BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.This article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.Wellcome Trust (grant number WT098051)Published (open access

Moisture-induced stress and distortion of wood : A numerical and experimental study of wood's drying and long-term behaviour

With the current advances made in three-dimensional modelling of wood, it is possible to provide an overall picture of moisture flow, and moisture-induced stress and deformations, whereas previously, experiments only provided local measurements. The main aim of the doctoral thesis is to investigate the possibilities of the developed three-dimensional numerical model to predict the behaviour of wood when simultaneously exposed to a mechanical load and a particular climate. Three applications in the fields of wood drying and long-term behaviour of wood are considered: 1) the effect of green-state moisture content on the drying behaviour of timber boards, 2) the calibration of the numerical model based on a long-term four-point bending tests using small wood beams subjected to a constant temperature and systematic relative humidity (RH) changes, and 3) the validation of the numerical model by means of a long-term four-point bending test on solid timber beams subjected to Northern European climate. As part of the second application, an experimental methodology and analytical method were designed. The numerical model was developed in finite element software Abaqus FEA® and consists of several user-subroutines to include material orientation (i.e. annual ring pattern, conical shape and spiral grain), and the selected constitutive behaviour and required boundary conditions. To simulate the moisture flow, a nonlinear single-Fickian approach was combined with a nonlinear Neumann boundary condition, which describes the flux normal to the exchange surface based on a moisture and temperature dependent surface emission coefficient. A strain relation was used that accounts for hygro-expansion, and the elastic, creep and mechano-sorptive behaviour. The analytical method describes the elastic and creep deflection in the constant moment area of the four-point bending setup, and was used to isolate and assess the mechano-sorption deflection in the cumulative moisture content domain. The results show that the three-dimensional character of the numerical model contributed to the analysis and visualisation of the different stress states and deformations that are affected by material properties that vary (i.e. from pith to bark, between heartwood and sapwood, and due to temperature and moisture content), fibre orientation and climate. The simulations made on timber boards clarified phenomena, such as stress reversal and casehardening associated with wood drying, and showed that the green-state moisture content affected the time, size and frequency with which extremes in tangential tensile stress developed inside the timber during drying. The results of the calibration and validation indicated that the numerical model is able to describe moisture change and gradients in the considered temperature and relative humidity ranges (between -2-60℃ and 40-80% RH), as well as the deflection. The experimental methodology and analytical method led to a successful identification of each deflection component and isolation of the mechano-sorptive deflection curves. The experimental methodology benefitted the calibration of the numerical model. In conclusion, the presented three-dimensional numerical model compatible with Abaqus FEA® provides a powerful tool for scientists and timber engineers to study the combined effect of load and climate on stress state and deformations of various timber products in a wide field of applications

An overview of lab-based micro computed tomography aided finite element modelling of wood and its current bottlenecks

Microscopic lab-based X-ray computed tomography (XµCT) aided finite element (FE) modelling is a popular method with increasing nature within material science to predict local material properties of heterogeneous materials, e.g. elastic, hygroexpansion and diffusion. This method is relatively new to wood and lacks a clear methodology. Research intended to optimise the XµCT aided FE process often focuses on specific aspects within this process such as the XµCT scanning, segmentation or meshing, but not the entirety of the process. The compatibility and data transfer between aspects have not been investigated to the same extent, which creates errors that propagate and negatively impact the end results. In the current study, a methodology for the XµCT aided FE process of wood is suggested and its bottlenecks are identified based on a thorough literature review. Although the complexity of wood as a material makes it difficult to automate the XµCT aided FE process, the proposed methodology can assist in a more considered design and execution of this process. The main challenges that were identified include an automatic procedure to reconstruct the fibre orientation and to perform segmentation and meshing. A combined deep-learning segmentation method with geometry-based meshing can be suggested

A numerical study of the effect of green-state moisture content on stress development in timber boards during drying

Timber boards manufactured with a traditional sawing pattern often contain both heartwood andsapwood. In such boards, internal constraints can occur during drying because of a radial variation in greenstate(GS) MC between the heartwood (30-60%) and sapwood region (120-200%). Despite such knowledge,the initial MC is seldom considered when evaluating kiln-drying schedules. The effect of GS MC on thedevelopment of tangential tensile stress during drying is studied for four types of timber boards. A numericalmodel was developed that can simulate transient nonlinear orthotropic moisture flow and moisture–inducedstress and distortion in wood with the use of the finite element method. The stress analysis considers elastic,hygroscopic, and mechano-sorptive strain. The study shows that the GS MC does not significantly influencethe maximum stress state, but that it does influence the time at which the maximum tangential tensile stressoccurs at different exchange surfaces. This results in several periods in the drying schedule where unfavorablehigh stress situations in the tangential direction arise, which could lead to crack propagation

Numerical simulation of moisture driven fracture in mechanical timber connection using XFEM

Structural timber and glulam elements are an appealing alternative when it comes to choosing between structural elements as load bearing parts in e.g. halls, arenas and residential buildings. The wooden material is relatively strong in respect to its weight and its stiffness is sufficient enough to allow its use in a wide range of applications. However, there are also challenges associated with handling the material, one of which is the dimensional instability associated with moisture changes. The effect of climate variations on moisture induced deformations, stresses and failure in timber structures has already been addressed by several researchers, see e.g. [1] and [2]. A numerical model developed in the finite element package Abaqus is proposed herein to simulate crack propagation caused by variation in climate. In mechanical connections moisture induced strains in combination with boundary conditions that introduces constraints can lead to crack development and in turn weakening of wooden structures. Previous application of fracture mechanics typically focused on crack development caused by pure mechanical loading, see e.g. [3] for methods summarized and typical applications. Within the scope of the current work a numerical model is presented to simulate moisture driven crack growth within the beam/column dowel group connection shown in Figure 1. The model consists of two dimensional hygro-mechanical plane stress and XFEM analysis coupled to a nonlinear transient moisture flow analysis. A visualization of the considered problem is given in Figure 1. This figure shows a beam to column connection, which is exposed to natural climate variation (a). A schematic description of the problem is shown in Figure 1 (b). Figure 1 (c) shows simulated moisture content gradient and significant cracked beam because of the deformation constraints imposed by the dowels. The transient non-linear moisture flow was modelled using Fick’s law of orthotropic diffusion, using different diffusion coefficient in the two main directions, the length direction of the beam (assumed parallel to the fibers) and the direction perpendicular to that. The moisture transport in parallel direction was taken to be dominant. The shrinkage coefficients experience different values in perpendicular and parallel direction, αperp and αpar, respectively. For the fracture model, the critical energy release rate, GIC, is set to 300 J/m2, the strength in the perpendicular direction, ft,perp, to 2.5 MPa and the stiffness perpendicular and parallel to the length directions of the fibres are Eperp= 500 MPa and Epar= 10 000 MPa respectively

Numerical analysis of wood subjected to bending and northern European climate

Due to the natural process of sorption, wood constantly interacts with the surrounding climate to establish an equilibrium moisture content, even without the direct influence of rain, solar radiation or wind. However, when wood is subjected to a combination of a change in moisture content and a state of stress brought on by e.g. mechanical load, differential shrinkage or swelling, or differences in material properties, a continuous change in the level of stress and the occurrence of deformations and fracture can be the result. The techniques available for in-situ monitoring of changes in moisture content and hygro-mechanical and viscoelastic behaviour can only be employed in specific locations in or around the wood. Whereas, modern techniques employed in laboratories, such as digital image correlation and computed tomography are laborious and time consuming. With recent developments in three-dimensional modelling, endless predictions can be made both of moisture flow and of the hygro-mechanical and visco-elastic behaviour of wood in three-dimensional space, requiring experimental data only to calibrate and validate the model. A three-dimensional numerical model was created in finite element software Abaqus FEA® to simulate both the transient nonlinear moisture flow and the moisture-dependent distortion and stress, while account is being taken of the fibre orientation (annual ring pattern, conical shape and spiral grain). A nonlinear single-Fickian model in connection with a nonlinear Neumann boundary condition is used to describe the moisture flow. For a moisture-sensitive and visco-elastic material such as wood, it is common to describe the total strain rate as a summation of the elastic, hygro-expansion, visco-elastic creep and mechano-sorptive strain rates. The aim was to determine whether the model was able to simulate in an adequate way the beam bending that occurs under northern European climate conditions. To accomplish this, the following steps were taken: 1) on the basis of experimental data available in literature, a set of expressions was created to describe the moisture- and temperature-dependent diffusion coefficient and surface emission coefficient, 2) experimental results obtained for small beams tested under constant temperature and systematic relative humidity (controlled climatic) conditions were used to calibrate the numerical model, account being taken of the spiral grain that applied and the annual ring curvature, and 3) test results for solid beams tested in northern European (natural) climatic conditions were used to validate the numerical model, account being taken of the fibre orientation. The results obtained showed a clear distinction between the effect of moisture on the stress development caused by mechanical load and the stress development caused solely by changes in climate. The changes in moisture that occurred were found to have the strongest effect on the stress state that developed in areas in which the tangential direction of the material was aligned with the exchange surface of the beams. Such areas were found to be exposed to high-tension stress during drying and to a stress overturn brought about by wetting. The material orientation showed to have a strong effect on the estimated deflection, calibrated material parameters and normative stress states

A three-dimensional numerical analysis of moisture flow in wood and of the wood's hygro-mechanical and visco-elastic behaviour

A three-dimensional numerical model was employed in simulating nonlinear transient moisture flow in wood and the wood's hygro-mechanical and visco-elastic behaviour under such conditions. The model was developed using the finite element software Abaqus FEA, while taking account of the fibre orientation of the wood. The purpose of the study was to assess the ability of the model to simulate the response of wood beams to bending and to the climate of northern Europe. Four-point bending tests of small and clear wood specimens exposed to a constant temperature and to systematic changes in relative humidity were conducted to calibrate the numerical model. A validation of the model was then performed on the basis of a four-point bending test of solid timber beams subjected to natural climatic conditions but sheltered from the direct effects of rain, wind and sunlight. The three-dimensional character of the model enabled a full analysis of the effects of changes in moisture content and in fibre orientation on stress developments in the wood. The results obtained showed a clear distinction between the effects of moisture on the stress developments caused by mechanical loads and the stress developments caused solely by changes in climate. The changes in moisture that occurred were found to have the strongest effect on the stress state that developed in areas in which the tangential direction of the material was aligned with the exchange surface of the beams. Such areas were found to be exposed to high-tension stress during drying and to stress reversal brought about by the uneven drying and shrinkage differences that developed between the outer surface and the inner sections of the beams

A numerical study of the effect of green-state moisture content on stress development in timber boards during drying

Timber boards manufactured with a traditional sawing pattern often contain both heartwood andsapwood. In such boards, internal constraints can occur during drying because of a radial variation in greenstate(GS) MC between the heartwood (30-60%) and sapwood region (120-200%). Despite such knowledge,the initial MC is seldom considered when evaluating kiln-drying schedules. The effect of GS MC on thedevelopment of tangential tensile stress during drying is studied for four types of timber boards. A numericalmodel was developed that can simulate transient nonlinear orthotropic moisture flow and moisture–inducedstress and distortion in wood with the use of the finite element method. The stress analysis considers elastic,hygroscopic, and mechano-sorptive strain. The study shows that the GS MC does not significantly influencethe maximum stress state, but that it does influence the time at which the maximum tangential tensile stressoccurs at different exchange surfaces. This results in several periods in the drying schedule where unfavorablehigh stress situations in the tangential direction arise, which could lead to crack propagation