Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Clock genes and their genomic distributions in three species of salmonid fishes: Associations with genes regulating sexual maturation and cell cycling

<p>Abstract</p> <p>Background</p> <p>Clock family genes encode transcription factors that regulate clock-controlled genes and thus regulate many physiological mechanisms/processes in a circadian fashion. Clock1 duplicates and copies of Clock3 and NPAS2-like genes were partially characterized (genomic sequencing) and mapped using family-based indels/SNPs in rainbow trout (RT)(<it>Oncorhynchus mykiss</it>), Arctic charr (AC)(<it>Salvelinus alpinus</it>), and Atlantic salmon (AS)(<it>Salmo salar</it>) mapping panels.</p> <p>Results</p> <p>Clock1 duplicates mapped to linkage groups RT-8/-24, AC-16/-13 and AS-2/-18. Clock3/NPAS2-like genes mapped to RT-9/-20, AC-20/-43, and AS-5. Most of these linkage group regions containing the Clock gene duplicates were derived from the most recent 4R whole genome duplication event specific to the salmonids. These linkage groups contain quantitative trait loci (QTL) for life history and growth traits (i.e., reproduction and cell cycling). Comparative synteny analyses with other model teleost species reveal a high degree of conservation for genes in these chromosomal regions suggesting that functionally related or co-regulated genes are clustered in syntenic blocks. For example, anti-müllerian hormone (amh), regulating sexual maturation, and ornithine decarboxylase antizymes (oaz1 and oaz2), regulating cell cycling, are contained within these syntenic blocks.</p> <p>Conclusions</p> <p>Synteny analyses indicate that regions homologous to major life-history QTL regions in salmonids contain many candidate genes that are likely to influence reproduction and cell cycling. The order of these genes is highly conserved across the vertebrate species examined, and as such, these genes may make up a functional cluster of genes that are likely co-regulated. CLOCK, as a transcription factor, is found within this block and therefore has the potential to cis-regulate the processes influenced by these genes. Additionally, clock-controlled genes (CCGs) are located in other life-history QTL regions within salmonids suggesting that at least in part, trans-regulation of these QTL regions may also occur via Clock expression.</p

Hot or not: response inhibition reduces the hedonic value and motivational incentive of sexual stimuli.

The motivational incentive of reward-related stimuli can become so salient that it drives behavior at the cost of other needs. Here we show that response inhibition applied during a Go/No-go task not only impacts hedonic evaluations but also reduces the behavioral incentive of motivationally relevant stimuli. We first examined the impact of response inhibition on the hedonic value of sex stimuli associated with strong behavioral-approach responses (Experiment 1). Sexually appealing and non-appealing images were both rated as less attractive when previously encountered as No-go (inhibited) than as Go (non-inhibited) items. We then discovered that inhibition reduces the motivational incentive of sexual appealing stimuli (Experiment 2). Prior Go/No-go status affected the number of key-presses by heterosexual males to view erotic-female (sexually appealing) but not erotic-male or scrambled-control (non-appealing) images. These findings may provide a foundation for developing inhibition-based interventions to reduce the hedonic value and motivational incentive of stimuli associated with disorders of self-control

Cognitive-behavioral and electrophysiological evidence of the affective consequences of ignoring stimulus representations in working memory

Ignoring visual stimuli in the external environment leads to decreased liking of those items, a phenomenon attributed to the affective consequences of attentional inhibition. Here we investigated the generality of this “distractor devaluation” phenomenon by asking whether ignoring stimuli represented internally within visual working memory has the same affective consequences. In two experiments we presented participants with two or three visual stimuli and then, after the stimuli were no longer visible, provided an attentional cue indicating which item in memory was the target they would have to later recall, and which were task-irrelevant distractors. Participants subsequently judged how much they liked these stimuli. Previously-ignored distractors were consistently rated less favorably than targets, replicating prior findings of distractor devaluation. To gain converging evidence, in Experiment 2, we also examined the electrophysiological processes associated with devaluation by measuring individual differences in attention (N2pc) and working memory (CDA) event-related potentials following the attention cue. Larger amplitude of an N2pc-like component was associated with greater devaluation, suggesting that individuals displaying more effective selection of memory targets—an act aided by distractor inhibition—displayed greater levels of distractor devaluation. Individuals showing a larger post-cue CDA amplitude (but not pre-cue CDA amplitude) also showed greater distractor devaluation, supporting prior evidence that visual working-memory resources have a functional role in effecting devaluation. Together, these findings demonstrate that ignoring working-memory representations has affective consequences, and adds to the growing evidence that the contribution of selective-attention mechanisms to a wide range of human thoughts and behaviors leads to devaluation

The affective consequences of cognitive inhibition: devaluation or neutralization?

Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite effects for stimuli that were initially positive or negative in valence. We tested this hypothesis by presenting trustworthy and untrustworthy faces (Experiment 1), strongly positive and negative photographs (Experiment 2), and monetary gain- and loss-associated patterns (Experiment 3) in a Go/No-Go task and assessing subsequent affective ratings. Evaluations of prior No-Go (inhibited) stimuli were more negative than of prior Go (noninhibited) stimuli, regardless of a priori affective valence. Ratings of No-Go stimuli also became increasingly negative (vs. increasingly neutral) when preexisting salience was increased via stimulus repetition (Experiment 4). Our results suggest inhibition leads to affective devaluation, not affective neutralization

Cognitive-behavioral and electrophysiological evidence of the affective consequences of ignoring stimulus representations in working memory

Ignoring visual stimuli in the external environment leads to decreased liking of those items, a phenomenon attributed to the affective consequences of attentional inhibition. Here we investigated the generality of this “distractor devaluation” phenomenon by asking whether ignoring stimuli represented internally within visual working memory has the same affective consequences. In two experiments we presented participants with two or three visual stimuli and then, after the stimuli were no longer visible, provided an attentional cue indicating which item in memory was the target they would have to later recall, and which were task-irrelevant distractors. Participants subsequently judged how much they liked these stimuli. Previously-ignored distractors were consistently rated less favorably than targets, replicating prior findings of distractor devaluation. To gain converging evidence, in Experiment 2, we also examined the electrophysiological processes associated with devaluation by measuring individual differences in attention (N2pc) and working memory (CDA) event-related potentials following the attention cue. Larger amplitude of an N2pc-like component was associated with greater devaluation, suggesting that individuals displaying more effective selection of memory targets—an act aided by distractor inhibition—displayed greater levels of distractor devaluation. Individuals showing a larger post-cue CDA amplitude (but not pre-cue CDA amplitude) also showed greater distractor devaluation, supporting prior evidence that visual working-memory resources have a functional role in effecting devaluation. Together, these findings demonstrate that ignoring working-memory representations has affective consequences, and adds to the growing evidence that the contribution of selective-attention mechanisms to a wide range of human thoughts and behaviors leads to devaluation

The affective consequences of cognitive inhibition: devaluation or neutralization?

Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite effects for stimuli that were initially positive or negative in valence. We tested this hypothesis by presenting trustworthy and untrustworthy faces (Experiment 1), strongly positive and negative photographs (Experiment 2), and monetary gain- and loss-associated patterns (Experiment 3) in a Go/No-Go task and assessing subsequent affective ratings. Evaluations of prior No-Go (inhibited) stimuli were more negative than of prior Go (noninhibited) stimuli, regardless of a priori affective valence. Ratings of No-Go stimuli also became increasingly negative (vs. increasingly neutral) when preexisting salience was increased via stimulus repetition (Experiment 4). Our results suggest inhibition leads to affective devaluation, not affective neutralization

Manipulations of attention enhance self-regulation.

Successful goal-directed behavior requires self-regulation to override competing impulses. Emerging evidence suggests that attention may mediate such acts, but little is known about the specific operations through which attention might influence self-regulation. Here we test this often-implicit assumption by manipulating attention mechanisms in two ways: one controlling the inhibition of inappropriate responses; the other controlling the breadth of attention. Participants significantly improved their performance on a self-regulation task after practice on a response inhibition task (Experiment 1) and after the induction of a broad focus of attention in a visual discrimination task (Experiment 2). We propose that such manipulations enhance self-regulation by engaging mechanisms that enhance the salience of goal-related representations and reduce the activation of competing goal-irrelevant neural representations. By more efficiently resolving conflict among the signals vying to drive behavior, pre-engaging attention may also help to conserve resources needed for continued self-regulation