Case report: a novel deep intronic splice-altering variant in DMD as a cause of Becker muscular dystrophy

We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291–13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD

Generating Secure and Gentle Grip on Soft Substrates

Generation of grip on soft tissue in the surgical field is most commonly done with forceps that generate friction grip, that is, the translation of normal (pinch) forces into shear forces. Errors made with these surgical grippers are often force-related: applying too low pinch forces results in slipping of the tissue out of the gripper, and too high pinch forces may lead to tissue damage. One possible solution for generating tissue grip that is secure yet gentle is the adhesive grip. In this case, contact between tissue and gripper is maintained by attracting gripper-tissue interactions, and gripping strength does not depend on the applied pinch forces. Inspiration for the design of such a gripper can be derived from the tree frog, an animal that uses adhesive grip to grip on a range of substrates in its habitat. The main aim of this thesis is to translate grip-generating principles used by tree frogs into designs of artificial adhesives that can generate firm yet gentle grip on soft substrates. The designs of the artificial adhesives in this thesis are inspired by two important characteristics of the tree frog’s attachment apparatus: the hierarchical surface pattern on the tree-frog toe-pad and reinforcing fibrillar structures located inside the pad. Specifically, the aim of this thesis is to mimic function rather than form, and focuses on mechanisms underlying the tree-frog attachment apparatus to satisfy two main requirements for strong grip: (1) contact formation and (2) preservation of the formed contact.Medical Instruments & Bio-Inspired Technolog

Nanostructure and microstructure fabrication:from desired properties to suitable processes

\u3cp\u3eWhen designing a new nanostructure or microstructure, one can follow a processing-based manufacturing pathway, in which the structure properties are defined based on the processing capabilities of the fabrication method at hand. Alternatively, a performance-based pathway can be followed, where the envisioned performance is first defined, and then suitable fabrication methods are sought. To support the latter pathway, fabrication methods are here reviewed based on the geometric and material complexity, resolution, total size, geometric and material diversity, and throughput they can achieve, independently from processing capabilities. Ten groups of fabrication methods are identified and compared in terms of these seven moderators. The highest resolution is obtained with electron beam lithography, with feature sizes below 5 nm. The highest geometric complexity is attained with vat photopolymerization. For high throughput, parallel methods, such as photolithography (≈10\u3csup\u3e1\u3c/sup\u3e m\u3csup\u3e2\u3c/sup\u3e h\u3csup\u3e−1\u3c/sup\u3e), are needed. This review offers a decision-making tool for identifying which method to use for fabricating a structure with predefined properties.\u3c/p\u3

Chain Dynamics in Supramolecular Polymer Networks

Supramolecular polymer networks consist of macromolecules that are cross linked by transient physical interactions such as hydrogen bonding or transition metal complexation. The utility of these networks is based on their mechanical properties, which lay between those of permanent networks and that of mechanically entangled, viscoelastic polymer solutions, depending on the strength of transient chain cross linking. To benefit from this interplay, it is necessary to understand it. To promote this understanding, we use a modular toolkit to form supramolecular polymer networks that exhibit greatly varying strength of transient chain cross linking but that are all derived from the very same precursor polymer. This strategy allows the impact of the strength of transient chain cross linking on the network dynamics and mechanics to be studied with high consistency. We follow this approach to evaluate the diffusive mobility of labeled tracer chains within these transient networks. Our results reveal that the concentration dependence of the tracer chain diffusivity is in agreement with theoretical predictions derived from the sticky reptation model by Rubinstein and Semenov, provided the chain association is stronger than a certain threshol

Implementation of anisotropic soft pads in a surgical gripper for secure and gentle grip on vulnerable tissues

Current surgical grippers rely on friction grip, where normal loads (i.e. pinch forces) are translated into friction forces. Operating errors with surgical grippers are often force-related, including tissue slipping out of the gripper because of too low pinch forces and tissue damaging due to too high pinch forces. Here, we prototyped a modular surgical gripper with elastomeric soft pads reinforced in the shear direction with a carbon-fiber fabric. The elastomeric component provides low normal stiffness to maximize contact formation without the need of applying high normal loads (i.e. pinch forces), whereas the carbon-fiber fabric offers high shear stiffness to preserve the formed contact under the lateral loads (i.e. shear forces) that occur during tissue lifting. Additionally, we patterned the pads with a sub-surface micropattern, to further reduce the normal stiffness and increase shear stiffness. The body of the prototype gripper, including shaft, joints, and gripper tips, was fabricated in a single step using 3D printing, followed by manual attachment of the soft pads to the gripper. The gripping performance of the newly developed soft gripper on soft tissues was experimentally compared to reference grippers equipped with metal patterned pads. The soft-pad gripper generated similar gripping forces but significantly lower pinch forces than metal-pad grippers. We conclude that grippers with anisotropic-stiffness pads are promising for secure and gentle tissue grip.</p

A modular construction kit for supramolecular polymer gels

Supramolecular polymer gels are swollen networks of macromolecules interconnected by transient, non covalent bonds; they form an extraordinarily useful class of soft, stimuli sensitive materials. To optimize the use of supramolecular polymer gels in applications, their physical and chemical properties must be understood. This understanding is ideally achieved using model systems that allow the type and strength of supramolecular chain crosslinking to be varied to a great extent without concurrent alteration of the properties of the covalent polymer backbones. We introduce a system that provides these requirements. We use linear chains of electrophilic methacryl succinimidyl MASI modified poly N isopropylacrylamide pNIPAAm . These polymers can be modified in a modular fashion by replacing their electrophilic MASI units by nucleophilic amine functionalized derivatives of custom, supramolecular crosslinkable functionalities. We follow this approach and prepare a set of pNIPAAm polymers that consist of exactly the same polymer backbone functionalized with different types of crosslinkable sidegroups. These polymers are then crosslinked by addition of low molecular weight linkers that are complementary to the motifs on the polymer. We use multiple hydrogen bonding based on diaminotriazine and maleimide, cyanuric acid and Hamilton wedges, and diaminotriazine and cyanuric acid; we also use metal complexation based on terpyridine and different metal salts. This approach creates supramolecular networks of greatly varying rheological properties, from low viscous liquids to elastic gels, each showing consistent and quantitative correlation between the gel mechanical properties and the binding strength of the respective constituent supramolecular crosslinking motifs. Exploiting the good solubility of the common pNIPAAm backbone polymer in a variety of solvents allows these networks to be prepared and studied in different media with unprecedented consistency and flexibilit