Genetics of child aggression, a systematic review.

Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.

Effects of Operating Mechanical Conditions and Polymer Networks of Nematic Elastomers on Photo-Induced Mechanical Performances.

Photoresponsive liquid-crystalline elastomers (LCEs) are promising candidates for light-controlled soft actuators. Photoinduced stress/strain originates from the changes in mechanical properties after light irradiation. However, the correlation between the photoinduced mechanical performance and in-use conditions such as stress/strain states and polymer network properties (such as effective crosslink density and dangling chain density) remains unexplored for practical applications. Here, isometric photo-induced stress or isotonic strain is investigated at different operating strains or stresses, respectively, on LCEs with polymer network variations, produced by different amounts of solvent during polymerization. As the solvent volume increases, the moduli and photoinduced stresses decrease. However, the photo-induced strain, fracture strain, fracture stress, and viscosity increase. The optical response performance initially increases with the operating strain/stress, peaks at a higher actuation strain/stress, and then, decreases depending on the polymer network. The maximum work densities, which also depend on the operating stress, are in the range of ≈200-300 kJm-3. These findings, highlighting the significant variations in the mechanical performance with the operating stress/strain ranges and amount of solvent used in the synthesis, are critical for designing LCE-based mechanical devices.

COMT Val/Met, stressful life events and externalizing behaviors in youth: A longitudinal study from the ABCD sample.

Early adolescence is a crucial time for understanding and detecting the risk factors that may influence youth externalizing/disruptive behaviors and disorders. Previous literature reported evidence that risk factors for disruptive behaviors include catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and environmental influences. An unanswered question is whether there is a change in these risk factors over stages of youth development. This longitudinal study examines the interaction effect of Val158Met and stressful life events (SLE) on youth externalizing behaviors from ages 9-11. Participants were 2363 children of European ancestry recruited as part of the Adolescent Brain Cognitive Development study. Repeated measures linear mixed models were used to examine the effect of the interaction between Val158Met and SLE (G × E) on disruptive behaviors over development. Externalizing behaviors were analyzed at both baseline and two-year follow-up. Both Val158Met genotype and SLE scores demonstrated significant main effects on disruptive behaviors in youth, and those effects were consistent at both time points. G × E was not associated with externalizing behaviors. Youth who carried the Val allele and/or were exposed to higher SLE consistently had increased externalizing behavior scores. To our knowledge, this is the first study to longitudinally examine the interaction effects of Val158Met and SLE on externalizing behaviors in youth. The results highlight the importance of understanding the genetic and environmental factors underlying externalizing behaviors for better detection of at-risk youth, helping further with early prevention efforts. The findings propose that COMT Val158Met genotype may act as a biomarker for development of novel treatment strategies for disruptive behaviors.

Exploring the association of interleukin polymorphisms with aggression and internalizing behaviors in children and adolescents.

BACKGROUND: There is growing evidence that inflammation influences mental health. Blood interleukin levels, which regulate inflammation, have been linked to aggression and internalizing behaviors. We performed a hypothesis-driven genetic study to (1) evaluate the association of IL1B, IL2, and IL6 gene variants with aggression and internalizing behaviors and (2) explore gene-environment interactions with childhood adversity in a deeply phenotyped childhood-onset aggression sample including 255 cases and 226 controls of European ancestry. METHODS: We evaluated the association of putative functional and tag SNPs within IL1B, IL2, and IL6 with aggression case status, parent-reported internalizing problems, self-reported anxiety symptoms, and self-reported depressive symptoms in our sample. We also performed exploratory GxE analyses within cases, testing for statistical interaction between interleukin SNP genotype and childhood adversity for depressive symptoms. RESULTS: No significant association was observed between any of the interleukin SNPs and childhood-onset aggression. We observed association of IL6 variant rs2069827 with depressive symptoms (p = 7.15×10-4 ), and trends for an interaction between severe childhood adversity and SNPs in IL1B and IL2 for depressive symptoms. CONCLUSIONS: Our findings provide preliminary evidence that common variation in IL6 may be associated with depressive symptoms in children and adolescents, and that common variation in interleukin genes may sensitize individuals to the depressogenic effects of traumatic life experiences. Replication in independent samples is needed.

Halogen bond-directed self-assembly in bicomponent blends at the solid/liquid interface: effect of the alkyl chain substitution position.

The fabrication of well-organised molecular assemblies on surfaces is fundamental for the creation of functional molecular systems applicable to nanoelectronic and molecular devices. In this study, we investigated the effect of substitution positions of alkyl chains on the formation of halogen-bonded molecular networks. For this purpose, building blocks with different head groups (i.e., pyridine (Py) or tetrafluoro-iodobenzene (FI)) were substituted with hexadecyloxy chains at either the 3,4- or the 3,5-positions. The two-dimensional assembly of each compound as a single-component system was studied using scanning tunnelling microscopy (STM) at the highly oriented pyrolytic graphite (HOPG)/1-phenyloctane interface. All compounds displayed linear structures in which the alkyl chains were aligned along one of the HOPG axes. In the exceptional case of FI bearing hexadecyloxy chains at the 3,5-positions (denoted as FI-3,5), hexagonal arrays were tentatively formed owing to the triangular molecular arrangement induced by halogen bonding. A bicomponent blend of Py-3,4/FI-3,5 (1 : 1 molar ratio) enabled the formation of a honeycomb structure, whereas that of Py-3,5/FI-3,4 (1 : 1 molar ratio) produced a rectangular assembly that was periodically arranged in a zig-zag fashion. Finally, based on the observed blend ratio dependence, the formation of these different two-dimensional structures by variation in the substitution positions of the alkyl chains was discussed in terms of molecule-molecule and molecule-substrate interactions.

Photo-Rewritable Glaring Patterns Composed of Stripe Domains in Nematic Elastomers.

Dynamic ordered micropatterns in polymeric materials provide an effective approach for the on-demand tuning of optical properties toward a smart optical material. In this study, it is shown that glaring patterns exhibiting strong anisotropic light diffusion can be developed at specific locations in nematic liquid-crystal elastomers with light-sensitive azobenzene units. Glaring originates from the stripe domains of the nematic directors that self-organize in light-irradiated regions after a simple uniaxial stretching and releasing process without any complicated lithographic technique. The nematic order transiently reduced by the photo-induced cis azobenzene isomers unlocks entropic elasticity, which induces local uniaxial shrinkage that causes buckling of the directors forming stripe domains. The written pattern on the film is tangibly visible with the backlight owing to the difference in anisotropic light diffusion. Furthermore, this pattern can be erased by light irradiation or thermal annealing. These films can be applied to optical elements for achieving augmented luminaries, security labeling, and sign-sheeting applications.

COMT Val/Met and Psychopathic Traits in Children and Adolescents: A Systematic Review and New Evidence of a Developmental Trajectory toward Psychopathy.

Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase (COMT) may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of COMT's role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of COMT Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the COMT Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of COMT Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the COMT genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies.

Association of the MAOA-uVNTR polymorphism with psychopathic traits may change from childhood to adolescence.

Psychopathic traits can lead to violence, making it a serious public health concern. Genetic factors contribute to the aetiology of psychopathy. We examined whether monoamine oxidase A (MAOA-uVNTR) was associated with psychopathic traits measured quantitatively from controls through clinically aggressive youth (n = 336). Subjects were sub-categorized into at or above, and below age 13 years. Results reveal that males below age 13 were more likely to display psychopathic traits with the MAOA long variant, whereas males above age 13 years were more likely to display with the short variant. This suggests that developmental factors may be crucial for understanding the role of the MAOA polymorphism in psychopathic traits in males.

Cephalopods-Inspired Rapid Self-Healing Nanoclay Composite Coatings with Oxygen Barrier and Super-Bubble-Phobic Properties.

Polymeric coatings with oxygen barrier properties are an important technology in food packaging that can extend the shelf life of food products and reduce waste. Although a typical technology in practical use is the deposition of metal or inorganic materials between multilayer films to reduce the oxygen transmission rate, once the film is damaged, oxygen permeates through the damaged area, damaging the packaged food. In addition, nanobrick wall structures consisting of nanoplatelet bricks have the potential to replace barrier films made of inorganic materials; however, they similarly lack repair performance or have slow repair speed despite having repair performance. Inspired by the rapid self-repair mechanism of cephalopods, the study develops a nanoclay-containing coating that can rapidly repair surface damage via water within 10 s. By introducing CaCl2-derived counterions and montmorillonite for nanobrick wall structures into polyelectrolyte multilayers stacked by layer-by-layer self-assembly, the noncovalent polymer network is increased, resulting in mimicking a strong cephalopod-derived ß-sheet structure and noncovalent intermolecular interactions derived from cephalopods. The high water retention at the surface showed super-bubble-phobicity in water and inhibited gas permeation. The oxygen permeability of the coatings with more than a certain amount of montmorillonite was less than 1/100 of that of bare polyethylene. The ultrafast self-healing gas barrier coating has the potential to be used not only for food products but also for electronics and pharmaceutical packaging and gas separation applications. The key technology developed in this study provides novel insights into the construction of self-healing membranes made of composite materials and will contribute to the formation of a sustainable society.

Evidence for association of vasopressin receptor 1A promoter region repeat with childhood onset aggression.

OBJECTIVE: Childhood onset aggression can cause major suffering to affected families and is associated with many negative outcomes in the child's later life, including poor academic performance, adolescent delinquency, drug abuse, depression and antisocial personality disorder. Currently available prevention and intervention strategies have limited efficacy, but a better understanding of underlying genetic and neurobiological factors can lead to more effective prevention and treatment strategies, through genetic screening programs and novel therapies. METHOD: This study examined the RS1 (n = 299 aggression, n = 192 controls) and RS3 (n = 291 aggression, n = 189 controls) microsatellite repeats within the promoter region of the vasopressin receptor 1A gene (AVPR1A) and their association with extreme childhood aggression, as assessed by the Child Behavior Checklist (CBCL), as well as the Teacher Report Form (TRF) and Youth Self Report (YSR). Binary logistic regression was used to model the relationship between microsatellite length and childhood aggression. Age and sex were used as covariates. RESULTS: Logistic regression revealed a nominally significant association between one specific RS3 repeat and non-aggressive status. No association was found for any of the RS1 repeats. In a separate model, grouping repeats into short and long, carriers of long RS3 repeats were nominally significantly associated with non-aggressive status. CONCLUSIONS: These findings suggest a role for AVPR1A and its RS3 microsatellite in extreme childhood aggression and could lead to a better understanding of the biological pathways of aggressive behavior. However, independent replication and further research into the functionality of studied genetic variants is required.

Increased levels of circulating cell-free mtDNA in plasma of late life depression subjects.

BACKGROUND: Oxidative stress (OS) has been implicated in the pathophysiology of late-life depression (LLD). Mitochondria are the primary source of oxidative stress and can be significantly damaged with increased OS. Circulating cell-free mtDNA (ccf-mtDNA) is a marker of cellular stress and mitochondria damage triggered by oxidative stress. METHODS: We evaluated the plasma levels of ccf-mtDNA in between 32 LLD and 21 never-depressed participants. We also investigated the association between ccf-mtDNA and the severity of depressive episodes and cognition performance. RESULTS: We found a higher ccf-mtDNA level in LLD cases compared with controls (t = -2.91, p = 0.005). Also, ccf-mtDNA was significantly correlated with the severity of depression (r = 0.42, p = 0.001). There was no significant correlation between ccf-mtDNA and measures of cognitive decline. LIMITATIONS: The small sample size and cross-sectional design were the main limitations of this study. CONCLUSION: Our results suggest that LLD is associated with elevated mitochondrial damage and cellular stress. If validated, the measurement of ccf-mtDNA in LLD can guide the development of novel treatments focused on cytoprotection and reduction of mitochondrial dysfunction for this condition.

Genome-wide association study of suicidal behaviour severity in mood disorders.

OBJECTIVE: Suicide is a major public health problem and it has a prominent genetic component. We performed a genome-wide association study (GWAS) of suicidal behaviour severity. METHODS: Suicide behaviour severity was assessed within the Schedules for Clinical Assessment in Neuropsychiatry in our mood disorder sample (n = 3506) for the GWAS. We also performed polygenic risk score analyses to explore genetic sharing between suicidal behaviour severity and a number of phenotypes, including bipolar disorder, major depressive disorder, alcoholism, post-traumatic stress disorder, impulsivity, insomnia, educational attainment, loneliness, maltreatment, and amygdala volume. RESULTS: We did not detect genome-wide significant findings at the single-marker or gene level. We report a number of suggestive single-marker and gene-based findings. Our polygenic risk score analyses did not yield significant findings with these phenotypes. CONCLUSIONS: Larger sample sizes are required to detect moderate effects.

Pharmacogenomic Studies in Intellectual Disabilities and Autism Spectrum Disorder: A Systematic Review.

BACKGROUND: Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID. METHODS: We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects). RESULTS: A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The DRD3 Ser9Gly (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the SLC6A4 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of CYP2D6 and DRD2 Taq1A polymorphisms, respectively, yielding mostly negative study findings. CONCLUSIONS: There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.

Dynamic host-guest behavior in halogen-bonded two-dimensional molecular networks investigated by scanning tunneling microscopy at the solid/liquid interface.

The fabrication of supramolecularly engineered two-dimensional (2D) networks using simple molecular building blocks is an effective means for studying host-guest chemistry at surfaces toward the potential application of such systems in nanoelectronics and molecular devices. In this study, halogen-bonded molecular networks were constructed by the combination of linear halogen-bond donor and acceptor ligands, and their 2D structures at the highly oriented pyrolytic graphite/1-phenyloctane interface were studied by scanning tunneling microscopy. The bi-component blend of the molecular building blocks possessing tetradecyloxy chains formed a lozenge structure via halogen bonding. Upon the introduction of an appropriate guest molecule (e.g., coronene) into the system, the 2D structure transformed into a hexagonal array, and the central pore of this array was occupied by the guest molecules. Remarkably, the halogen bonding of the original structure was maintained after the introduction of the guest molecule. Thus, the halogen-bonded molecular networks are applicable for assembling guest species on the substrate without the requirement of the conventional rigid molecular building blocks with C 3 symmetry.

Predicting risk of suicidal ideation in youth using a multigene panel for impulsive aggression.

Childhood traumatic experiences and impulsive aggression are strong predictors of suicide ideation in youth.  This study examines whether a gene panel previously associated with impulsive aggression, together with a measure of traumatic experience, will predict suicidal ideation in youth. The sample consisted of 158 youth (ages 9-17 years) of European ancestry that participated in a case-control study for childhood aggression.  The Massachusetts Youth Screening Instrument (MAYSI-2) was used to examine suicide ideation and traumatic experiences. The impulsive aggression gene panel consists of 5 markers across 5 susceptibility genes (CRH, CRHR2, MC2R, OXTR, BDNF). A multi-gene risk score (MRS) for each individual was calculated by taking the total number of risk genotypes for that person. The covariates for the multiple regression model included sex, age, symptoms of anxiety/depression, MRS, traumatic experiences, and MRS x traumatic experience interaction. Results show the MRS x traumatic experience interaction term and the anxious/depressed symptoms to be significant predictors of suicide ideation in the full model. Importantly, genetic susceptibility to impulsive aggression and traumatic experiences remained a significant predictor for suicide ideation over and above the youth's level of anxiety and depression. This finding may have important implications for early intervention for youth suicide-related behaviors.

Hexagonal array formation by intermolecular halogen bonding using a binary blend of linear building blocks: STM study.

Hexagonal arrays were fabricated via intermolecular halogen bonding between two linear molecular building blocks in a bicomponent blend. The substitution position of the pyridine N atom involved in the halogen bond plays an important role in the formation of the hexagonal structures.

Microwave Flow: A Perspective on Reactor and Microwave Configurations and the Emergence of Tunable Single-Mode Heating Toward Large-Scale Applications.

Microwave heating in chemical reactions was first reported in 1986. There have since been many reports employing microwave heating in organic chemistry, where microwave heating has afforded higher yields of products in shorter time periods. However, such reactions are challenging to scale in batch due to the limited penetration depth of microwaves as well as the wave propagation dependence on cavity size. Continuous flow has addressed both these issues, enabling scalability of microwave processes. As such, a host of reports employing microwave flow chemistry have emerged, employing various microwave heating and reactor configurations in the context of either custom-built or commercial apparatus. The focus of this review is to present the benefits of microwave heating in the context of continuous flow and to characterize the different types of microwave flow apparatus by their design (oscillator, cavity type and reactor vessel). We advocate the adoption of tunable, solid-state oscillator single-mode microwave flow reactors which are more versatile heaters, impart better process control and energy efficiency toward laboratory and larger-scale synthetic chemistry applications.

Light-induced mechanical response in crosslinked liquid-crystalline polymers with photoswitchable glass transition temperatures.

Energy conversion of light into mechanical work is of fundamental interest in applications. In particular, diligent molecular design on nanoscale, in order to achieve efficient photomechanical effects on macroscopic scale, has become one of the most interesting study topics. Here, by incorporating a "photomelting" azobenzene monomer crosslinked into liquid crystalline (LC) networks, we generate photoresponsive polymer films that exhibit reversible photoswitchable glass transition temperatures (Tg) at room temperature (~20 °C) and photomechanical actuations under the stimulus of UV/visible light. The trans-to-cis isomerization of azo chromophores results in a change in Tg of the crosslinked LC polymers. The Tg of the polymer network is higher than room temperature in the trans-form and lower than room temperature in the cis-form. We demonstrate the photoswitchable Tg contribute to the photomechanical bending and a new mechanism for photomechanical bending that attributes the process to an inhomogeneous change in Tg of the film is proposed.

Cannabis use, other substance use, and co-occurring mental health concerns among youth presenting for substance use treatment services: Sex and age differences.

Cannabis use among youth is of significant concern given the potential negative health impacts on young people. This study describes the mental health characteristics, cannabis use, and substance use profiles of youth aged 14 to 24 years seen at the Youth Addiction and Concurrent Disorders Service at the Centre for Addiction and Mental Health, through an age and gender lens. Almost all participating youth indicated lifetime cannabis use. Substance use and mental health profiles among those indicating a history of cannabis use differed along sex and age. Male youth were more likely to use cannabis more frequently, while female youth were more likely to use greater variety of substances and display more co-occurring mental health problems. Adolescent problematic substance use tended to co-occur with externalizing problems whereas problematic young adult substance use tended to co-occur with internalizing problems. Implications for the integrated, coordinated care of substance use and mental health concerns, with attention to the unique needs of subgroups of youth, are discussed.

Selective, Scalable Synthesis of C60-Fullerene/Indene Monoadducts Using a Microwave Flow Applicator.

The synergy of continuous processing and microwave heating technologies has unlocked scalable (g/h), safe and efficient reaction conditions for synthesis of fullerene/indene-based organic photovoltaic acceptor materials in a nonchlorinated solvent with levels of productivity unparalleled by previous syntheses. The microwave flow reactor sustains high temperature while employing short residence times, reaction conditions which uniquely allow the selective synthesis of fullerene/indene monoadducts. Design of experiments analysis revealed residence time as the most crucial factor for conversion and selectivity control.