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As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/ STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD., Introduction Low back pain (LBP), the leading cause of disability worldwide and the second most common reason for medical consultation in industrialized countries, is the most prevalent and burdensome musculoskeletal [...]

Objective Methods Results Conclusion Multi‐segmental total en bloc spondylectomy (TES) gradually became more commonly used by clinicians. However, the choice of surgical strategy is unclear. This study aims to investigate the biomechanical performance of different prosthesis types and fixation ranges in multisegmental TES.In this study, a validated finite element model of T12–L2 post‐spondylectomy operations were carried out. The prostheses of these models used either 3D‐printed artificial vertebrae or titanium mesh cages. The fixed range was two or three segment levels. Range of motion, stress distribution of the endplate and internal fixation system, intervertebral disc pressure, and facet joint surface force of four postoperative models and intact model in flexion and extension, as well as lateral bending and rotation were analyzed and compared.The type of prosthesis used in the anterior column reconstruction mainly affected the stress of the adjacent endplate and the prosthesis itself. The posterior fixation range had a greater influence on the overall range of motion (ROM), the ROM of the adjacent segment, the stress of the screw‐rod system, and adjacent facet joint surface force. For the model of the same prosthesis, the increase of fixed length resulted in an obvious reduction of ROM. The maximal decrease was 70.23% during extension, and the minimal decrease was 30.19% during rotation.In three‐segment TES, the surgical strategy of using 3D‐printed artificial prosthesis for anterior column support and pedicle screws for posterior fixation at both two upper and lower levels respectively can reduce the stress on internal fixation system, endplates, and adjacent intervertebral discs, resulting in a reduced risk of internal fixation failure, and ASD development. [ABSTRACT FROM AUTHOR]

This study investigated the effects of additives on fermentation quality, in vitro digestibility and microbial communities of Korshinsk peashrub (Caragana korshinskii Kom.) silages at different maturity stages. Korshinsk peashrub was harvested at budding (S1) and blooming (S2) stages, and ensiled without additives (CON), or with 5% molasses (M0), or a combination of 5% molasses and either L. plantarum CLP (M1) or L. plantarum L694 (M2). Each treatment was triplicated and ensiled for 60 days. Delayed harvest increased water soluble carbohydrates (WSC), neutral detergent fibre (aNDF) and acid detergent fibre (ADF) in silages at S2 stage, whereas crude protein (CP) was lower in silages at S1 stage. Compared with the CON group, the additives treated silages had lower pH, greater lactic acid (LA), acetic acid (AA), and WSC concentrations (p <.05). Application of molasses alone or in combination with CLP had a noticeable effect on bacterial communities, with an increase in Lactobacillus in silages at both stages, whereas M2 silages presented more unfavourable microorganisms. Spearman's rank correlation analysis showed that LA concentration in silage was positively correlated with Lactobacillus relative abundance at both stages, while ammonia nitrogen (NH3‐N) concentration was positively correlated with the relative abundances of unclassified‐f‐Enterobacteriaceae and Enterobacter. In conclusion, delayed harvest could result in greater WSC and aNDF but lower CP in Korshinsk peashrub silage. Low WSC is the primary limiting factor affecting silage quality, and ensiling with molasses accelerated lactic acid fermentation in Korshinsk peashrub silage, providing a high‐quality forage resource for livestock production. [ABSTRACT FROM AUTHOR]

Background: Growing evidence has suggested the role of stem cell‐derived small extracellular vesicles (sEVs) in intervertebral disc degeneration (IVDD). The cargo sorting of sEVs, particularly miRNAs, may be influenced when the donor cell is subjected to oxidative stress. Here, we discovered that miRNAs containing specific motifs are selectively sorted into intraluminal vesicles within mesenchymal stem cells (MSCs) in response to oxidative stress. Methods: Analysis of miRNA cargoes in sEVs derived from normal MSCs (C‐sEVs) or stressed MSCs (T‐sEVs) was conducted using miRNA sequencing. Differential expressed miRNAs in sEVs and the identification of motifs were evaluated through bioinformatics analysis. Protein binding was assessed using immunofluorescent staining and immunoprecipitation analysis. Additionally, RNA pull down and RNA immunoprecipitation (RIP) immunoprecipitation were employed to determine the binding between miRNAs and proteins. The effects of C‐sEVs and T‐sEVs on IVDD were compared by detecting the expression levels of phenotypic genes in vitro or histological evaluation in vivo. Results: The sorting process of miRNAs is mediated by the nucleocytoplasmic transport of heterogeneous nuclear ribonucleoproteins, which in turn facilitates the phosphorylation of SNAP25 and promotes the transport and secretion of sEVs. Additionally, CHMP1B plays a role in membrane repair and protects against cell ferroptosis upon oxidative stress, concurrently affecting the release of sEVs. Notably, stem cell‐derived sEVs associated with ferroptosis impair the therapeutic efficacy for IVDD. However, the application of engineered sEVs containing a specific miRNA inhibitor exhibits the potential to reinstate the therapeutic efficacy for IVDD both in vitro and in vivo. Conclusions: Taken together, our findings shed light on the mechanism of miRNAs sorting into sEVs and offer new insights for the optimization of sEV‐based treatments during intervertebral disc regeneration. regeneration. [ABSTRACT FROM AUTHOR]