Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables T cells to specifically recognize tumor-associated antigens through genetic engineering technology, thus ...exerting antitumor effects, and it has achieved encouraging outcomes in leukemia and lymphoma. Building on excellent progress, CAR-T therapy is also expected to work well in solid tumors. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed at an advanced stage. Current management options for HCC remain limited, and although previous studies have indicated the feasibility of CAR-T cells, ideal therapeutic effects have not yet been achieved. This is, in part, due to the heterogeneity of tumor antigens, high intratumor pressure, immunosuppressive microenvironment, CAR-T cell exhaustion, and serious adverse reactions, which compromise the therapeutic efficiency of CAR-T immunotherapy in HCC. To overcoming these challenges, many ongoing preclinical and clinical studies were conducted. This review summarizes current CAR-T therapy targets in the treatment of HCC, discusses current obstacles and possible solutions in the process, and describes potential strategies to improve the efficacy of CAR-T cells for patients with HCC.
Regulated necrosis (necroptosis) and apoptosis are crucially involved in severe cardiac pathological conditions, including myocardial infarction, ischemia-reperfusion injury and heart failure. ...Whereas apoptotic signaling is well defined, the mechanisms that underlie cardiomyocyte necroptosis remain elusive. Here we show that receptor-interacting protein 3 (RIP3) triggers myocardial necroptosis, in addition to apoptosis and inflammation, through activation of Ca(2+)-calmodulin-dependent protein kinase (CaMKII) rather than through the well-established RIP3 partners RIP1 and MLKL. In mice, RIP3 deficiency or CaMKII inhibition ameliorates myocardial necroptosis and heart failure induced by ischemia-reperfusion or by doxorubicin treatment. RIP3-induced activation of CaMKII, via phosphorylation or oxidation or both, triggers opening of the mitochondrial permeability transition pore and myocardial necroptosis. These findings identify CaMKII as a new RIP3 substrate and delineate a RIP3-CaMKII-mPTP myocardial necroptosis pathway, a promising target for the treatment of ischemia- and oxidative stress-induced myocardial damage and heart failure.
Controlled tuning of interface adhesion is crucial to a broad range of applications, such as space technology, micro-fabrication, flexible electronics, robotics, and bio-integrated devices. Here, we ...show a robust and predictable method to continuously regulate interface adhesion by exciting the mechanical micro-vibration in the adhesive system perpendicular to the contact plane. An analytic model reveals the underlying mechanism of adhesion hysteresis and dynamic instability. For a typical PDMS-glass adhesion system, the apparent adhesion strength can be enhanced by 77 times or weakened to 0. Notably, the resulting adhesion switching timescale is comparable to that of geckos (15 ms), and such rapid adhesion switching can be repeated for more than 2 × 10
vibration cycles without any noticeable degradation in the adhesion performance. Our method is independent of surface microstructures and does not require a preload, representing a simple and practical way to design and control surface adhesion in relevant applications.
Nonprecious metal single‐atom materials have attracted extensive attention in the field of electrocatalysis due to their low cost, high reactivity, high selectivity, and high atomic utilization. ...However, the high surface energy of a single atom causes agglomeration during preparation and catalytic measurement, resulting in damage to the catalytic sites. The strong interaction between substrate and monoatoms is the key factor to prevent the aggregation of individual metal atoms, and the geometry and electronic structure of the catalysts can be adjusted to optimize the catalytic activity. Due to the hierarchically pores, high specific surface area, and defect effect, nitrogen‐doped porous carbon (NPC) has been widely studied as an ideal nonprecious metal single‐atom support, which synergistically enhance the electrocatalytic performance toward oxygen reduction reaction, oxygen evolution reaction, hydrogen evolution reaction, carbon dioxide reduction reaction, and nitrogen reduction reaction with non‐noble metal single atoms. This review summarizes the controllable synthesis, characterization, theoretical calculation, and application of M (M = Co, Fe, Ni, Cu, Zn, Mo, etc.) single atoms on nitrogen‐doped porous carbon. Finally, the future development and challenges of nitrogen‐doped porous carbon supported nonprecious metal single‐atom electrocatalysts for practical commercialization are concluded.
Nonprecious metal single atoms dispersed on nitrogen‐doped porous carbon present superior electrocatalytic performance toward oxygen reduction reaction, oxygen evolution reaction, hydrogen evolution reaction, carbon dioxide reduction reaction, and nitrogen reduction reaction.
Airborne light detection and ranging (LiDAR) technology has become the mainstream data source in geosciences and environmental sciences. Point cloud filtering is a prerequisite for almost all ...LiDAR-based applications. However, it is challenging to select a suitable filtering algorithm for handling high-density point clouds over complex landscapes. Therefore, to determine an appropriate filter on a specific environment, this paper comparatively assessed the performance of five representative filtering algorithms on six study sites with different terrain characteristics, where three plots are located in urban areas and three in forest areas. The representative filtering methods include simple morphological filter (SMRF), multiresolution hierarchical filter (MHF), slope-based filter (SBF), progressive TIN densification (PTD) and segmentation-based filter (SegBF). Results demonstrate that SMRF performs the best in urban areas, and compared to MHF, SBF, PTD and SegBF, the total error of SMRF is reduced by 1.38%, 48.21%, 48.25% and 31.03%, respectively. MHF outperforms the others in forest areas, and compared to SMRF, SBF, PTD and SegBF, the total error of MHF is reduced by 1.98%, 35.87%, 45.11% and 9.42%, respectively. Moreover, both SMRF and MHF keep a good balance between type I and II errors, which makes the produced DEMs much similar to the references. Overall, SMRF and MHF are recommended for urban and forest areas, respectively, and MHF averagely performs slightly better than SMRF on all areas with respect to kappa coefficient.
A mechanical model for a type of vibro-bot Meng, Junmiao; Guo, Jiaojiao; Shui, Langquan
Archive of applied mechanics (1991),
07/2024, Letnik:
94, Številka:
7
Journal Article
Recenzirano
Thanks to compact structural integration and high locomotion performance, introducing vibration and asymmetric interaction with the ground is known as an important driving strategy in medium-sized ...(roughly cm ~ dm scale) mobile robots. For vibrations of different relative intensities, the vibro-bot may be in a continuous sliding state during movement (sliding locomotion), or may be in intermittent jumping and sliding states (hopping locomotion). Herein we conduct a mechanical analysis to reveal the locomotion mechanism of the vibro-bot. Specifically, the nonlinear governing equation of the vibro-bot is derived first. By approximately solving the governing equation, the trigger conditions of the sliding and locomotion modes are predicted, the detailed motion process is outlined, and the optimal design strategies to improve sports performance are clarified. This work not only promotes the design of mobile motion robots, but also has enlightening implications for understanding the locomotion behavior of animals with similar motion characteristics.
Target azimuth information can help further improve the accuracy of magnetic orientation, but the current periodic magnetic field generated by the magnetic beacon is multivalued, so it is not ...suitable for azimuth measurement. According to the distribution of a rotating magnetic field and the phase angle measuring principle, we put forward a new magnetic source structure design of a multiple rotating permanent magnet array by adjusting the spacing d, the rotating speed ω and the initial rotation angle φ, and then verified the mathematical model using COMSOL simulation software. A triple structure was obtained by comparison (d3=3d1=3d2=43 m, d3=3d1=3d2=43 m, φ1=0, φ2=4π5 rad. φ3=π rad), which can produce a strong characteristic magnetic signal similar to a heart-shaped field pattern. Finally, a signal transceiver system was set up for the experiment. The experimental result shows that the waveform of the magnetic signal generated by the real beacon meets the requirement of having a unique maximum value and good directivity within a period, which proves the practical application effect of the structure.
BACKGROUND:Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently ...induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis.
METHODS:Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays.
RESULTS:Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker.
CONCLUSIONS:Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.
This paper investigates the dynamic response of space flexible structures with control moment gyroscopics (CMGs) in which uncertain-but-bounded parameters are considered. The uncertainties in the ...dynamic modeling of flexible structure are treated as interval parameters and an interval gyroscopic model is established. Afterwards, a rational series expansion-interval perturbation finite element method (RSE-IPFEM) is proposed to estimate the upper and lower bounds of the interval dynamic response of the gyroscopic flexible structure. Meanwhile, the Monte Carlo method is presented to provide a reference solution. Two numerical cases are given to demonstrate the effectiveness and feasibility of the RSE-IPFEM. The results show that the uncertainties of Young’s modulus and rotor speed have a great impact on the dynamic response of the gyroscopic flexible structure.
Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated ...glucose disposal, the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.
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