Tackling Anti-Social Behaviour: A Critical Review

Over the past decade, anti-social behaviour (henceforth referred to as ASB) has become a focus of much policy-making and debate within central and local government and the police. Clear definitions of ASB are lacking, but the term is usually understood to refer to relatively minor criminal activity and non-criminal ‘nuisance’ behaviour that affects the social and/or physical environment of public or semi-public places. The term ASB is frequently used synonymously with ‘disorder’, and is sometimes associated with the concept of ‘incivilities’. Policy-makers and strategists, at national and local levels alike, reiterate that problems of ASB can have a massively detrimental effect on neighbourhoods as a whole, and on the lives of individuals. Hence strenuous and wide-ranging efforts are being made to support, develop and implement schemes for tackling ASB – involving a variety of enforcement and preventive measures

Letter, 1960 March 21, from Millie A. Hynson to Eva Jessye

2 pages, Hynson is a song writer

An automated attentional set-shifting task in HAP, LAP, and alcohol-exposed cHAP mice

Indiana University-Purdue University Indianapolis (IUPUI)Alcoholics often experience difficulties ceasing drinking, potentially related to excessive behavioral inflexibility that either precedes or results from high alcohol consumption. Components of the Wisconsin Card-Sorting Task (WCST) a type of Attentional Set-Shifting (AttSS) task measuring impairments in behavioral flexibility have been modified to measure similar constructs within animals. Previous work has shown impaired AttSS in abstinent alcoholics and nonalcoholic individuals with a family history of alcoholism, as well as in mice exposed to chronic-intermittent alcohol vapor (Gierski et al., 2013; Hu et al., 2015; Oscar-Berman et al., 2009). The aim of the current study was to assess whether selectively-bred High- vs. Low- Alcohol Preferring (HAP vs LAP) mice display behavioral inflexibility as measured by an operant AttSS task, and furthermore, whether a history of voluntary drinking in cross-bred HAP (cHAP) mice further increases inflexibility. Impairments in the AttSS task are assessed by evaluating the number of trials to reach criterion, as well as the number and types of errors committed during the second experimental phase. In Experiment 1, male and female HAP and LAP mice first learned to press one of two levers signaled by a visual cue, but random with respect to spatial orientation, for a 0.1% saccharin solution reward. The following experimental phase consisted of an egocentric discrimination, such that side (left or right) now signaled correct reinforcement and the location of the visual cue was irrelevant. In Experiment 2, prior to identical operant procedures as Experiment 1, male and female cHAP mice were given free-choice access to 10% alcohol or water for seven weeks. Ethanol-exposed animals drank an average of 29.6 g/kg/day

Examining Simultaneous Alcohol and ∆9-Tetrahydrocannabinol Self-Administration on Behavioral Flexibility and Dorsal Striatal CB1 Expression in cHAP Mice

Indiana University-Purdue University Indianapolis (IUPUI)Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug-exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use

Innate and Acquired Quinine‐Resistant Alcohol, but not Saccharin, Drinking in Crossed High–Alcohol‐Preferring Mice

Background Alcohol consumption despite aversive consequences is often a key component of an alcoholism diagnosis. Free‐choice alcohol consumption despite bitter quinine adulteration in rodents has been seen following several months of free‐choice drinking, but there has been little study of whether prolonged access to other palatable substances such as saccharin yields quinine resistance. Selectively bred crossed high–alcohol‐preferring (cHAP) mice average blood alcohol levels of over 250 mg/dl during free‐choice access, considerably higher than other models. We hypothesized that higher intakes would yield more rapid development of quinine‐resistant alcohol (QRA) drinking and quinine‐resistant saccharin (QRS) drinking. Methods All experiments used male and female cHAP mice. Experiment 1 compared mice with either 0 or 5 weeks of alcohol drinking history, testing varying (0.032, 0.10, 0.32 g/l) quinine concentrations in ethanol. Experiment 2 examined whether innate QR may exist, comparing animals with a 1 or zero day of drinking history. Experiment 3 examined the effect of varying histories (0, 2, or 5 weeks) of free‐choice 10% alcohol drinking on QR alcohol consumption at high quinine concentrations. Finally, Experiment 4 investigated the development of QRS drinking. Results We found that we could not detect a history effect in commonly used quinine concentrations, indicating that cHAP mice are innately quinine resistant to 0.10 g/l quinine. However, we were able to determine that a 2‐week drinking history was sufficient to induce QRA drinking in cHAP mice at extremely high quinine concentrations (0.74 and 0.32 g/l). However, the history effect was specific to QRA, a saccharin drinking history, did not yield QRS drinking. Conclusions These data suggest that an alcohol drinking history induces maladaptive behaviors, such as drinking in spite of negative consequences, a pattern not seen with saccharin. Furthermore, a strong genetic predisposition to drink may promote an innate aversion resistance compared with commonly used inbred strains

Snapshots of an evolved DNA polymerase pre- and post-incorporation of an unnatural nucleotide

The next challenge in synthetic biology is to be able to replicate synthetic nucleic acid sequences efficiently. The synthetic pair, 2-amino-8-(1-beta-d-2'- deoxyribofuranosyl) imidazo [1,2-a]-1,3,5-triazin-[8H]-4-one (trivially designated P) with 6-amino-3-(2'-deoxyribofuranosyl)-5-nitro-1H-pyridin-2-one (trivially designated Z), is replicated by certain Family A polymerases, albeit with lower efficiency. Through directed evolution, we identified a variant KlenTaq polymerase (M444V, P527A, D551E, E832V) that incorporates dZTP opposite P more efficiently than the wild-type enzyme. Here, we report two crystal structures of this variant KlenTaq, a post-incorporation complex that includes a template-primer with P:Z trapped in the active site (binary complex) and a pre-incorporation complex with dZTP paired to template P in the active site (ternary complex). In forming the ternary complex, the fingers domain exhibits a larger closure angle than in natural complexes but engages the template-primer and incoming dNTP through similar interactions. In the binary complex, although many of the interactions found in the natural complexes are retained, there is increased relative motion of the thumb domain. Collectively, our analyses suggest that it is the post-incorporation complex for unnatural substrates that presents a challenge to the natural enzyme and that more efficient replication of P:Z pairs requires a more flexible polymerase

Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Damned if they do, damned if they don't: negotiating the tricky context of anti-social behaviour and keeping safe in disadvantaged urban neighbourhoods

Young people's relationship with anti-social behaviour (ASB) is complicated. While their behaviours are often stereotyped as anti-social (e.g. ‘hanging about’), they also experience ASB in their neighbourhood. In this study, we explore young people's own perspectives on ASB, comparing results from ‘go-along’ interviews and focus groups conducted in disadvantaged neighbourhoods in Glasgow, Scotland. This article discusses how young people's everyday experience of ASB was contextualised by social factors such as cultural stereotyping of marginalised groups, poor social connectivity and spatial marginalisation within their neighbourhood. Furthermore, we found that these social factors were mutually reinforcing and interacted in a way that appeared to leave young people in a ‘no-win’ situation regarding their association with ASB. Participation in ASB and attempts to avoid such involvement were seen to involve negative consequences: participation could entail violence and spatial restrictions linked to territoriality, but avoidance could lead to being ostracised from their peer group. Regardless of involvement, young people felt that adults stereotyped them as anti-social. Our findings therefore provide support for policies and interventions aimed at reducing ASB (perpetrated by residents of all ages); in part by better ensuring that young people have a clear incentive for avoiding such behaviours