Bidirectional rescue of extreme genetic predispositions to anxiety: impact of CRH receptor 1 as epigenetic plasticity gene in the amygdala

The continuum of physiological anxiety up to psychopathology is not merely dependent on genes, but is orchestrated by the interplay of genetic predisposition, gene x environment and epigenetic interactions. Accordingly, inborn anxiety is considered a polygenic, multifactorial trait, likely to be shaped by environmentally driven plasticity at the genomic level. We here took advantage of the extreme genetic predisposition of the selectively bred high (HAB) and low anxiety (LAB) mouse model exhibiting high vs low anxiety-related behavior and tested whether and how beneficial (enriched environment) vs detrimental (chronic mild stress) environmental manipulations are capable of rescuing phenotypes from both ends of the anxiety continuum. We provide evidence that (i) even inborn and seemingly rigid behavioral and neuroendocrine phenotypes can bidirectionally be rescued by appropriate environmental stimuli, (ii) corticotropin-releasing hormone receptor 1 (Crhr1), critically involved in trait anxiety, shows bidirectional alterations in its expression in the basolateral amygdala (BLA) upon environmental stimulation, (iii) these alterations are linked to an increased methylation status of its promoter and, finally, (iv) binding of the transcription factor Yin Yang 1 (YY1) to the Crhr1 promoter contributes to its gene expression in a methylation-sensitive manner. Thus, Crhr1 in the BLA is critically involved as plasticity gene in the bidirectional epigenetic rescue of extremes in trait anxiety

Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.Grant sponsor: National Institute of Health; Grant numbers: U19 CA148127-01 (PI: Amos) and 1U19CA148127-02 (PI: Bickeb€oller); Grantsponsor:Canadian Cancer Society Research Institute; Grant number: 020214 (PI: Hung); Grant sponsor: National Institute of Health; Grantnumber:U19 CA148065; Grant sponsor: National Institute of Health; Grant number: U19 CA148065; Grant sponsor: National Institute ofHealth;Grant numbers: U19 CA148107; R01 CA81488, P30 CA014089; Grant sponsor: GAME-ON U19 initiative for prostate cancer; Grantnumber:U19 CA148537; Grant sponsor: National Institute of Health; Grant number: U19 CA148107; R01 CA81488, P30 CA014089; Grantsponsor: GAME-ON U19 initiative for prostate cancer; Grant number: U19 CA148537; Grant sponsor: National Institutes of Health;Grant number: U19 CA148112-01 (PI: Sellers) and R01-CA149429 (Phelan); Grant sponsors: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services;Grant numbers: U01 CA137088 and R01 CA059045; Grant sponsors: RegionalCouncil of Pays de la Loire, the Groupement des Entreprises Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne deBretagne Genetique and the Ligue Regionale Contre le Cancer [(LRCC); ASTERISK: a Hospital Clinical Research Program (PHRC)];Grantsponsor:German Research Council; Grant numbers: BR 1704/6–1, BR 1704/6–3, BR 1704/6–4 and CH 117/1–1); Grant sponsor: GermanFederal Ministry of Education and Research;Grant numbers: 01KH0404 and 01ER0814; Grant sponsor: National Institutes of Health;Grant number: R01 CA48998 (to M.L.S.); Grant sponsor: National Institutes of Health; Grant numbers: P01 CA 055075, UM1 CA167552,R01 137178, R01 CA 151993 and P50 CA 127003;Grant sponsor: National Institutes of Health; Grant numbers: R01 CA137178, P01 CA087969, R01 CA151993 and P50 CA 127003);Grant sponsor: National Institutes of Health; Grant number: R01 CA042182; Grant sponsor:National Institutes of Health (through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer; see CFR section);Grant number: U01 CA074783; Grant sponsors: Ontario Research Fund, the Canadian Institutes of Health Research, and the OntarioInstitute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation (Additional funding towardgenetic analyses of OFCCR);Grant sponsors: National Cancer Institute [NIH, Division of Cancer Prevention, DHHS (PLCO: IntramuralResearch Program of the Division of Cancer Epidemiology and Genetics)];Grant sponsor: National Institutes of Health (NIH) and Genes,Environment, and Health Initiative [GEI (Lung Cancer and Smoking study)];Grant numbers: Z01 CP 010200, NIH U01 HG004446 andNIH GEI U01 HG 004438;Grant sponsor: GENEVA Coordinating Center provided assistance with genotype cleaning and general studycoordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping (For the lung study);Grantsponsor:National Institutes of Health; Grant number: R01 CA076366 (to PA Newcomb); Grant sponsor: .; Grant sponsor: NationalInstitutes of Health;Grant number: K05 CA154337; Grant sponsor: National Heart, Lung, and Blood Institute, National Institutes ofHealth, US Department of Health and Human Services;Grant numbers: HHSN268201100046C, HHSN268201100001C,HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C;Grant sponsor: Swedish CancerFoundation;Grant numbers: 09–0677, 11–484, 12–823; Grant sponsor: The Cancer Risk Prediction Center (CRisP; www.crispcenter.org), aLinneus Centre;Grant number: 70867902; Grant sponsor: Swedish Research Council; Grant numbers: K2010-70X-20430–04-3, 2014–2269;Grant sponsor: Canadian Institutes of Health Research (European Commission’s Seventh Framework Programme grant agreement; CRUKGWAS);Grant number:223175 (HEALTH-F2-2009–223175); Grant sponsor: Cancer Research UK; Grant numbers: C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692 and C16913/A6135;Grant sponsor: National Institute of Health (NIH; Cancer Post-Cancer GWASinitiative grant);Grant number: 1 U19 CA 148537–01 (the GAME-ON initiative); Grant sponsors: The Institute of Cancer Research and TheEveryman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal,The National Cancer Research Network UK and The National Cancer Research Institute (NCRI) UK;Grant sponsor: NIHR (NIHR BiomedicalResearch Cent re at The In stitute of Cancer Research and The Royal Marsden NHS Foundation Trust);Grant sponsor: The National Health andMedical Research Council, Australia (The Prostate Cancer Program of Cancer Council Victoria);Grant numbers: 126402, 209057, 251533,396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296,);Grant sponsors: VicHealth, Cancer Council Victoria, The Pros tateCancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersa ll’s;Grant sponsor: National Human GenomeResearch Institute for their support (EAO, DMK, and EMK acknowledge the Intramural Program

Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses

The Adult Repetitive Behaviours Questionnaire-2 (RBQ-2A): A Self-Report Measure of Restricted and Repetitive Behaviours

In two studies we developed and tested a new self-report measure of restricted and repetitive behaviours (RRB) suitable for adults. In Study 1, The Repetitive Behaviours Questionnaire-2 for adults (RBQ-2A) was completed by a sample of 163 neurotypical adults. Principal components analysis revealed two components: Repetitive Motor Behaviours and Insistence on Sameness. In Study 2, the mean RBQ-2A scores of a group of adults with autism spectrum disorder (ASD; N = 29) were compared to an adult neurotypical group (N = 37). The ASD sample had significantly higher total and subscale scores. These results indicate that the RBQ-2A has utility as a self-report questionnaire measure of RRBs suitable for adults, with potential clinical application