Impaired type I interferons (IFNs) may cause immune deficiency in tumours. Current supplementary IFN therapy partially restores anticancer immunity but simultaneously induces immune evasion by ...upregulating multiple immune checkpoints. Here we create a T lymphocyte membrane-decorated epigenetic nanoinducer that is engineered with programmed cell death protein 1 (PD1), which we call OPEN, for the delivery of the IFN inducer ORY-1001. OPEN increases IFNs and blocks IFN-induced immune checkpoint upregulation. OPEN also targets tumours that express programmed cell death ligand 1 (PDL1) through PDL1/PD1 recognition and subsequently triggers the internalization of OPEN and immune checkpoint proteins. OPEN, which is loaded with ORY-1001, upregulates intratumoural IFNs and downstream major histocompatibility complex I and PDL1. The replenished PDL1 enables further ligation of OPEN, which in turn blocks PDL1. These sequential processes result in an eight- and 29-fold increase of the intratumoural densities of total and active cytotoxic T lymphocytes, respectively, and a strong inhibition of xenograft tumour growth. This T lymphocyte membrane-decorated epigenetic nanoinducer presents a generalizable platform to boost antitumour immunity.
Abstract
Background
Increasing studies suggest that circular RNAs (circRNAs) are critical regulators of cancer development and progression. However, the biological roles and mechanisms of circRNAs in ...gastric cancer (GC) remain largely unknown.
Methods
We identified the differentially expressed circRNAs in GC by analyzing Gene Expression Omnibus (GEO) datasets. We explored the biological roles of circRNAs in GC by in vitro functional assays and in vivo animal studies. We performed tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), mass spectrometry (MS), RNA sequencing, luciferase reporter assays, and rescue experiments to investigate the mechanism of circRNAs in GC.
Results
Downregulated expression of circular RNA EIF4G3 (circEIF4G3; hsa_circ_0007991) was found in GC and was associated with poor clinical outcomes. Overexpression of circEIF4G3 suppressed GC growth and metastasis through the inhibition of β-catenin signaling, whereas knockdown of circEIF4G3 showed the opposite effects. Mechanistic studies revealed that circEIF4G3 bound to δ-catenin protein to promote its TRIM25-mediated ubiquitin degradation and interacted with miR-4449 to upregulate SIK1 expression.
Conclusion
Our findings uncovered a tumor suppressor function of circEIF4G3 in GC through the regulation of δ-catenin protein stability and miR-4449/SIK1 axis. CircEIF4G3 may act as a promising prognostic biomarker and therapeutic target for GC.
Inorganic polyphosphate (polyP) is an ancient energy metabolite and phosphate store that occurs ubiquitously in all organisms. The vacuolar transporter chaperone (VTC) complex integrates cytosolic ...polyP synthesis from ATP and polyP membrane translocation into the vacuolar lumen. In yeast and in other eukaryotes, polyP synthesis is regulated by inositol pyrophosphate (PP-InsP) nutrient messengers, directly sensed by the VTC complex. Here, we report the cryo-electron microscopy structure of signal-activated VTC complex at 3.0 Å resolution. Baker's yeast VTC subunits Vtc1, Vtc3, and Vtc4 assemble into a 3:1:1 complex. Fifteen trans-membrane helices form a novel membrane channel enabling the transport of newly synthesized polyP into the vacuolar lumen. PP-InsP binding orients the catalytic polymerase domain at the entrance of the trans-membrane channel, both activating the enzyme and coupling polyP synthesis and membrane translocation. Together with biochemical and cellular studies, our work provides mechanistic insights into the biogenesis of an ancient energy metabolite.
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•The LB-CA model is developed to investigate the flow and soot loading.•Non-virtual porous structure wall is considered in the filtration process.•The effects of upstream velocities ...on flow field and soot distribution are studied.•The distribution of soot particles is also simulated by LB-Lagrangian model.•The deposited particles dynamic evolution and its effect on flow field are studied.
A two-dimensional mesoscopic gas-solid two-phase flow model has been developed to investigate the flow and soot loading in the micro-channel of diesel particulate filters. Soot particle size examined is in the range of 10 nm–1 µm. The flow is solved by an incompressible lattice Boltzmann model and the transport of solid particles is described by the cell automation probabilistic model. The lattice Boltzmann-cell automation probabilistic model (LB-CA model) is validated with the results of previous studies. The effects of different upstream velocities on the flow field in channels are investigated. The distribution and deposition of soot particles with different sizes in clean channels are simulated based on the LB-CA method and the LB-Lagrangian method respectively. The effects of deposited soot particles on flow field are evaluated in real soot particle capture process. The results show that the distributions of velocity field and pressure field in the channel are significantly affected by the upstream velocity. Compared with the effect of the particle size, the upstream velocity is more influential on the particle deposition distributions. The profiles of deposition distribution from the LB-CA method are in close agreement with those from the LB-Lagrangian method. The deposition distributions of particles with different diameters at the top of the porous wall are similar to the distributions of wall velocity along the channel length. Generally, the deposited soot particles increase the axial pressure and decrease the axial velocity in the inlet channel. The evolution trend of the areas where wall velocity undergoes changes is consistent with that of the solid nodes made of the captured soot particles.
The subgrade frost heave of high-speed railways has an inevitable effect on track irregularity in severely cold regions. To research the influence of the subgrade frost heave on the dynamic behavior ...of high-speed railway vehicles, a multi-body dynamics rigid vehicle model and the finite element method flexible track model are coupled using the rigid-flexible coupling dynamics method. The typical frost heave deformation is used as the excitation source, and the effects on dynamic behaviors of the wheel/rail system are analyzed considering various conditions of frost heave, slab track stochastic irregularity, and train speed. The calculation results show that subgrade frost heave has a significant influence on the safety index (the vertical wheel/rail force and the wheel load reduction rate) and the stability index (the vertical acceleration of the carbody and the vertical sperling index) of the vehicle. Both the safety index and the stability index increases linearly as the frost heave amplitude grows and decreases nonlinearly as the frost heave wavelength grows. The safety index is more sensitive to the wavelength, while the stability index is more sensitive to the amplitude. The frost heave region that has an amplitude greater than 15 mm and a wavelength of less than 15 m should be focused on more. Compared to the frost heave deformation, the growth of slab track stochastic irregularity has greater influence on the vertical wheel/rail force. The influence on the other vertical indexes are relatively insignificant. Higher train speeds lead to a worse safety and stability index, and slowing down the speed is an effective way to ensure the safe and stable operation of the high-speed vehicle.
•The subgrade frost heave has a significant influence on the safety index and the stability index of the vehicle.•The frost heave section with the amplitude greater than 15 mm and the wavelength less than 15 m needs more attentions.•The safety and stability index increase linearly with the amplitude and decreases nonlinearly with the wavelength.•The subgrade thaw settlement has a minor effect on the vehicle dynamics due to the small amplitude in the frost heave areas.•The temporary speed limit in the subgrade frost heave areas can ensure the safety and comfort of the high-speed railway.
Acupuncture has been used for chronic constipation, but evidence for its effectiveness remains scarce.
To determine the efficacy of electroacupuncture (EA) for chronic severe functional constipation ...(CSFC).
Randomized, parallel, sham-controlled trial. (ClinicalTrials.gov: NCT01726504).
15 hospitals in China.
Patients with CSFC and no serious underlying pathologic cause for constipation.
28 sessions of EA at traditional acupoints or sham EA (SA) at nonacupoints over 8 weeks.
The primary outcome was the change from baseline in mean weekly complete spontaneous bowel movements (CSBMs) during weeks 1 to 8. Participants were followed until week 20.
1075 patients (536 and 539 in the EA and SA groups, respectively) were enrolled. The increase from baseline in mean weekly CSBMs during weeks 1 to 8 was 1.76 (95% CI, 1.61 to 1.89) in the EA group and 0.87 (CI, 0.73 to 0.97) in the SA group (between-group difference, 0.90 CI, 0.74 to 1.10; P < 0.001). The change from baseline in mean weekly CSBMs during weeks 9 to 20 was 1.96 (CI, 1.78 to 2.11) in the EA group and 0.89 (CI, 0.69 to 0.95) in the SA group (between-group difference, 1.09 CI, 0.94 to 1.31; P < 0.001). The proportion of patients having 3 or more mean weekly CSBMs in the EA group was 31.3% and 37.7% over the treatment and follow-up periods, respectively, compared with 12.1% and 14.1% in the SA group (P < 0.001). Acupuncture-related adverse events during treatment were infrequent in both groups, and all were mild or transient.
Longer-term follow-up was not assessed. Acupuncturists could not be blinded.
Eight weeks of EA increases CSBMs and is safe for the treatment of CSFC. Additional study is warranted to evaluate a longer-term treatment and follow-up.
Ministry of Science and Technology of the People's Republic of China through the Twelfth Five-Year National Science and Technology Pillar Program.
The circadian clock system orchestrates daily behavioral and physiological rhythms, facilitating adaptation to environmental and internal oscillations. Disruptions in circadian rhythms have been ...linked to increased susceptibility to various diseases and can exacerbate existing conditions. This review delves into the intricate regulation of diurnal gene expression and cell function by circadian clocks across diverse tissues. . Specifically, we explore the rhythmicity of gene expressions, behaviors, and functions in both immune and non‐immune cells, elucidating the regulatory effects and mechanisms imposed by circadian clocks. A detailed discussion is centered on elucidating the complex functions of circadian clocks in regulating key cellular signaling pathways. We further review the circadian regulation in diverse diseases, with a focus on inflammatory diseases, cancers, and systemic diseases. By highlighting the intimate interplay between circadian clocks and diseases, especially through clock‐controlled cell function, this review contributes to the development of novel disease intervention strategies. This enhanced understanding holds significant promise for the design of targeted therapies that can exploit the circadian regulation mechanisms for improved treatment efficacy.
Circadian clocks regulate diurnal variations in an array of genes, delineating the roles and intracellular pathways of cells. Disruption in circadian orchestrations compromises the immune system, precipitating disturbances in cell coordination and signaling pathways, thus promoting the progression of diseases. This review indicates the rhythmicity of gene expressions, behaviors, and functions in cells and elucidates the regulatory mechanisms of cell function by the circadian clock. A detailed discussion is devoted to unraveling the multifaceted roles of circadian clocks in governing pivotal signaling pathways. We further provide a comprehensive discussion on circadian regulation across a spectrum of diseases, with a spotlight on inflammatory diseases, cancers, and systemic diseases.
The fifth wheel is a connecting device between the semi-trailer and the tractor, which plays the role of connecting and steering. According to the finite element analysis technology, the fifth wheel ...model is established by CREO software, and import the established model into HyperWorks software, the static analysis and lightweight design of the structure are carried out by finite element simulation. Finally, the optimal solution of fifth wheel structure is obtained, The static performance of the optimized fifth wheel is verified, which proves that the optimized structure is reasonable and meets the requirements of strength and stiffness. After the optimization of fifth wheel for actual production test, the optimized fifth wheel to meet the requirements of national standards.
Bone destruction and pain caused by cancer is one of the most devastating complications of cancer patients with bone metastases, and it seriously affects the quality of patients' life. Extracellular ...matrix metalloproteinase inducer (EMMPRIN) is a cell adhesion molecule with increased expression in a variety of tumors. This study focused to clarify the specific function of EMMPRIN in bone metastasis of breast cancer.
Adenovirus with shRNA-EMMPRIN was transfected into MRMT-1 rat breast carcinoma cells, and the MRMT-1 cells with different expression levels of EMMPRIN were implanted into the bone marrow cavity of rat tibia. Next, the effect of down-regulation of EMMPRIN was evaluated as follows: bone damage was detected by X-ray radiological and tartrate-resistant acid phosphatase staining; the tumor burden was evaluated by hematoxylin and eosin staining; the test of pain-related behaviors was assessed used the bilateral paw withdrawal mechanical threshold; and the levels of secretory factors in tumor conditioned medium were determined by using enzyme-linked immunosorbent assay.
We found that down-regulation of EMMPRIN in tumor cells can simultaneously reduce tumor burden, relieve cancer-induced bone destruction and pain.
EMMPRIN is expected to be a therapeutic target for relieving bone metastasis of breast cancer and alleviating cancer-induced bone destruction and pain. The method of targeting EMMPRIN may be a promising strategy for the treatment of cancer in the future.
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