620
5.  Underdiagnosed and Undertreated Allergic Rhinitis in Urban School-Aged Children with Asthma 
Allergic rhinitis (AR) is a risk factor for the development of asthma, and if poorly controlled, it may exacerbate asthma. We sought to describe AR symptoms and treatment in a larger study about asthma, sleep, and school performance. We examined the proportion (1) who met criteria for AR in an urban sample of school children with persistent asthma symptoms, (2) whose caregivers stated that they were not told of their child's allergies, (3) who had AR but were not treated or were undertreated for the disease, as well as (4) caregivers and healthcare providers' perceptions of the child's allergy status compared with study assessment, and (5) associations between self-report of asthma and AR control over a 4-week monitoring period. One hundred sixty-six children with persistent asthma participated in a clinical evaluation of asthma and rhinitis, including allergy testing. Self-report of asthma control and rhinitis control using the Childhood Asthma Control Test (C-ACT) and Rhinitis Control Assessment Test (RCAT) were measured 1 month after the study clinic session. Persistent rhinitis symptoms were reported by 72% of participants; 54% of rhinitis symptoms were moderate in severity, though only 33% of the sample received adequate treatment. AR was newly diagnosed for 53% during the clinic evaluation. Only 15% reported using intranasal steroids. Participants with poorly controlled AR had poorer asthma control compared with those with well-controlled AR. This sample of urban school-aged children with persistent asthma had underdiagnosed and undertreated AR. Healthcare providers and caregivers in urban settings need additional education about the role of allergies in asthma, recognition of AR symptoms, and AR's essential function in the comanagement of asthma. Barriers to linkages with allergy specialists need to be identified.
doi:10.1089/ped.2014.0344
PMCID: PMC4062104  PMID: 24963455
6.  Differences in Environmental Control and Asthma Outcomes Among Urban Latino, African American, and Non–Latino White Families 
Latino and African American children with asthma are at increased risk for asthma morbidity compared with non–Latino White children. Environmental control (ie, environmental exposures and family strategies to control them) may contribute to greater asthma morbidity for ethnic minority children living in urban environments. This study examined ethnic differences in a semi-structured assessment of environmental control, associations between environmental control and asthma outcomes (asthma control, functional limitation, and emergency department [ED] use), and ethnic differences in environmental triggers in a sample of urban Latino, African American, and non–Latino White families. One hundred thirty-three children (6–13 years of age) and their caregivers completed demographic questionnaires, measures of asthma control and morbidity, and a semi-structured interview assessing environmental control. Reported environmental control differed significantly by ethnicity (P<0.05), with Latino families reporting higher levels of environmental control. Reported environmental control was significantly associated with asthma control (P<0.017) and functional limitation (P<0.017). Reported environmental control and ED use were significantly associated in Latino families (P<0.05). Non–Latino White and African American families reported more secondhand smoke exposure than Latino families (P<0.001). Latino families reported more optimal home environmental control than other ethnic groups. Substantial ethnic differences in asthma triggers suggest that observed ethnic disparities in asthma may be due, at least in part, to differences in the home environment.
doi:10.1089/ped.2011.0081
PMCID: PMC3255502  PMID: 22276226

Results 1-6 (6)