Tubular organs display a wide variety of surface morphologies including circumferential and longitudinal folds, square and hexagonal undulations, and finger-type protrusions. Surface morphology is closely correlated to tissue function and serves as a clinical indicator for physiological and pathological conditions, but the regulators of surface morphology remain poorly understood. Here, we explore the role of geometry and elasticity on the formation of surface patterns. We establish morphological phase diagrams for patterns selection and show that increasing the thickness or stiffness ratio between the outer and inner tubular layers induces a gradual transition from circumferential to longitudinal folding. Our results suggest that physical forces act as regulators during organogenesis and give rise to the characteristic circular folds in the esophagus, the longitudinal folds in the valves of Kerckring, the surface networks in villi, and the crypts in the large intestine.

BackgroundAlzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.Methodology/Principal FindingsWe applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR = 1.85, 95% CI:1.04–3.23) in particular for females (OR = 2.19, 95% CI:1.06–4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.ConclusionsOur results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.

Cite this article as: V. Balbi, E. Kuhl and P. Ciarletta, Morphoelastic control of gastro-intestinal organogenesis: Theoretical predictions and numerical insights, AbstractWith nine meters in length, the gastrointestinal tract is not only our longest, but also our structurally most diverse organ. During embryonic development, it evolves as a bilayered tube with an inner endodermal lining and an outer mesodermal layer. Its inner surface displays a wide variety of morphological patterns, which are closely correlated to digestive function. However, the evolution of these intestinal patterns remains poorly understood. Here we show that geometric and mechanical factors can explain intestinal pattern formation. Using the nonlinear field theories of mechanics, we model surface morphogenesis as the instability problem of constrained differential growth. To allow for internal and external expansion, we model the gastrointestinal tract with homogeneous Neumann boundary conditions. To establish estimates for the folding pattern at the onset of folding, we perform a linear stability analysis supplemented by the perturbation theory. To predict pattern evolution in the post-buckling regime, we perform a series of nonlinear finite element simulations. Our model explains why longitudinal folds emerge in the esophagus with a thick and stiff outer layer, whereas circumferential folds emerge in the jejunum with a thinner and softer outer layer. In intermediate regions like the feline esophagus, longitudinal and circumferential folds emerge simultaneously. Our model could serve as a valuable tool to explain and predict alterations in esophageal morphology as a result of developmental disorders or certain digestive pathologies including food allergies.

Villi are ubiquitous structures in the intestine of all vertebrates, originating from the embryonic development of the epithelial mucosa. Their morphogenesis has similar stages in living organisms but different forming mechanisms. In this work, we model the emergence of the bi-dimensional undulated patterns in the intestinal mucosa from which villi start to elongate. The embryonic mucosa is modelled as a growing thick-walled cylinder, and its mechanical behaviour is described using an hyperelastic constitutive model, which also accounts for the anisotropic characteristics of the reinforcing fibres at the microstructural level. The occurrence of surface undulations is investigated using a linear stability analysis based on the theory of incremental deformations superimposed on a finite deformation. The Stroh formulation of the incremental boundary value problem is derived, and a numerical solution procedure is implemented for calculating the growth thresholds of instability. The numerical results are finally discussed with respect to different growth and materials properties. In conclusion, we demonstrate that the emergence of intestinal villi in embryos is triggered by a differential growth between the mucosa and the mesenchymal tissues. The proposed model quantifies how both the geometrical and the mechanical properties of the mucosa drive the formation of previllous structures in embryos.

We investigate experimentally and model theoretically the mechanical behaviour of brain matter in torsion. Using a strain-controlled rheometer we perform torsion tests on fresh porcine brain samples. We quantify the torque and the normal force required to twist a cylindrical sample at constant twist rate. Data fitting gives a mean value for the shear modulus µ = 900 ± 312 Pa and for the second Mooney-Rivlin parameter c2 = 297 ± 189 Pa, indicative of extreme softness. Our results show that brain always displays a positive Poynting effect; in other words, it expands in the direction perpendicular to the plane of twisting. We validate the experiments with Finite Element simulations and show that when a human head experiences a twisting motion in the horizontal plane, the brain can experience large forces in the axial direction.

The theory of quasi-linear viscoelasticity (QLV) is modified and developed for transversely isotropic (TI) materials under finite deformation. For the first time, distinct relaxation responses are incorporated into an integral formulation of nonlinear viscoelasticity, according to the physical mode of deformation. The theory is consistent with linear viscoelasticity in the small strain limit and makes use of relaxation functions that can be determined from small-strain experiments, given the time/deformation separability assumption. After considering the general constitutive form applicable to compressible materials, attention is restricted to incompressible media. This enables a compact form for the constitutive relation to be derived, which is used to illustrate the behaviour of the model under three key deformations: uniaxial extension, transverse shear and longitudinal shear. Finally, it is demonstrated that the Poynting effect is present in TI, neo-Hookean, modified QLV materials under transverse shear, in contrast to neo-Hookean elastic materials subjected to the same deformation. Its presence is explained by the anisotropic relaxation response of the medium.

Organoids are prototypes of human organs derived from cultured human stem cells. They provide a reliable and accurate experimental model to study the physical mechanisms underlying the early developmental stages of human organs morphogenesis and, in particular, the early morphogenesis of the cortex. Here, we propose a mathematical model to elucidate the role played by two mechanisms which have been experimentally proven to be crucial in shaping human brain organoids: the contraction of the inner core of the organoid and the microstructural remodeling of the outer cortex. Our results show that both mechanisms are crucial for the final shape of the organoid and can explain the origin of brain pathologies such as lissencephaly (smooth brain). arXiv:1811.01893v1 [cond-mat.soft]

We study the occurrence of torsional instabilities in soft, incompressible, thick-walled tubes with both circumferential and axial pre-stretches. Assuming a neo-Hookean strain energy function, we investigate the helical buckling under a finite torsion in three different classes of boundary conditions: (a) no applied loads at the internal and external surfaces of the cylindrical tube, (b) a pressure load P acting on the external surface or (c) on the internal surface. We perform a linear stability analysis on the axisymmetric solutions using the method of small deformations superposed on finite strains. Applying a helical perturbation, we derive the Stroh formulation of the incremental boundary value problems and we solve it using a numerical procedure based on the surface impedance method. The threshold values of the torsion rate and the associated critical circumferential and longitudinal modes at the onset of the instability are examined in terms of the circumferential and axial pre-stretches, and of the initial geometry of the soft tube.