Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is... Show moreFacioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder that mainly affects the muscles of the face, shoulders and upper arms. Skeletal muscle wasting in FSHD is caused by the failure to epigenetically repress the transcription factor DUX4 that is typically expressed during early development. DUX4 expression in skeletal muscle induces several myotoxic cascades that ultimately lead to the death of skeletal muscles cells. At the moment there is no molecular therapy that can delay or stop disease progression. The work described in this thesis mainly aims to gain more insight in the different FSHD mouse models and the in vivo testing of new therapies in FSHD mice. We describe the generation of one new mouse model and the characterization of two other FSHD mouse models. In addition, we tested a RNA therapy that blocks the DUX4 transcript in vivo. We show that this therapy could reduce DUX4 and DUX4 target genes in FSHD mice. In addition, the therapy alleviated the severity of skeletal muscle pathology. With the data described in this thesis we hope to accelerate the development and testing of new therapies for a disease that cannot be treated until this day. Show less
To advance our understanding of the histone acylation regulators and the response to DNA replication stress, we employ a variety of genetic screening techniques together with follow-up experiments... Show moreTo advance our understanding of the histone acylation regulators and the response to DNA replication stress, we employ a variety of genetic screening techniques together with follow-up experiments in yeast. By employing Epi-ID, we interrogated a common chromatin locus in the yeast deletion and DaMP collection. This was successful in identifying new histone acetylation and acylation regulators and we describe the crotonyltransferase activities of the ADA and NuA4 complexes. Increased crotonylation levels stimulated gene expression dependent on the activity of the HATs Gcn5 and Esa1, suggesting a role for these enzymes in the crotonylation-dependent transcriptional regulation. Additionally, extensive antibody validation studies revealed that non-acetyl pan-lysine specific acylation antibodies had a severe lack of specificity.To identify new regulators of replication stress, we developed a novel approach called Replication-Identifier (Repli-ID), which we used to investigate the accumulation of replicative polymerase ε near a barcoded origin of replication in mutant yeast collections. We demonstrate that this method is effective for studying DNA polymerase occupancy directly on chromatin and we identify new regulators of DNA replication fork progression/stability.Finally, we identify and characterize the Mediator complex in the replication stress response. We show how Mediator reduces replication stress by preventing R-loop formation. Show less
Epigenetic regulation of gene expression by chromatin modifiers is one of the fundamental cellular processes that allow the different cell types in the body to develop from the totipotent embryonic... Show moreEpigenetic regulation of gene expression by chromatin modifiers is one of the fundamental cellular processes that allow the different cell types in the body to develop from the totipotent embryonic stem cells. However, when this epigenetic control mechanism becomes compromised, such as by mutations in chromatin modifiers, it can lead to the development of disease. An example of such epigenetic disease is facioscapulohumeral muscular dystrophy (FSHD), in which the chromatin structure of the D4Z4 macrosatellite repeat is compromised. The loss of a repressive D4Z4 chromatin structure either by contraction of the repeat to a size of 1-10 D4Z4 units (FSHD1), or by mutations in D4Z4 chromatin repressors such as SMCHD1 (FSHD2), results in inappropriate expression of the DUX4 gene from the repeat in skeletal muscle, which is considered the root cause of FSHD.In FSHD, DUX4 expression causes apoptosis, leading to muscle wasting in the patient. In this thesis, we studied the functionality of SMCHD1, and aimed to understand the DUX4 repressive processes in which SMCHD1 is involved. Furthermore, we gathered information on the different roles that SMCHD1 fulfills, such as X-chromosome inactivation in female cells and telomere maintenance. Show less
Maas, S.C.E.; Vidaki, A.; Teumer, A.; Costeira, R.; Wilson, R.; Dongen, J. van; ... ; Kayser, M. 2021
Background Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol... Show moreBackground Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 +/- 0.06, while the 5 and 23 CpG models achieved 0.83 +/- 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 +/- 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets. Conclusions The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications. Show less
Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to... Show morePsychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks ('modules') using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes. Show less
Abu Hamdeh, S.; Tenovuo, O.; Peul, W.; Marklund, N. 2021
Background To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete... Show moreBackground To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics. Methods In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI. Results The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI. Conclusion The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future. Show less
Bacalini, M.G.; Reale, A.; Malavolta, M.; Ciccarone, F.; Moreno-Villanueva, M.; Dolle, M.E.T.; ... ; Zampieri, M. 2021
Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give... Show moreAgeing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated. Show less
Melanoma is the most aggressive and lethal type of skin cancer since it has the ability to spread to other organs in the body making it harder to control the disease.In this thesis, we aim to... Show moreMelanoma is the most aggressive and lethal type of skin cancer since it has the ability to spread to other organs in the body making it harder to control the disease.In this thesis, we aim to explore the degree to which epigenetics play a role in melanoma, namely, inherited and acquired epigenetic alterations in melanoma susceptibility and development. Show less
Bouwman, L.F.; Hamer, B. den; Verveer, E.P.; Lerink, L.J.S.; Krom, Y.D.; Maarel, S.M. van der; Greef, J.C. de 2020
Background Facioscapulohumeral muscular dystrophy (FSHD) is a skeletal muscle disorder that is caused by derepression of the transcription factor DUX4 in skeletal muscle cells. Apart from SMCHD1,... Show moreBackground Facioscapulohumeral muscular dystrophy (FSHD) is a skeletal muscle disorder that is caused by derepression of the transcription factor DUX4 in skeletal muscle cells. Apart from SMCHD1, DNMT3B was recently identified as a disease gene and disease modifier in FSHD. However, the exact role of DNMT3B at the D4Z4 repeat array remains unknown. Methods To determine the role of Dnmt3b on DUX4 repression, hemizygous mice with a FSHD-sized D4Z4 repeat array (D4Z4-2.5 mice) were cross-bred with mice carrying an in-frame exon skipping mutation inDnmt3b(Dnmt3b(MommeD14)mice). Additionally, siRNA knockdowns ofDnmt3bwere performed in mouse embryonic stem cells (mESCs) derived from the D4Z4-2.5 mouse model. Results In mESCs derived from D4Z4-2.5 mice, Dnmt3b was enriched at the D4Z4 repeat array and DUX4 transcript levels were upregulated after a knockdown ofDnmt3b. In D4Z4-2.5/Dnmt3b(MommeD14)mice, Dnmt3b protein levels were reduced; however, DUX4 RNA levels in skeletal muscles were not enhanced and no pathology was observed. Interestingly, D4Z4-2.5/Dnmt3b(MommeD14)mice showed a loss of DNA methylation at the D4Z4 repeat array and significantly higher DUX4 transcript levels in secondary lymphoid organs. As these lymphoid organs seem to be more sensitive to epigenetic modifiers of the D4Z4 repeat array, different immune cell populations were quantified in the spleen and inguinal lymph nodes of D4Z4-2.5 mice crossed with Dnmt3b(MommeD14)mice or Smchd1(MommeD1)mice. Only in D4Z4-2.5/Smchd1(MommeD1)mice the immune cell populations were disturbed. Conclusions Our data demonstrates that loss of Dnmt3b results in derepression of DUX4 in lymphoid tissues and mESCs but not in myogenic cells of D4Z4-2.5/Dnmt3b(MommeD14)mice. In addition, the Smchd1(MommeD1)variant seems to have a more potent role in DUX4 derepression. Our studies suggest that the immune system is particularly but differentially sensitive to D4Z4 chromatin modifiers which may provide a molecular basis for the yet underexplored immune involvement in FSHD. Show less
Greco, A.; Goossens, R.; Engelen, B. van; Maarel, S.M. van der 2020
Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1... Show moreFacioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus. Show less
Background Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450... Show moreBackground Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. Results Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 x 10(-08)) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. Conclusions This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD. Show less
Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications.... Show moreInferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 +/- 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC(crossvalidation) 0.925 +/- 0.021, AUC(externalvalidation)0.914), former (0.766 +/- 0.023, 0.699) and never smoking (0.830 +/- 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 +/- 0.068, 0.796; 15 pack-years 0.767 +/- 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 +/- 0.024, 0.760; 10 years 0.766 +/- 0.033, 0.764; 15 years 0.767 +/- 0.020, 0.754). Model application to children revealed highly accurate inference of the true non- smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications. Show less
The studies presented in the work show the potential of the integrative use of biophysical data in defining the structural basis of protein interactions. Even if the results obtained hold a... Show moreThe studies presented in the work show the potential of the integrative use of biophysical data in defining the structural basis of protein interactions. Even if the results obtained hold a degree of ambiguity, this approach allows to iteratively refine and validate the model and interpret its meaning for the molecular basis of protein function. Often all three points at the same time. This dynamic nature makes the use of structural models in the design of therapeutic compounds especially useful since the inhibition of a certain protein function might not require a structure to be accurate down to the last atom but rather highlight key interactions or structural features that can be addressed in context of small molecule or peptide inhibitors. Presented are the use of strucutral biochemistry techniques to investigate the mechanism of how the ubiquitine ligase PSIP1 obtains its target specificity. Furthermore, another epigenetic effector protein PSIP1 is investigated with the aim to develop a workflow for the design of potential peptide-based inhibitors. Show less
In human cells, a meter-long DNA is condensed inside a micrometer-sized cell nucleus. Simultaneously, the genetic code must remain accessible for its replication and transcription to functional... Show moreIn human cells, a meter-long DNA is condensed inside a micrometer-sized cell nucleus. Simultaneously, the genetic code must remain accessible for its replication and transcription to functional proteins. Such plasticity of the genome is maintained by dynamic folding and unfolding of DNA-protein spools called nucleosomes. It is unclear, however, how this process is controlled when multiple nucleosomes stack on top of each other and form compact chromatin fibers. This is particularly important since nucleosomes are rarely present in isolation inside a densely packed cell nucleus. Therefore, the aim of this thesis was to increase the understanding of the chromatin fiber structure and its dynamics. Knowing these details would provide many new insights into the mechanisms of gene expression (epigenetic regulation) which, upon malfunction, may cause severe diseases. The presented work consists of an experimental approach involving the application of single-molecule force spectroscopy, and makes use of theoretical modelling based on statistical mechanics. By using magnetic tweezers, we stretched and twisted individual chromatin fibers reconstituted in vitro in order to unfold its nucleosomes. These studies show that folding of nucleosomes into chromatin fibers opens up a plethora of regulatory pathways for controlling the level of DNA organization in cells. Show less
Cardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to... Show moreCardiovascular disease (CVD) is the collective term for diseases that involve the heart or circulation and CVDs are a major cause of mortality and morbidity worldwide. The aim of thesis was to investigate the role of inflammation in CVD related cardiac and vascular remodelling, which may lead to potential therapeutic agents. We investigated the therapeutic potential of antibodies directed against phosphorylcholine (PC), an endogenous ligand capable of triggering the innate immune system, which is expressed by apoptotic cells and oxidized LDL, in mouse models for myocardial infarction (MI). We found that treatment with anti-PC antibodies reduces adverse cardiac remodelling after both permanent MI as myocardial ischemia reperfusion (MI-R) injury. Furthermore, we found that treatment with annexin A5 also reduces adverse cardiac remodelling after MI-R injury. Interestingly, both anti-PC as annexin A5 treatment reduced the post MI inflammatory response. Next, we investigated the role of PCAF, an inflammatory related epigenetic factor, in vascular remodelling. We found that PCAF deficiency and treatment with a PCAF inhibitor reduces adverse vascular remodelling. Finally, we investigated the role of microRNAs, small RNA molecules that can affect expression of many different gene simultaneously, in vascular remodelling. We show that inhibition of microRNA-495 reduces adverse vascular remodelling. Show less
Numerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and... Show moreNumerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and environmental factors are involved in the onset of autoimmunity. Which mechanisms explain the contribution of these genetic and environmental factors to disease pathogenesis, and how the different factors interplay remain unanswered key questions. The studies presented in this thesis aimed at identifying and unravelling some of the enigmatic mechanisms in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Show less
In this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric... Show moreIn this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. In FSHD there is hypomethylation of the macrosatellite repeat D4Z4 and the associated DUX4 gene, which is caused by a repeat contraction and/or variants in chromatin modifiers essential for a repressive D4Z4 chromatin structure in somatic cells. In ICF there is hypomethylation of centromeric repeats, which is caused by recessive variants in one of four ICF genes, of which two are established chromatin modifiers. In this thesis, the mutation spectrum of FSHD and ICF has been expanded. The SMCHD1 mutation spectrum in FSHD2 has been expanded with the discovery of exonic SMCHD1 variants, intronic SMCHD1 variants, and whole SMCHD1 gene deletions. In addition, we identified heterozygous variants in a new FSHD2 gene, DNMT3B, in two FSHD2 families. For ICF syndrome we expanded the mutation spectrum in the two most common ICF genes, DNMT3B and ZBTB24. Show less
The work presented in this thesis provides important new clues on the neurobiology of juvenile psychopathic traits in clinically antisocial juveniles. The data specifically shows that these... Show moreThe work presented in this thesis provides important new clues on the neurobiology of juvenile psychopathic traits in clinically antisocial juveniles. The data specifically shows that these traits are ostensibly underpinned by highly specific corticolimbic network dysfunctions, in which amygdala subregional networks seem particularly relevant. That data additionally suggests that some of these network dysfunctions and their associated neurocognitive deficits are possibly driven by alterations in the oxytocinergic system. Interestingly, the data also provides preliminary neurobiological support for the scientific utility of using juvenile psychopathic traits to subtype the highly heterogeneous group of clinically antisocial teens. While these data may represent important new steps towards a deeper understanding of clinical youth antisociality, their significance has to be evaluated by replication studies that further explore and validate the findings presented here. Show less
Bacalini, M.G.; Deelen, J.; Pirazzini, C.; Cecco, M. de; Giuliani, C.; Lanzarini, C.; ... ; Garagnani, P. 2017
