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Molecular genetics and antisocial behavior: Where do we stand?
No full textOver the last two decades, it has become increasingly evident that control of aggressive behavior is modulated by the individual genetic profile as well. Several candidate genes have been proposed to play a role in the risk to develop antisocial behavior, and distinct brain imaging studies have shown that specific cortical areas may be functionally and/or structurally impaired in impulsive violent subjects on the basis of their genotypes. In this paper, we review the findings regarding four polymorphisms-MAOA (Monoamine oxidase A) uVNTR, SLC6A4 (solute carrier family 6 (neurotransmitter transporter), member 4) 5HTTLPR, COMT (Catechol-O-methyltransferase) Val158Met and DRD4 (dopamine D4 receptor) VNTR 1-11-that all have been found to be associated with an increased vulnerability for antisocial and impulsive behavior in response to aversive environmental conditions. These results, however, have not been replicated by other studies, likely because of crucial methodological discrepancies, including variability in the criteria used to define antisocial behavior and assessment of environmental factors. Finally, it has been recently proposed that these genetic variants may actually increase the individual susceptibility not merely to the negative environmental factors, but to the positive ones as well. In this view, such alleles would play a wider modulatory role, by acting as "plasticity" rather than "vulnerability" genes. Overall, these findings have potential important implications that span well outside of neuroscience and psychiatry, to embrace ethics, philosophy, and the law itself, as they pose new challenges to the very notion of Free Will. Novel properly controlled studies that examine multi-allelic genetic profiles, rather than focusing on distinct single variants, will make it possible to achieve a clearer understanding of the molecular underpinnings of the nature by nurture interaction
Gene by gender interplay in moral choices
No full textWhile philosophers, psychologists and cognitive scientists have proposed distinct definitions of moral judgment, recent studies suggest that moral choices are modulated by neurobiological mechanisms.
The pioneering works by Greene showed that certain brain areas may be considered “specific” for moral decision and provided support for a dual-process theory, according to which two different patterns of neural activity are involved in moral choices: a fast, unconscious "emotional" system, and a slow, conscious "cognitive" system1, 2, 3. Furthermore, genetic associations between two allelic variants in serotonin transporter and oxytocin receptor genes, and moral judgment have been reported4, 5.
Because of their described association with impulsive behavior6, 7, 8, 9, we questioned whether four polymorphisms in genes involved in serotonergic and dopaminergic neurotransmission (SLC6A3–VNTR, DRD4-VNTR, DRD4 rs1800955, COMT rs4680) would modulate the cognitive and emotional processes at the basis of controversial moral choices.
After signing an informed consent, 200 (102F) University students were recruited in a moral dilemma paradigm (N=56) designed to assess three variables: moral action type (Means vs Side Effect), life expectancy (Normal vs Reduced), self-involvement (Involvement vs Non-Involvement). They also provided saliva samples for DNA collection and completed the Impulsivity-Venturesomeness-Empathy Questionnaire (I7).
Significant differences between males and females were observed in the I7 scale scores. Moreover, only in males Venturesomeness scores correlated with the number of utilitarian responses.
Males, compared to females, gave a higher number of utilitarian responses, showed longer response times for non-utilitarian answers and judged as more acceptable the endorsed moral actions.
Interestingly, only females showed a significant association between allelic variants involved in dopamine level regulation in striatum and prefrontal cortex, and moral choices.
Our results are the first ones showing that impulsivity and genetic profile influence moral judgment in a gender-related manner, thus shedding new light on the neurobiological mechanisms underlying moral choices.
BIBLIOGRAPHY
1. Greene JD, Sommerville RB, Nystrom LE, Darley JM, Cohen JD (2001). An fMRI investigation of emotional engagement in moral judgment. Science 293(5537): 2105–2108.
2. Greene JD, Nystrom LE, Engell AD, Darley JM, Cohen JD (2004). The neural bases of cognitive conflict and control in moral judgment. Neuron 44(2): 389–400.
3. Greene JD (2009). Dual-process morality and the personal/impersonal distinction: a reply to McGuire, Langdon, Coltheart, and Mackenzie. J Exp Soc Psychol 45(3): 581-584.
4. Marsh AA, Crowe SL, Yu HH, Gorodetsky EK, Goldman D, Blair RJR (2011). Serotonin transporter genotype (5-HTTLPR) predicts utilitarian moral judgments. Plos One 6(10): e25148.
5. Walter NT, Montag C, Markett S, Felten A, Voigt G, Reuter M (2012). Ignorance is no excuse: moral judgments are influenced by a genetic variation on the oxytocin receptor gene. Brain and Cognition 78(3): 268-273.
6. Munafò MR, Yalcin B, Willis-Owen SA, Flint J (2008). Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry 63(2): 197-206.
7. Joyce PR, McHugh PC, Light KJ, Rowe S, Miller AL, Kennedy MA (2009). Relationships between angry-impulsive personality traits and genetic polymorphisms of the dopamine transporter. Biol Psychiatry 66(8): 717-721.
8. Reiner I, Spangler G (2011). Dopamine D4 receptor exon III polymorphism, adverse life events and personality traits in a nonclinical German adult sample. Neuropsychobiology 63(1): 52-58.
9. Soeiro-De-Souza MG, Stanford MS, Bio DS, Machado-Vieira R, Moreno RA (2013). Association of the COMT Met158 allele with trait impulsivity in healthy young adult. Mol Med Rep 7(4): 1067-1072
Ipoacusia neurosensoriale progressiva nell’unico orecchio udente; casistica personale e ricerca di anticorpi contro la coclina
No full textPsychological and genetic correlates of controversial moral choices in professional insurance brokers
No full textPsychological and genetic correlates of controversial moral choices in professional insurance brokers, From segregation to integration: The complexity of human brain functions. It represents a new way to investigate human choices in a decision with a strong impact on human life
Human Neural Stem Cell Aging Is Counteracted by α-Glycerylphosphorylethanolamine
No full textNeural stem cells (NSCs) represent a subpopulation of cells, located in specific regions of the adult mammalian brain, with the ability of self-renewing and generating neurons and glia. In aged NSCs, modifications in the amount and composition of membrane proteins/lipids, which lead to a reduction in membrane fluidity and cholinergic activities, have been reported. In this respect, molecules that are effective at normalizing the membrane composition and cholinergic signaling could counteract stem cell aging. α-Glycerylphosphorylethanolamine (GPE), a nootropic drug, plays a role in phospholipid biosynthesis and acetylcholine release. Herein, GPE was assayed on human NSC cultures and on hydroxyurea-aged cells. Using cell counting, colorimetric, and fluorimetric analyses, immunoenzymatic assays, and real time PCR experiments, NSC culture proliferation, senescence, reactive oxygen species, and ADP/ATP levels were assessed. Aged NSCs exhibited cellular senescence, decreased proliferation, and an impairment in mitochondrial metabolism. These changes included a substantial induction in the nuclear factor NF-κB, a key inflammatory mediator. GPE cell treatment significantly protected the redox state and functional integrity of mitochondria, and counteracted senescence and NF-κB activation. In conclusion, our data show the beneficial properties of GPE in this model of stem cell aging
Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study
No full textAbstract Background BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. Methods We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. Results 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. Conclusions Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity.</p
Interpreting the gene expression microarray results: a user-based experience.
No full textIn recent years many tools have been developed to cope with the interpretation of gene expression results from microarray experiments. The effectiveness of these tools largely depends on their ease of use by biomedical researchers. Tools based on effective computational methods, indeed, cannot be fully exploited by users if they are not supported by an intuitive interface, a large set of utilities and effective outputs.
In this paper, ten tools for the interpretation of gene expression microarray results have been tested on eleven microarray datasets and evaluated according to eight assessment criteria: 1. interface design and usability, 2. easiness of input submission, 3. effectiveness of output representation, 4. efficacy of the downloaded outputs, 5. possibility to submit multiple gene IDs, 6. sources of information, 7. provision of different statistical tests and 8. supply of multiple test correction methods. Strengths and weaknesses of each tool are highlighted: a. to provide useful tips to users dealing with the biological interpretation of microarray results; b. to draw the attention of software developers on the usability of their tools
Analisi del ruolo del gene Xbsx nello sviluppo dell'organo pineale di Xenopus Laevis
No full textL’organo pineale nei vertebrati è un importante sito di produzione della melatonina, un ormone coinvolto nella regolazione di ritmi vitali come quelli circadiani e della riproduzione. In tutti i vertebrati la produzione di questo ormone è sottoposta al controllo di un orologio endogeno il quale, a sua volta, è regolato in parte dalle condizioni ambientali, essenzialmente dalla luce. Nei vertebrati superiori, in particolare nei mammiferi, la struttura che costituisce l’orologio endogeno principale e il luogo di produzione della melatonina sono separati; infatti l’orologio endogeno è situato nel nucleo suprachiasmatico e la melatonina è prodotta nell’organo pineale. Nei vertebrati inferiori, come ad esempio l’anfibio anuro Xenopus laevis, invece troviamo che l’organo pineale è la sede di entrambi: svolge direttamente la funzione di orologio endogeno e rappresenta il sito principale di produzione dell’ormone melatonina.
Esistono geni la cui trascrizione ha un andamento che corrisponde nettamente ad un ritmo giorno-notte. In particolare, dalla letteratura conosciamo geni espressi nell’organo pineale che codificano per enzimi della via di biosintesi della melatonina, come Aanat (Serotonina-N-acetil-transferasi) e Tph (Triptofano idrossilasi), la cui trascrizione ha un andamento ciclico con un’ espressione alta di notte e bassa di giorno. Inoltre sono stati individuati alcuni geni considerati fondamentali per l’orologio circadiano, tra cui i fattori di trascrizione Clock e B-mal; alcuni di questi geni hanno a loro volta un’espressione ritmica.
Nel mio lavoro di tesi ho studiato Brain Specific homeobox (Xbsx), un gene espresso specificamente nel territorio dell’organo pineale durante lo sviluppo di Xenopus laevis. Attualmente la funzione di questo gene non è nota, ma data la presenza della sequenza homeobox si può ipotizzare che codifichi per un fattore di trascrizione.
Informazioni cruciali per la determinazione del ruolo svolto da Xbsx possono essere ottenute da un’analisi dettagliata dell’espressione di questo gene.
In una prima serie di esperimenti ho voluto valutare se Xbsx fosse espresso in cellule in proliferazione o in differenziamento. Utilizzando l’analogo di base bromodeossiuridina (che viene incorporato dalle cellule in divisione) e confrontando la sua incorporazione con l’espressione di Xbsx a vari stadi (24, 32, 37 e 40) ho trovato che a stadio 24 Xbsx è espresso soprattutto in cellule differenziate con una piccola sovrapposizione con la zona in proliferazione, mentre a stadio 32 e negli stadi successivi è nettamente espresso soltanto in cellule differenziate.
Visto ciò, ho cercato di capire in quali tipi di cellule differenziate Xbsx fosse espresso. Nell’organo pineale ci sono essenzialmente due tipi di cellule: i fotorecettori e le cellule gangliari. Ho confrontato, mediante ibridazione in situ su sezione, l’espressione di Xbsx con quella di XOtx5, un gene espresso specificamente nei fotorecettori e con quella di Hermes, un marcatore di cellule gangliari. I dati ottenuti hanno dimostrato che Xbsx è espresso soltanto nei fotorecettori, avendo un’espressione completamente sovrapponibile a quella di XOtx5 e complementare ad Hermes.
Essendo un gene espresso specificamente nei fotorecettori, nei quali è prodotta la melatonina, ho poi cercato un possibile coinvolgimento di Xbsx nella regolazione dei ritmi circadiani. In particolare ho voluto accertare se la sua espressione fosse di tipo ritmico. A questo scopo ho confrontato la sua espressione con quelle di geni noti avere un’espressione circadiana in Xenopus laevis, come Aanat-2 e Tph. Ho quindi utilizzato un sistema di crescita degli embrioni in dodici ore di luce e dodici di buio alternate fino allo stadio 46. A questo stadio ho fissato gli embrioni ad orari prestabiliti (6:30, 12:30, 18:30, 00:30) e ne ho prelevato i cervelli. Sui cervelli ho effettuato ibridazioni in situ whole-mount, confrontando l’espressione di Xbsx con quelle di Aanat-2 e Tph. Questi esperimenti hanno dimostrato che i livelli di espressione di Xbsx sono analoghi a quelli di questi due geni, cioè di tipo ritmico, alti di notte e bassi di giorno.
Avendo studiato questi aspetti descrittivi, in futuro potrà essere utile procedere ad analisi di tipo funzionale, esaminando gli effetti della perdita e del guadagno di funzione di Xbsx. Uno dei metodi più efficaci per generare la perdita di funzione in Xenopus consiste nella microiniezione di oligonucleotidi antisenso. In particolare ho intenzione di utilizzare un morpholino di cui per ora ho saggiato la specificità. Il saggio di specificità consiste nell’utilizzare due costrutti recanti una parte della regione codificante per la proteina Myc riconosciuta da anticorpi commerciali. Un costrutto contiene, oltre a questa regione, la sequenza bersaglio esatta del morpholino mentre l’altro presenta una mutazione in questa sequenza. Ho quindi microiniettato questi costrutti in embrioni a stadio di 2 cellule ed ho effettuato un’analisi di western blotting per verificare la presenza delle proteine di fusione negli embrioni a stadio 10. Così ho potuto verificare che il nostro morpholino è effettivamente specifico: soltanto negli embrioni microiniettati con la sequenza bersaglio esatta è stata inibita la traduzione della proteina di fusione. Esperimenti futuri saranno volti a determinare se la perdita di funzione di Xbsx sia in grado di influenzare in qualche modo l’espressione di geni chiave dell’orologio circadiano come Clock, Bmal e Period e anche quella degli stessi Aanat-2 e Tph
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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