Selective Autophagy Receptor NBR1 Retards Nucleus Pulposus Cell Senescence by Directing the Clearance of SRBD1.

Intervertebral disc degeneration (IDD) is a prevalent degenerative disorder that closely linked to aging. Numerous studies have indicated the crucial involvement of autophagy in the development of IDD. However, the non-selective nature of autophagy substrates poses great limitations on the application of autophagy-related medications. This study aims to enhance our comprehension of autophagy in the development of IDD and investigate a novel therapeutic approach from the perspective of selective autophagy receptor NBR1. Proteomics and immunoprecipitation and mass spectrometry analysis, combined with in vivo and in vitro experimental verification were performed. NBR1 is found to be reduced in IDD, and NBR1 retards cellular senescence and senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPCs), primarily through its autophagy-dependent function. Mechanistically, NBR1 knockdown leads to the accumulation of S1 RNA-binding domain-containing protein 1 (SRBD1), which triggers cellular senescence via AKT1/p53 and RB/p16 pathways, and promotes SASP via NF-κß pathway in NPCs. Our findings reveal the function and mechanism of selective autophagy receptor NBR1 in regulating NPCs senescence and degeneration. Targeting NBR1 to facilitate the clearance of detrimental substances holds the potential to provide novel insights for IDD treatment.

Copper-Loaded Nanoheterojunction Enables Superb Orthotopic Osteosarcoma Therapy via Oxidative Stress and Cell Cuproptosis.

Catalytic tumor therapy based on two-dimensional (2D) nanomaterials is a burgeoning and promising tumor therapeutic modality. However, the inefficient utilization and conversion of exogenous stimulation, single catalytic modality, and unsatisfactory therapeutic efficiency in the tumor microenvironment (TME) have seriously restricted their further application in tumor therapy. Herein, the heterogeneous carbon nitride-based nanoagent named T-HCN@CuMS was successfully developed, which dramatically improved the efficiency of the tumor therapeutic modality. Benefiting from the donor-acceptor (triazine-heptazine) structure within the heterogeneous carbon nitride nanosheets (HCN) and the construction of interplanar heterostructure with copper loaded metallic molybdenum bisulfide nanosheets (CuMS), T-HCN@CuMS presented a favorable photo-induced catalytic property to generate abundant reactive oxygen species (ROS) under near-infrared (NIR) light irradiation. Besides, the choice of CuMS simultaneously enabled this nanoagent to efficiently catalyze the Fenton-like reaction and trigger cell cuproptosis, a recently recognized regulated cell death mode characterized by imbalanced intracellular copper homeostasis and aggregation of lipoylated mitochondrial proteins. Moreover, upon surface modification with cRGDfk-PEG2k-DSPE, T-HCN@CuMS was prepared and endowed with improved dispersibility and αvß3 integrins targeting ability. In general, through the rational design, T-HCN@CuMS was facilely prepared and had achieved satisfactory antitumor and antimetastasis outcomes both in vitro and in a high-metastatic orthotopic osteosarcoma model. This strategy could offer an idea to treat malignant diseases based on 2D nanomaterials.

Experimental demonstration of weak-light inter-spacecraft clock jitter readout for TianQin.

The space-based gravitational wave detection mission, TianQin, requires high-level synchronization between independent clocks of all spacecrafts to extract the gravitational wave signals. It is necessary to measure the inter-spacecraft relative clock jitter based on laser phase-sideband clock transfer. The main challenge is the tracking and locking of clock sideband beatnote signals with low signal-to-noise ratio and frequency variation. In this paper, a systematic scheme of inter-spacecraft clock jitter readout is reported. The requirement of the clock transfer link for TianQin based on the time-delay interferometry algorithm is derived. A bi-directional laser interferometer system with a transmission optical power below 1 nW and a time delay of ∼50 µs is built up to demonstrate the weak-light clock transfer. In this scheme, frequency modulation is performed on the laser to simulate the inter-spacecraft Doppler frequency shift and its variation. Based on electrical and optical clock transfer comparison experiments, it is demonstrated that the GHz frequency synthesizer is the main noise source below the 50 mHz frequency range. The residual clock jitter noise introduced by the optical transfer link is below 40 fs/Hz1/2 above the 6 mHz frequency range, and the fractional frequency instability is less than 6.7 × 10-17 at 1000 s, which meets the requirement of the TianQin mission. Ultimately, The carrier phase measurement accuracy reaches 1 × 10-4 cycles/Hz1/2 above 6 mHz after differential clock noise correction using measured clock jitter.