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Cybercrime is a growing problem, with increasing numbers of people reporting they have been a victim. However, the literature has tended to focus on the characteristics of the perpetrator and has often neglected to examine how the individual differences of victims may have an impact. This paper investigates how the Dark Triad - Machiavellianism, narcissism, and psychopathy - may increase the chances of being a victim of online crime. To do this, the Cyber Routine Activities Theory was applied, which suggests victimization is a result of two things: 1) a user's routine online activity which may bring them into contact with nefarious others and/or makes them an attractive target, and 2) the lack of a "capable guardian" who can defend against such nefarious others. Using an online survey ( N  = 328), we measured Internet users' Dark Triad traits, along with their engagement in various online activities and the preventative measures used against potential criminals. Findings demonstrated that narcissism and psychopathy increased the likelihood of victimization, but Machiavellianism did not. These relationships were moderated by gender. However, contrary to other work using the Cyber-RAT, preventative measures (e.g. knowledge of computers, presence of anti-virus programs) did not seem to impact on the likelihood of victimization. The challenges of using these findings to reduce cybercrime and future work are then discussed.

The profession of religion gives rise to myriad inferences and connotations, yet surprisingly little research has examined how it may influence with whom we choose to work. Two experiments conducted at a UK university investigated how religiosity by prospective collaborators affected attitudes and behaviour towards them. Participants in experiment 1 ( N  = 96) and experiment 2 ( N  = 120) demonstrated that individuals have a greater preference for, and are more likely to choose, a partner who shares their religious tendencies, but only when they anticipate working face-to-face. When electronic communication was anticipated, this bias disappeared. The implications for these findings are then discussed, particularly with regard to how they may impact on real-life issues such as online recruitment.

The two major endocannabinoid transmitters, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are degraded by distinct enzymes in the nervous system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. FAAH and MAGL inhibitors cause elevations in brain AEA and 2-AG levels, respectively, and reduce pain, anxiety, and depression in rodents without causing the full spectrum of psychotropic behavioral effects observed with direct cannabinoid receptor-1 (CB1) agonists. These findings have inspired the development of several classes of endocannabinoid hydrolase inhibitors, most of which have been optimized to show specificity for either FAAH or MAGL or, in certain cases, equipotent activity for both enzymes. Here, we investigate an unusual class of O-hydroxyacetamide carbamate inhibitors and find that individual compounds from this class can serve as selective FAAH or dual FAAH/MAGL inhibitors in vivo across a dose range (0.125-12.5 mg kg(-1)) suitable for behavioral studies. Competitive and click chemistry activity-based protein profiling confirmed that the O-hydroxyacetamide carbamate SA-57 is remarkably selective for FAAH and MAGL in vivo, targeting only one other enzyme in brain, the additional 2-AG hydrolase ABHD6. These data designate O-hydroxyacetamide carbamates as a versatile chemotype for creating endocannabinoid hydrolase inhibitors that display excellent in vivo activity and tunable selectivity for FAAH-anandamide versus MAGL (and ABHD6)-2-AG pathways.

Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.

The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.

Introduction: The amyloid precursor protein is first cleaved by β-secretase to generate a 99-residue membrane-bound CTF (C99 or β-CTF), which is subsequently cleaved by γ-secretase to generate amyloid β (Aβ) peptides and the APP intracellular domain. The amyloidogenic Aβ42 has attracted considerable attention because it is thought to be the most pathogenic species associated with Alzheimer's disease progression. New classes of compounds, called γ-secretase modulators (GSMs), have been shown to selectively lower Aβ42 production without shutting down key γ-secretase-dependent signaling pathways. This has become an important therapeutic strategy aimed at modulating Aβ production., Areas Covered: The progress on the clinical development of γ-secretase inhibitors is briefly covered in this review, followed by a discussion of the potential differentiating attributes of GSMs. Then, the patent literature covering novel GSMs is reviewed, focusing on patents from 2008 to 2010., Expert Opinion: Much progress has been made in the past 2 years on developing GSMs with improved potency for lowering the production of Aβ42. However, many of these chemotypes are in a challenging chemical space and generally possess higher lipophilicity than most CNS drugs. It will be important to gain a better understanding of the specific target(s) that these GSMs interact with in order to facilitate future drug design efforts.

According to the strength model, self-control is a finite resource that determines capacity for effortful control over dominant responses and, once expended, leads to impaired self-control task performance, known as ego depletion. A meta-analysis of 83 studies tested the effect of ego depletion on task performance and related outcomes, alternative explanations and moderators of the effect, and additional strength model hypotheses. Results revealed a significant effect of ego depletion on self-control task performance. Significant effect sizes were found for ego depletion on effort, perceived difficulty, negative affect, subjective fatigue, and blood glucose levels. Small, nonsignificant effects were found for positive affect and self-efficacy. Moderator analyses indicated minimal variation in the effect across sphere of depleting and dependent task, frequently used depleting and dependent tasks, presentation of tasks as single or separate experiments, type of dependent measure and control condition task, and source laboratory. The effect size was moderated by depleting task duration, task presentation by the same or different experimenters, intertask interim period, dependent task complexity, and use of dependent tasks in the choice and volition and cognitive spheres. Motivational incentives, training on self-control tasks, and glucose supplementation promoted better self-control in ego-depleted samples. Expecting further acts of self-control exacerbated the effect. Findings provide preliminary support for the ego-depletion effect and strength model hypotheses. Support for motivation and fatigue as alternative explanations for ego depletion indicate a need to integrate the strength model with other theories. Findings provide impetus for future investigation testing additional hypotheses and mechanisms of the ego-depletion effect.

The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.

Studies of reputation use in social interactions have indicated that when individuals can acquire a positive or negative reputation, they are motivated to act in a cooperative fashion. However, few researchers have examined how the opportunity to confer this reputation on a partner may influence an individual's behavior in a mixed-motive situation. In the present study, an experiment using a trust-game paradigm indicated that participants felt that they had more control over their partner's reputation when they could leave feedback regarding the outcome of their interaction with their partner. However, the participants would only donate a substantial portion of their initial endowment (i.e., over 50%) when they could leave feedback for a partner and when they felt that their partner was concerned about his or her own reputation. The author discusses these findings in regard to how they might apply to real-world reputation use and how possible future studies may further expand knowledge in this area.

Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.

Three studies explore mental processes underlying spontaneous trait inferences about self-informants and the spontaneous trait transference characterizing third-party informants. Process differences are suggested in that instructions prompting a nontrait inference (truth or lie?) reduce self-informant trait-savings effects and lower self-informant trait judgments. For third-party informants, such instructions have no effect on these outcome variables. Results of a third study are inconsistent with cognitive load as an explanation for these effects. Taken together, these results indicate that inferences, and not merely associations, spontaneously form when processing information about self-informants. The results also show that the inferences and judgments that occur in spontaneous trait transference are not caused by the misidentification of third-party informants as self-informants.

Longitudinally sliced embryonic axes from pea and lentil mature seeds cocultivated with A. tumefaciens carrying a gus reporter gene in its T-DNA provided a convenient means to evaluate the efficiency of gene transfer to tissues in different cultivars and cocultivation conditions. Use of this technique demonstrated wide variation in susceptibility to Agrobacterium among several pea and lentil commercial genotypes.

There is potential to accelerate cultivar development with a doubled haploid system for breeding line production. Anther culture methodology was evaluated for U.S.A. spring barley (Hordeum vulgare L.) breeding applications. Gelrite was found to be an acceptable replacement for ficoll in the induction medium to reduce costs while maintaining embryoid and plant production levels. Beneficial effects of 28 d cold pretreatment of donor spikes for anther culture were confirmed with Pacific Northwest USA barley genotypes. A 3 d mannitol solution pretreatment of fresh anthers was shown to be less effective for green plant production compared to 28 d cold pretreatment of donor spikes. Extended donor spike cold pretreatment from 28 to 42 d did not reduce anther culture productivity. Based on this research, anther culture techniques show promise for economical and convenient application in spring barley breeding.