A model of tension-induced fiber growth predicts white matter organization during brain folding

The past decade has experienced renewed interest in the physical processes that fold the developing cerebral cortex. Biomechanical models and experiments suggest that growth of the cortex, outpacing growth of underlying subcortical tissue (prospective white matter), is sufficient to induce folding. However, current models do not explain the well-established links between white matter organization and fold morphology, nor do they consider subcortical remodeling that occurs during the period of folding. Here we propose a framework by which cortical folding may induce subcortical fiber growth and organization. Simulations incorporating stress-induced fiber elongation indicate that subcortical stresses resulting from folding are sufficient to induce stereotyped fiber organization beneath gyri and sulci. Model predictions are supported by high-resolution ex vivo diffusion tensor imaging of the developing rhesus macaque brain. Together, results provide support for the theory of cortical growth-induced folding and indicate that mechanical feedback plays a significant role in brain connectivity.

Cystic Fibrosis Transmembrane Conductance Regulator Folding Mutations Reveal Differences in Corrector Efficacy Linked to Increases in Immature Cystic Fibrosis Transmembrane Conductance Regulator Expression

Background: Most cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to protein misfolding and degradation by the ubiquitin–proteasome system. Previous studies demonstrated that PIAS4 facilitates the modification of wild-type (WT) and F508del CFTR by small ubiquitin-like modifier (SUMO)-1, enhancing CFTR biogenesis by slowing immature CFTR degradation and producing increased immature CFTR band B.Methods: We evaluated two correction strategies using misfolding mutants, including the common variant, F508del. We examined the effects on mutant expression of co-expression with PIAS4 (E3 SUMO ligase), and/or the corrector, C18. To study the impact of these correction conditions, we transfected CFBE410- cells, a bronchial epithelial cell line, with a CFTR mutant plus: (1) empty vector, (2) empty vector plus overnight 5 μM C18, (3) PIAS4, and (4) PIAS4 plus C18. We assessed expression at steady state by immunoblot of CFTR band B, and if present, band C, and the corresponding C:B band ratio. The large PIAS4-induced increase in band B expression allowed us to ask whether C18 could act on the now abundant immature protein to enhance correction above the control level, as reported by the C:B ratio.Results: The data fell into three mutant CFTR categories as follows: (1) intransigent: no observable band C under any condition (i.e., C:B = 0); (2) throughput responsive: a C:B ratio less than control, but suggesting that the increased band C resulted from PIAS4-induced increases in band B production; and (3) folding responsive: a C:B ratio greater than control, reflecting C18-induced folding greater than that expected from increased throughput due to the PIAS4-induced band B level.Conclusion: These results suggest that the immature forms of CFTR folding intermediates occupy different loci within the energetic/kinetic folding landscape of CFTR. The evaluation of their properties could assist in the development of correctors that can target the more difficult-to-fold mutant conformations that occupy different sites within the CFTR folding pathway.

Engineering A Fluorescent Protein Color Switch Using Entropy-driven Beta Strand Exchange

Protein conformational switches are widely used in biosensing. They are typically composed of an input domain (which binds a target ligand) fused to an output domain (which generates an optical readout). A central challenge in designing such switches is to develop mechanisms for coupling the input and output signals via conformational change. Here, we create a biosensor in which binding-induced folding of the input domain drives a conformational shift in the output domain that results in a 6-fold green-to-yellow ratiometric fluorescence change in vitro, and a 35-fold intensiometric fluorescence increase in cultured cells. The input domain consists of circularly permuted FK506 binding protein (cpFKBP) that folds upon binding its target ligand (FK506 or rapamycin). cpFKBP folding induces the output domain, an engineered GFP variant, to replace one of its β-strands (containing T203 and specifying green fluorescence) with a duplicate β-strand (containing Y203 and specifying yellow fluorescence) in an intramolecular exchange reaction. This mechanism employs the loop-closure entropy principle, embodied by folding of the partially disordered cpFKBP domain, to couple ligand binding to the GFP color shift. This proof-of-concept design has the advantages of full genetic encodability, ratiometric or intensiometric response, and potential for modularity. The latter attribute is enabled by circular permutation of the input domain.

Flow-induced Folding in Multi-scaled Bulk Forming of Flanged Parts and its Prediction and Avoidance

The quality of manufactured parts and the efficiency of forming processes are crucial in deformation-based manufacturing. In product miniaturization and micro-manufacturing, size effect induces many unknowns. Flow-induced folding related to size effect is one of them and has not yet been fully studied. In this research, the formation mechanism of folding defects in axisymmetric bulk forming was investigated, and a design-based method was employed to evaluate different tooling and process route designs for making a case-study multi-flanged part with three features and to explore the design-based avoidance of folding defects. In addition, a design evaluating framework of folding-free bulk forming was proposed, implemented and validated. Via analysis of the material flow, energy consumption, folding formation, and product precision of the four proposed forming processes for the case-study part, an upsetting-extrusion forming method via using a nested punch was found to be the most desirable. It was then implemented in the physical forming with three size scales. The results revealed that the flow-induced folding in the macropart was severe and regularly circuitous, but it is slight and irregular in meso and microscale. These findings are useful in the defect-free forming of multi-flanged structures and multi-scaled axisymmetric parts

Sequentially Working Origami Multi-Physics Simulator (SWOMPS): A Versatile Implementation

This work presents the underlying implementation of a new origami simulator (SWOMPS) that allows for adaptability and versatility with sequential analyses and multi-physical behaviors of active origami systems. The implementation allows for easy updating of origami properties, realistic simulation with multi-physics based actuation, and versatile application of different loadings in arbitrary number and sequence. The presented simulator can capture coupling between multiple origami behaviors including electro-thermo-mechanical actuation, heat transfer, self-stress induced folding, inter panel contact, applied loading forces, and kinematic/mechanical deformations. The simulator contains five different solvers, including three for mechanical loading, one for self-folding, and one for thermal loading. The paper presents details of this code package and uses three practical examples to highlight the versatility and efficiency of the package. Because various loadings and different origami behaviors can be modeled simultaneously and/or sequentially, this simulator is well suited for capturing origami behaviors in practical real-world scenarios. Furthermore, the ability to apply an arbitrary number and sequence of loadings is useful for design, optimization, or system control studies where an unknown set of loads are needed to fold functional active origami. The coded implementation for this simulator and additional examples are made available to encourage future expansions of this work where new sequential and multi-physical behaviors in origami can be explored.