PRKCA Polymorphism Changes the Neural Basis of Episodic Remembering in Healthy Individuals

Everyday functioning relies on episodic memory, the conscious retrieval of past experiences, but this crucial cognitive ability declines severely with aging and disease. Vulnerability to memory decline varies across individuals however, producing differences in the time course and severity of memory problems that complicate attempts at diagnosis and treatment. Here we identify a key source of variability, by examining gene dependent changes in the neural basis of episodic remembering in healthy adults, targeting seven polymorphisms previously linked to memory. Scalp recorded Event-Related Potentials (ERPs) were measured while participants remembered words, using an item recognition task that requires discrimination between studied and unstudied stimuli. Significant differences were found as a consequence of a Single Nucleotide Polymorphism (SNP) in just one of the tested genes, PRKCA (rs8074995). Participants with the common G/G variant exhibited left parietal old/new effects, which are typically seen in word recognition studies, reflecting recollection-based remembering. During the same stage of memory retrieval participants carrying a rarer A variant exhibited an atypical pattern of brain activity, a topographically dissociable frontally-distributed old/new effect, even though behavioural performance did not differ between groups. Results replicated in a second independent sample of participants. These findings demonstrate that the PRKCA genotype is important in determining how episodic memories are retrieved, opening a new route towards understanding individual differences in memory

Prefrontal dopamine and the dynamic control of human long-term memory

Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test—a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism. The COMT Val108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories

A Combination of Dopamine Genes Predicts Success by Professional Wall Street Traders

What determines success on Wall Street? This study examined if genes affecting dopamine levels of professional traders were associated with their career tenure. Sixty professional Wall Street traders were genotyped and compared to a control group who did not trade stocks. We found that distinct alleles of the dopamine receptor 4 promoter (DRD4P) and catecholamine-O-methyltransferase (COMT) that affect synaptic dopamine were predominant in traders. These alleles are associated with moderate, rather than very high or very low, levels of synaptic dopamine. The activity of these alleles correlated positively with years spent trading stocks on Wall Street. Differences in personality and trading behavior were also correlated with allelic variants. This evidence suggests there may be a genetic basis for the traits that make one a successful trader

Inequalities in public water supply fluoridation in Brazil: An ecological study

Background. The literature is scarce on the social and geographic inequalities in the access to and implementation of the fluoridation of public water supplies. This study adds knowledge to the Brazilian experience of the chronic privation of water and wastewater policies, access to potable water and fluoridation in the country. Thus, the aim of this study was to verify possible inequalities in the population's access to fluoridated drinking water in 246 Brazilian municipalities. Methods. The information on the process of water fluoridation in the municipalities and in the macro region in which each municipality is located was obtained from the national epidemiological survey which was concluded in 2003. The data relating to the human development index at municipal level (HDI-M) and access to mains water came from the Brazilian Human Development Atlas, whilst the size of the population was obtained from a governmental source. The Fisher exact test (P < 0.05) was employed to identify significant associations between the explanatory variables and their ability to predict the principal outcomes of interest to this study, namely the presence or absence of the water fluoridation process in the municipalities as well as the length of time during which this measure has been implemented. Linear regression was used to observe the associations between the relevant variables in a multivariate environment. Results. The results clearly showed that there is a relationship between municipalities with larger populations, located in more socio-economically advantaged regions and with better HDI-M, and where fluoridation is both present and has been implemented for a longer period of time (started before 1990). Conclusion. The findings suggest that the aim of treating water with fluoride may not be being adequately achieved, requiring more effective strategies so that access to this measure can be expanded equitably.81Hart, J.T., The inverse care law (1971) Lancet, 1 (7696), pp. 405-12. , 4100731Victora, C.G., Vaughan, J.P., Barros, F.C., Silva, A.C., Tomasi, E., Explaining trends in inequities: Evidence from Brazilian child health studies (2000) Lancet, 356 (9235), pp. 1093-98. , 10.1016/S0140-6736(00)02741-0 11009159Basting, R.T., Pereira, A.C., Meneghim, M.C., Evaluation of dental caries prevalence in students from Piracicaba, SP, Brazil, after 25 years of fluoridation of the public water supply (1997) Rev Odontol Univ São Paulo, 11 (4), pp. 287-92. , 10.1590/S0103-06631997000400010Lawrence, H.P., Sheiham, A., Caries progression in 12 to 16-year-old schoolchildren in fluoridated and fluoride-deficient areas in Brazil (1997) Community Dent Oral Epidemiol, 25 (6), pp. 402-11. , 10.1111/j.1600-0528.1997.tb01730.x 9429812Pereira, A.C., Mialhe, F.L., Bianchini, F.L.C., Prevalence of caries and dental floozies in scholars from cities with different fluoride concentrations in drinking water (2001) Rev Bras Odontol Sade Coletiva, 2 (1), pp. 34-9For Disease Control, C., Prevention, Achievementsin Public Health, 1900-1999: Fluoridation of drinking water to prevent dental caries (1999) Morbidity and Mortality Weekly Report, 48 (41), pp. 933-40For Disease Control, C., Prevention, Ten great public health achievements -United Sates, 1900-1999 (1999) Morbidity and Mortality Weekly Report, 48 (12), pp. 241-3. , 10220250American Health Organization, P., XV Directing Council of the Pan American Health Organization - Resolutions, 1964, , http://www.paho.org/English/GOV/CD/ftcd_15.htm(2003) The World Oral Health Report 2003, , http://www.who.int/oral_health, Geneva: WHOMcDonagh, M.S., Whiting, P.F., Wilson, P.M., Sutton, A.J., Chestnutt, I., Cooper, J., Misso, K., Kleijnen, J., Systematic review of water fluoridation (2000) BMJ, 321 (7265), pp. 855-9. , 11021861 10.1136/bmj.321.7265.855Bratthall, D., Hänsel-Petersson, G., Sundberg, H., Reasons for the caries decline: What do the experts believe? (1996) Eur J Oral Sci, 104 (4 PART 2), pp. 416-22. , 10.1111/j.1600-0722.1996.tb00104.x 8930592Narvai, P.C., Dental caries and fluorine: A twentieth century relation (2000) Cinc Sade Coletiva, 5 (2), pp. 381-92. , 10.1590/S1413-81232000000200011Peres, M.A., Fernandes, L.S., Peres, K.G., Inequality of water fluoridation in Southern Brazil - The inverse equity hypothesis revisited (2004) Soc Sci Med, 58 (6), pp. 1181-9. , 10.1016/S0277-9536(03)00289-2 14723912Peres, M.A., Antunes, J.L.F., Peres, K.G., Is water fluoridation effective in reducing inequalities in dental caries distribution in developing countries? (2006) Sozial und Präventiv Medizin, 51 (5), pp. 1-9Peres, K.G., Bastos, J.R., Mrdo, L., Relationship between severity of dental caries and social and behavioral factors in children (2000) Rev Saude Publica, 34 (4), pp. 402-8. , 10973161Maltz, M., Barbachan Silva, E.B., Relationship between caries, gingivitis and fluorosis and the socioeconomic status among school children (2001) Rev Saude Publica, 35 (2), pp. 170-6. , 11359204Moysés, S.J., Desigualdades em Sade Bucal e Desenvolvimento Humano: Um ensaio em preto, branco e alguns tons de cinza (2001) Rev Bras Odontol Sade Coletiva, 1 (1), pp. 7-17Patussi, M.P., Marcenes, W., Croucher, R., Sheiham, A., Social deprivation, income inequality, social cohesion and dental caries in Brazilian school children (2001) Soc Sci Med, 53 (7), pp. 915-25. , 10.1016/S0277-9536(00)00391-9 11522137Antunes, J.L.F., Frazão, P., Narvai, P.C., Bispo, C.M., Pegoretti, T., Spatial analysis to identify differentials in dental needs by area-based measures (2002) Community Dent Oral Epidemiol, 30 (2), pp. 133-42. , 10.1034/j.1600-0528.2002.300207.x 12000354Peres, M.A., Peres, K.G., Antunes, J.L.F., Junqueira, S.R., Frazão, P., Narvai, P.C., The association between socioeconomic development at the town level and the distribution of dental caries in Brazilian children (2003) Rev Panam Salud Publica, 14 (3), pp. 149-57. , 10.1590/S1020-49892003000800001 14653902Antunes, J.L.F., Narvai, P.C., Nugent, Z.J., Measuring inequalities in the distribution of dental caries (2004) Community Dent Oral Epidemiol, 32 (1), pp. 41-8. , 10.1111/j.1600-0528.2004.00125.x 14961839Antunes, J.L.F., Peres, M.A., De Campos Mello, T.R., Waldman, E.A., Multilevel assessment of determinants of dental caries experience in Brazil (2006) Community Dent Oral Epidemiol, 34 (2), pp. 146-152. , 10.1111/j.1600-0528.2006.00274.x 16515679Narvai, P.C., Frazão, P., Roncalli, A.G., Antunes, J.L.F., Dental caries in Brazil: Decline, polarization, inequality and social exclusion (2006) Rev Panam Salud Publica, 19 (6), pp. 385-93. , 10.1590/S1020-49892006000600004 16968593Projeto, S.B., Brasil, Condiçes de sade bucal da população brasileira 2002-2003. Resultados principais (2004) Brasília-DF: Ministério da Sade, Secretaria de Atenção Sade, Departamento de Atenção Básica, Coordenação Nacional de Sade BucalCarmichael, C.L., Rugg-Gunn, A.J., French, A.D., Cranage, J.D., The effect of fluoridation upon the relationship between caries experience and social class in 5-year-old children in Newcastle and Northumberland in 1987 (1980) Br Dent J, 149 (6), pp. 163-7. , 10.1038/sj.bdj.4804479 6931610Bradnock, G., Marchment, M.D., Anderson, R.J., Social background, fluoridation and caries experience in 5-year-old population in the West Midlands (1984) Br Denl J, 156 (4), pp. 127-31. , 10.1038/sj.bdj.4805287 6584119Jones, C.M., Taylor, G.O., Whittle, J.G., Evans, D., Trotter, D.P., Water fluoridation, tooth decay in 5 years olds, and social deprivation measured by the Jarman score: Analysis of data from British dental surveys (1997) BMJ, 315 (7107), pp. 514-17. , 9329305Riley, J.C., Lennon, M.A., Ellwood, R.P., The effect of water fluoridation and social inequalities on dental caries in 5-year-old children (1999) Int Dent J, 28 (2), pp. 300-5. , 10342695Congresso Nacional, Brasil., Lei Federal no. de 19/09/1990 (1990) Diário Oficial da União 20 Set, p. 18055Morgenstern, H., Ecological studies (1998) Modern Epidemiology, pp. 459-80. , Baltimore: Lippincot Williamns & Wilkins Rothman K, Greenland S(2000) Informaçes de Sade: População Residente, , http://w3.datasus.gov.br/datasus/datasus.php?area= 359A1B379C6D0E0F359G23HIJd6L26M0N&VInclude=./site/infsaude.php, Departamento de Informática do Sistema nico de Sade (DATASUS)(2003) Atlas Do Desenvolvimento Humano No Brasil, Versão 1.0.0, , Programa das Naçes Unidas para o Desenvolvimento Brasília: PNUDLallo, R., Myburgh, N.G., Hobdell, M.H., Dental caries, socio-economic development and national oral health profiles (1999) Int Dent J, 49, pp. 196-202. , 10858754Baldani, M.H., Narvai, P.C., Antunes, J.L.F., Cárie dentária e condiçes scio-econômicas no Estado do Paraná, Brasil, 1996 (2002) Cad Sade Pblica, 18 (3), pp. 755-63. , 10.1590/S0102-311X2002000300024Qizilbash, M., On the Measurement of Human Development (2002) UNDP, , http://hdr.undp.org/docs/training/oxford/presentations/ Qizilbash_HDIcritique.pdfBurt, B.A., Fluoridation and social equity (2002) J Public Health Dent, 62 (4), pp. 195-200. , 10.1111/j.1752-7325.2002.tb03445.x 12474623For Disease Control, C., Prevention, Recommendation focusing fluoride to prevent and control dental caries in the United States (2001) Morbidity and Mortality Weekly Report, 50 (14), pp. 1-42Griffin, S.O., Jones, K., Tomar, S.L., An economic evaluation of community water fluoridation (2001) J Public Health Dent, 61 (2), pp. 78-86. , 10.1111/j.1752-7325.2001.tb03370.x 11474918Bleicher, L., Frota, F.H.S., Fluoretação da água: Uma questão de política pblica - O caso do Estado do Ceará (2006) Cin Sade Coletiva, 11 (1), pp. 71-8Frias, A.C., Narvai, P.C., Arajo, M.E., Zilbovicius, C., Antunes, J.L.F., Custo da fluoretação das águas de abastecimento pblico, estudo de caso -Município de São Paulo, Brasil, período de 1985-2003 (2006) Cad Sade Pblica, 22 (6), pp. 1237-46. , 10.1590/S0102-311X2006000600013Congresso Nacional, Brasil., (1974) Lei Federal No. 6.050, 3, p. 107. , Brasília: Departamento de Imprensa Nacional Atos do Poder Legislativo. Leis de Abril a JunhoDuarte, C.M.R., Eqüidade na legislação: Um princípio do sistema de sade brasileiro? (2000) Cin Sade Coletiva, 5 (2), pp. 443-63Whitehead, M., The concepts and principles of equity and health (1992) Int J Health Serv, 22 (3), pp. 429-45. , 10.2190/986L-LHQ6-2VTE-YRRN 164450

Five views of a secret: does cognition change during middle adulthood?

This study examined five aspects of change (or stability) in cognitive abilities in middle adulthood across a 12-year period. Data come from the Interdisciplinary Study on Adult Development. The sample consisted of N = 346 adults (43.8 years on average, 48.6% female). In total, 11 cognitive tests were administered to assess fluid and crystallized intelligence, memory, and processing speed. In a first series of analyses, strong measurement invariance was established. Subsequently, structural stability, differential stability, stability of divergence, absolute stability, and the generality of changes were examined. Factor covariances were shown to be equal across time, implying structural stability. Stability coefficients were around .90 for fluid and crystallized intelligence, and speed, indicating high, yet not perfect differential stability. The coefficient for memory was .58. Only in processing speed the variance increased across time, indicating heterogeneity in interindividual development. Significant mean-level changes emerged, with an increase in crystallized intelligence and decline in the other three abilities. A number of correlations among changes in cognitive abilities were significant, implying that cognitive change

The macroecology of chemical communication in lizards: do climatic factors drive the evolution of signalling glands?

Chemical communication plays a pivotal role in shaping sexual and ecological interactions among animals. In lizards, fundamental mechanisms of sexual selection such as female mate choice have rarely been shown to be influenced by quantitative phenotypic traits (e.g., ornaments), while chemical signals have been found to potentially influence multiple forms of sexual and social interactions, including mate choice and territoriality. Chemical signals in lizards are secreted by glands primarily located on the edge of the cloacae (precloacal glands, PG) and thighs (femoral glands), and whose interspecific and interclade number ranges from 0 to >100. However, elucidating the factors underlying the evolution of such remarkable variation remains an elusive endeavour. Competing hypotheses suggest a dominant role for phylogenetic conservatism (i.e., species within clades share similar numbers of glands) or for natural selection (i.e., their adaptive diversification results in deviating numbers of glands from ancestors). Using the prolific Liolaemus lizard radiation from South America (where precloacal glands vary from 0-14), we present one of the largest-scale tests of both hypotheses to date. Based on climatic and phylogenetic modelling, we show a clear role for both phylogenetic inertia and adaptation underlying gland variation: (i) solar radiation, net primary productivity, topographic heterogeneity and precipitation range have a significant effect on number of PG variation, (ii) humid and cold environments tend to concentrate species with a higher number of glands, (iii) there is a strong phylogenetic signal that tends to conserve the number of PG within clades. Collectively, our study confirms that the inertia of niche conservatism can be broken down by the need of species facing different selection regimes to adjust their glands to suit the demands of their specific environments

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS

mTOR: from growth signal integration to cancer, diabetes and ageing

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.National Institutes of Health (U.S.)Howard Hughes Medical InstituteWhitehead Institute for Biomedical ResearchJane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France