Attention-deficit/hyperactivity disorder and adverse health outcomes : from association to prevention

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder, characterized by persistent inattention and/or hyperactivity-impulsivity that are inappropriate for one’s developmental stage. Individuals with ADHD suffer from adverse outcomes including somatic and psychiatric comorbidities. ADHD is also associated with increased risk of factors that may impose higher mortality risks. However, evidence has been limited on the association between ADHD and somatic diseases such as asthma. Also, the association between ADHD and premature death, as well as the potential effects of ADHD medication treatment is largely unknown. The overarching aim of this thesis is to investigate the associations between ADHD and specific adverse outcomes including asthma and premature death. Individual studies were conducted to clarify the magnitude and etiology of the associations, as well as potential effects from medication treatment that may prevent poor prognosis. In Study I, we combined a meta-analysis of existing studies and a Swedish national population-based analysis to investigate the population-level association between asthma and ADHD. In the meta-analysis, we found a significant cross-sectional association between asthma and ADHD when considering both unadjusted and adjusted odds ratios. The sub-group and meta-regression analyses showed consistently robust results across study settings. Estimates of the association from the Swedish population analysis were similar with the pooled results from the meta-analysis, and the association remained statistically significant after adjustment of potential confounders in the population-based analysis. In Study II, we investigated the familial liability to the comorbidity between asthma and ADHD. In the familial co-aggregation analysis, relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma. The association was strongest in monozygotic twins and attenuated with decreasing degree of genetic relatedness. Results from the twin modelling analysis supported that a substantial part of the association between asthma and ADHD was explained by genetic factors. Estimates for contributions from shared and non-shared environment factors were not statistically significant. In Study III, we investigated the all-cause and cause-specific mortality risks in ADHD and the role of psychiatric comorbidity. We found that ADHD was associated with significantly increased all-cause and cause-specific mortality risks, with suicide and unintentional injuries being the leading causes of death. Psychiatric comorbidity largely mediated the elevated mortality risks in ADHD, as the mortality risks increased substantially with the number of comorbid psychiatric disorders. Early-onset disorders such as conduct disorders contributed substantially to the association for natural deaths, while later-onset disorders such as substance use disorders may have mediated most of the risk for unnatural deaths in ADHD. In Study IV, we investigated how ADHD medication initiation and continuation associated with mortality risks among individuals with ADHD. During follow-up to a maximum of 2 years, the mortality rates due to any cause and unnatural causes were significantly lower among those who initiated medication treatment compared to those who had not initiated medication. Among individuals who had been on ADHD medication for up to 6 months after diagnosis, continuation of medication treatment was significantly associated with substantially lower all-cause and unnatural cause-specific mortality risks including suicide and unintentional injuries compared to discontinuation. In summary, results of Study I and II together support the significant association between asthma and ADHD. The comorbidity may largely be explained by shared etiology, with substantial influences from shared genetic factors. The findings also point out shared genetic factors as an important direction to understand the mechanisms of adverse conditions related to ADHD other than asthma. Study III and IV together reveal that ADHD is associated with significantly increased all-cause and cause-specific mortality risks, and ADHD medication treatment may help to reduce the risks. The findings point out medication treatment as a promising way to prevent extremely severe adverse outcomes among individuals with ADHD. In conclusion, findings from this thesis work support that individuals with ADHD are at increased risk of adverse outcomes including somatic conditions such as asthma and severe adversities such as premature death. Shared genetic factors largely explained the association between asthma and ADHD, indicating the significance of detecting within-individual and family history of either disorder for preventing delayed diagnosis of the other condition. Moreover, psychiatric comorbidities and medication treatment play crucial roles in understanding the mechanisms of ADHD associated mortality risks and in preventing premature deaths among individuals with ADHD

Co-community Structure in Time-varying Networks

In this report, we introduce the concept of co-community structure in time-varying networks. We propose a novel optimization algorithm to rapidly detect co-community structure in these networks. Both theoretical and numerical results show that the proposed method not only can resolve detailed co-communities, but also can effectively identify the dynamical phenomena in these networks.Comment: 5 pages, 6 figure

The Dynamics Analysis of Two Delayed Epidemic Spreading Models with Latent Period on Heterogeneous Network

Two novel delayed epidemic spreading models with latent period on scale-free network are presented. The formula of the basic reproductive number and the analysis of dynamical behaviors for the models are presented. Meanwhile, numerical simulations are given to verify the main results

The recombinant adeno-associated virus vector (rAAV2)-mediated apolipoprotein B mRNA-specific hammerhead ribozyme: a self-complementary AAV2 vector improves the gene expression

BACKGROUND: In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels of apoB mRNA, we have designed an apoB mRNA-specific hammerhead ribozyme targeted at nucleotide sequences GUA(6679 )(RB15) mediated by adenovirus, which efficiently cleaves and decreases apoB mRNA by 80% in mouse liver and attenuates the hyperlipidemic condition. In the current study, we used an adeno-associated virus vector, serotype 2 (AAV2) and a self-complementary AAV2 vector (scAAV2) to demonstrate the effect of long-term tissue-specific gene expression of RB15 on the regulation apoB mRNA in vivo. METHODS: We constructed a hammerhead ribozyme RB15 driven by a liver-specific transthyretin (TTR) promoter using an AAV2 vector (rAAV2-TTR-RB15). HepG2 cells and hyperlipidemic mice deficient in both the low density lipoprotein receptor and the apoB mRNA editing enzyme genes (LDLR-/-Apobec1-/-; LDb) were transduced with rAAV2-TTR-RB15 and a control vector rAAV-TTR-RB15-mutant (inactive ribozyme). The effects of ribozyme RB15 on apoB metabolism and atherosclerosis development were determined in LDb mice at 5-month after transduction. A self-complementary AAV2 vector expressing ribozyme RB15 (scAAV2-TTR-RB15) was also engineered and used to transduce HepG2 cells. Studies were designed to compare the gene expression efficiency between rAAV2-TTR-RB15 and scAAV2-TTR-RB15. RESULTS: The effect of ribozyme RB15 RNA on reducing apoB mRNA levels in HepG2 cells was observed only on day-7 after rAAV2-TTR-RB15 transduction. And, at 5-month after rAAV2-TTR-RB15 treatment, the apoB mRNA levels in LDb mice were significantly decreased by 43%, compared to LDb mice treated with control vector rAAV2-TTR-RB15-mutant. Moreover, both the rAAV2-TTR-RB15 viral DNA and ribozyme RB15 RNA were still detectable in mice livers at 5-month after treatment. However, this rAAV2-TTR-RB15 vector mediated a prolonged but low level of ribozyme RB15 gene expression in the mice livers, which did not produce the therapeutic effects on alteration the lipid levels or the inhibition of atherosclerosis development. In contrast, the ribozyme RB15 RNA mediated by scAAV2-TTR-RB15 vector was expressed immediately at day-1 after transduction in HepG2 cells. The apoB mRNA levels were decreased 47% (p = 0.001), compared to the control vector scAAV2-TTR-RB15-mutant. CONCLUSION: This study provided evidence that the rAAV2 single-strand vector mediated a prolonged but not efficient transduction in mouse liver. However, the scAAV2 double-strand vector mediated a rapid and efficient gene expression in liver cells. This strategy using scAAV2 vectors represents a better approach to express small molecules such as ribozyme

Biomolecular network querying: a promising approach in systems biology

The rapid accumulation of various network-related data from multiple species and conditions (e.g. disease versus normal) provides unprecedented opportunities to study the function and evolution of biological systems. Comparison of biomolecular networks between species or conditions is a promising approach to understanding the essential mechanisms used by living organisms. Computationally, the basic goal of this network comparison or 'querying' is to uncover identical or similar subnetworks by mapping the queried network (e.g. a pathway or functional module) to another network or network database. Such comparative analysis may reveal biologically or clinically important pathways or regulatory networks. In particular, we argue that user-friendly tools for network querying will greatly enhance our ability to study the fundamental properties of biomolecular networks at a system-wide level

Nonlinear dynamic analysis for high speed gear-rotor-bearing system of the large scale wind turbine

In this paper, an eight-degree-of-freedom (8-DOF) lumped parameter dynamic model considering the coupled lateral-torsional vibration is proposed and the coupled multi-body dynamics of the spur gear rotor bearing system is studied containing backlash, transmission error, eccentricity, gravity and time-variant mesh stiffness. Based on the dynamical equations, the coupled dynamic response of the system is investigated using the Runge-Kutta method and the effects of error fluctuation and load fluctuation on the dynamic responses are demonstrated by 3-D frequency spectrum bifurcation diagram, etc. The results show that a diverse range of nonlinear dynamic characteristics such as periodic, chaotic behaviors and impacts exhibited in the system are strongly attributed to the interaction between internal and external excitations. For gear system, the dynamic behaviors are analyzed in light, middle and high rotational speed conditions. With the increase rotational speed, the vibration amplitude increase markedly and the region of the chaotic motion become narrow gradually. At the low rotational speed, the chaos behavior turns out more easily, and the vibration intensity relatively weak. With the increase rotational speed, the vibration amplitude obvious increase, and the characteristics of the chaos strengthen and turns backward. This study may contribute to a further understanding about the spur gear bearing system with the coupled internal and external excitation

Revealing divergent evolution, identifying circular permutations and detecting active-sites by protein structure comparison

BACKGROUND: Protein structure comparison is one of the most important problems in computational biology and plays a key role in protein structure prediction, fold family classification, motif finding, phylogenetic tree reconstruction and protein docking. RESULTS: We propose a novel method to compare the protein structures in an accurate and efficient manner. Such a method can be used to not only reveal divergent evolution, but also identify circular permutations and further detect active-sites. Specifically, we define the structure alignment as a multi-objective optimization problem, i.e., maximizing the number of aligned atoms and minimizing their root mean square distance. By controlling a single distance-related parameter, theoretically we can obtain a variety of optimal alignments corresponding to different optimal matching patterns, i.e., from a large matching portion to a small matching portion. The number of variables in our algorithm increases with the number of atoms of protein pairs in almost a linear manner. In addition to solid theoretical background, numerical experiments demonstrated significant improvement of our approach over the existing methods in terms of quality and efficiency. In particular, we show that divergent evolution, circular permutations and active-sites (or structural motifs) can be identified by our method. The software SAMO is available upon request from the authors, or from and . CONCLUSION: A novel formulation is proposed to accurately align protein structures in the framework of multi-objective optimization, based on a sequence order-independent strategy. A fast and accurate algorithm based on the bipartite matching algorithm is developed by exploiting the special features. Convergence of computation is shown in experiments and is also theoretically proven