Structure-function investigation of 3-methylaspartate ammonia lyase reveals substrate molecular determinants for the deamination reaction

The enzymatic reactions leading to the deamination of β-lysine, lysine, or 2-aminoadipic acid are of great interest for the metabolic conversion of lysine to adipic acid. Enzymes able to carry out these reactions are not known, however ammonia lyases (EC 4.3.1.-) perform deamination on a wide range of substrates. We have studied 3-methylaspartate ammonia lyase (MAL, EC 4.3.1.2) as a potential candidate for protein engineering to enable deamination towards β-lysine, that we have shown to be a competitive inhibitor of MAL. We have characterized MAL activity, binding and inhibition properties on six different compounds that would allow to define the molecular determinants necessary for MAL to deaminate our substrate of interest. Docking calculations showed that β-lysine as well as the other compounds investigated could fit spatially into MAL catalytic pocket, although they probably are weak or very transient binders and we identified molecular determinants involved in the binding of the substrate. The hydrophobic interactions formed by the methyl group of 3-methylaspartic acid, together with the presence of the amino group on carbon 2, play an essential role in the appropriate binding of the substrate. The results showed that β-lysine is able to fit and bind in MAL catalytic pocket and can be potentially converted from inhibitor to substrate of MAL upon enzyme engineering. The characterization of the binding and inhibition properties of the substrates tested here provide the foundation for future and more extensive studies on engineering MAL that could lead to a MAL variant able to catalyse this challenging deamination reaction

Association of alcohol control policies with adolescent alcohol consumption and with social inequality in adolescent alcohol consumption : a multilevel study in 33 countries and regions

Funding: The Health Behaviour in School-aged Children (HBSC) is an international study carried out in collaboration with WHO Europe. This research is funded by public sources in each member country. Specifically, ELL, CMM, and ISQ are supported by the Ministry de Health, Spain. CMM is supported by the VI Plan Propiode Investigación de la Universidad de Sevilla 2018, under the action “II.5B Contrato de acceso al Sistema Españolde Ciencia, Tecnología e Innovación para el Desarrollo del Programa Propio de I + D + i de la Universidad de Sevilla”. JI is supported by the UK Medical Research Council (MC_UU_12017/12) and the Chief Scientist Office (SPHSU12).Background  Previous research found inconsistent associations between alcohol control policies and socioeconomic inequality with adolescent drinking outcomes. This study expands the focus beyond individual associations to examine whether a combination of policies is related to socioeconomic inequality in adolescent drinking outcomes and whether this relationship varies across survey years. Methods  Multilevel modelling of 4 waves of repeat cross-sectional survey data (2001/02, 2005/06, 2009/10, and 2013/14) from the Health Behaviour in School-aged Children (HBSC) study was carried out. The sample was composed of 671,084 adolescents (51% girls) aged 11, 13, and 15 (mean age=13.58; SD=1.65) from 33 European and North American countries/regions. The dependent variables were lifetime alcohol consumption, weekly alcohol consumption, and lifetime drunkenness. Independent variables were of three types: individual-level variables (age, sex, Family Affluence Scale, and the Perceived Family Wealth), time-level variable (survey year), and context-level variables (minimum legal drinking age, physical availability, advertising restrictions, a total alcohol policy index, and affordability of alcohol). Results  The total alcohol policy index showed a negative relationship with both lifetime and weekly consumption. Higher affordability of alcohol was related to higher lifetime and weekly consumption and higher lifetime drunkenness. Family Affluence Scale was positively related to all three alcohol measures and Perceived Family Wealth was negatively related to lifetime drunkenness, with these associations increasing across survey years. The total alcohol policy index buffered the associations of Family Affluence Scale and Perceived Family Wealth with adolescent drinking outcomes. Conclusion  A combination of alcohol control policies is more effective in reducing adolescent drinking outcomes than single policy measures. Reducing the affordability of alcohol stood out as the most successful single measure. Socioeconomic inequalities (i.e. higher alcohol consumption and drunkenness in adolescents with higher family affluence and higher drunkenness in adolescents perceiving their families to be poor) have persisted and even increased across survey years. A combined alcohol control policy can help in tackling them.PostprintPublisher PDFPeer reviewe

Drug use and nightlife: more than just dance music

<p>Abstract</p> <p>Background</p> <p>Research over the last decade has focused almost exclusively on the association between electronic music and MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") or other stimulant drug use in clubs. Less attention has been given to other nightlife venues and music preferences, such as rock music or southern/funky music. This study aims to examine a broader spectrum of nightlife, beyond dance music. It looks at whether certain factors influence the frequency of illegal drug and alcohol use: the frequency of going to certain nightlife venues in the previous month (such as, pubs, clubs or goa parties); listening to rock music, dance music or southern and funky music; or sampling venues (such as, clubs, dance events or rock festivals). The question of how these nightlife variables influence the use of popular drugs like alcohol, MDMA, cannabis, cocaine and amphetamines is addressed.</p> <p>Methods</p> <p>The study sample consisted of 775 visitors of dance events, clubs and rock festivals in Belgium. Study participants answered a survey on patterns of going out, music preferences and drug use. Odds ratios were used to determine whether the odds of being an illegal substance user are higher for certain nightlife-related variables. Furthermore, five separate ordinal regression analyses were used to investigate drug use in relation to music preference, venues visited during the last month and sampling venue.</p> <p>Results</p> <p>Respondents who used illegal drugs were 2.5 times more likely to report that they prefer dance music. Goa party visitors were nearly 5 times more likely to use illegal drugs. For those who reported visiting clubs, the odds of using illegal drugs were nearly 2 times higher. Having gone to a pub in the last month was associated with both more frequent alcohol use and more frequent illegal substance use. People who reported liking rock music and attendees of rock festivals used drugs less frequently.</p> <p>Conclusions</p> <p>It was concluded that a more extended recreational environment, beyond dance clubs, is associated with frequent drug use. This stresses the importance of targeted prevention in various recreational venues tailored to the specific needs of the setting and its visitors.</p

Drug Use Changes at the Individual Level: Results from a Longitudinal, Multisite Survey in Young Europeans Frequenting the Nightlife Scene

Background: Monitoring emerging trends in the increasingly dynamic European drug market is vital; however, information on change at the individual level is scarce. In the current study, we investigated changes in drug use over 12 months in European nightlife attendees. / Method: In this longitudinal online survey, changes in substances used, use frequency in continued users, and relative initiation of use at follow-up were assessed for 20 different substances. To take part, participants had to be aged 18–34 years; be from Belgium, Italy, the Netherlands, Sweden, or the UK; and have attended at least 6 electronic music events in the past 12 months at baseline. Of 8,045 volunteers at baseline, 2,897 completed the survey at both time points (36% follow-up rate), in 2017 and 2018. / Results: The number of people using ketamine increased by 21% (p < 0.001), and logarithmized frequency of use in those continuing use increased by 15% (p < 0.001; 95% CI: 0.07–0.23). 4-Fluoroamphetamine use decreased by 27% (p < 0.001), and logarithmized frequency of use in continuing users decreased by 15% (p < 0.001, 95% CI: −0.48 to −0.23). The drugs with the greatest proportion of relative initiation at follow-up were synthetic cannabinoids (73%, N = 30), mephedrone (44%, N = 18), alkyl nitrites (42%, N = 147), synthetic dissociatives (41%, N = 15), and prescription opioids (40%, N = 48). / Conclusions: In this European nightlife sample, ketamine was found to have the biggest increase in the past 12 months, which occurred alongside an increase in frequency of use in continuing users. The patterns of uptake and discontinuation of alkyl nitrates, novel psychoactive substances, and prescription opioids provide new information that has not been captured by existing cross-sectional surveys. These findings demonstrate the importance of longitudinal assessments of drug use and highlight the dynamic nature of the European drug landscape

Naar een integraal alcoholbeleid in België

The omnipresence and social acceptance of alcohol in Belgium in many cases masks the harmful effects of alcohol. In order to reduce the negative consequences of harmful alcohol consumption, much research has been done in recent years into the effectiveness of possible policy measures. Despite the recommendations of these studies and of several health organizations, there is still no national alcohol policy plan in force in Belgium. Measures in the areas of prevention, care, price, supply and marketing are necessary to effectively reduce the harmful effects of alcohol.De alomtegenwoordigheid en sociale aanvaarding van alcohol in België verbloemt in vele gevallen de schadelijke gevolgen die alcohol heeft. Om die gevolgen te reduceren, is er de afgelopen jaar veel onderzoek gedaan naar de effectiviteit van mogelijke overheidsmaatregelen. Onder andere de Wereldgezondheidsorganisatie adviseert landen over effectieve beleidsmaatregelen op basis van wetenschappelijke inzichten. Ondanks de aanbevelingen van de Wereldgezondheidsorganisatie en uit wetenschappelijke onderzoeken is er in België nog altijd geen sprake van een nationaal alcoholbeleidsplan waarin deze maatregelen integraal zijn opgenomen. Maatregelen op het vlak van preventie, hulpverlening, prijs, aanbod en marketing zijn noodzakelijk om de schadelijke gevolgen van alcohol effectief te reduceren

Drug use changes at the individual level : Results from a longitudinal, multisite survey in young europeans frequenting the nightlife scene

Background: Monitoring emerging trends in the increasingly dynamic European drug market is vital; however, information on change at the individual level is scarce. In the current study, we investigated changes in drug use over 12 months in European nightlife attendees. Method: In this longitudinal online survey, changes in substances used, use frequency in continued users, and relative initiation of use at follow-up were assessed for 20 different substances. To take part, participants had to be aged 18–34 years; be from Belgium, Italy, the Netherlands, Sweden, or the UK; and have attended at least 6 electronic music events in the past 12 months at baseline. Of 8,045 volunteers at baseline, 2,897 completed the survey at both time points (36% follow-up rate), in 2017 and 2018. Results: The number of people using ketamine increased by 21% (p < 0.001), and logarithmized frequency of use in those continuing use increased by 15% (p < 0.001; 95% CI: 0.07–0.23). 4-Fluoroamphetamine use decreased by 27% (p < 0.001), and logarithmized frequency of use in continuing users decreased by 15% (p < 0.001, 95% CI: −0.48 to −0.23). The drugs with the greatest proportion of relative initiation at follow-up were synthetic cannabinoids (73%, N = 30), mephedrone (44%, N = 18), alkyl nitrites (42%, N = 147), synthetic dissociatives (41%, N = 15), and prescription opioids (40%, N = 48). Conclusions: In this European nightlife sample, ketamine was found to have the biggest increase in the past 12 months, which occurred alongside an increase in frequency of use in continuing users. The patterns of uptake and discontinuation of alkyl nitrates, novel psychoactive substances, and prescription opioids provide new information that has not been captured by existing cross-sectional surveys. These findings demonstrate the importance of longitudinal assessments of drug use and highlight the dynamic nature of the European drug landscape

Drug use and nightlife: more than just dance music

<p>Abstract</p> <p>Background</p> <p>Research over the last decade has focused almost exclusively on the association between electronic music and MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") or other stimulant drug use in clubs. Less attention has been given to other nightlife venues and music preferences, such as rock music or southern/funky music. This study aims to examine a broader spectrum of nightlife, beyond dance music. It looks at whether certain factors influence the frequency of illegal drug and alcohol use: the frequency of going to certain nightlife venues in the previous month (such as, pubs, clubs or goa parties); listening to rock music, dance music or southern and funky music; or sampling venues (such as, clubs, dance events or rock festivals). The question of how these nightlife variables influence the use of popular drugs like alcohol, MDMA, cannabis, cocaine and amphetamines is addressed.</p> <p>Methods</p> <p>The study sample consisted of 775 visitors of dance events, clubs and rock festivals in Belgium. Study participants answered a survey on patterns of going out, music preferences and drug use. Odds ratios were used to determine whether the odds of being an illegal substance user are higher for certain nightlife-related variables. Furthermore, five separate ordinal regression analyses were used to investigate drug use in relation to music preference, venues visited during the last month and sampling venue.</p> <p>Results</p> <p>Respondents who used illegal drugs were 2.5 times more likely to report that they prefer dance music. Goa party visitors were nearly 5 times more likely to use illegal drugs. For those who reported visiting clubs, the odds of using illegal drugs were nearly 2 times higher. Having gone to a pub in the last month was associated with both more frequent alcohol use and more frequent illegal substance use. People who reported liking rock music and attendees of rock festivals used drugs less frequently.</p> <p>Conclusions</p> <p>It was concluded that a more extended recreational environment, beyond dance clubs, is associated with frequent drug use. This stresses the importance of targeted prevention in various recreational venues tailored to the specific needs of the setting and its visitors.</p