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This paper presents a data-driven fault detection and isolation (FDI) for a multirotor system using Koopman operator and Luenberger observer. Koopman operator is an infinite-dimensional linear operator that can transform nonlinear dynamical systems into linear ones. Using this transformation, our aim is to apply the linear fault detection method to the nonlinear system. Initially, a Koopman operator-based linear model is derived to represent the multirotor system, considering factors like non-diagonal inertial tensor, center of gravity variations, aerodynamic effects, and actuator dynamics. Various candidate lifting functions are evaluated for prediction performance and compared using the root mean square error to identify the most suitable one. Subsequently, a Koopman operator-based Luenberger observer is proposed using the lifted linear model to generate residuals for identifying faulty actuators. Simulation and experimental results demonstrate the effectiveness of the proposed observer in detecting actuator faults such as bias and loss of effectiveness, without the need for an explicitly defined fault dataset.

Emery–Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD. Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms without addressing the underlying cause—lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs have been studied for decades and have recently been used clinically for vaccination and treatment of a myriad of diseases. Here, we show that the treatment of emerin-null myogenic progenitors with LNPs encapsulating emerin mRNA causes robust emerin protein expression that persists for at least 4 days. The treatment of differentiating emerin-null myogenic progenitors with 2.5 pg/cell emerin LNPs significantly improved their differentiation. The toxicity profiling of emerin mRNA LNP (EMD-LNP) dosing shows little toxicity at the effective dose. These data support the potential use of EMD-LNPs as a viable treatment option and establishes its utility for studying EDMD pathology.

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.

Background Emery–Dreifuss muscular dystrophy (EDMD) is a progressive genetic myopathy that mainly affects the muscles used for movement (skeletal muscles) and the heart (cardiac muscles). The disease is frequently associated with mutations in genes encoding nuclear envelope proteins, most notably LMNA, which encodes lamin A—a critical structural component of the nuclear lamina. Lamin A plays a pivotal role in maintaining nuclear architecture and mechanotransduction. In contrast to most other cell types, nuclei in healthy skeletal muscle fibres are typically localized at the periphery of the myofiber. However, muscle biopsies from EDMD patients often reveal aberrant nuclear morphology and ectopic nuclear positioning, with nuclei clustered or mislocalized toward the centre of the myofiber. Despite these characteristic nuclear abnormalities, the molecular mechanisms underlying nuclear mispositioning in EDMD remain incompletely understood. In particular, the interaction networks between EDMD‐related mutant lamin A and other nuclear and cytoskeletal components that govern nuclear positioning are poorly characterized in the current literature. Methods EDMD‐related lamin A variants (L35V, L38F or Y45C), which are located within the Coil‐1a domain, were overexpressed in RD cells. Mesenchymal stem cells (MSCs) were generated by redifferentiating induced pluripotent stem cells (iPSCs), which were derived from fibroblasts of an EDMD (L35P) patient. To investigate morphological and molecular abnormalities caused by mutations, immunofluorescence imaging, immunoblotting and subcellular fractionation were performed. Functional consequences of these morphological alterations were evaluated by assessing mechanotransduction signalling and cell viability. Results EDMD‐related LMNA mutations (L35V, L38F, Y45C) in the Coil‐1a domain induced multilobular nuclear morphology, accompanied by a decrease in nuclear contour ratio (1.9–3.0‐fold vs. WT, p < 0.0001). Similarly, patient‐derived MSCs (L35P‐MSCs) exhibited a ~2.28‐fold decrease in contour ratio relative to healthy subject‐derived MSCs. Abnormal nuclear shape was associated with structural alterations in nuclear‐cytoskeletal proteins and nuclear positioning regulators. Mechanosensing activity, assessed by YAP1 nuclear translocation, was increased (~1.72‐fold vs. Nor‐CTRL, p < 0.01), and nuclear fragility under physical stress was elevated by ~20% (vs. Nor‐CTRL, p < 0.0001). Treatment with mutation‐specific ASOs in patient‐derived MSCs restored the contour ratio (~1.97‐fold vs. NC‐CTRL, p < 0.01), normalized nuclear‐cytoskeletal organization, reduced mechanosensing response (~1.65‐fold vs. NC‐CTRL, p < 0.01) and decreased nuclear fragility by ~11% (vs. NC‐CTRL, p < 0.0001). Conclusions Our findings indicate that nuclear morphological alterations contribute to the impaired nuclear‐cytoskeletal integrity and nuclear positioning, which are closely linked to cellular mechanics and function. Mutation‐specific ASO treatment alleviated these nuclear defects, suggesting that ASO‐based therapeutic strategies may provide a mutation‐targeted approach to correcting nuclear abnormalities in EDMD.

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.

No genotype-phenotype correlation could be made. [...]our study indicates that mutation spanning few amino acids of evolutionary highly conserved regions result in phenotypes with strikingly different symptoms and varying severity and point to the role of other factors in determining phenotype. [...]the identification of patients like DAP, Oar and NM13 presenting an EDMD phenotype with cardiac conduction defects and no mutations in either LMNA or STA indicates that other genes have to be identified to fully explain the EDMD phenotype Acknowledgement: We thank the patients and their families for agreeing to participate in this project.

In muscle cells subjected to mechanical stimulation, LINC complex and cytoskeletal proteins are basic to preserve cellular architecture and maintain nuclei orientation and positioning. In this context, the role of lamin A/C remains mostly elusive. This study demonstrates that in human myoblasts subjected to mechanical stretching, lamin A/C recruits desmin and plectin to the nuclear periphery, allowing a proper spatial orientation of the nuclei. Interestingly, in Emery-Dreifuss Muscular Dystrophy (EDMD2) myoblasts exposed to mechanical stretching, the recruitment of desmin and plectin to the nucleus and nuclear orientation were impaired, suggesting that a functional lamin A/C is crucial for the response to mechanical strain. While describing a new mechanism of action headed by lamin A/C, these findings show a structural alteration that could be involved in the onset of the muscle defects observed in muscular laminopathies.

Flow around a body moving at a high subsonic velocity in a tube filled with rarefied gas is studied. This aerodynamic problem is considered as applied to the task of designing a high-speed vacuum transport at finite Knudsen numbers. Parameters that are close to target characteristics of such systems are chosen, more precisely, speed of about 1000 km/h, significant transverse size of the body, and nitrogen–oxygen mixture (air) as the filling gas are chosen. The problem was solved in a three-dimensional statement.

Emery–Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD, LMNA, SYNE1, SYNE2, and other related genes. The disease is characterized by joint contractures, muscle weakening and wasting, and heart conduction defects associated with dilated cardiomyopathy. Previous studies demonstrated the activation of fibrogenic molecules such as TGFbeta 2 and CTGF in preclinical models of EDMD2 and increased secretion of TGFbeta 2 in patient serum. A wide screening of patient cells suggested fibrosis, metabolism, and myogenic signaling as the most affected pathways in various EDMD forms. In this study, we show that alpha-smooth muscle actin-positive myofibroblasts are overrepresented in patient fibroblast cultures carrying EMD, LMNA, or SYNE2 mutations, and profibrotic miRNA-21 is upregulated. Upon CRISPR/Cas correction of the mutated EMD or LMNA sequence in EDMD1 or EDMD2 fibroblasts, respectively, we observe a reduced expression of fibrogenic molecules. However, in patient myoblasts, neither fibrogenic proteins nor miRNA-21 were upregulated; instead, miRNA-21-5p was downregulated along with muscle-specific miRNA-133b and miRNA-206, which have a crucial role in muscle cell homeostasis. These observations suggest that the conversion of laminopathic fibroblasts into a profibrotic phenotype is a determinant of EDMD-associated muscle fibrosis, while miRNA-206-dependent defects of laminopathic myoblasts, including altered regulation of VEGF levels, contribute to muscle cell deterioration. Notably, our study provides a proof-of-principle for the application of gene correction to EDMD1 and EDMD2 and presents EDMD1 isogenic cells that exhibit an almost complete rescue of a disease-specific miRNA signature. These cells can be used as experimental models for studying muscular laminopathies.

We consider a data-driven method, which combines Koopman operator theory with Extended Dynamic Mode Decomposition. We apply this method to the hypergeometric equation which is the Fuchsian equation with three regular singular points. The space of solutions at any of its singular points is a two-dimensional linear vector space on the field of reals when the independent variable is restricted to take values in the real axis and the unknown function is restricted to be a real-valued function of a real variable. A basis of the linear vector space of solutions is spanned by the hypergeometric function and its products with appropriate powers of the independent variable or the logarithmic function depending on the roots of the indicial equation of the hypergeometric equation. With our work, we obtain a new representation of the fundamental solutions of the hypergeometric equation and relate them to the spectral analysis of the finite approximation of the Koopman operator associated with the hypergeometric equation. We expect that the usefulness of our results will come more to the fore when we extend our study into the complex domain.