Development of pyrimidone D1 dopamine receptor positive allosteric modulators

MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure–activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators

Semi-empirical catalog of early-type galaxy-halo systems: dark matter density profiles, halo contraction and dark matter annihilation strength

With SDSS galaxy data and halo data from up-to-date N-body simulations we construct a semi-empirical catalog (SEC) of early-type systems by making a self-consistent bivariate statistical match of stellar mass (M_star) and velocity dispersion (sigma) with halo virial mass (M_vir). We then assign stellar mass profile and velocity dispersion profile parameters to each system in the SEC using their observed correlations with M_star and sigma. Simultaneously, we solve for dark matter density profile of each halo using the spherical Jeans equation. The resulting dark matter density profiles deviate in general from the dissipationless profile of NFW or Einasto and their mean inner density slope and concentration vary systematically with M_vir. Statistical tests of the distribution of profiles at fixed M_vir rule out the null hypothesis that it follows the distribution predicted by N-body simulations for M_vir ~< 10^{13.5-14.5} M_solar. These dark matter profiles imply that dark matter density is, on average, enhanced significantly in the inner region of halos with M_vir ~< 10^{13.5-14.5} M_solar supporting halo contraction. The main characteristics of halo contraction are: (1) the mean dark matter density within the effective radius has increased by a factor varying systematically up to ~ 3-4 at M_vir = 10^{12} M_solar, and (2) the inner density slope has a mean of ~ 1.3 with rho(r) ~ r^{-alpha} and a halo-to-halo rms scatter of rms(alpha) ~ 0.4-0.5 for 10^{12} M_solar ~< M_vir ~< 10^{13-14} M_solar steeper than the NFW profile (alpha=1). Based on our results we predict that halos of nearby elliptical and lenticular galaxies can, in principle, be promising targets for gamma-ray emission from dark matter annihilation.Comment: 43 pages, 20 figures, JCAP, revised and accepted versio

The reproductive capacity of Monk Parakeets Myiopsitta monachus is higher in their invasive range

Breeding parameters for Monk Parakeets Myiopsitta monachus nesting in Barcelona, Spain, were collected for 651 nests over five breeding seasons. This invasive population has a high reproductive capacity compared with the species in the native range: fledging success was double, the percentage of pairs attempting second broods three times higher and 55% of first-year birds bred compared with almost zero in South America

All-Sky Near Infrared Space Astrometry

Instrumentatio

Constraining Running Non-Gaussianity

The primordial non-Gaussian parameter fNL has been shown to be scale-dependent in several models of inflation with a variable speed of sound. Starting from a simple ansatz for a scale-dependent amplitude of the primordial curvature bispectrum for two common phenomenological models of primordial non-Gaussianity, we perform a Fisher matrix analysis of the bispectra of the temperature and polarization of the Cosmic Microwave Background (CMB) radiation and derive the expected constraints on the parameter nNG that quantifies the running of fNL(k) for current and future CMB missions such as WMAP, Planck and CMBPol. We find that CMB information alone, in the event of a significant detection of the non-Gaussian component, corresponding to fNL = 50 for the local model and fNL = 100 for the equilateral model of non-Gaussianity, is able to determine nNG with a 1-sigma uncertainty of Delta nNG = 0.1 and Delta nNG = 0.3, respectively, for the Planck mission. In addition, we consider a Fisher matrix analysis of the galaxy power spectrum to determine the expected constraints on the running parameter nNG for the local model and of the galaxy bispectrum for the equilateral model from future photometric and spectroscopic surveys. We find that, in both cases, large-scale structure observations should achieve results comparable to or even better than those from the CMB, while showing some complementarity due to the different distribution of the non-Gaussian signal over the relevant range of scales. Finally, we compare our findings to the predictions on the amplitude and running of non-Gaussianity of DBI inflation, showing how the constraints on a scale-dependent fNL(k) translate into constraints on the parameter space of the theory.Comment: 37 pages, 14 figure

Entropic force approach to noncommutative Schwarzschild black holes signals a failure of current physical ideas

Recently, a new perspective of gravitational-thermodynamic duality as an entropic force arising from alterations in the information connected to the positions of material bodies is found. In this paper, we generalize some aspects of this model in the presence of noncommutative Schwarzschild black hole by applying the method of coordinate coherent states describing smeared structures. We implement two different distributions: (a) Gaussian and (b) Lorentzian. Both mass distributions prepare the similar quantitative aspects for the entropic force. Our study shows, the entropic force on the smallest fundamental unit of a holographic screen with radius $r_0$ vanishes. As a result, black hole remnants are unconditionally inert even gravitational interactions do not exist therein. So, a distinction between gravitational and inertial mass in the size of black hole remnant is observed, i.e. the failure of the principle of equivalence. In addition, if one considers the screen radius to be less than the radius of the smallest holographic surface at the Planckian regime, then one encounters some unusual dynamical features leading to gravitational repulsive force and negative energy. On the other hand, the significant distinction between the two distributions is conceived to occur around $r_0$, and that is worth of mentioning: at this regime either our analysis is not the proper one, or non-extensive statistics should be employed.Comment: 15 pages, 2 figures, new references added, minor revision, Title changed, to appear in EPJ Plu

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

The BRCA2 c.68-7T > A variant is not pathogenic : A model for clinical calibration of spliceogenicity

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44x10(-115). There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.Peer reviewe

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk