Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but ...the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77-22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80-32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21-5.85) and full siblings (OR=4.59, 95% CI: 4.39-4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.
The root cap surrounding the tip of plant roots is thought to protect the delicate stem cells in the root meristem. We discovered that the first layer of root cap cells is covered by an ...electron-opaque cell wall modification resembling a plant cuticle. Cuticles are polyester-based protective structures considered exclusive to aerial plant organs. Mutations in cutin biosynthesis genes affect the composition and ultrastructure of this cuticular structure, confirming its cutin-like characteristics. Strikingly, targeted degradation of the root cap cuticle causes a hypersensitivity to abiotic stresses during seedling establishment. Furthermore, lateral root primordia also display a cuticle that, when defective, causes delayed outgrowth and organ deformations, suggesting that it facilitates lateral root emergence. Our results show that the previously unrecognized root cap cuticle protects the root meristem during the critical phase of seedling establishment and promotes the efficient formation of lateral roots.
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•At early developmental stages, root caps of primary and lateral roots form a cuticle•This polyester-rich cuticle is lost with the removal of the first root cap cell layer•During germination, the root cap cuticle protects the sensitive root meristem•The cuticle of young lateral roots facilitates invasive growth and root emergence
A cuticle-like cell wall structure on plant root caps protects seedlings from abiotic stress and contributes to proper lateral root outgrowth.
The ability to reverse protein aggregation is vital to cells
. Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their ...central pore
. This model of disaggregation is appealing, as it could explain how polypeptides entangled within aggregates can be extracted and subsequently refolded with the assistance of Hsp70
. However, the model is also controversial, as the necessary motor activity has not been identified
and recent findings indicate non-processive mechanisms such as entropic pulling or Brownian ratcheting
. How loop formation would be accomplished is also obscure. Indeed, cryo-electron microscopy studies consistently show single polypeptide strands in the Hsp100 pore
. Here, by following individual ClpB-substrate complexes in real time, we unambiguously demonstrate processive translocation of looped polypeptides. We integrate optical tweezers with fluorescent-particle tracking to show that ClpB translocates both arms of the loop simultaneously and switches to single-arm translocation when encountering obstacles. ClpB is notably powerful and rapid; it exerts forces of more than 50 pN at speeds of more than 500 residues per second in bursts of up to 28 residues. Remarkably, substrates refold while exiting the pore, analogous to co-translational folding. Our findings have implications for protein-processing phenomena including ubiquitin-mediated remodelling by Cdc48 (or its mammalian orthologue p97)
and degradation by the 26S proteasome
.
Floral organs display tremendous variation in their exterior that is essential for organogenesis and the interaction with the environment. This diversity in surface characteristics is largely ...dependent on the composition and structure of their coating cuticular layer. To date, mechanisms of flower organ initiation and identity have been studied extensively, while little is known regarding the regulation of flower organs surface formation, cuticle composition, and its developmental significance. Using a synthetic microRNA approach to simultaneously silence the three SHINE (SHN) clade members, we revealed that these transcription factors act redundantly to shape the surface and morphology of Arabidopsis flowers. It appears that SHNs regulate floral organs' epidermal cell elongation and decoration with nanoridges, particularly in petals. Reduced activity of SHN transcription factors results in floral organs' fusion and earlier abscission that is accompanied by a decrease in cutin load and modified cell wall properties. SHN transcription factors possess target genes within four cutin- and suberin-associated protein families including, CYP86A cytochrome P450s, fatty acyl-CoA reductases, GSDL-motif lipases, and BODYGUARD1-like proteins. The results suggest that alongside controlling cuticular lipids metabolism, SHNs act to modify the epidermis cell wall through altering pectin metabolism and structural proteins. We also provide evidence that surface formation in petals and other floral organs during their growth and elongation or in abscission and dehiscence through SHNs is partially mediated by gibberellin and the DELLA signaling cascade. This study therefore demonstrates the need for a defined composition and structure of the cuticle and cell wall in order to form the archetypal features of floral organs surfaces and control their cell-to-cell separation processes. Furthermore, it will promote future investigation into the relation between the regulation of organ surface patterning and the broader control of flower development and biological functions.
ADHD is frequently diagnosed in children and adults. The disorder is highly heritable. However, the genetic architecture of ADHD is complex, with multiple genetic variants of individually small ...effect size contributing to disease in most patients.
In our own studies as well as in the large mega-analyses of the ENIGMA ADHD Working Group, we have investigated the brain substrates of ADHD. We find the disorder to be characterized by delayed sub–cortical and cortical growth of gray matter in childhood, which gradually normalizes in adulthood: sub–cortical volumes as well as cortical thickness and surface area are smaller in children with ADHD, but become indistinguishable from healthy individuals in adulthood. The situation looks different for white matter connectivity: both in childhood and adulthood, widespread differences in the major white matter tracts are found. The pattern of findings suggests that alterations in myelination might lie at the basis of such case-control differences. Since the disorder and many brain structural measures affected in ADHD are highly heritable, we investigated the overlap of genetic risk factors for ADHD with genetic factors involved in brain volume. This resulted in the identification of several genetic variants contributing to disease risk as well as ADHD-related brain phenotype.
In conclusion, we find ADHD to be a disorder of delayed brain maturation in terms of gray matter, but of persistently altered white matter connectivity across the lifespan. Genetic factors influencing both disease risk and brain measures might improve our understanding of disease etiology and persistence.
Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic ...variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.
Plants deposit hydrophobic polymers, such as lignin or suberin, in their root cell walls to protect inner tissues and facilitate selective uptake of solutes. Insights into how individual root tissues ...contribute to polymer formation are important for elucidation of ultrastructure, function, and development of these protective barriers. Although the pathways responsible for production of the barrier constituents are established, our models lack spatiotemporal resolution—especially in roots—thus, the source of monomeric barrier components is not clear. This is mainly due to our restricted ability to manipulate synthesis of the broadly important phenylpropanoid pathway, as mutants in this pathway display lethal or pleiotropic phenotypes. Here, we overcome this challenge by exploiting highly controlled in vivo repression systems. We provide strong evidence that autonomous production of phenylpropanoids is essential for establishment of the endodermal Casparian strip as well as adherence of the suberin matrix to the cell wall of endodermis and cork. Our work highlights that, in roots, the phenylpropanoid pathway is under tight spatiotemporal control and serves distinct roles in barrier formation across tissues and developmental zones. This becomes evident in the late endodermis, where repression of phenylpropanoid production leads to active removal of suberin in pre-suberized cells, indicating that endodermal suberin depositions might embody a steady state between continuous synthesis and degradation.
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•Autonomous production of phenylpropanoids is required for Casparian strip formation•Phenylpropanoids are essential for suberin deposition in endodermis and cork•Cork differentiation requires autonomous production of phenylpropanoids•Spatiotemporal repression of phenylpropanoids can dissect barrier functions
Andersen et al. show here that cell-autonomous phenylpropanoid production is required for root barrier formation and integrity.
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a ...major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. Here we report a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options.
The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in ...clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.
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