552 research outputs found
Advanced cellular models for rare disease study: exploring neural, muscle and skeletal organoids
Organoids are self-organized, three-dimensional structures derived from stem cells that can mimic the structure and physiology of human organs. Patient-specific induced pluripotent stem cells (iPSCs) and 3D organoid model systems allow cells to be analyzed in a controlled environment to simulate the characteristics of a given disease by modeling the underlying pathophysiology. The recent development of 3D cell models has offered the scientific community an exceptionally valuable tool in the study of rare diseases, overcoming the limited availability of biological samples and the limitations of animal models. This review provides an overview of iPSC models and genetic engineering techniques used to develop organoids. In particular, some of the models applied to the study of rare neuronal, muscular and skeletal diseases are described. Furthermore, the limitations and potential of developing new therapeutic approaches are discussed
Transmission-selective muscle pathology induced by the active propagation of mutant huntingtin across the human neuromuscular synapse
Neuron-to-neuron transmission of aggregation-prone, misfolded proteins may potentially explain the spatiotemporal accumulation of pathological lesions in the brains of patients with neurodegenerative protein-misfolding diseases (PMDs). However, little is known about protein transmission from the central nervous system to the periphery, or how this propagation contributes to PMD pathology. To deepen our understanding of these processes, we established two functional neuromuscular systems derived from human iPSCs. One was suitable for long-term high-throughput live-cell imaging and the other was adapted to a microfluidic system assuring that connectivity between motor neurons and muscle cells was restricted to the neuromuscular junction. We show that the Huntington's disease (HD)-associated mutant HTT exon 1 protein (mHTTEx1) is transmitted from neurons to muscle cells across the human neuromuscular junction. We found that transmission is an active and dynamic process that starts before aggregate formation and is regulated by synaptic activity. We further found that transmitted mHTTEx1 causes HD-relevant pathology at both molecular and functional levels in human muscle cells, even in the presence of the ubiquitous expression of mHTTEx1. In conclusion, we have uncovered a causal link between mHTTEx1 synaptic transmission and HD pathology, highlighting the therapeutic potential of blocking toxic protein transmission in PMDs
Analytical validation of innovative magneto-inertial outcomes: a controlled environment study.
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Development of skeletal muscle models to study ageing and associated conditions
Rapid ageing of the population together with raised prevalence of chronic metabolic diseases provokes huge economic burden on healthcare systems. Furthermore, age-related loss of skeletal muscle is associated with increase in disability, injuries, dependency and eventually mortality. Given the importance of skeletal muscle mass in both locomotion and homeostasis, developing countermeasures to hinder the raising prevalence of sarcopenia is critical.
Human skeletal muscle experiments in vivo are limited due to ethical and safety concerns, and animal models are poor predictors of clinical outcomes and drug responses in humans. Therefore, developing biologically advanced in vitro systems to investigate regulation of skeletal muscle mass and underlying mechanisms is pivotal. Hence, the aim of this project was to develop advanced models to study age related changes in skeletal muscle. This study focused on a) expanding our knowledge on biomarkers regulating muscle ageing and the effect of exercise on these markers; b) investigating the causes of impaired regeneration in aged muscle; and c) developing tissue engineered muscle model with structural and functional properties of native muscle.
The findings in this study indicate that using artificial neural network inference (ANNI) analysis we could identify novel age- and exercise related genes such as USP54, JAK2, CHAD, ZDBF2, EIF4A2, NIPAL3, SCFD1 and KDM5D previously not associated with skeletal muscle. Furthermore, we characterise an in vitro human muscle regeneration model and describe the development of novel non-custom-made inserts to fabricate high-throughput tissue engineered muscle. Together, the findings suggest that established models in this project have a potential to contribute to research on muscle ageing by providing high-fidelity platform to further examine regulation of muscle mass across the lifespan and to investigate potential effects of drugs and/or therapies
Building blocks of microphysiological system to model physiology and pathophysiology of human heart
Microphysiological systems (MPS) are drawing increasing interest from academia and from biomedical industry due to their improved capability to capture human physiology. MPS offer an advanced in vitro platform that can be used to study human organ and tissue level functions in health and in diseased states more accurately than traditional single cell cultures or even animal models. Key features in MPS include microenvironmental control and monitoring as well as high biological complexity of the target tissue. To reach these qualities, cross-disciplinary collaboration from multiple fields of science is required to build MPS. Here, we review different areas of expertise and describe essential building blocks of heart MPS including relevant cardiac cell types, supporting matrix, mechanical stimulation, functional measurements, and computational modelling. The review presents current methods in cardiac MPS and provides insights for future MPS development with improved recapitulation of human physiology.Peer reviewe
Gold nanoparticle-based strategies against SARS-CoV-2: A review
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 has been an immense threat to global public health and has also had a negative socioeconomic impact worldwide. However, although the pandemic is now under control, it has demonstrated that society is unprepared to use analysis methods that are applicable to various types of viruses nor apply new therapies to prevent infections, considering the extensive time needed for vaccine development. The use of nanomaterial-based diagnostics and therapeutics can provide essential strategies for both virus detection and treatment. Gold nanoparticles (AuNPs) are the nanomaterials most commonly used to enhance virus detection because of their bioconjugation, high plasmon resonance, and excellent electrical, optical, and catalytic properties. The present review outlines the recent advances reported in the literature regarding using AuNPs for their antiviral activities with respiratory viruses, analysis techniques such as AuNP-assisted polymerase chain reaction, biosensors (electrochemical, piezoelectric, and optical), lateral flow analysis, nucleic acid assays, and gene and vaccine therapy. Finally, as a potential antiviral treatment, this review provides in vitro and in vivo toxicity results of AuNPs for respiratory viruses, as well as those related to their toxicity in humans, to evaluate their use as a future antiviral treatment
Developing new 3D hydrogel models of the human mammary gland to investigate breast cancer initiation
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