Item response modeling of DSM-IV mania symptoms in two representative US epidemiological samples

BACKGROUND: There is considerable debate surrounding the effective measurement of DSM-IV symptoms used to assess manic disorders in epidemiological samples. METHODS: Using two nationally representative datasets, the National Epidemiological Survey of Alcohol and Related Conditions (NESARC, N=43,093 at Wave 1, N=34,653 at 3-year follow-up) and the National Comorbidity Survey-Replication (NCS-R, N=9,282), we examined the psychometric properties of symptoms used to assess DSM-IV mania. The predictive utility of the mania factor score was tested using the 3-year follow-up data in NESARC. RESULTS: Criterion B symptoms were unidimensional (single factor) in both samples. The symptoms assessing flight of ideas, distractibility and increased goal-directed activities had high factor loadings (0.70–0.93) with moderate rates of endorsement thus providing good discrimination between individuals with and without mania. The symptom assessing grandiosity performed less well in both samples. The quantitative mania factor score was a good predictor of more severe disorders at 3-year follow-up in the NESARC sample, even after controlling for a past history of DSM-IV diagnosis of manic disorder. CONCLUSION: These analyses suggest that questions based on some DSM symptoms effectively discriminate between individuals at high and low liability to mania, while others do not. A quantitative mania factor score may aid in predicting recurrence for patients with a history of mania. Methods for assessing mania using structured interviews in the absence of clinical assessment require further refinement

Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer's disease.

Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer's disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium's modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD

Molecular basis for functional diversity among microbial Nep1-like proteins

Necrosis and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) are secreted by several phytopathogenic microorganisms. They trigger necrosis in various eudicot plants upon binding to plant sphingolipid glycosylinositol phosphorylceramides (GIPC). Interestingly, HaNLP3 from the obligate biotroph oomycete Hyaloperonospora arabidopsidis does not induce necrosis. We determined the crystal structure of HaNLP3 and showed that it adopts the NLP fold. However, the conformations of the loops surrounding the GIPC headgroup-binding cavity differ from those of cytotoxic Pythium aphanidermatum NLPPya. Essential dynamics extracted from \u3bcs-long molecular dynamics (MD) simulations reveals a limited conformational plasticity of the GIPC-binding cavity in HaNLP3 relative to toxic NLPs. This likely precludes HaNLP3 binding to GIPCs, which is the underlying reason for the lack of toxicity. This study reveals that mutations at key protein regions cause a switch between nontoxic and toxic phenotypes within the same protein scaffold. Altogether, these data provide evidence that protein flexibility is a distinguishing trait of toxic NLPs and highlight structural determinants for a potential functional diversification of non-toxic NLPs utilized by biotrophic plant pathogens

The Evolution of Circumstellar Disks in Ophiuchus Binaries

Four Ophiuchus binaries, two Class I systems and two Class II systems, with separations of ~450-1100 AU, were observed with the Owens Valley Radio Observatory (OVRO) millimeter interferometer. In each system, the 3 mm continuum maps show dust emission at the location of the primary star, but no emission at the position of the secondary. This result is different from observations of less evolved Class 0 binaries, in which dust emission is detected from both sources. The nondetection of secondary disks is, however, similar to the dust distribution seen in wide Class II Taurus binaries. The combined OVRO results from the Ophiuchus and Taurus binaries suggest that secondary disk masses are significantly lower than primary disk masses by the Class II stage, with initial evidence that massive secondary disks are reduced by the Class I stage. Although some of the secondaries retain hot inner disk material, the early dissipation of massive outer disks may negatively impact planet formation around secondary stars. Masses for the circumprimary disks are within the range of masses measured for disks around single T Tauri stars and, in some cases, larger than the minimum mass solar nebula. More massive primary disks are predicted by several formation models and are broadly consistent with the observations. Combining the 3 mm data with previous 1.3 mm observations, the dust opacity power-law index for each primary disk is estimated. The opacity index values are all less than the scaling for interstellar dust, possibly indicating grain growth within the circumprimary disks

Characteristics of Bipolar I patients grouped by externalizing disorders

BACKGROUND: Bipolar disorder co-occurs with a number of disorders with externalizing features. The aim of this study is to determine whether Bipolar I (BPI) subjects with comorbid externalizing disorders and a subgroup with externalizing symptoms prior to age 15 have different clinical features than those without externalizing disorders and whether these could be attributed to specific genetic variations. METHODS: A large cohort (N=2505) of Bipolar I subjects was analyzed. Course of illness parameters were compared between an Externalizing Group, an Early-Onset Subgroup and a Non-Externalizing Group in the Discovery sample (N=1268). Findings were validated using an independent set of 1237 BPI subjects (Validation sample). Genetic analyses were carried out. RESULTS: Subjects in the Externalizing Group (and Early-Onset Subgroup) tended to have a more severe clinical course, even in areas specifically related to mood disorder such as cycling frequency and rapid mood switching. Regression analysis showed that the differences are not completely explainable by substance use. Genetic analyses identified nominally associated SNPs; calcium channel genes were not enriched in the gene variants identified. LIMITATIONS: Validation in independent samples is needed to confirm the genetic findings in the present study. CONCLUSIONS: Our findings support the presence of an externalizing disorder subphenotype within BPI with greater severity of mood disorder and possible specific genetic features

Social contexts of remission from DSM-5 alcohol use disorder in a high-risk sample

BACKGROUND: Measures of social context, such as marriage and religious participation, are associated with remission from alcohol use disorders (AUDs) in population-based and treatment samples, but whether these associations hold among individuals at high familial risk for AUD is unknown. This study tests associations of measures of social context and treatment with different types of remission from DSM-5 AUD in a high-risk sample. METHODS: Subjects were 686 relatives of probands (85.7% first-degree) who participated in a high-risk family study of alcohol dependence. All subjects met criteria for AUD at baseline and were re-interviewed 5 years later. Follow-up status was categorized as persistent AUD, high-risk drinking, remitted low-risk drinking, and abstinence. Social context measures were defined as stable or changing from baseline to follow-up, and their bivariate and multivariate associations with follow-up status were tested. RESULTS: At follow-up, 62.8% of subjects had persistent AUD, 6.4% were high-risk drinkers, 22.2% were remitted low-risk drinkers, and 8.6% were abstinent. Birth of first child during the interval was the only measure of social context associated with remitted low-risk drinking and was significant for women only. Abstinent remission was characterized by being stably separated or divorced for women, new marriage for both sexes, experiencing low levels of family support and high levels of friend support, and receiving treatment. High-risk drinkers were more likely than individuals with persistent AUD to have a stable number of children and to have been recently unemployed. CONCLUSIONS: The social contexts accompanying different types of remission in this high-risk sample resemble those found in population-based and clinical samples. Low-risk drinkers resemble natural remitters from population-based samples who change their drinking habits with life transitions. Abstainers resemble clinical samples in marital context, support from friends, and treatment. High-risk drinkers appear to continue to experience negative consequences of heavy drinking

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression

Abstract Background Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions. Methods/Design To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression. Study eligibility criteria: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias. Data sources: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants. The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results. Discussion Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.http://deepblue.lib.umich.edu/bitstream/2027.42/112319/1/12888_2013_Article_1474.pd

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

Background As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation. Results The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10−16) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10−18). Conclusion Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses

Evolution of Cold Circumstellar Dust Around Solar-Type Stars

We present submillimeter (CSO 350um) and millimeter (SEST 1.2 mm, OVRO 3 mm) photometry for 125 solar-type stars from the FEPS Spitzer Legacy program that have masses between ~0.5 and 2.0 Msun and ages from 3 Myr to 3 Gyr. Continuum emission was detected toward four stars with a signal to noise ratio >= 3$: the classical T Tauri stars RX J1842.9-3532, RX J1852.3-3700, and PDS 66 with SEST, and the debris disk system HD 107146 with OVRO. RXJ1842.9-3532 and RXJ1852.3-3700 are located in projection nearby the R CrA molecular cloud with estimated ages of ~10 Myr, while PDS66 is a probable member of the 20 Myr old Lower Centaurus-Crux subgroup of the Sco-Cen OB association. The continuum emission toward these three sources is unresolved at the 24'' SEST resolution and likely originates from circumstellar accretion disks, each with estimated dust masses of ~5x10**-5 Msun. Analysis of the visibility data toward HD107146 (age 80-200 Myr) indicates that the 3 mm continuum emission is centered on the star within the astrometric uncertainties and resolved with a gaussian-fit FWHM size of (6.5'' +/- 1.4'') x (4.2''+/-1.3''), or 185 AUx120 AU. The results from our continuum survey are combined with published observations to quantify the evolution of dust mass with time by comparing the mass distributions for samples with different stellar ages. The frequency distribution of circumstellar dust masses around solar-type stars in the Taurus molecular cloud (age ~2 Myr) is distinguished from that around 3-10 Myr and 10-30 Myr old stars at a significance level of ~1,5sigma and 3sigma respectively. These results suggest a decrease in the mass of dust contained in small dust grains and/or changes in the grain properties by stellar ages of 10-30 Myr, consistent with previous conclusions. (abridged)Comment: 37 pages, 8 figures, accepted for publication in the Astronomical Journa