Genetics of Alcoholism

Purpose of Review We review the search for genetic variants that affect the risk for alcohol dependence and alcohol consumption. Recent Findings Variations in genes affecting alcohol metabolism (ADH1B, ALDH2) are protective against both alcohol dependence and excessive consumption, but different variants are found in different populations. There are different patterns of risk variants for alcohol dependence vs. consumption. Variants for alcohol dependence, but not consumption, are associated with risk for other psychiatric illnesses. Summary ADH1B and ALDH2 strongly affect both consumption and dependence. Variations in many other genes affect both consumption and dependence—or one or the other of these traits—but individual effect sizes are small. Evidence for other specific genes that affect dependence is not yet strong. Most current knowledge derives from studies of European-ancestry populations, and large studies of carefully phenotyped subjects from different populations are needed to understand the genetic contributions to alcohol consumption and alcohol use disorders

Network-aware Evaluation Environment for Reputation Systems

Parties of reputation systems rate each other and use ratings to compute reputation scores that drive their interactions. When deciding which reputation model to deploy in a network environment, it is important to find the most suitable model and to determine its right initial configuration. This calls for an engineering approach for describing, implementing and evaluating reputation systems while taking into account specific aspects of both the reputation systems and the networked environment where they will run. We present a software tool (NEVER) for network-aware evaluation of reputation systems and their rapid prototyping through experiments performed according to user-specified parameters. To demonstrate effectiveness of NEVER, we analyse reputation models based on the beta distribution and the maximum likelihood estimation

Flexible and dynamic replication control for interdependent distributed real-time embedded systems

Replication is a proven concept for increasing the availability of distributed systems. However, actively replicating every software component in distributed embedded systems may not be a feasible approach. Not only the available resources are often limited, but also the imposed overhead could significantly degrade the system’s performance. This paper proposes heuristics to dynamically determine which components to replicate based on their significance to the system as a whole, its consequent number of passive replicas, and where to place those replicas in the network. The activation of passive replicas is coordinated through a fast convergence protocol that reduces the complexity of the needed interactions among nodes until a new collective global service solution is determined

History-sensitive versus future-sensitive approaches to security in distributed systems

We consider the use of aspect-oriented techniques as a flexible way to deal with security policies in distributed systems. Recent work suggests to use aspects for analysing the future behaviour of programs and to make access control decisions based on this; this gives the flavour of dealing with information flow rather than mere access control. We show in this paper that it is beneficial to augment this approach with history-based components as is the traditional approach in reference monitor-based approaches to mandatory access control. Our developments are performed in an aspect-oriented coordination language aiming to describe the Bell-LaPadula policy as elegantly as possible. Furthermore, the resulting language has the capability of combining both history- and future-sensitive policies, providing even more flexibility and power.Comment: In Proceedings ICE 2010, arXiv:1010.530

Enhancing dependability through flexible adaptation to changing requirements

This paper describes an architectural approach that facilitates the dynamic adaptation of systems to changing domain rules. The approach relies on 'coordination contracts', a modelling and implementation primitive we have developed for run-time reconfiguration. Our framework includes an engine that, whenever a service is called, checks the domain rules that are applicable and configures the response of the service before proceeding with the call. This approach enhances dependability in two essential ways: on the one hand, it guarantees that system execution is always consistent with the domain logic because service response is configured automatically (i.e., without any need for programmer intervention); on the other hand, it makes it possible for changes to be incorporated into existing domain rules, and from new rules to be created, with little effort, because coordination contracts can be superposed dynamically without having to change neither the client nor the service code. Our approach is illustrated through a case study in financial systems, an area in which dependability arises mainly in the guise of business concerns like adherence to agreed policies and conditions negotiated on a case-by-case basis. We report on an information system that ATX Software developed for a company specialised in recovering bad credit. We show in particular how, by using this framework, we have devised a way of generating rule-dependent SQL code for batch-oriented services

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Alcohol metabolizing genes and alcohol phenotypes in an Israeli household sample

BACKGROUND: Alcohol dehydrogenase 1B and 1C (ADH1B and ADH1C) variants have been robustly associated with alcohol phenotypes in East Asian populations, but less so in non-Asian populations where prevalence of the most protective ADH1B allele is low (generally <5%). Further, the joint effects of ADH1B and ADH1C on alcohol phenotypes have been unclear. Therefore, we tested the independent and joint effects of ADH1B and ADH1C on alcohol phenotypes in an Israeli sample, with higher prevalence of the most protective ADH1B allele than other non-Asian populations. METHODS: A structured interview assessed lifetime drinking and alcohol use disorders (AUDs) in adult Israeli household residents. Four single nucleotide polymorphisms (SNPs) were genotyped: ADH1B (rs1229984, rs1229982, and rs1159918) and ADH1C (rs698). Regression analysis examined the association between alcohol phenotypes and each SNP (absence vs. presence of the protective allele) as well as rs698/rs1229984 diplotypes (also indicating absence or presence of protective alleles) in lifetime drinkers (n = 1,129). RESULTS: Lack of the ADH1B rs1229984 protective allele was significantly associated with consumption- and AUD-related phenotypes (OR = 1.77 for AUD; OR = 1.83 for risk drinking), while lack of the ADH1C rs698 protective allele was significantly associated with AUD-related phenotypes (OR = 2.32 for AUD). Diplotype analysis indicated that jointly ADH1B and ADH1C significantly influenced AUD-related phenotypes. For example, among those without protective alleles for ADH1B or ADH1C, OR for AUD was 1.87 as compared to those without the protective allele for ADH1B only and was 3.16 as compared to those with protective alleles for both ADH1B and ADH1C. CONCLUSIONS: This study adds support for the relationship of ADH1B and ADH1C and alcohol phenotypes in non-Asians. Further, these findings help clarify the mixed results from previous studies by showing that ADH1B and ADH1C jointly effect AUDs, but not consumption. Studies of the association between alcohol phenotypes and either ADH1B or ADH1C alone may employ an oversimplified model, masking relevant information

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis.

Despite substantial evidence for sex differences in addiction epidemiology, addiction-relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction

Orchestrating Tuple-based Languages

The World Wide Web can be thought of as a global computing architecture supporting the deployment of distributed networked applications. Currently, such applications can be programmed by resorting mainly to two distinct paradigms: one devised for orchestrating distributed services, and the other designed for coordinating distributed (possibly mobile) agents. In this paper, the issue of designing a pro- gramming language aiming at reconciling orchestration and coordination is investigated. Taking as starting point the orchestration calculus Orc and the tuple-based coordination language Klaim, a new formalism is introduced combining concepts and primitives of the original calculi. To demonstrate feasibility and effectiveness of the proposed approach, a prototype implementation of the new formalism is described and it is then used to tackle a case study dealing with a simplified but realistic electronic marketplace, where a number of on-line stores allow client applications to access information about their goods and to place orders