51 research outputs found

    Lysine 63-Polyubiquitination Guards against Translesion Synthesis–Induced Mutations

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    Eukaryotic cells possess several mechanisms to protect the integrity of their DNA against damage. These include cell-cycle checkpoints, DNA-repair pathways, and also a distinct DNA damage–tolerance system that allows recovery of replication forks blocked at sites of DNA damage. In both humans and yeast, lesion bypass and restart of DNA synthesis can occur through an error-prone pathway activated following mono-ubiquitination of proliferating cell nuclear antigen (PCNA), a protein found at sites of replication, and recruitment of specialized translesion synthesis polymerases. In yeast, there is evidence for a second, error-free, pathway that requires modification of PCNA with non-proteolytic lysine 63-linked polyubiquitin (K63-polyUb) chains. Here we demonstrate that formation of K63-polyUb chains protects human cells against translesion synthesis–induced mutations by promoting recovery of blocked replication forks through an alternative error-free mechanism. Furthermore, we show that polyubiquitination of PCNA occurs in UV-irradiated human cells. Our findings indicate that K63-polyubiquitination guards against environmental carcinogenesis and contributes to genomic stability

    Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

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    INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

    Developing a new national MDMA policy:Results of a multi-decision multi-criterion decision analysis

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    BACKGROUND: Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) has a relatively low harm and low dependence liability but is scheduled on List I of the Dutch Opium Act (‘hard drugs’). Concerns surrounding increasing MDMA-related criminality coupled with the possibly inappropriate scheduling of MDMA initiated a debate to revise the current Dutch ecstasy policy. METHODS: An interdisciplinary group of 18 experts on health, social harms and drug criminality and law enforcement reformulated the science-based Dutch MDMA policy using multi-decision multi-criterion decision analysis (MD-MCDA). The experts collectively formulated policy instruments and rated their effects on 25 outcome criteria, including health, criminality, law enforcement and financial issues, thematically grouped in six clusters. RESULTS: The experts scored the effect of 22 policy instruments, each with between two and seven different mutually exclusive options, on 25 outcome criteria. The optimal policy model was defined by the set of 22 policy instrument options which gave the highest overall score on the 25 outcome criteria. Implementation of the optimal policy model, including regulated MDMA sales, decreases health harms, MDMA-related organised crime and environmental damage, as well as increases state revenues and quality of MDMA products and user information. This model was slightly modified to increase its political feasibility. Sensitivity analyses showed that the outcomes of the current MD-MCDA are robust and independent of variability in weight values. CONCLUSION: The present results provide a feasible and realistic set of policy instrument options to revise the legislation towards a rational MDMA policy that is likely to reduce both adverse (public) health risks and MDMA-related criminal burden

    Candidate Glutamatergic Neurons in the Visual System of Drosophila

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    The visual system of Drosophila contains approximately 60,000 neurons that are organized in parallel, retinotopically arranged columns. A large number of these neurons have been characterized in great anatomical detail. However, studies providing direct evidence for synaptic signaling and the neurotransmitter used by individual neurons are relatively sparse. Here we present a first layout of neurons in the Drosophila visual system that likely release glutamate as their major neurotransmitter. We identified 33 different types of neurons of the lamina, medulla, lobula and lobula plate. Based on the previous Golgi-staining analysis, the identified neurons are further classified into 16 major subgroups representing lamina monopolar (L), transmedullary (Tm), transmedullary Y (TmY), Y, medulla intrinsic (Mi, Mt, Pm, Dm, Mi Am), bushy T (T), translobula plate (Tlp), lobula intrinsic (Lcn, Lt, Li), lobula plate tangential (LPTCs) and lobula plate intrinsic (LPi) cell types. In addition, we found 11 cell types that were not described by the previous Golgi analysis. This classification of candidate glutamatergic neurons fosters the future neurogenetic dissection of information processing in circuits of the fly visual system

    Use characteristics and harm potential of ecstasy in The Netherlands

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    Introduction: Ecstasy (MDMA) is a popular recreational drug, but its illegal production and trade in the Netherlands have developed into a serious public order and ecological problem which endanger and question the harm reduction approach of the Dutch ecstasy policy. Methods: The market characteristics, adverse health effects, risk profile, and link to criminal activity of ecstasy were reviewed. Results: Ecstasy is often used in combination with other substances (i.e. polydrug use). Compared to several other illicit drugs and alcohol, ecstasy has a very low abuse and dependence liability and, as yet, there is little evidence of long-term harm. A potential health risk associated with ecstasy is acute hyperthermia, however this occurs at an unknown incidence rate and seems to be more prevalent when ecstasy is consumed in combination with heavy exercise at high ambient temperatures or when used in combination with other substances, including alcohol. Organized crime related to the production and trafficking of ecstasy in the Netherlands is a growing problem. Conclusions: This review provides a science-based summary that can be used to assist the public and political debate surrounding future Dutch ecstasy policy to reduce ecstasy-related organized crime while maintaining the principle of harm reduction

    Alcohol- and drug-related public violence in Europe

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    This study summarizes the literature about alcohol- and drug-related public violence in Europe. The proportion of all public violent incidents linked to alcohol was about 50 percent in the UK and ranged from 26 percent to 43 percent in Germany, Austria and the Netherlands. Public violence related to drugs is much lower (1.5–18.0 percent). Relatively many public violent incidents occur in relation to nightlife (80 percent of alcohol-related incidents). Though a considerable proportion of public violence was alcohol or drug related, the actual use of such substances was rarely ascertained in perpetrators’ specimens. Such analysis is a prerequisite to heavier penalize alcohol- or drug-intoxicated perpetrators of public violence. More capacity should be deployed to measure alcohol and drugs in the specimens of violent perpetrators by analytical-chemical tests. As a result, more accurate estimates of substance-related public violence are obtained, which will serve policy makers and police enforcement officials to take measures for securing a safer public environment and sustainable nightlife industry in the futur

    Associations between psychoactive substance use and sensation seeking behavior among drivers in Norway

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    Background/aim Drug use and risky driving is associated with sensation seeking. The aim of this study was to investigate the association between use of psychoactive substances and levels of the sensation seeking personality trait as measured with the Brief Sensation Seeking Scale 4 among drivers in Norway. Method A cross-sectional design was applied to estimate the association between psychoactive substance use and sensation seeking behavior. Drivers in normal traffic were included in two roadside surveys: one in the north (September 2014 – October 2015) and the other in the south-east of Norway (April 2016 – April 2017). Oral fluid was analyzed for alcohol and psychoactive drugs, and data on sex, age and time of participation were recorded. Participants filled in the Brief Sensation Seeking Scale 4 questionnaire. Results A total of 8053 drivers were included, of which 32% were women and 62% were under 40 years. The prevalence of alcohol was 0.3%, stimulants 0.6%, tetrahydrocannabinol 1.4%, benzodiazepines and/or z-hypnotics 2.0% and polydrug use 0.6%. Associations were found between the use of tetrahydrocannabinol or benzodiazepines and/or z-hypnotics and a low score on the “thrill and adventure seeking” domain of the Brief Sensation Seeking Scale 4 (OR = 1.723, 95% C.I. = 1.001–2.966). Associations were also found between the use of stimulants and the highest scores on the “experience seeking” (OR = 2.085, 95% C.I. = 1.084–4.009) and “disinhibition” (OR = 4.791, 95% C.I. =1.748–13.135) domains of the Brief Sensation Seeking Scale 4. No associations were found between sensation seeking behavior and alcohol or polydrug use. Conclusion A high degree of sensation seeking was found among drivers who had used stimulating drugs, in contrast to drives who had used tetrahydrocannabinol and benzodiazepines and/or z-hypnotics who showed a low degree of sensation seeking. The combination of sensation seeking behavior and the use of stimulants might lead to increased risky behavior and thus traffic crashes

    False Memories in the Field: Impact of Substance Intoxication and Sleep Restriction on False Memory Formation

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    We conducted a field study at a music festival to examine effects of naturally occurring sleep deficits and substance intoxication on false memory formation and susceptibility to suggestion, using two paradigms. In a misinformation task, sleep restriction was associated with increased levels of susceptibility to suggestion and false alarms to nonsuggestive questions for a virtual reality eyewitness scenario. Use of tetrahydrocannabinol and amphetamines was also related to increased false alarms to nonsuggestive questions, indicating that such questions might be sensitive to use of those drugs. In an implantation paradigm, neither sleep restriction, substances, nor exposure to fake social media content increased the likelihood of falsely believing or recollecting a purportedly experienced festival event. However, some people came to falsely believe (13%, n = 30) or falsely remember (6%, n = 14) the false suggested event. Findings indicate that some established lab effects can also be observed in a less controlled environment
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