A 3'-pre-tRNA-derived small RNA tRF-1-Ser regulated by 25(OH)D promotes proliferation and stemness by inhibiting the function of MBNL1 in breast cancer.

BACKGROUND: We explored the potential novel anticancer mechanisms of 25-hydroxyvitamin D (25(OH)D), a vitamin D metabolite with antitumour effects in breast cancer. It is stable in serum and is used to assess vitamin D levels in clinical practice. Transfer RNA-derived small RNAs are small noncoding RNAs that generate various distinct biological functions, but more research is needed on their role in breast cancer. METHODS: Small RNA microarrays were used to explore the novel regulatory mechanism of 25(OH)D. High-throughput RNA-sequencing technology was used to detect transcriptome changes after 25(OH)D treatment and tRF-1-Ser knockdown. RNA pull-down and high-performance liquid chromatography-mass spectrometry/mass spectrometry were used to explore the proteins bound to tRF-1-Ser. In vitro and in vivo functional experiments were conducted to assess the influence of 25(OH)D and tRF-1-Ser on breast cancer. Semi-quantitative PCR was performed to detect alternative splicing events. Western blot assay and qPCR were used to assess protein and mRNA expression. RESULTS: The expression of tRF-1-Ser is negatively regulated by 25(OH)D. In our breast cancer (BRCA) clinical samples, we found that the expression of tRF-1-Ser was higher in cancer tissues than in paired normal tissues, and was significantly associated with tumour invasion. Moreover, tRF-1-Ser inhibits the function of MBNL1 by hindering its nuclear translocation. Functional experiments and transcriptome data revealed that the downregulation of tRF-1-Ser plays a vital role in the anticancer effect of 25(OH)D. CONCLUSIONS: In brief, our research revealed a novel anticancer mechanism of 25(OH)D, unveiled the vital function of tRF-1-Ser in BRCA progression, and suggested that tRF-1-Ser could emerge as a new therapeutic target for BRCA.

Machine Learning-Based Integrated Multiomics Characterization of Colorectal Cancer Reveals Distinctive Metabolic Signatures.

The metabolic signature identification of colorectal cancer is critical for its early diagnosis and therapeutic approaches that will significantly block cancer progression and improve patient survival. Here, we combined an untargeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry and the machine learning approach to analyze metabolites in 173 pairs of cancer samples and matched normal tissue samples to build robust metabolic signature models for diagnostic purposes. Screening and independent validation of metabolic signatures from colorectal cancers via machine learning methods (Logistic Regression_L1 for feature selection and eXtreme Gradient Boosting for classification) was performed to generate a panel of seven signatures with good diagnostic performance (the accuracy of 87.74%, sensitivity of 85.82%, and specificity of 89.66%). Moreover, seven signatures were evaluated according to their ability to distinguish between cancer and normal tissues, with the metabolic molecule PC (30:0) showing good diagnostic performance. In addition, genes associated with PC (30:0) were identified by multiomics analysis (combining metabolic data with transcriptomic data analysis) and our results showed that PC (30:0) could promote the proliferation of colorectal cancer cell SW480, revealing the correlation between genetic changes and metabolic dysregulation in cancer. Overall, our results reveal potential determinants affecting metabolite dysregulation, paving the way for a mechanistic understanding of altered tissue metabolites in colorectal cancer and design interventions for manipulating the levels of circulating metabolites.

Predicting effect of anti-PD-1/PD-L1 inhibitors therapy for hepatocellular carcinoma by detecting plasma metabolite based on UHPLC-MS.

Introduction: Anti-PD-1/PD-L1 inhibitors therapy has become a promising treatment for hepatocellular carcinoma (HCC), while the therapeutic efficacy varies significantly among effects for individual patients are significant difference. Unfortunately, specific predictive biomarkers indicating the degree of benefit for patients and thus guiding the selection of suitable candidates for immune therapy remain elusive.no specific predictive biomarkers are available indicating the degree of benefit for patients and thus screening the preferred population suitable for the immune therapy. Methods: Ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS) considered is an important method for analyzing biological samples, since it has the advantages of high rapid, high sensitivity, and high specificity. Ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS) has emerged as a pivotal method for analyzing biological samples due to its inherent advantages of rapidity, sensitivity, and specificity. In this study, potential metabolite biomarkers that can predict the therapeutic effect of HCC patients receiving immune therapy were identified by UHPLC-MS. Results: A partial least-squares discriminant analysis (PLS-DA) model was established using 14 glycerophospholipid metabolites mentioned above, and good prediction parameters (R2 = 0.823, Q2 = 0.615, prediction accuracy = 0.880 and p < 0.001) were obtained. The relative abundance of glycerophospholipid metabolite ions is closely related to the survival benefit of HCC patients who received immune therapy. Discussion: This study reveals that glycerophospholipid metabolites play a crucial role in predicting the efficacy of immune therapy for HCC.

Dynamics of respiratory infectious diseases under rapid urbanization and COVID-19 pandemic in the subcenter of Beijing during 2014-2022.

Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014-2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014-2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014-2022, and the incidence rate of NRIDs was higher during 2017-2019 (153/100 000) than during 2014-2016 (930/100 000) and during 2020-2022 (371/100 000), respectively (both P < 0.001). The CIU constantly increased with slight fluctuation in 2016 and 2018, respectively. The incidence rate of NRIDs showed an increase along with the CIU during 2014-2019 (r = 0.95, P = 0.004), while the incidence rate's tendency was interrupted by COVID-19 during 2020 with slight decrease in 2020-2021 and rebounded in 2022. For the patients aged <15 years, the incidence rate of NRIDs revealed a very sharp rise at the urbanization period without COVID-19 pandemic compared with that under pre-urbanization period (RR = 7.93, 95 % CI 7.63-8.24), and dropped off to the similar level as of pre-urbanization period when COVID-19 pandemic spread. Conclusions: Urbanization process may increase the incidence of NRIDs but constrained by COVID-19. Certain measures should be taken to prevent and control the effects by urbanization process, such as good natural environment with less population density, ecological environment with good air quality, promoted hand hygiene, mask wearing, keeping interpersonal distance, vaccination, media publicity for NRIDs' prevention and control.

[Effect of Thermal Hydrolysis Pretreatment Time on Microbial Community Structure in Sludge Anaerobic Digestion System].

To evaluate the effect of thermal hydrolysis pretreatment time on the sludge anaerobic digestion system of wastewater treatment plants (WWTPs) in Daxing district, Beijing, the structure and diversity of microbial communities in primary sludge and an activated sludge anaerobic digestion system with different thermal hydrolysis pretreatment times (15 min, 30 min, and 45 min) were analyzed using Illumina MiSeq high-throughput sequencing. The results showed that the dominant groups of digested sludge were mainly distributed in Firmicutes, Cloacimonadota, Chloroflexi, and Synergistota, with W5 being the most common genus. The sum of relative abundance of the dominant phylum was greater than 60%, and W5 accounted for 20.8%-54.5%, showing a high abundance of a few dominant species. During the anaerobic digestion of thermo-hydrolyzed sludge, the relative abundance of acetogenic methanogens decreased due to high levels of volatile fatty acids (VFAs) and ammonia nitrogen (NH4+-N) concentrations, which suggested that the hydrogenophilic methanogenic pathway was more than that of the acetogenic methanogenic pathway. Correlation analysis showed that the soluble protein and pH of thermo-hydrolyzed sludge, NH4+-N of digested sludge, and thermal hydrolysis pretreatment time were the four main environmental factors affecting microbial community structure, and NH4+-N of digested sludge had the largest negative correlation with methanogens. The thermal hydrolysis pretreatment time was negatively correlated with both the Chao index and Shannon index, so longer thermal hydrolysis pretreatment time was not conducive to microbial flora during anaerobic digestion.

Efficient generation of induced pluripotent stem cell lines from healthy donors' peripheral blood mononuclear cells of different genders.

Peripheral blood mononuclear cell (PBMC) are recognized as a conveniently collected reprogramming resource. Several methods are available in academia to reprogram PBMC into induced pluripotent stem cells (iPSC). In this research, we reprogrammed PBMC of different genders by using non-integrative non-viral liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The three obtained iPSC cell lines were karyotypically normal and showed significant tritiated differentiation potential in vitro and in vivo. Our study provided an efficient procedure for reprogramming PBMC into iPSC and obtained three well-functioning iPSC, that may contribute to advance personalized cell therapy in the future.

Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis.

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

Combined BSA-Seq and RNA-Seq Reveal Genes Associated with the Visual Stay-Green of Maize (Zea mays L.).

Maize has become one of the most widely grown grains in the world, and the stay-green mutant allows these plants to maintain their green leaves and photosynthetic potential for longer following anthesis than in non-mutated plants. As a result, stay-green plants have a higher production rate than non-stay-green varieties due to their prolonged grain-filling period. In this study, the candidate genes related to the visual stay-green at the maturation stage of maize were investigated. The F2 population was derived from the T01 (stay-green) and the Xin3 (non-stay-green) cross. Two bulked segregant analysis pools were constructed. According to the method of combining ED (Euclidean distance), Ridit (relative to an identified distribution unit), SmoothG, and SNP algorithms, a region containing 778 genes on chromosome 9 was recognized as the candidate region associated with the visual stay-green in maize. A total of eight modules were identified using WGCNA (weighted correlation network analysis), of which green, brown, pink, and salmon modules were significantly correlated with visual stay-green. BSA, combined with the annotation function, discovered 7 potential candidate genes, while WGCNA discovered 11 stay-green potential candidate genes. The candidate range was further reduced due through association analysis of BSA-seq and RNA-seq. We identified Zm00001eb378880, Zm00001eb383680, and Zm00001eb384100 to be the most likely candidate genes. Our results provide valuable insights into this new germplasm resource with reference to increasing the yield for maize.

An investigation into the effect of audiences on the soccer penalty kick.

BACKGROUND: The effects of audiences in boosting the performance of the home team (i.e., home advantage) in sports like soccer have been studied extensively. However, much less attention has been paid to how audiences influence the performance of individual team members. OBJECTIVE: This study aimed to investigate the effect of audiences on the performance of home and away teams during penalty kicks. METHODS: The current study compared in-game penalty kicks taken by home and away teams in eight major European leagues with audiences in the 2018-2019 season to kicks taken without audiences in the 2020-2021 season during the COVID-19 pandemic. RESULTS AND CONCLUSION: The results indicated no unequivocal evidence for home or away team advantage with respect to penalty outcome (i.e., goal, no goal). Yet, results did show that the number of missed penalties of home teams (i.e., penalties kicked at or outside the frame of the goal) significantly reduced when no audience was present. This supports the hypothesis that home audiences increase anxiety of penalty takers and thus the likelihood of choking. However, the reduced number of missed penalties did not significantly increase penalty outcome of home teams when playing without audiences, suggesting additional, unidentified effects of audiences, possibly also including opponent goalkeepers. Finally, when no audience was present, away teams demonstrated significantly poorer penalty outcome. Future research investigating the effects of audiences on the penalty kick should consider more detailed performance measures of both penalty takers and goalkeepers."

The effectiveness of penalty takers' deception: A scoping review.

Attackers are supposed to take advantage of producing deceptive actions in competitive ball sports, particularly in penalty situations. We conducted a scoping review of the experimental literature to scrutinize whether penalty takers do indeed benefit from using deceptive actions in penalty situations, especially by increasing the likelihood to score a goal. Studies using video-based and in-situ tasks in which soccer and handball goalkeepers try to save a penalty were evaluated. Results showed that penalty takers' manipulation of spatial information available to the goalkeeper during deception (i.e., by using misleading and/or disguising actions) is less effective in in-situ than video-based studies. We argue that this difference occurs because goalkeepers adapt differently to the spatiotemporal constraints in the video-based and in-situ tasks. Goalkeepers appear to prioritize picking up spatial information in video-based tasks while prioritizing temporal information in-situ tasks. Therefore, the manipulation of spatial information appears to be less effective in the more representative in-situ studies than in video-based studies. In order to deceive, penalty takers are advised to manipulate temporal information during on-field penalty situations.

Decreased acetylation of HDGF improves oviduct production in Rana dybowskii, Rana amurensis, and Rana huanrenensis.

The oviduct of female Rana dybowskii is a functional food and can be used as a component of Traditional Chinese medicine. The differentially expressed genes enriched was screened in cell growth of three Rana species. We quantitatively analyzed 4549 proteins using proteomic techniques, enriching the differentially expressed proteins of Rana for growth and signal transduction. The results showed that log2 expression of hepatoma-derived growth factor (HDGF) was increased. We further verified 5 specific differential genes (EIF4a, EIF4g, HDGF1, HDGF2 and SF1) and found that HDGF expression was increased in Rana dybowskii. Through acetylation modification analysis, we identified 1534 acetylation modification sites in 603 proteins, including HDGF, and found that HDGF acetylation expression was significantly reduced in Rana dybowskii. Our results suggest that HDGF is involved in the development of oviductus ranae, which is regulated by acetylation modification.

Single Component Organic Photosensitizer with NIR-I Emission Realizing Type-I Photodynamic and GSH-Depletion Caused Ferroptosis Synergistic Theranostics.

Phototheranostic agents have thrived as prominent tools for tumor luminescence imaging and therapies. Herein, a series of organic photosensitizers (PSs) with donor-acceptors (D-A) are elaborately designed and synthesized. In particular, PPR-2CN exhibits stable near infrared-I (NIR-I) emission, excellent free radicals generation and phototoxicity. Experimental analysis and calculations imply that a small singlet-triplet energy gap (ΔES1-T1 ) and large spin-orbit coupling (SOC) constant boost the intersystem crossing (ISC), leading to type-I photodynamic therapy (PDT). Additionally, the specific glutamate (Glu) and glutathione (GSH) consumption abilities of PPR-2CN inhibit the intracellular biosynthesis of GSH, resulting in redox dyshomeostasis and GSH-depletion causing ferroptosis. This work first realizes that single component organic PS could be simultaneously used as a type-I photodynamic agent and metal-free ferroptosis inducer for NIR-I imaging-guided multimodal synergistic therapy.

A new strategy for searching determinants in colorectal cancer progression through whole-part relationship combined with multi-omics.

The high incidence and mortality of colorectal cancer (CRC) and the lack of adequate diagnostic molecules have led to poor treatment outcomes for colorectal cancer, making it particularly important to develop methods to obtain molecular with significant diagnostic effects. Here, we proposed a whole and part study strategy (early-stage colorectal cancer as "part" and colorectal cancer as "whole") to identify specific and co-pathways of change in early-stage and colorectal cancers and to discover the determinants of colorectal cancer development. Metabolite biomarkers discovered in plasma may not necessarily reflect the pathological status of tumor tissue. To explore the determinant biomarkers associated with plasma and tumor tissue in the CRC progression, multi-omics were performed on three phases of biomarker discovery studies (discovery, identification and validation) including 128 plasma metabolomes and 84 tissue transcriptomes. Importantly, we observe that the metabolic levels of oleic acid and FA (18:2) in patients with colorectal cancer were much higher than in healthy people. Finally, biofunctional verification confirmed that oleic acid and FA (18:2) can promote the growth of colorectal cancer tumor cells and be used as plasma biomarkers for early-stage colorectal cancer. We propose a novel research strategy to discover co-pathways and important biomarkers that may be targeted for a potential role in early colorectal cancer, and our work provides a promising tool for the clinical diagnosis of colorectal cancer.

Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease.

Microglial hyperactivation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild-type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48-linked polyubiquitination in microglia. The loss of Parkin activity in LPS-induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin-induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin-mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD.

Fine-grained Lesion Classification Framework for Early Auxiliary Diagnosis.

The deep neural networks are envisaged for the early disease diagnosis from medical images. However, in the early stage of the disease, the medical images of patients and healthy people have only subtle visual differences. Distinguishing the medical images for early diagnosis belongs to the Fine-Grained Visual Classification (FGVC) task. Many recent works are based on a standard FGVC learning paradigm: locate the discriminative regions first and then classify by fusing the information of these regions. However, it is still not enough for medical images. Because the shape and size of the lesions are variable, and the relationship between lesions and the background is complex. In order to solve these problems, we propose a fine-grained lesion classification framework for early auxiliary diagnosis. We first locate and extract multiple lesions with different sizes and shapes from the original image and then fuse the feature of lesion and background based on attention mechanism. As shown by experiment results in two real-world clinical data sets, our model can locate accurately and perform better.

Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation.

Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.

Nanoparticle albumin-bound paclitaxel-based neoadjuvant regimen: A promising treatment option for HER2-low-positive breast cancer.

This study aimed to compare the efficacy of neoadjuvant systemic therapy (NST) with solvent-based paclitaxel (Sb-P), liposomal paclitaxel (Lps-P), nanoparticle albumin-bound paclitaxel (Nab-P), and docetaxel in human epidermal growth factor receptor 2 (HER2)-low-positive and HER2-zero breast cancers. A total of 430 patients receiving 2-weekly dose-dense epirubicin and cyclophosphamide (EC) followed by 2-weekly paclitaxel (Sb-P, Lps-P, or Nab-P), or 3-weekly EC followed by 3-weekly docetaxel for NST were enrolled in the study. In HER2-low-positive patients, the pathological complete response (pCR) rate in Nab-P group was significantly higher than that in the other three paclitaxel groups (2.8 % in Sb-P group, 4.7 % in Lps-P group, 23.2 % in Nab-P group and 3.2 % in docetaxel group, p < 0.001). In HER2-zero patients, the pCR rate did not differ significantly among the four paclitaxel groups (p = 0.278). The NST regimen containing Nab-P could be considered a promising treatment option in HER2-low-positive breast cancer.

ASC specks exacerbate α­synuclein pathology via amplifying NLRP3 inflammasome activities.

BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson's disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α­synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α­synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α­synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α­synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.

Exercise combined with administration of adipose-derived stem cells ameliorates neuropathic pain after spinal cord injury.

Experimental studies have shown that exercise and human adipose-derived stem cells (ADSCs) play positive roles in spinal cord injury (SCI). However, whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear. Thus, there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI. In this study, a thoracic 11 (T11) SCI contusion model was established in adult C57BL/6 mice. Exercise was initiated from 7 days post-injury and continued to 28 days post-injury, and approximately 1 × 105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI. Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale, von Frey filament test, Hargreaves method, and cold plate test. Histological studies (Eriochrome cyanine staining and immunohistochemistry) were performed at the end of the experiment (28 days post-injury). Exercise combined with administration of ADSCs partially improved early motor function (7, 14, and 21 days post-injury), mechanical allodynia, mechanical hypoalgesia, thermal hyperalgesia, and thermal hypoalgesia. Administration of ADSCs reduced white and gray matter loss at the lesion site. In addition, fewer microglia and astrocytes (as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, respectively) were present in the lumbar dorsal horn in the SCI + ADSCs and SCI + exercise + ADSCs groups compared with the sham group. Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCI-induced neuropathic pain.

Nocardia seriolae mediates liver granulomatous chronic inflammation in Micropterus salmoides through pyroptosis.

Granulomatous diseases caused by Nocardia seriously endanger the health of cultured fish. These bacteria are widely distributed, but prevention and treatment methods are very limited. Chronic granulomatous inflammation is an important pathological feature of Nocardia infection. However, the molecular mechanisms of granuloma formation and chronic inflammation are still unclear. Constructing a granuloma infection model of Nocardia is the key to exploring the pathogenesis of the disease. In this study, we established a granuloma model in the liver of largemouth bass (Micropterus salmoides) and assessed the infection process of Nocardia seriolae at different concentrations by analysing relevant pathological features. By measuring the expression of pro-inflammatory cytokines, transcription factors and a pyroptosis-related protein, we revealed the close relationship between pyroptosis and chronic inflammation of granulomas. We further analysed the immunofluorescence results and the expression of pyroptosis-related protein of macrophage infected by N. seriolae and found that N. seriolae infection induced macrophage pyroptosis in vitro. These results were proved by flow cytometry analysis of infection experiment in vivo. Our results indicated that the pyroptosis effect may be the key to inducing chronic inflammation in the fish liver and further mediating granuloma formation. In this study, we explored the molecular mechanism underlying chronic inflammation of granulomas and developed research ideas for understanding the occurrence and development of granulomatous diseases in fish.