Declines in prevalence of adolescent substance use disorders and delinquent behaviors in the USA: a unitary trend?

BACKGROUND: Downward trends in a number of adolescent risk behaviors including violence, crime, and drug use have been observed in the USA in recent years. It is unknown whether these are separate trends or whether they might relate to a general reduction in propensity to engage in such behaviors. Our objectives were to quantify trends in substance use disorders (SUDs) and delinquent behaviors over the 2003-2014 period and to determine whether they might reflect a single trend in an Externalizing-like trait. METHODS: We analyzed data from 12 to 17 year old participants from the National Survey on Drug Use and Health, a representative survey of the household dwelling population of the USA, across the 2003-2014 period (N = 210 599). Outcomes included past-year prevalence of six categories of substance use disorder and six categories of delinquent behavior. RESULTS: Trend analysis suggested a net decline of 49% in mean number of SUDs and a 34% decline in delinquent behaviors over the 12-year period. Item Response Theory models were consistent with the interpretation that declines in each set of outcomes could be attributed to changes in mean levels of a latent, Externalizing-like trait. CONCLUSIONS: Our findings suggest that declines in SUDs and some delinquent behaviors reflect a single trend related to an Externalizing-like trait. Identifying the factors contributing to this trend may facilitate continued improvement across a spectrum of adolescent risk behaviors.

Smoking cessation is associated with lower rates of mood/anxiety and alcohol use disorders.

BACKGROUND: The psychological outcomes that accompany smoking cessation are not yet conclusive but positive outcomes could help to persuade quitting. METHOD: We used data from the longitudinal National Epidemiological Study of Alcohol and Related Conditions. Logistic regression was used to examine associations between cigarette smoking reduction and Wave 2 status of addiction/mental health disorder among daily smokers at Wave 1, stratified by status of the diagnosis of interest at Wave 1. We adjusted for differences in baseline covariates between smokers with different levels of smoking reduction between Wave 1 and Wave 2 using propensity score regression adjustment. RESULTS: After adjusting for propensity scores and other mental health/addiction co-morbidities at Wave 2, among daily smokers who had current or lifetime history diagnosis of the outcome of interest at Wave 1, quitting by Wave 2 predicted a decreased risk of mood/anxiety disorder [adjusted odds ratio (aOR) 0.6, 95% confidence interval (CI) 0.4-0.9] and alcohol disorder (aOR 0.7, 95% CI 0.5-0.99) at Wave 2. Among daily smokers with no lifetime history diagnosis of the outcome of interest at Wave 1, quitting smoking by Wave 2 predicted a decreased risk of drug use disorder at Wave 2 (aOR 0.3, 95% CI 0.1-0.9). CONCLUSIONS: There is no support in our data for the concern that smoking cessation would result in smokers' increased risk of some mental disorders. To the contrary, our data suggest that smoking cessation is associated with risk reduction for mood/anxiety or alcohol use disorder, even among smokers who have had a pre-existing disorder.

The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans.

Several independent studies show that the chromosome 15q25.1 region, which contains the CHRNA5-CHRNA3-CHRNB4 gene cluster, harbors variants strongly associated with nicotine dependence, other smoking behaviors, lung cancer and chronic obstructive pulmonary disease. We investigated whether variants in other cholinergic nicotinic receptor subunit (CHRN) genes affect the risk of nicotine dependence in a new sample of African Americans (AAs) (N = 710). We also analyzed this AA sample together with a European American (EA) sample (N = 2062, 1608 of which have been previously studied), allowing for differing effects in the two populations. Cases are current nicotine-dependent smokers and controls are non-dependent smokers. Variants in or near CHRND-CHRNG, CHRNA7 and CHRNA10 show modest association with nicotine dependence risk in the AA sample. In addition, CHRNA4, CHRNB3-CHRNA6 and CHRNB1 show association in at least one population. CHRNG and CHRNA4 harbor single nucleotide polymorphisms (SNPs) that have opposite directions of effect in the two populations. In each of the population samples, these loci substantially increase the trait variation explained, although no loci meet Bonferroni-corrected significance in the AA sample alone. The trait variation explained by three key associated SNPs in CHRNA5-CHRNA3-CHRNB4 is 1.9% in EAs and also 1.9% in AAs; this increases to 4.5% in EAs and 7.3% in AAs when we add six variants representing associations at other CHRN genes. Multiple nicotinic receptor subunit genes outside chromosome 15q25 are likely to be important in the biological processes and development of nicotine dependence, and some of these risks may be shared across diverse populations.

Role of electrostatic interactions in SH2 domain recognition: salt-dependence of tyrosyl-phosphorylated peptide binding to the tandem SH2 domain of the Syk kinase and the single SH2 domain of the Src kinase.

SH2 domains are small protein domains that bind specifically to tyrosyl-phosphorylated sequences. Because phosphorylation contributes a large part of the binding free energy, it has been postulated that electrostatic interactions may play an important role in SH2 domain recognition. To test this hypothesis, we have examined the salt dependence of the interaction between tyrosyl-phosphorylated peptides and SH2 domains. The dependence of the binding constant, K(obs), on [NaCl] was shown to be strong for binding of the tandem SH2 domain of the Syk kinase (Syk-tSH2) to doubly phosphorylated peptides derived from immune-receptor tyrosine activation motifs (dpITAMs): the slopes of plots of log(K(obs)) versus log [NaCl], designated SK(obs), ranged from -2.6 +/- 0.1 to -3.1 +/- 0.2. Binding of the single SH2 domain of the Src kinase to its consensus singly phosphorylated peptide (sequence pYEEI where pY indicates a phosphotyrosine) was also highly dependent on [NaCl] with a SK(obs) value of -2.4 +/- 0.1. The ability of salt to disrupt the interactions between Syk-tSH2 and dpITAM peptides was shown to be anion-dependent with the inhibitory effect following the order: phosphate > Cl(-) > F(-). For the Syk-tSH2 system, interactions in the pY-binding pockets were shown to be responsible for a large portion of the total salt dependence: removal of either phosphate from the dpITAM peptide reduced the magnitude of SK(obs) by 40-60% and weakened binding by 2-3 orders of magnitude. Consistent with this finding, binding of the single amino acid Ac-pY-NH(2) was characterized by a large salt dependence of binding and was also dependent on the identity of the perturbing anion. The role of peptide residues C-terminal to the pY, which are implicated in determining the specificity of the phosphopeptide-SH2 domain interaction, was next probed by comparing the binding of the Src SH2 domain to a peptide containing the pYEEI sequence with that of a lower affinity variant pYAAI peptide: the magnitude of SK(obs) for the variant peptide was reduced to -1.3 +/- 0.1 as compared to -2.4 +/- 0.1 for the pYEEI peptide, indicating that in addition to pY, residues conferring peptide binding specificity contribute significantly to the salt dependence of SH2 domain binding. This study shows that electrostatic interactions play important roles not only in mediating pY recognition and binding but also in contributing to the specificity of the interactions between tyrosyl phosphopeptides and SH2 domains.

Thermodynamic study of the binding of the tandem-SH2 domain of the Syk kinase to a dually phosphorylated ITAM peptide: evidence for two conformers.

The cytosolic tyrosine kinase Syk is recruited to immune cell receptors via interactions of its tandem-SH2 domain with tyrosine-phosphorylated sequences called immune receptor tyrosine activation motifs (ITAMs). We have characterized the binding of the tandem-SH2 domain of Syk (Syk-tSH2) to a dually phosphorylated peptide derived from the ITAM of the T cell receptor CD3-epsilon subunit. The CD3-epsilon peptide binds with an affinity of 18-81 nM at 150 mM NaCl over the 4.5-30 degrees C temperature range that was studied. The enthalpy of binding, DeltaH degrees obs, shows an unusual nonlinear dependence on temperature, suggesting the possibility of a temperature-dependent conformational equilibrium coupled to binding. This hypothesis was tested and confirmed by examining the temperature dependence of (1) the on-rate constant for binding and (2) the fluorescence of Syk-tSH2 and its CD3-epsilon peptide complex. The DeltaH degrees obs, Kobs, fluorescence, and kinetic data are all well described by a model incorporating the hypothesized conformational equilibrium. Circular dichroism spectra at various temperatures indicate that the conformational change is not due to a partial unfolding of the protein. We suggest that the conformational equilibrium enables Syk-tSH2 to exhibit flexibility in its binding modality, which may be necessitated by Syk's involvement in a wide variety of signal tranduction pathways.

Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide.

The Syk family of kinases, consisting of ZAP-70 and Syk, play essential roles in a variety of immune and non-immune cells. This family of kinases is characterized by the presence of two adjacent SH2 domains which mediate their localization to the membrane through receptor encoded tyrosine phosphorylated motifs. While these two kinases share many structural and functional features, the more ubiquitous nature of Syk has suggested that this kinase may accommodate a greater variety of motifs to mediate its function. We present the crystal structure of the tandem SH2 domain of Syk complexed with a dually phosphorylated ITAM peptide. The structure was solved by multiple isomorphous replacement at 3.0 A resolution. The asymmetric unit comprises six copies of the liganded protein, revealing a surprising flexibility in the relative orientation of the two SH2 domains. The C-terminal phosphotyrosine-binding site is very different from the equivalent region of ZAP-70, suggesting that in contrast to ZAP-70, the two SH2 domains of Syk can function as independent units. The conformational flexibility and structural independence of the SH2 modules of Syk likely provides the molecular basis for the more ubiquitous involvement of Syk in a variety of signal transduction pathways.

Probing the "two-pronged plug two-holed socket" model for the mechanism of binding of the Src SH2 domain to phosphotyrosyl peptides: a thermodynamic study.

Src homology 2 (SH2) domains are protein modules that specifically bind to tyrosyl phosphorylated peptides on signaling proteins. X-ray crystallographic studies of the SH2 domain of the Src kinase have probed the mechanism of binding, leading to the "two-pronged plug two-holed socket" mechanism whereby binding is hypothesized to resemble a two-pronged plug (the peptide) inserting into a two-holed socket (the SH2 domain). This binding model predicts (1) a hydrophobic basis for high-affinity binding largely determined by the level of insertion of the third residue C-terminal to the phosphotyrosine in the peptide into a primarily hydrophobic pocket (the +3 binding pocket) of the SH2 domain, and (2) a binding mechanism involving no significant conformational changes in the SH2 domain. In this study, we have probed these predictions by using isothermal titration calorimetry to extract complete thermodynamic profiles (Delta G degrees, Delta H degrees, Delta S degrees, Delta Cp degrees) for the binding of the Src SH2 domain to two series of tyrosyl phosphopeptides. One series consisted of peptides that have been determined by X-ray crystallography to have different levels of insertion of the peptide's +3 position into the +3 binding pocket. The other series consisted of peptides with progressively smaller hydrophobic side chains (I, L, V, and A) at the +3 position. Consistent with a binding mechanism that does not involve substantial conformational changes, the Delta Cp degrees values for all peptides were small and, at least for the high-affinity interactions, similar to the Delta Cp degrees values predicted from surface area calculations. However, unexpectedly, this study reveals that high-affinity binding was only partially determined by the interactions between the +3 residue in the peptide and the +3 binding pocket. Furthermore, the Delta Cp degrees values for all peptides studied were similar, implying similar degrees of desolvation of the +3 binding pocket upon binding. These results indicate that the "two-pronged plug two-holed socket" model is an oversimplification of the Src SH2 domain binding mechanism.

pH-Dependent self-association of the Src homology 2 (SH2) domain of the Src homologous and collagen-like (SHC) protein.

The Src homologous and collagen-like (SHC) protein plays an essential role in signal transduction pathways in that it participates in the chain of events that leads to the activation of the protein Ras. The crystal structure of the SH2 domain of SHC has been determined using the method of multiple isomorphous replacement at a resolution of 2.5 A. The SH2 domain of SHC is similar in fold to other SH2 domains. The peptide-binding surfaces resemble that of the SH2 domain of Src in that a deep pocket is formed where the third amino acid C-terminal to the phosphotyrosine can insert. A novel feature of this structure is the observation of a disulfide bond and an extensive dimer interface between two symmetry-related molecules. Solution studies under reducing conditions using analytical centrifugation and PAGE suggest that the SH2 domain of SHC dimerizes in a pH-dependent manner where low pH conditions (approximately 4.5) are conducive to dimer formation. Dimerization of SHC may have important biological implications in that it may promote the assembly of large heteromultimeric signaling complexes.