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MCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1 -ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1 -ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1 -ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1 -ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.

Treatment resistance is a major hurdle in diffuse large B-cell lymphoma (DLBCL) therapy. Here, we assessed the relevance of the Musashi (MSI) RNA-binding protein family for DLBCL treatment efficacy. As important gene expression regulators, these proteins have previously been associated with tumorigenesis, treatment failure, and reduced survival in other malignancies, making them promising candidates for assessment in the context of DLBCL outcome and therapy resistance. We first leveraged publicly available gene expression studies to determine expression and prognostic relevance of MSI1 and MSI2 in DLBCL. We then characterized MSI2 co-expressed therapy-relevant signaling. After performing MSI2 knockdown experiments we investigated subsequent effects on DLBCL gene expression using qPCR, Western blot, protein arrays, and flow cytometry. Finally, cell viability assays and clonogenic assessments were used to assess resistance to radiation, vincristine, and doxorubicin chemotherapy. MSI2 was overexpressed and prognostically unfavorable in univariable and multivariable analyses in DLBCL while MSI1 showed very low expression. High MSI2 expression was associated with increased stemness and DNA repair signaling. MSI2 knockdown led to a loss of stemness-associated markers and compromised DNA repair protein activation while increasing radiation-induced DNA double-strand break levels. Cell survival after either radiotherapy, vincristine or doxorubicin chemotherapy was impaired after MSI2 knockdown in follow-up analyses, suggesting a radio- and chemosensitizing effect. We propose that MSI2, a prognostic marker, may modulate the susceptibility of DLBCL towards genotoxic therapy. Suppressing MSI2 may hold promise to sensitize DLBCL to DNA-targeted treatment.

Inspired by the starfish's unique ability to achieve flexibility and posture-holding with minimal energy expenditure, we present a novel bioinspired morphing structure. Our two-component design, consisting of a thermoplastic mesh and elastomeric jacket, effectively mimics the functions of the starfish's ossicles, mutable collagenous tissues, and derma. This structure exhibits a remarkable combination of self-healing, time-dependent shape memory, and self-posture-holding properties. Systematic variations in mesh geometry demonstrate precise control over structural stiffness and thermal response, enabling customization for specific applications. The structure's scalability and ease of fabrication further enhance its adaptability. We experimentally demonstrate the potential of our biomimetic morphing structure using several prototypes. This work lays the foundation for developing a new type of versatile morphing structures with applications in diverse fields, including robotics, biomedical devices, and adaptive structures.

Arthropods and in particular insects show a great variety of different exoskeletal sensors. For most arthropods, spatial orientation and gravity perception is not fully understood. In particular, the interaction of the different sensors is still a subject of ongoing research. A disadvantage of most of the experimental methods used to date to study the spatial orientation of arthropods in behavioral experiments is that the body or individual body parts are fixed partly in a non-natural manner. Therefore, often only the movement of individual body segments can be used to evaluate the experiments. We here present a novel experimental method to easily study 3D-escape movements in insects and analyze whole-body reaction. The animals are placed in a transparent container, filled with a lightweight substrate and rotating around two axes. To verify our setup, house crickets (Acheta domesticus) with selectively manipulated gravity-perceiving structures were analyzed. The spatial orientation behavior was quantified by measuring the time individuals took to escape toward the surface and the angular deviation toward the gravitational vector. These experiments confirm earlier results and therefore validated our experimental setup. Our new approach thus allows to investigate several comprehensive questions regarding the spatial orientation of insects and other animals.

In insect exoskeletons, articular membranes connect the sclerotized hard segments within joints, ensuring protection, mobility, and resilience to mechanical stresses. During exoskeletal movement, these membranes experience tensile and compressive forces, leading to either stretching or the formation of cuticular folds. The mechanisms underlying cuticular folding remain unclear, particularly whether folds are regular (specific) or irregular (non-specific) and how cuticle ultrastructure influences folding patterns. To address these questions, we examined the femur–tibia joints in the mesothoracic legs of locusts (Locusta migratoria) using non-destructive micro-CT, histological methods, and scanning electron microscopy. The joints were analyzed at different flexion angles and maturity stages to characterize membrane folding. Our findings reveal distinct scales of cuticular folds in the femur–tibia joint: macrofolds associated with internal structures such as muscle attachment sites and microfolds potentially linked to cuticle ultrastructure, surface properties, or membrane thickness differences.

Autonomous and remotely operated underwater vehicles allow us to reach places which have previously been inaccessible and perform complex repair, exploration and analysis tasks. As their navigation is not infallible, they may cause severe damage to themselves and their often fragile surroundings, such as flooded caves, coral reefs, or even accompanying divers in case of a collision. In this study, we used a shallow neural network, consisting of interlinking PID controllers, and trained by a genetic algorithm, to control a biologically inspired AUV with a soft and compliant exoskeleton. Such a compliant structure is a versatile and passive solution which reduces the accelerations induced by collisions to 56% of the original mean value acting upon the system, thus, notably reducing the stress on its components and resulting reaction forces on its surroundings. The segmented structure of this spherical exoskeleton protects the encased system without limiting the use of cameras, sensors or manipulators.

Marinesco–Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident chaperone BiP which controls a plethora of essential processes in the endoplasmic reticulum. In this study we made use of the spontaneous Sil1 mouse mutant woozy to explore pathomechanisms leading to Sil1 deficiency-related skeletal muscle pathology. We found severe, progressive myopathy characterized by alterations of the sarcoplasmic reticulum, accumulation of autophagic vacuoles, mitochondrial changes, and prominent myonuclear pathology including nuclear envelope and nuclear lamina alterations. These abnormalities were remarkably similar to the myopathy in human patients with MSS. In particular, the presence of perinuclear membranous structures which have been reported as an ultrastructural hallmark of MSS-related myopathy could be confirmed in woozy muscles. We found that these structures are derived from the nuclear envelope and nuclear lamina and associate with proliferations of the sarcoplasmic reticulum. In line with impaired function of BiP secondary to loss of its nucleotide exchange factor Sil1, we observed activation of the unfolded protein response and the endoplasmic-reticulum-associated protein degradation-pathway. Despite initiation of the autophagy–lysosomal system, autophagic clearance was found ineffective which is in agreement with the formation of autophagic vacuoles. This report identifies woozy muscle as a faithful phenocopy of the MSS myopathy. Moreover, we provide a link between two well-established disease mechanisms in skeletal muscle, dysfunction of chaperones and nuclear envelope pathology.

Echinoderms and vertebrates both possess mesodermal endoskeletons. In vertebrates, the response to mechanical loads and the capacity to remodel the ultrastructure of the skeletal system are fundamental attributes of their endoskeleton. To determine whether these characteristics are also inherent in Echinoderms, we conducted a comprehensive biomechanical and morphological study on the endoskeleton of Asterias rubens, a representative model organism for Echinoderm skeletons. Our analysis involved high-resolution X-ray CT scans of entire individual ossicles, covering the full stereom distribution along with the attached muscles. Leveraging this data, we conducted finite element analysis to explore the correlation between mechanical loads acting on an ossicle and its corresponding stereom structure. To understand the effects of localized stress concentration, we examined stereom regions subjected to high mechanical stress and compared them to areas with lower mechanical stress. Additionally, by comparing the stereom structures of ossicles in various developmental stages, we assessed the general remodeling capacity of these ossicles. Our findings suggest that the ability to adapt to mechanical loads is a common feature of mesoderm endoskeletons within the Deuterostomia taxonomic group. However, the material remodelling may be a specific trait unique to vertebrate endoskeletons.

Many insects are able to precisely control their jumping movements. Previous studies have shown that many falling insects have some degree of control of their landing-orientation, indicating a possible significant biomechanical role of the exoskeleton in air righting mechanisms. Once in the air, the properties of the actual landing site are almost impossible to predict. Falling insects thus have to cope mostly with the situation at impact. What exactly happens at the impact? Do locusts actively 'prepare for landing' while falling, or do they just 'crash' into the substrate? Detailed impact analyses of free falling Schistocerca gregaria locusts show that most insects typically crashed onto the substrate. There was no notable impact-reducing behaviour (protrusion of legs, etc.). Independent of dropping angle, both warm and cooled locusts mostly fell onto head and thorax first. Our results also show that alive warm locusts fell significantly faster than inactive or dead locusts. This indicates a possible tradeoff between active control vs. reduced speed. Looking at the morphology of the head-thorax connection in locusts, we propose that the anterior margin of the pronotum might function as a 'toby collar' structure, reducing the risk of impact damage to the neck joint. Interestingly, at impact alive insects also tended to perform a bending movement of the body. This biomechanical adaptation might reduce the rebound and shorten the time to recover. The adhesive pads also play an important role to reduce the time to recover by anchoring the insect to the substrate.