Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma

Osteosarcoma(OS)is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity.Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities.However,the underlying molecular mechanism of these discrepancies remains unclear.The potential role of mechanotransduction in tumorigenicity is of particular interest.To this end,we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo.We utilized a sphere culture model,a soft agar assay,and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells.Additionally,we quantified the expression of sensor proteins,including four kinases and seven cytoskeletal proteins,in OS cell lines.The upstream core transcription factors of rigidity-sensing proteins were further investigated.We detected anoikis resistance in transformed OS cells.The mechanosensing function of transformed OS cells was also impaired,with general downregulation of rigidity-sensing components.We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells.We further uncovered a novel TP53 mutation(R156P)in transformed OS cells,which acquired gain of function to inhibit rigidity sensing,thus sustaining transformed growth.Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment.In addition,the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.

O_(2)-generating multifunctional polymeric micelles for highly efficient and selective photodynamic-photothermal therapy in melanoma

Photothermal therapy(PTT)and photodynamic therapy(PDT)have received tremendous attention owing to their great potential for tumor treatment.However,two main issues hamper the antitumor performance of PDT:overexpression of glutathione(GSH)in tumors,which consumes PDT-induced reactive oxygen species(ROS),and hypoxia within the tumor microenvironment.The drawbacks of PTT include uneven temperature distribution and the upregulation of the heat-shock proteins in tumors,both of which result in ineffective treatment.To address these issues,a MnO_(2)doped nano-delivery system(HTIM-PMs)was synthesized by one-step self-assembly of disulfide bond bridged copolymers for indocyanine green(ICG)and MnO_(2)loading.The surface of polymeric micelles was layered with hyaluronan(HA)and transactivator(TAT)peptides to improve active targeting and increase cell penetration.After internalization,HTIM-PMs showed responsiveness to the tumor microenvironment(acid pH,high glutathione,high H_(2)O_(2)).Breaking the disulfide bond reduced the intratumoral GSH level and simultaneously released the MnO_(2)and ICG.The released MnO_(2)further reduced the GSH level and promoted O_(2)generation,thus enhancing the PDT effect.The PTT-mediated hyperthermia accelerated blood flow,which is beneficial for O_(2)distribution,and promotes ROS diffusion.These PTT-mediated adjuvant effects further overcame the limitations of PDT and the robust PDT effect in turn compensated for the deficiency of PTT.This promising platform exhibited a significant improvement in the PTT-PDT cancer treatment strategy compared to previously reported nanostructures.

Research on modelling accuracy and test validation for biomimetic flapping-wing drone

Scientific advances in drone design have enabled a wide range of services,underpinned by different drones that have various aerodynamic performance.However,research to date is mostly limited focusing on conventional drones.Unconventional drones such as biomimetic drones attracted much attention due to their advantages,including precise point accessibility,altitude manoeuvrability,and no topography restriction for landing.To model the flight dynamics for biomimetic drones,the modelling accuracy is the key indicator to be determined;thus,it requires further analysis.After reviewing previous research,this paper develops a more accurate model by using appropriate methods for error mitigation.To reflect the flapping pattern of biomimetic drones,this model adopts an advanced numerical method(i.e.,a quasi-steady model)to calculate their aerodynamics.The aerodynamics is also affected by the wind(acting on the drone),determined via wind-generated lift and drag terms.Therefore,this paper develops a combined aerodynamic and wind model applicable to biomimetic drones including flapping-wing drones with the following contributions.Comparative analysis discovers that the difference of drones is unsteady flows;thus,a rigorous physical model is built for flow modelling,and its novelty is a quasi-steady method to realistically quantify drone aerodynamics and wind influence.This model is demonstrated by a valid case study of the most stringent application in relation to the motion of a novel flapping-wing drone.The motion simulation of such drone is performed,and then a three-dimensional engineering prototype is built for flight test validation.This case study is implemented and the modelling performance in terms of accuracy is quantified,validating that the new model increases modelling accuracy based on research to date.

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases.However,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese subjects.We have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue.Using an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and FGF21.Additionally,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy.In light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it.Thus,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.