ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure

Context: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. Objective: To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs)with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations. Design: Case-control genetic association study that included 2 control groups (lacking an established optimal control group). Setting: Semistructured psychiatric interviews. Participants: A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample. Main Outcome Measure: Lifetime heroin dependence. Results: Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P≥.01); a similar comparison with neighborhood controls revealed greater differences (P≥1.8×10-4). Comparing cases (n=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n=340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio=1.59; 95% CI, 1.32-1.92; P=9.7×10-7), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n=191) and nondependent (n=340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P=2.7×10-9 for the risk-associated linear trend). Conclusions: Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence

Role of Nicotine Dependence in the Association between the Dopamine Receptor Gene DRD3 and Major Depressive Disorder

Peer reviewe

The experimental power of FR900359 to study Gq-regulated biological processes.

Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq

Retinoid X receptor gamma signaling accelerates CNS remyelination

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS

World Society of Emergency Surgery (WSES) guidelines for management of skin and soft tissue infections

Peer reviewe

A Systematic Concept Exploration Methodology Applied to Venus In Situ Explorer

This presentation was part of the session : Probe Missions to the Giant Planets, Titan and VenusSixth International Planetary Probe WorkshopA critical task in any design process is the initial conversion of customer or program objectives into a baseline system architecture. This task becomes particularly important for space exploration systems that have unique requirements which, in many cases, have never been met before. A useful tool to the space systems engineer would be a methodology which helps to make this objectives-to-design conversion more systematic and efficient. Presented in this paper is such a methodology frequently used at the Georgia Institute of Technology, and in this paper the methodology is applied to initial concept formulation for the Venus In Situ Explorer (VISE) mission. VISE is one of six New-Frontiers-class missions to occur within the next 30 years that NASA addresses in its Solar System Exploration Roadmap. VISE is envisioned as an aerial mission that will study Venus' atmospheric composition as well as descend briefly to the surface to acquire samples for later analysis at more benign altitudes. Common to both VISE and its successor, Venus Mobile Explorer, is the challenge to operate under the extreme temperatures (about 730 K) and pressures (about 90 atm) present at the Venusian surface. In order to establish a baseline mission and vehicle concept for VISE, the methodology presented here begins with problem definition and the generation of functional and operational architectures. Customer requirements and engineering targets are set through an established set of tools known as the seven management and planning tools and through the use of a quality function deployment (QFD). A morphological matrix is used to identify 12.4 billion potential solutions in the concept space. From this concept space, six representative designs are chosen to demonstrate how alternatives from the morphological matrix may be ranked through multi-attribute decision making (MADM) techniques such as the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) and Pugh concept selection matrices. Two of the six concepts are eliminated based on these MADM techniques, and the remaining four concepts are recognized as requiring more in-depth study to allow definitive rankings to be assigned. A notional modeling and simulation framework for this problem is formed which could be used to complete such an in-depth, quantitative study. This paper principally serves to illustrate an example of how a systematic objectives definition, concept generation, and downselection methodology can be applied to advanced interplanetary missions (specifically in the example of Venus In Situ Explorer). The methodology and tools presented here are shown as a helpful guide and addition to the toolbox of the space systems engineer during the advanced planning stages of design.Georgia Institute of Technology ; National Institute of Aerospac

NORTHEASTERN MINNESOTA MOOSE MANAGEMENT - A CASE STUDY IN COOPERATION

This paper provides an overview of moose management in northeastern Minnesota with an emphasis on relationships between the State and Tribal entities that share management responsibility. Specific topics discussed include settlement of treaty rights issues, harvest allocation and strategies, and the evolving State-Tribal partnerships that have been created during the past 15 years. Brief updates on the status of moose in Minnesota, population monitoring efforts, population goals, and the future direction of management are provided

COMPOSITIONAL ANALYSIS OF MOOSE HABIAT IN NORTHEASTERN MINNESOTA

ABSTRACT: It is well accepted that moose often use early successional habitats in the boreal forest.  It is not clear, however, whether use of disturbed habitats represents a preference or simply that moose are more detectable. Previous research based on visual observations assumed that moose were equally detectable in all cover types.  We evaluated habitat selection of moose in northeastern Minnesota using telemetry locations and LULC cover type information. We calculated second- and third-order habitat selection using composition analysis. The analyses indicated that while the Cutover cover type ranked highest in summer and winter in both second- and third-order selection, its rank was not significantly different from most other cover types during the winter. Third-order analysis indicated that the rank of Cutover was significantly higher than other cover types during the summer.  Selection for aquatic habitats during the summer was not evident in our analysis.  Cover types that could provide lower operative temperatures from shade ranked higher than aquatic cover types. Inferences from these analyses should be treated with caution because of inherent weaknesses of use-availability analyses