Engineering circular RNA medicines
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Engineering bone/cartilage organoids: strategy, progress, and application
The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.
Mechanism of expression regulation of head-to-head overlapping protein-coding genes INO80E and HIRIP3
Although the existence of overlapping protein-coding genes in eukaryotic genomes is known for decades, their role in regulating expression remains far from fully understood. Here, the mechanism regulating the expression of head-to-head overlapping genes, a pair of INO80E and HIRIP3 genes is presented. Based on a series of experiments, we show that the expression of these genes is strongly dependent on sense/antisense interactions. The overlapping transcripts form an RNA:RNA duplex that has a stabilizing effect on the mRNAs involved, and this stabilization may be mediated by the ELAVL1 protein. We also show that the transcription factor RARG is important for the transcription of both genes studied. In addition, we demonstrate that the overlapping isoform of INO80E forms an R-loop that may positively regulate HIRIP3 isoforms. We propose that both structures, dsRNA and R-loops, help to keep the DNA loop open to allow the transcription of the remaining variants of both genes. However, experiments suggest that RNA:RNA duplex formation plays a major role, while R-loops play only a complementary one. The absence of this dsRNA structure leads to the loss of a stable DNA opening and consequently to transcriptional interference.
The DEAD-box helicase eIF4A1/2 acts as RNA chaperone during mitotic exit enabling chromatin decondensation
During mitosis, chromosomes condense and decondense to segregate faithfully and undamaged. The exact molecular mechanisms are not well understood. We identify the DEAD-box helicase eIF4A1/2 as a critical factor in this process. In a cell-free condensation assay eIF4A1/2 is crucial for this process, relying on its RNA-binding ability but not its ATPase activity. Reducing eIF4A1/2 levels in cells consistently slows down chromatin decondensation during nuclear reformation. Conversely, increasing eIF4A1/2 concentration on mitotic chromosomes accelerates their decondensation. The absence of eIF4A1/2 affects the perichromatin layer, which surrounds the chromosomes during mitosis and consists of RNA and mainly nucleolar proteins. In vitro, eIF4A1/2 acts as an RNA chaperone, dissociating biomolecular condensates of RNA and perichromatin proteins. During mitosis, the chaperone activity of eIF4A1/2 is required to regulate the composition and fluidity of the perichromatin layer, which is crucial for the dynamic reorganization of chromatin as cells exit mitosis.
Taking control with RNA
RNA roles RNA seized the global limelight when a modified RNA was used in the vaccine against the virus SARS-CoV-2 that caused a global pandemic.…
Colloidal clusters as models for circular microswimmers
Circular swimmers, particles that propel in circular trajectories, are gaining traction due to their potential for novel collective behaviors. However, synthetic active particles capable of controlled circular propulsion remain scarce. We present a facile experimental strategy to fabricate synthetic swimmers using chemically cross-linked Janus colloid clusters, driven by induced charge electrophoresis. By quantifying the propulsion dynamics of active clusters, we demonstrate that cluster geometry dictates orbit diameter, angular velocity, and chirality. Through statistical analysis of clusters, we identify compact clusters as promising candidates for tunable circular propulsion. To scale up fabrication, we employ capillary-assisted assembly for achieving monodisperse clusters. Our validation of the kinetic model for active trimers and tetramers suggests that clustering as a strategy for circular propulsion extends to Janus colloids propelled by different mechanisms. Our findings establish Janus clusters as versatile systems for controlled circular propulsion, enabling new experimental studies on the collective behavior of circular microswimmers.
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