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To conduct a large-scale national cohort study to identify the current etiological risk factors for problem gambling in Canada.A cohort of 10,119 Canadian gamblers completed a comprehensive self-administered online questionnaire in 2018 and were reassessed in 2019. At baseline, the sample contained 1,388 at-risk gamblers, 1,346 problem gamblers, and 2,710 with a major DSM-5 mental health disorder. A total of 108 independent variables (IVs) were available for analysis, as well as the self-report of perceived causes of gambling-related problems for 1,261 individuals.The strongest multivariate predictors of current and future problem gambling were "gambling-related" variables (i.e., current and past problem gambling, intensive gambling involvement, playing electronic gambling machines (EGMs), gambling fallacies, socializing with other people having gambling-related problems, and family history of having gambling-related problems). Beyond gambling-related variables, greater impulsivity and lower household income were robustly predictive. Thirteen additional variables were either concurrently or prospectively predictive, but not both. In contrast to the many different quantitative predictors, self-reported causes tended to be singular and psychologically oriented (i.e., desire to win money, boredom, stress, poor self-control).The predictors of problematic gambling in the present study are very similar to the predictors identified in prior international longitudinal and cross-sectional research. This implies core cross-cultural risk factors, with gambling-related variables and impulsivity being most important, and comorbidities and demographic variables having more modest contributions. The additional value of the present results is that they comprehensively identify the relative importance of all known etiologically relevant variables within a current Canadian context. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Microglia are crucial players in the pathogenesis of late onset Alzheimer’s Disease (AD), with evidence for both deleterious and beneficial effects. Identifying interventions to modulate microglial responsiveness, to promote Amyloid β (Aβ) clearance, disrupt plaque formation or to dampen excessive inflammation has therapeutic potential. Bioavailable flavonoids such as the flavan 3-ols are of interest due to their antioxidant, metal chelating, signalling and anti-inflammatory potential. Primary microglia were treated with a series of structurally related flavanol 3-ols to assess effects on phagocytosis, cytokine release and transcriptional responses by RNA sequencing. Data indicated that the extent of hydroxylation and the presence of the galloyl moiety were strong determinants of flavan 3-ol activity. Epigallocatechin gallate (EGCG) was the most effective flavan-3-ol tested and strongly inhibited phagocytosis of Aβ independent of any metal chelating properties suggesting a more direct modulation of microglia responsiveness. EGCG was broadly anti-inflammatory, reducing cytokine release and downregulating transcription particularly of components of the microglia extracellular matrix such as MMP3 and SerpinB2. Collectively this brings new insight into the actions of flavonoids on microglial responsiveness with potential implications for the therapeutic use of EGCG and structurally related flavanol-3-ols in AD.

Objective: The relationship between the level of gambling fallacy endorsement and type of gambler (nongambler, recreational gambler, at-risk gambler, and problem/pathological gambler) was assessed both concurrently and prospectively in a large national cohort of Canadian adults. Method: This cohort (n = 10,199 at baseline; 18-24 years, n = 481, 43% female; 25-34 years, n = 1,335, 62% female; 35-44 years, n = 1,543, 55% female, 45-54 years, n = 1,985, 58% female; 55-64 years, n = 2,459, 55% female; 65-74 years, n = 1,865, 44% female, 75+ years, n = 531, 43% female) was recruited from LEO, Leger Opinion's registered online panelists. The follow-up survey was completed by 55.9% of the cohort, 1 year after baseline. The full survey can be viewed at https://www.ucalgary.ca/research/national-gambling-study/. For the current study, scores on the Gambling Fallacies Measure, the Problem and Pathological Gambling Measure, Gambling Participation Instrument, and Impulsivity were analyzed. Results: There were three main findings. The first is that gambling fallacies are common in all categories of gamblers but somewhat more prevalent in problem and pathological gamblers. Second, the multivariate analysis determined that gambling fallacies are significant concurrent and prospective predictors of the problem/pathological gambling category, but not strong predictors relative to other variables. Third, problem gambling and heavier gambling involvement are also predictors of a future higher level of gambling fallacies. Conclusions: Collectively, these results show that gambling fallacies have some etiological relationship to problem gambling but are not the main cause of problem gambling and should not be the exclusive focus of problem gambling treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The current study investigated the impact of the COVID pandemic lockdown on gambling and problem gambling in Canada. The AGRI National Project's online panel participants (N = 3449) provided baseline gambling data 6 months prior to the pandemic. Re-surveying this sample during the lockdown provided an opportunity to make quantitative comparisons of the changes. Nearly one-third of gamblers reported ceasing gambling altogether during the lockdown. For the continuing gamblers, quantitative data indicated significant decreases in gambling frequency, time spent in gambling sessions, money spent, and the number of game types played. Qualitative perceptions of changes in gambling were examined and the accuracy of these reports were not closely aligned with actual changes in gambling. Gambling platform was the only gambling engagement metric where increases were found with ~ 17% of the gambling sample migrating to online gambling during the lockdown. Although problem gambling within the sample generally declined, consistent with previous literature, it was also found that gambling online-among other biopsychosocial factors-was a significant predictor for classification as a problem gambler during the lockdown. COVID-specific influences on health, employment, leisure time and social isolation were moderately associated with problem gambling scores but were not independent predictors of changes in gambling engagement during lockdown. Future studies are required to assess if the pandemic related changes in gambling evidenced in this study remain stable, or if engagement reverts to pre-pandemic levels when the pandemic response allows for the re-opening of land-based gambling venues.

This study analyzed the Responsible Gambling Check patron survey data from Canadian casinos and racinos collected from 2011-2019 (18,580 patrons and 75 venues). The results indicated increasing awareness and use over time of harm minimization tools among more frequent patrons. Despite these promising trends, it is concerning that a substantial percentage of gamblers are still unaware of the harm minimization tools available. Further, the actual impact of this awareness on responsible gambling behaviour is largely unknown. We suggest greater efforts are needed nation-wide to promote the awareness, utilization, and evaluation of these harm minimization tools.

Fishes represent an important natural resource and yet their diversity and function in dynamic estuaries with relatively high levels of human pressure such as Sydney Harbour have rarely been quantified. Further, Eastern Australia supports the survival and persistence of an increasing number of tropical species found within temperate estuaries owing to increasing average ocean temperatures. A re-valuation of the number of fish species known from Sydney Harbour is therefore needed. In this study, we generated an up-to-date and annotated checklist of fishes recorded from Sydney Harbour based on verified natural history records as well as newly available citizen science records based on opportunistic observations and structured surveys. We explored the spatial and temporal distribution of these records. In addition, we quantified the function, conservation status, and commercial importance of the identified fishes. The number of fish species recorded from Sydney Harbour now stands at 675, an increase of 89 species (15 %) when compared to the most recent evaluation in 2013. We attribute this increase in fish diversity over a relatively short time to the contribution of newer citizen science programs as well as the influx and survival of fishes in the Harbour with preferences for warmer waters. Some fish families were also overrepresented in the more urbanized and polluted sections of the Harbour. In forecasting further environmental impacts on the fishes of Sydney Harbour, we recommend increased integration of collaborative citizen science programs and natural history collections as a means to track these changes.

The present study provides a profile of Canadian Indigenous gambling and problem gambling using the 2018 Canadian Community Health Survey (CCHS) (n = 23,952 adults; 1,324 Indigenous) and an online panel survey of 10,199 gamblers (n = 589 Indigenous). The relative popularity of different types of gambling was similar between Indigenous and non-Indigenous samples. However, there was higher Indigenous participation in electronic gambling machines (EGMs), bingo, instant lotteries, overall gambling and a higher rate of problem gambling (2.0% versus 0.5%). Variables predictive of Indigenous problem gambling were EGM participation, gambling fallacies, having a mental or substance use disorder, sports betting, and male gender. Compared to non-Indigenous problem gamblers, Indigenous problem gamblers had higher substance use and lower impulsivity. In general, variables predictive of Indigenous problem gambling were the same ones predictive of problem gambling in all populations, with elevated Indigenous problem gambling rates primarily being due to elevated rates of these generic risk factors. Many of these risk factors are modifiable. Particular consideration should be given to reducing the disproportionate concentration of EGMs in geographic areas having the highest concentration of Indigenous people and ameliorating the disadvantageous social conditions in this population that are conducive to mental health and substance use problems.

Invasive species are one of the main causes of biodiversity loss worldwide. As introduced, populations increase in abundance and geographical range, so does the potential for negative impacts on native communities. As such, there is a need to better understand the processes driving range expansion as species become established in recipient landscapes. Through an investigation into capacity for population growth and range expansion of introduced populations of a non‐native lizard (Podarcis muralis), we aimed to demonstrate how multi‐scale factors influence spatial spread, population growth, and invasion potential in introduced species. We collated location records of P. muralis presence in England, UK through data collected from field surveys and a citizen science campaign. We used these data as input for presence‐background models to predict areas of climate suitability at a national‐scale (5 km resolution), and fine‐scale habitat suitability at the local scale (2 m resolution). We then integrated local models into an individual‐based modeling platform to simulate population dynamics and forecast range expansion for 10 populations in heterogeneous landscapes. National‐scale models indicated climate suitability has restricted the species to the southern parts of the UK, primarily by a latitudinal cline in overwintering conditions. Patterns of population growth and range expansion were related to differences in local landscape configuration and heterogeneity. Growth curves suggest populations could be in the early stages of exponential growth. However, annual rates of range expansion are predicted to be low (5–16 m). We conclude that extensive nationwide range expansion through secondary introduction is likely to be restricted by currently unsuitable climate beyond southern regions of the UK. However, exponential growth of local populations in habitats providing transport pathways is likely to increase opportunities for regional expansion. The broad habitat niche of P. muralis, coupled with configuration of habitat patches in the landscape, allows populations to increase locally with minimal dispersal., We investigated the potential for population growth and range expansion of introduced populations of a non‐native lizard (Podarcis muralis), considering multi‐scale factors influencing growth, and spatial spread. National‐scale models indicated climate suitability restricted to the southern parts of the UK, limited by a latitudinal cline in overwintering conditions. Patterns of local population growth and range expansion were related to differences in local landscape configuration and heterogeneity. The broad habitat niche of P. muralis, coupled with configuration of habitat patches in the landscape, allows populations to increase locally with minimal dispersal

Attempts to develop a disease modifying intervention for Alzheimer’s disease (AD) through targeting amyloid β (Aβ) have so far been unsuccessful. There is, therefore, a need for novel therapeutics against alternative targets coupled with approaches which may be suitable for early and sustained use likely required for AD prevention. Numerous in vitro and in vivo studies have shown that flavonoids can act within processes and pathways relevant to AD, such as Aβ and tau pathology, increases in BDNF, inflammation, oxidative stress and neurogenesis. However, the therapeutic development of flavonoids has been hindered by an ongoing lack of clear mechanistic data that fully takes into consideration metabolism and bioavailability of flavonoids in vivo. With a focus on studies that incorporate these considerations into their experimental design, this review will evaluate the evidence for developing specific flavonoids as therapeutics for AD. Given the current lack of success of anti-Aβ targeting therapeutics, particular attention will be given to flavonoid-mediated regulation of tau phosphorylation and aggregation, where there is a comparable lack of study. Reflecting on this evidence, the obstacles that prevent therapeutic development of flavonoids will be examined. Finally, the significance of recent advances in flavonoid metabolomics, modifications and influence of the microbiome on the therapeutic capacity of flavonoids in AD are explored. By highlighting the potential of flavonoids to target multiple aspects of AD pathology, as well as considering the hurdles, this review aims to promote the efficient and effective identification of flavonoid-based approaches that have potential as therapeutic interventions for AD.

The purpose of this study is to provide an updated profile of gamblers and problem gamblers in Canada and to identify characteristics most strongly associated with problem gambling.An assessment of gambling participation and problem gambling was included in the 2018 Canadian Community Health Survey and administered to 23,952 individuals 18 years and older. Descriptive statistics provided a demographic profile for each type of gambling involvement as well as category of gambler (non-gambler, non-problem gambler, at-risk gambler, problem gambler). A logistic regression identified characteristics that best distinguished problem from non-problem gamblers.Gambling participation and problem gambling both varied as a function of gender, income, educational attainment, and race/ethnicity. However, multivariate analysis identified electronic gambling machine (EGM) participation to be the primary predictor of problem gambling status, with race/ethnicity, presence of a mood disorder, male gender, casino table game participation, older age, a greater level of smoking, participation in speculative financial activity, instant lottery participation, lower household income, and lottery or raffle ticket participation providing additional predictive power. Provincial EGM density and EGM participation rates are also very strong predictors of provincial rates of at-risk and problem gambling.Problem gambling has a biopsychosocial etiology, determined by personal vulnerability factors combined with the presence of riskier types of gambling such as EGMs. Effective prevention requires a multifaceted approach, but constraints on the availability and operation of EGMs would likely have the greatest single public health benefit.RéSUMé: OBJECTIFS: Présenter un profil actualisé des joueurs et des joueurs pathologiques au Canada et cerner les caractéristiques les plus fortement associées au jeu pathologique. MéTHODE: Une évaluation de la participation au jeu de hasard et du jeu pathologique figurant dans l’Enquête sur la santé dans les collectivités canadiennes de 2018 a été administrée à 23 952 personnes de 18 ans et plus. Le profil démographique de chaque type de participation au jeu de hasard et la catégorie de joueur (non-joueur, joueur non pathologique, joueur à risque, joueur pathologique) ont été établis par statistique descriptive. Une régression logistique a permis de cerner les caractéristiques qui distinguaient le mieux les joueurs pathologiques des joueurs non pathologiques. RéSULTATS: La participation au jeu de hasard et le jeu pathologique variaient tous les deux en fonction du sexe, du revenu, du niveau d’instruction et de la race/l’ethnicité. L’analyse multivariée a cependant déterminé que l’utilisation d’appareils électroniques de jeu (AÉJ) était la principale variable prédictive du jeu pathologique, et que la race/l’ethnicité, la présence d’un trouble de l’humeur, le sexe masculin, la participation aux jeux de table dans les casinos, l’âge avancé, le tabagisme important, la participation à des activités financières spéculatives, la participation aux loteries instantanées, le faible revenu du ménage et l’achat de billets de loterie ou de tirage au sort amélioraient le pouvoir de prédiction. La densité provinciale des AÉJ et les taux d’utilisation des AÉJ étaient aussi de très fortes variables prédictives des taux provinciaux de jeu à risque et de jeu pathologique. CONCLUSION: Le jeu pathologique présente une étiologie biopsychosociale déterminée par des facteurs de vulnérabilité personnels combinés à la présence de types de jeu de hasard plus risqués, comme les AÉJ. Une prévention efficace nécessite une démarche pluridimensionnelle, mais l’imposition de limites à la disponibilité et à l’utilisation des AÉJ serait probablement la solution la plus avantageuse sur le plan de la santé publique.

Background There is little longitudinal evidence on the cumulative risk of harm from gambling associated with excess spending and frequency of play. The present study sought to assess the risk of gambling problems over a five-year period in adults who exceed previously derived low-risk gambling limits compared to those who remain within the limits after controlling for other modifiable risk factors. Methods Participants were adults (N = 4212) drawn from two independent Canadian longitudinal cohort studies who reported gambling in the past year and were free of problem gambling at time 1. Multivariate Cox regression was employed to assess the impact over time of gambling above low-risk gambling thresholds (frequency ≥ 8 times per month; expenditure ≥75CAD per month; percent of household income spent on gambling ≥1.7%) on developing moderate harm and problem gambling. Covariates included presence of a DSM5 addiction or mental health disorder at time 1, irrational gambling beliefs, number of stressful life events in past 12 months, number of game types played each year, and playing electronic gaming machines or casino games. Results In both samples, exceeding the low-risk gambling limits at time 1 significantly increased the risk of moderate harm (defined as ≥2 consequences on the Problem Gambling Severity Index [PGSI]) within 5 years after controlling for other modifiable risk factors. Other significant predictors of harm were presence of a mental disorder at time 1, cognitive distortions about gambling, stressful life events, and playing electronic gaming machines or casino games. In one sample, the five-year cumulative survival rate for moderate harm among individuals who stayed below all the low-risk limits was 95% compared to 83% among gamblers who exceeded all limits. Each additional low-risk limit exceeded increased the cumulative probability of harm by 30%. Similar results were found in models when the outcome was problem gambling. Conclusions Level of gambling involvement represents a highly modifiable risk factor for later harm. Staying below empirically derived safe gambling thresholds reduces the risk of harm over time.

Cannabis use frequently co-occurs with gambling, and evidence indicates that both acute and chronic cannabis use may influence gambling behavior. The primary aim of the present study was to further contribute to the literature on this relationship by examining data collected from a Canadian national study of gambling.Respondents consisted of 10,054 Canadian gamblers recruited from Leger Opinion's (LEO) online panel. In this study, gamblers who used cannabis were compared with non-users across a number of gambling as well as demographic and mental health variables.Of the total sample, 25.4 % reported past 12-month cannabis use. Among the 2,553 cannabis-users, 21.3 % reported daily use, and 69.9 % reported using once a month or more. A total of 56.2 % indicated they had used cannabis while gambling in the past 12 months. Bivariate analysis found significant differences between cannabis use and non-use on numerous demographic, mental health, and gambling-related variables. Individuals with greater problem gambling severity scores, more hours gambling, and a larger range of gambling activities were more likely to endorse using cannabis. Hierarchical logistic regression revealed that tobacco use, and having experienced significant child abuse were predictors of cannabis use. Non-use of cannabis was associated with older age, less engagement in online gambling, and being less likely to consume alcohol.The present findings both corroborate previous studies and expand upon the relationship between cannabis and gambling.

The human-assisted movement of species beyond their native range facilitates novel interactions between invaders and native species that can determine whether an introduced species becomes invasive and the nature of any consequences for native communities. Avoiding costly interactions through recognition and avoidance can be compromised by the naïvety of native species to novel invaders and vice versa. We tested this hypothesis using the common wall lizard, Podarcis muralis, and the native lizard species with which it may now interact in Britain (common lizard, Zootoca vivipara, sand lizard, Lacerta agilis) and on Vancouver Island (northern alligator lizard, Elgaria coerulea) by exploring species' responses (tongue flicks, avoidance behaviour) to heterospecific scent cues in controlled experiments. The tongue flick response of P. muralis depended on the different species’ scent, with significantly more tongue flicks directed to E. coerulea scent than the other species and the control. This recognition did not result in any other behavioural response in P. muralis (i.e. attraction, aggression, avoidance). Lacerta agilis showed a strong recognition response to P. muralis scent, with more tongue flicks occurring close to the treatment stimuli than the control and aggressive behaviour directed towards the scent source. Conversely, Z. vivipara spent less time near P. muralis scent cues than the control but its tongue flick rate was higher towards this scent in this reduced time, consistent with an avoidance response. There was no evidence of E. coerulea recognition of P. muralis scent in terms of tongue flicks or time spent near the stimuli, although the native species did show a preference for P. muralis-scented refuges. Our results suggest a variable response of native species to the scent of P. muralis, from an avoidance response by Z. vivipara that mirrors patterns of exclusion observed in the field to direct aggression observed in L. agilis and an ambiguous reaction from E. coerulea which may reflect a diminished response to a cue with a low associated cost. These results have significant implications for the invasive success and potential impacts of introduced P. muralis populations on native lizards.

α-Synuclein (αS) deposition is a defining characteristic of Parkinson’s disease (PD) pathology, and other synucleinopathies. αS aggregates in disease, leading to the generation of neuronal inclusions known as Lewy bodies. These accumulate in the cytoplasmic space of dopaminergic neurons in the substantia nigra pars compacta region of the brain, causing cell death, resulting in decreased dopamine levels, and ultimately PD symptoms. To date, a significant proportion of structural information has arisen from in vitro studies using recombinantly purified forms of the protein, often failing to acknowledge that αS is natively located in the presence of phospholipids, where it likely plays a direct role in regulating synaptic vesicle function and neurotransmission. Here we present a series of macromolecular αS assemblies not previously described that form in the presence of lipid vesicles. These fibrillar structures are striking in both their large size relative to those previously reported and by their varying helical content, from ribbons to wave-like helices of long pitch shortening to those more compact and bulkier. These studies provide the foundation for more detailed structural analysis, and may offer new possibilities to further define disease-relevant versions of the protein that are accessible to pharmacological intervention.

Background and aimsThe Conceptual Framework of Harmful Gambling moves beyond a symptoms-based view of harm and addresses a broad set of factors related to the risks and effects of gambling harmfully at the individual, family, and community levels. Coauthored by international research experts and informed by multiple stakeholders, Gambling Research Exchange (GREO) facilitated the framework development in 2013 and retains responsibility for regular updates and mobilization. This review article presents information about the revised version of the Conceptual Framework of Harmful Gambling completed in late 2018.MethodsWe describe eight interrelated factors depicted in the framework that represent major themes in gambling ranging from the specific (gambling environment, exposure, gambling types, and treatment resources) to the general (cultural, social, psychological, and biological influences). After outlining the framework development and collaborative process, we highlight new topics for the recent update that reflect changes in the gambling landscape and prominent discourses in the scientific community. Some of these topics include social and economic impacts of gambling, and a new model of understanding gambling related harm.Discussion and conclusionsWe address the relevance of the CFHG to the gambling and behavioral addictions research community. Harm-based frameworks have been undertaken in other areas of addiction that can both inform and be informed by a model dedicated to harmful gambling. Further, the framework brings a multi-disciplinary perspective to bear on antecedents and factors that co-occur with harmful gambling.

In Canada, up to 3% of individuals have or are at risk of gambling disorder. Among these individuals, a lack of awareness of their problem gambling is a common barrier to treatment and negatively affects treatment adherence. A secondary analysis was conducted on data from 1346 individuals (mean age = 43.4, SD = 14.4; 54.3 % male) with problem gambling who did and did not perceive having a problem with their gambling as assessed by the fifth item of the Problem Gambling Severity Index, "In the past twelve months, how often have you felt that you might have a problem with gambling?" Additionally, we investigated predictors of increased general awareness at 12-month follow-up. At baseline, individuals who perceived a problem with their gambling experienced more gambling-related harms (OR = 1.714), had greater total gambling losses (OR = 1.067), were more likely to have a family history of problem gambling (OR = 2.143), experienced a greater loss of control (OR = 1.313) and more often gambled alone than with others (OR = 0.879), accounting for 26.6 % of the variance in general awareness. Baseline problem awareness was positively associated with attempts to cut down or control gambling at follow-up (χ

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The non-receptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small-molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine-419 of SRC (IC50 ~ 100 nM) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS-mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244), and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and, cell viability was synergistically inhibited. In vivo, trametinib treatment of mice bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug-induced resistance to trametinib is not re-sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib-resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK-inhibitor combination strategies.

Casino employees regularly interact with problem and at-risk gamblers and thus have considerable potential to both prevent and reduce gambling-related harm. While harm minimization (HM) and responsible gambling (RG) are routinely espoused by the casino industry, the actual level of employee HM/RG training, knowledge, and behaviour is unknown. The present study investigated this issue in the Canadian context by examining employee surveys collected by the RG Check accreditation program (8,262 surveys from 78 Canadian casinos/racinos collected between 2011 and 2020). These surveys revealed that almost all casino employees receive HM/RG training, but the amount of training tends to be quite limited (one hour) except for supervisors, managers, and security personnel. Basic HM/RG knowledge among all employees appears adequate, although their understanding of probability is incomplete. The most important consideration is whether this training and knowledge translates into meaningful HM/RG behaviour towards patrons. The large majority of employees (83.1%) report engaging in at least one HM/RG interaction with a patron at some point during the course of their employment (median length of 4 to 9 years), with security personnel reporting the highest rates. However, the frequency, nature, and impact of these interactions is unknown.

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments allows us anticipate how cells adapt to targeted therapy enabling more informed prediction of rational drug combinations. The non-receptor tyrosine kinase SRC regulates many cellular signalling processes and pharmacological inhibition has long been a target of drug discovery projects for the treatment of cancer. Here we describe the in vitro and in vivo characterisation of the small molecule SRC inhibitor, AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine-416 of SRC (IC50 ∼ 100 nM) in many cancer cell lines; however inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a sub-set of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using Reverse Phase Protein Array analysis. We demonstrate that SRC is activated in response to MEK inhibitor (trametinib or AZD6244)-treatment of KRAS mutant colorectal cell lines (HCT116 and DLD1) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 revealed reduction of EGFR, FAK and SRC compensatory activation, and, synergistically inhibits cell viability in vitro. In vivo, trametinib-treatment of mice bearing HCT116 tumours increased phosphorylation of SRC on Tyr416, and when combined with AZD0424, inhibition of tumour growth is greater than trametinib alone. We also demonstrate that drug-induced resistance to trametinib is not re-sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however inhibition of SRC remains an effective way to block invasion of trametinib resistant tumour cells. These data imply that inhibiting SRC may offer a useful addition to MEK inhibitor combination strategies.

Misfolding and aggregation of alpha-synuclein (αS) within dopaminergic neurons is a key factor in the development and progression of a group of age-related neurodegenerative diseases, termed synucleinopathies, that include Parkinson's disease (PD). We previously derived a peptide inhibitor from a 209,952-member intracellular library screen by employing the preNAC region (45–54) as a design template. At least six single-point mutations firmly linked to early-onset Parkinson's disease (E46K, H50Q, G51D, A53T/E/V) are located within this region, strongly implicating a pathogenic role within αS that leads to increased cytotoxicity. A library-derived ten residue peptide, 4554W, was consequently shown to block αS aggregation at the point of primary nucleation via lipid induction, inhibiting its conversion into downstream cytotoxic species. Here we couple truncation with a full alanine scan analysis, to establish the effect upon the αS aggregation pathway relative to 4554W. This revealed the precise residues responsible for eliciting inhibitory interaction and function, as well as those potentially amenable to modification or functionalisation. We find that modification N6A combined with N-terminal truncation results in a peptide of significantly increased efficacy. Importantly, our data demonstrate that the peptide does not directly disrupt αS lipid-binding, a desirable trait since antagonists of αS aggregation and toxicity should not impede association with small synaptic neurotransmitter vesicles, and thus not disrupt dopaminergic vesicle fusion and recycling. This work paves the way toward the major aim of deriving a highly potent peptide antagonist of αS pathogenicity without impacting on native αS function.

We have developed the WebTimer, an Internet service, accessible through a browser, for checking the operation of stopwatches and timers. We explain its design, operation and performance. A detailed uncertainty budget has been developed to assist the user. The WebTimer has been available as a paid subscription service since July 2020.

This study analyzed the Responsible Gambling Check patron survey data from Canadian casinos and racinos collected from 2011-2019 (18,580 patrons and 75 venues). The results indicated increasing awareness and use over time of harm minimization tools among more frequent patrons. Despite these promising trends, it is concerning that a substantial percentage of gamblers are still unaware of the harm minimization tools available. Further, the actual impact of this awareness on responsible gambling behaviour is largely unknown. We suggest greater efforts are needed nation-wide to promote the awareness, utilization, and evaluation of these harm minimization tools.

Aggregation of the microtubule-associated protein tau into paired helical filaments (PHFs) and neurofibrillary tangles is a defining characteristic of Alzheimer’s Disease. Various plant polyphenols disrupt tau aggregation in vitro but display poor bioavailability and low potency, challenging their therapeutic translation. We previously reported that oral administration of the flavonoid (−)-epicatechin (EC) reduced Amyloid-β (Aβ) plaque pathology in APP/PS1 transgenic mice. Here, we investigated whether EC impacts on tau pathology, independent of actions on Aβ, using rTg4510 mice expressing P301L mutant tau. 4 and 6.5 months old rTg4510 mice received EC (∼18 mg/day) or vehicle (ethanol) via drinking water for 21 days and the levels of total and phosphorylated tau were assessed. At 4 months, tau appeared as two bands of ∼55 kDa, phosphorylated at Ser262 and Ser396 and was unaffected by exposure to EC. At 6.5 months an additional higher molecular weight form of tau was detected at ∼64 kDa which was phosphorylated at Ser262, Ser396 and additionally at the AT8 sites, indicative of the presence of PHFs. EC consumption reduced the levels of the ∼64 kDa tau species and inhibited phosphorylation at Ser262 and AT8 phosphoepitopes. Regulation of the key tau kinase glycogen synthase kinase 3β (GSK3β) by phosphorylation at Ser9 was not altered by exposure to EC in mice or primary neurons. Furthermore, EC did not significantly inhibit GSK3β activity at physiologically-relevant concentrations in a cell free assay. Therefore, a 21-day intervention with EC inhibits or reverses the development of tau pathology in rTg4510 mice independently of direct inhibition of GSK3β.

The present study tested tenets of the Pathways Model of problem gambling by completing a cross-sectional latent class analysis using an existing dataset. The sample in this study consisted...