A coding variant in ADH1B (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by DSM-IV criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio of 0.34, 95% confidence interval 0.24, 0.48) for alcohol dependence, with genome-wide significance (6.6 × 10−10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24 hour period (lifetime), with p = 3×10−13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults and demonstrated a significant protective effect. This variant has the strongest effect on risk for alcohol dependence of any tested in European populations.

Abstract. We report studies using an enhanced experimental system to investigate organization of nuclear pre-mRNA metabolism. It is based on the powerful genetic system and polytene nuclei of Drosophila. We observe (at steady state) movement of a specific premRNA between its gene and the nuclear surface. This movement is isotropic, at rates consistent with diffusion and is restricted to a small nuclear subcompartment defined by exclusion from chromosome axes and the nucleolus. Bulk polyadenylated nuclear pre-mRNA precisely localizes in this same subcompartment indieating that most or all pre-mRNAs use the same route of intranuclear movement.In addition to association with nascent transcripts, snRNPs are coconcentrated with pre-mRNA in this subcompartment. In contrast to constitutive splices, at least one regulated splice occurs slowly and may undergo execution remotely from the site of pre-mRNA synthesis. Details of our results suggest that retention of incompletely spliced pre-mRNA is a function of the nuclear surface.We propose a simple model-based on channeled diffusion-for organization of intranuclear transport and metabolism of pre-mRNAs in polytene nuclei. We argue that this model can be generalized to all metazoan nuclei. METAZOAN nuclei contain specific substructures implicated in pre-mRNA metabolism (see, for example, Fakan and Puvion, 1980; Lerner et al., 1981; McConnell et al., 1987;Lawrence et al., 1989;Spector, 1990;Fu and Maniatis, 1990;Carter et al., 1991; CarmoFonseca et al., 1991; Huang and Spector, 1991; Shermoen and O'Farrell, 1991;Wu et al., 1991;Xing and Lawrence, 1991;Li and Bingham, 1991;Kopczynski and Muskavitch, 1992). The capacity to extend these provocative observations is currently constrained by lack of a suitable genetic system for dissection of structure-function relationships and by inadequate convenience (EM) or resolution (light microscopy) among the various techniques for analysis of three dimensional organization in highly complex, compact nuclei.We report development of a new experimental system that both augments physical analytical techniques and permits application of a powerful genetic system. Our approach exploits resources uniquely available in Drosophila. First ,,o500) of an individual interphase chromatid are tightly synapsed in register to produce a giant, polytene chromosome (for review see Ashburner, 1989). In contrast to most diploid interphase chromosomes, individual polytene chromosome arms are readily identifiable as discrete structures in intact nuclei. Moreover, the simple arrangement of Drosophila chromosome arms is retained in these giant nuclei. Thus, polytene nuclei provide an "exploded" view of a simple nucleus. Under these conditions the relatively limited resolution of rapid, convenient light microscopic techniques is sufficient to allow clear visualization of relationships between extrachromosomal features and sites of pre-mRNA synthesis, Third, molecular genetic tools are available permitting construction of genes abundantly transcribed in polytene...

Objective: A low level of response (LR) to alcohol as measured through alcohol challenges is an early-appearing, genetically influenced characteristic that predicts the risk of heavier drinking and alcohol problems. A less expensive and more easily used measure of LR, the retrospective Self-Rating of the Effects of Alcohol (SRE) questionnaire, also relates to alcohol intake and problems but has not been evaluated for its ability to predict alcohol-related problems 5 years later. Method: At Time 1, 95 18-to 35-year-old (mean age: 25.9 years) subjects who were offspring from families participating at the San Diego site of the Collaborative Study on the Genetics of Alcoholism (COGA) were administered the SRE and evaluated regarding alcohol, drug, and demographic characteristics using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview. Follow-up interviews (Time 2) using the SSAGA were completed an average (SD) of 5.4 (1.34) years later for approximately 80% of the original sample. Re-

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ABSTRACT. Objective: The low level of response (LR) to alcohol is an endophenotype related to heavier drinking and alcohol problems. Structural equation models (SEMs) indicate LR affects alcohol outcomes (ALCOUT) both directly and through mediation by drinking in peers (PEER), alcohol expectancies (EXPECT), and drinking to cope with stress (COPE), with some variation depending on the sample tested. This article presents the fi rst full test of this LR-based model in young subjects from the Collaborative Study on the Genetics of Alcoholism (COGA). Method: Data were generated from 325 12-to 22-year-old (47.4% male) drinking offspring from COGA families, using the SelfReport of the Effects of Alcohol questionnaire to determine LR early in the drinking career and a validated, structured interview for demography and alcohol use/problem patterns. Standardized questionnaires were used to measure PEER, EXPECT, and COPE, with the model tested through the maximum likelihood estimation for analyses of the variance/covariance matrix using both Amos and Mplus. Results: The SEM yielded good fi t characteristics and explained 59% of the variance, with LR relating both directly to ALCOUT and as partially mediated by PEER and COPE. Although GENDER related to both LR and ALCOUT in the model, and AGE related to ALCOUT, the SEM results were invariant across both AGE and GENDER, with generally similar invariant results regarding the presence or absence of an alcohol-use disorder diagnosis. Conclusions:The results support the applicability of the LR-based model of heavy drinking and alcohol problems in the COGA offspring, a group with different demography compared with the two other samples of adolescents tested to date. The modest differences observed across samples will be evaluated in future research to enhance understanding of how the model operates across socioeconomic groups. (J. Stud. Alcohol Drugs 70: [436][437][438][439][440][441][442][443][444][445] 2009)

In Drosophila syncytial blastoderm embryos, centrosomes specify the position of actin-based interphase caps and mitotic furrows. Mutations in the scrambled locus prevent assembly of mitotic furrows, but do not block actin cap formation. The scrambled gene encodes a protein that localizes to the mitotic furrows and centrosomes. Sced localization, actin reorganization from caps into mitotic furrows, and centrosome-coordinated assembly of actin caps are not blocked by microtubule disruption. Our results indicate that centrosomes may coordinate assembly of cortical actin caps through a microtubule-independent mechanism, and that Scrambled mediates a second microtubule-independent process that drives mitotic furrow assembly

The TET (Ten-eleven translocation) 1, 2 and 3 proteins have been shown to function as DNA hydroxymethylases in vertebrates and their requirements have been documented extensively. Recently, the Tet proteins have been shown to also hydroxylate 5-methylcytosine in RNA. 5-hydroxymethylcytosine (5hmrC) is enriched in messenger RNA but the function of this modification has yet to be elucidated. Because Cytosine methylation in DNA is barely detectable in Drosophila, it serves as an ideal model to study the biological function of 5hmrC. Here, we characterized the temporal and spatial expression and requirement of Tet throughout Drosophila development. We show that Tet is essential for viability as Tet complete loss-of-function animals die at the late pupal stage. Tet is highly expressed in neuronal tissues and at more moderate levels in somatic muscle precursors in embryos and larvae. Depletion of Tet in muscle precursors at early embryonic stages leads to defects in larval locomotion and late pupal lethality. Although Tet knock-down in neuronal tissue does not cause lethality, it is essential for neuronal function during development through its affects upon locomotion in larvae and the circadian rhythm of adult flies. Further, we report the function of Tet in ovarian morphogenesis. Together, our findings provide basic insights into the biological function of Tet in Drosophila, and may illuminate observed neuronal and muscle phenotypes observed in vertebrates.

Chromium chrysoberyl undergoes a phase transformation from a paramagnetic state to a complex antiferromagnetic state at 28 K. The spiral spin structure of the antiferromagnetic state violates all the crystallographic symmetry elements, making Cr2BeO4 potentially ferroelectric. Chynoweth experiments conducted at low temperatures reveal a weak pyroelectric effect which disappears above 28 K. Cr2BeO4 ceramics can be poled electrically between 24 and 28 K, giving rise to remnant polarizations four to six orders of magnitude smaller than normal ferroelectrics. The pyroelectric coefficient and the remnant polarization reverse in sign with the poling field, but no anomalies in the electric permittivity or electric conductivity occur at the Nèel point.