Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

USP7 substrates identified by proteomics analysis reveal the specificity of USP7.

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of USP7and its closest homolog, USP47 Our proteome profiling for the first time revealed the proteome changes caused by USP7 and/or USP47 depletion. Combining protein profiling, transcriptome analysis, and tandem affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates that includes known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. We further showed that MGA deletion reduced cell proliferation, similar to what was observed in cells with USP7 deletion. In conclusion, our proteome-wide analysis uncovered potential USP7 substrates, providing a resource for further functional studies.

DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

PQSDC: a parallel lossless compressor for quality scores data via sequences partition and run-length prediction mapping.

MOTIVATION: The quality scores data (QSD) account for 70% in compressed FastQ files obtained from the short and long reads sequencing technologies. Designing effective compressors for QSD that counterbalance compression ratio, time cost, and memory consumption is essential in scenarios such as large-scale genomics data sharing and long-term data backup. This study presents a novel parallel lossless QSD-dedicated compression algorithm named PQSDC, which fulfills the above requirements well. PQSDC is based on two core components: a parallel sequences-partition model designed to reduce peak memory consumption and time cost during compression and decompression processes, as well as a parallel four-level run-length prediction mapping model to enhance compression ratio. Besides, the PQSDC algorithm is also designed to be highly concurrent using multicore CPU clusters. RESULTS: We evaluate PQSDC and four state-of-the-art compression algorithms on 27 real-world datasets, including 61.857 billion QSD characters and 632.908 million QSD sequences. (1) For short reads, compared to baselines, the maximum improvement of PQSDC reaches 7.06% in average compression ratio, and 8.01% in weighted average compression ratio. During compression and decompression, the maximum total time savings of PQSDC are 79.96% and 84.56%, respectively; the maximum average memory savings are 68.34% and 77.63%, respectively. (2) For long reads, the maximum improvement of PQSDC reaches 12.51% and 13.42% in average and weighted average compression ratio, respectively. The maximum total time savings during compression and decompression are 53.51% and 72.53%, respectively; the maximum average memory savings are 19.44% and 17.42%, respectively. (3) Furthermore, PQSDC ranks second in compression robustness among the tested algorithms, indicating that it is less affected by the probability distribution of the QSD collections. Overall, our work provides a promising solution for QSD parallel compression, which balances storage cost, time consumption, and memory occupation primely. AVAILABILITY AND IMPLEMENTATION: The proposed PQSDC compressor can be downloaded from https://github.com/fahaihi/PQSDC.

Precise Tuning of Hollow and Pore Size of Bimetallic MOFs Derivate to Construct High-Performance Nanoscale Materials for Supercapacitors and Sodium-Ion Batteries.

Precise control of pore volume and size of carbon nanoscale materials is crucial for achieving high capacity and rate performances of charge/discharge. In this paper, starting from the unique mechanism of the role of In, Zn combination, and carboxyl functional groups in the formation of the lumen and pore size, the composition of InZn-MIL-68 is regulated to precisely tune the diameter and wall pore size of the hollow carbon tubes. The hollow carbon nanotubes (CNT) with high-capacity storage and fast exchange of Na+ ions and charges are prepared. The CNT possess ultra-high specific capacitance and ultra-long cycle life and also offer several times higher Na+ ion storage capacity and rate performance than the existing CNTs. Density functional theory calculations and tests reveal that these superior characteristics are attributed to the spacious hollow structure, which provides sufficient space for Na+ storage and the tube wall's distinctive porosity of tube wall as well as open ends for facilitating Na+ rapid desorption. It is believed that precise control of sub-nanopore volume and pore size by tuning the composition of the carbon materials derived from bimetallic metal-organic frameworks (MOFs) will establish the basis for the future development of high-energy density and high-power density supercapacitors and batteries.

CRISPR/Cas9-mediated knockout of the abdominal-B homeotic gene in the global pest, fall armyworm (Spodoptera frugiperda).

The Homeotic complex (Hox) genes play a crucial role in determining segment identity and appendage morphology in bilaterian animals along the antero-posterior axis. Recent studies have expanded to agricultural pests such as fall armyworm (FAW), scientifically known as Spodoptera frugiperda J. E. Smith (Lepidoptera: Noctuidae), which significantly threatens global agricultural productivity. However, the specific role of the hox gene Sfabd-B in FAW remains unexplored. This research investigates the spatial and temporal expression patterns of Sfabd-B in various tissues at different developmental stages using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, we explored the potential function of the Sfabd-B gene located in the FAW genome using CRISPR/Cas9 technology. The larval mutant phenotypes can be classified into three subgroups as compared with wild-type individuals, that is, an excess of pedis in the posterior abdomen, deficient pedis due to segmental fusion and deviations in the posterior abdominal segments. Importantly, significant differences in mutant phenotypes between male and female individuals were also evident during the pupal and adult phases. Notably, both the decapentaplegic (dpp) and cuticular protein 12 (cp 12) genes displayed a substantial marked decrease in expression levels in the copulatory organ of male mutants and the ovipositor of female mutants compared with the wild type. These findings highlight the importance of Sfabd-B in genital tract patterning, providing a potential target for improving genetic control.

Iron-Catalyzed Gamma-Gamma Dimerization of Siloxydienes.

We report the oxidative dimerization reaction of siloxydienes derived from simple enones that creates a new gamma-gamma (γ-γ) C-C bond using catalytic iron and benzoyl peroxide as the terminal oxidant in acetonitrile solvent at ambient temperature. The reaction shows a broad substrate scope including cyclic and acyclic siloxydienes derived from ketones, aldehydes, and esters, which are converted to 1,8-dicarbonyl compounds under mild catalytic reaction conditions in 19-89 % yield across 30 examples. The method is suitable for the coupling of sterically demanding carbon centers, including the formation of vicinal quaternary centers. Conceptually, the dienol ether serves as a precursor to a conjugated radical cation, which undergoes highly site selective γ-dimerization reactions. The γ-γ dimerization strategy is applied to the synthesis of a bioactive analogue of honokiol.

Effect of weight loss interventions on metabolomic signatures in obese children with insulin resistance.

The obesity epidemic among children has become a major public health issue, and the presence of childhood insulin resistance (IR) has been demonstrated prior to the onset of type 2 diabetes mellitus. However, it is unclear whether the metabolomic signature is associated with weight loss interventions in obese children with IR. Thirty-six obese children with IR were selected from the weight loss camp (Shenzhen Sunshine Xing Yada health Technology Co., LTD). Clinical parameters were collected before and after weight loss intervention. Targeted metabolomics of plasma samples was performed by ultra-performance liquid chromatography coupled to the tandem mass spectrometry, and principal component analysis, variable importance in projection, and orthogonal partial least squares discriminant analysis were used to obtain the differentially expressed metabolites. Pathway analysis was conducted with the Homo sapiens (HSA) sets in the Kyoto Encyclopedia of Genes and Genomes. We used machine learning algorithms to obtain the potential biomarkers and Spearman correlation analysis to clarify the association between potential biomarkers and clinical parameters. We found that clinical parameters and metabolite clusters were significantly changed in obese children with IR before and after weight loss intervention. Mechanistically, weight loss intervention significantly changed 61 metabolites in obese children with IR. Furthermore, 12 pathways were significantly changed. Moreover, the machine learning algorithm found 6 important potential biomarkers. In addition, these potential biomarkers were strongly associated with major clinical parameters. These data indicate different metabolomic profiles in obese children with IR after weight loss intervention, providing insights into the clinical parameters and metabolite mechanisms involved in weight loss programs.

Evidence and Practical Applications of Site Occupancy Theory (SOT) of Eu3+ in Scheelite Compounds.

The determination of the site occupancy of activators in phosphors is essential for precise synthesis, understanding the relationship between their luminescence properties and crystal structure, and tailoring their properties by modifying the host composition. Herein, one simple method was proposed to help determine the sites at which the doping of rare earth ions or transition metal ions occupies in the host lattice through site occupancy theory (SOT) for ions doped into the matrix lattice. SOT was established based on the fact that doping ions preferentially occupy the sites with the lowest bonding energy deviations. In order to provide detailed experimental evidence to prove the feasibility of SOT, several scheelite-type compounds were successfully synthesized using a high-temperature solid-phase method. When Eu3+ ions occupy a similar surrounding environment site, the photoluminescence spectra of the activators Eu3+ are similar. Therefore, by comparing the intensity ratio of photoluminescence spectra and the mechanism of all transitions of KEu(WO4)2, KY(WO4)2:Eu3+, Na5Eu(WO4)4, and Na5Y(WO4)4:Eu3+, it was proved that SOT can successfully confirm the site occupation when doped ions enter the matrix lattice. SOT was further applied to the sites occupied by Eu3+ ion-doped LiAl(MoO4)2 and LiLu(MoO4)2.

A pig model of symptomatic spinal epidural hematoma.

PURPOSE: The purpose of this study was to establish an animal model capable of simulating the development and decompression process of symptomatic spinal epidural hematoma (SSEH). METHODS: A total of 16 male Bama miniature pigs were included in this study and randomly allocated into four groups: Group A (4 h 20 mmHg hematoma compression), Group B (4 h 24 mmHg hematoma compression), Group C (4 h 28 mmHg hematoma compression), and Group Sham (control). Real-time intra-wound hematoma compression values were obtained using the principle of connectors. Electrophysiological analyses, including the latency and amplitude of somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP), along with behavioral observations (Tarlov score), were performed to assess this model. RESULTS: ANOVA tests demonstrated significant differences in the latency and relative amplitude of SSEP and MEP between Groups C and Sham after 4 h of hematoma compression and one month after surgery (P < 0.01). Behavioral assessments 8 h after surgery indicated that animals subjected to 28 mmHg hematoma compression suffered the most severe spinal cord injury. Pearson correlation coefficient test suggested a negative correlation between the epidural pressure and Tarlov score (r = -0.700, p < 0.001). With the progression of compression and the escalation of epidural pressure, the latency of SSEP and MEP gradually increased, while the relative amplitude gradually decreased. CONCLUSIONS: When the epidural pressure reaches approximately 24 mmHg, the spinal cord function occurs progressive dysfunction. Monitoring epidural pressure would be an effective approach to assist to identify the occurrence of postoperative SSEH.

Perioperative complications of en bloc resection and anterior column reconstruction for thoracic and lumbar spinal tumors.

PURPOSE: To evaluate the perioperative clinical outcomes of en bloc resection and anterior column reconstruction for thoracolumbar spinal tumors. METHODS: This study conducted a retrospective analysis of prospective data collection of 86 consecutive patients, including 40 males and 46 females, with an average age of 39 years (ranged from 10 to 71 years). There were 35 cases of a malignant primary tumor,42 cases of an aggressive benign tumor, and nine cases of metastases. The main lesions were located in 65 cases of thoracic spine, 17 cases of lumbar spine, and 4 cases of thoracolumbar spine. Tumors involved one level in 45 patients, two levels in 12 patients, three levels in 21 patients, four levels in five patients, five levels in two patients, and six levels in one patient. RESULTS: According to the Weinstein-Boriani-Biagini surgical staging system, all patients achieved en bloc resections, including 74 cases of total en bloc spondylectomy and 12 cases of sagittal resections. The mean surgical time was 559 min (210-1208 min), and the mean total blood loss was 1528 ml (260-5500 ml). A total of 122 complications were observed in 62(72.1%) patients, of which 18(20.9%) patients had 25 major complications and one patient (1.2%) died of complications. The combined approach (P = 0.002), total blood loss (P = 0.003), staged surgery (P = 0.004), previous surgical history (P = 0.045), the number of involved vertebrae (P = 0.021) and lumbar location (P = 0.012) were statistically significant risk factors for major complication. When all above risk factors were incorporated in multivariate analysis, only the combined approach (P = 0.052) still remained significant. CONCLUSIONS: En bloc resection and anterior column reconstruction is accompanied by a high incidence of complications, especially when a combined approach is necessary.

Would the one-stage combined approach lead to better long-term neurological outcomes than the posterior approach alone in multilevel degenerative cervical myelopathy patients with T2-Weighted increased signal intensity? An 8-year follow-up results and propensity score matching analysis.

BACKGROUND: T2-weighted increased signal intensity (ISI) is commonly recognized as a sign of more severe spinal cord lesions, usually accompanied by worse neurological deficits and possibly worse postoperative neurological recovery. The combined approach could achieve better decompression and better neurological recovery for multilevel degenerative cervical myelopathy (MDCM). The choice of surgical approach for MDCM with intramedullary T2-weighted ISI remains disputed. This study aimed to compare the neurological outcomes of posterior and one-stage combined posteroanterior approaches for MDCM with T2-weighted ISI. METHODS: A total of 83 consecutive MDCM patients with confirmed ISI with at least three intervertebral segments operated between 2012 and 2014 were retrospectively enrolled. Preoperative demographic, radiological and clinical condition variables were collected, and neurological conditions were evaluated by the Japanese Orthopedic Assessment score (JOA) and Neck Disability Index (NDI). Propensity score matching analysis was conducted to produce pairs of patients with comparable preoperative conditions from the posterior-alone and combined groups. Both short-term and mid-term surgical outcomes were evaluated, including the JOA recovery rate (JOARR), NDI improvements, complications, and reoperations. RESULTS: A total of 83 patients were enrolled, of which 38 and 45 patients underwent posterior surgery alone and one-stage posteroanterior surgery, respectively. After propensity score matching, 38 pairs of comparable patients from the posterior and combined groups were matched. The matched groups presented similar preoperative clinical and radiological features and the mean follow-up duration were 111.6 ± 8.9 months. The preoperative JOA scores of the posterior and combined groups were 11.5 ± 2.2 and 11.1 ± 2.3, respectively (p = 0.613). The combined group presented with prolonged surgery duration(108.8 ± 28.0 and 186.1 ± 47.3 min, p = 0.028) and greater blood loss(276.3 ± 139.1 and 382.1 ± 283.1 ml, p<0.001). At short-term follow-up, the combined group presented a higher JOARR than the posterior group (posterior group: 50.7%±46.6%, combined group: 70.4%±20.3%, p = 0.024), while no significant difference in JOARR was observed between the groups at long-term follow-up (posterior group: 49.2%±48.5%, combined group: 59.6%±47.6%, p = 0.136). No significant difference was found in the overall complication and reoperation rates. CONCLUSIONS: For MDCM patients with ISI, both posterior and one-stage posteroanterior approaches could achieve considerable neurological alleviations in short-term and long-term follow-up. With greater surgical trauma, the combined group presented better short-term JOARR but did not show higher efficacy in long-term neurological function preservation in patients with comparable preoperative conditions.

Application of TCM Nursing in Post-anesthesia Recovery Room Under Integrated Management Mode.

Objective: To explore the effect of traditional Chinese medicine (TCM) nursing under the integrated management mode during anesthesia recovery. Methods: The researchers' hospital admitted 114 patients who underwent general anesthesia between August 2022 and April 2023. Based on the admission order, these patients were divided into a control group (N=57) and an observation group (N=57). The control group received routine nursing intervention, while the observation group received comprehensive TCM nursing management, which included therapies such as cupping, acupressure, massage, herbal decoction, and mirabilite application. The study evaluated the psychological status, recovery indexes after anesthesia, comfort level, incidence of complications, and patient satisfaction with nursing care. Results: Compared to the control group, the observation group showed significant improvement in their psychological well-being (P < .05) and better recovery outcomes after anesthesia (P < .05). Additionally, the observation group reported higher levels of comfort (P < .05), a lower incidence of complications (8.77% vs 29.82%, P < .05), and greater satisfaction with nursing care (98.25% vs 84.21%, P < .05) compared to the control group. Conclusion: Integrated management of traditional Chinese medicine effectively reduces postoperative adverse events, improves treatment outcomes, and facilitates patient recovery. Its benefits are evident, and its feasibility is well-established.

Formation of autotrophic nitrogen removal granular sludge driven by the dual-partition airlift internal circulation: Insights from performance assessment, community succession, and metabolic mechanism.

Granular sludge has been recognized as an effective method for the application and industrialization of the anammox-based process due to its good biomass retention capacity and environmental tolerance. In this study, a one-stage autotrophic nitrogen removal (ANR) dual-partition system with airlift internal circulation was implemented for 320 days. A high nitrogen removal efficiency of 84.6% was obtained, while the nitrogen removal rate reached 1.28 g-N/L/d. ANR granular sludge dominated by Nitrosomonas and Candidatus Brocadia was successfully cultivated. Results showed that activity and abundance of functional flora first increased with granulation process, but eventually declined slightly when particle size exceeded the optimal range. Total anammox activity was observed to be significantly correlated with protein content (R2 = 0.9623) and nitrogen removal performance (R2 = 0.8796). Correlation network revealed that AnAOB had complex interactions with other bacteria, both synergy for nitrogen removal and competition for substrate. Changes in abundances of genes encoding the Carbohydrate Metabolism, Energy Metabolism, and Membrane Transport suggested energy production and material transfer were possibly blocked with further sludge granulation. Formation of ANR granular sludge promoted the interactions and metabolism of functional microorganisms, and the complex nitrogen metabolic pathways improved the performance stability. These results validated the feasibility of granule formation in the airlift dual-partition system and revealed the response of the ANR system to sludge granulation.

PMFFRC: a large-scale genomic short reads compression optimizer via memory modeling and redundant clustering.

BACKGROUND: Genomic sequencing reads compressors are essential for balancing high-throughput sequencing short reads generation speed, large-scale genomic data sharing, and infrastructure storage expenditure. However, most existing short reads compressors rarely utilize big-memory systems and duplicative information between diverse sequencing files to achieve a higher compression ratio for conserving reads data storage space. RESULTS: We employ compression ratio as the optimization objective and propose a large-scale genomic sequencing short reads data compression optimizer, named PMFFRC, through novelty memory modeling and redundant reads clustering technologies. By cascading PMFFRC, in 982 GB fastq format sequencing data, with 274 GB and 3.3 billion short reads, the state-of-the-art and reference-free compressors HARC, SPRING, Mstcom, and FastqCLS achieve 77.89%, 77.56%, 73.51%, and 29.36% average maximum compression ratio gains, respectively. PMFFRC saves 39.41%, 41.62%, 40.99%, and 20.19% of storage space sizes compared with the four unoptimized compressors. CONCLUSIONS: PMFFRC rational usage big-memory of compression server, effectively saving the sequencing reads data storage space sizes, which relieves the basic storage facilities costs and community sharing transmitting overhead. Our work furnishes a novel solution for improving sequencing reads compression and saving storage space. The proposed PMFFRC algorithm is packaged in a same-name Linux toolkit, available un-limited at https://github.com/fahaihi/PMFFRC .

Therapeutic potential of melatonin in the intervertebral disc degeneration through inhibiting the ferroptosis of nucleus pulpous cells.

Ferroptosis, a novel type of cell death mediated by the iron-dependent lipid peroxidation, contributes to the pathogenesis of the intervertebral disc degeneration (IDD). Increasing evidence demonstrated that melatonin (MLT) displayed the therapeutic potential to prevent the development of IDD. Current mechanistic study aims to explore whether the downregulation of ferroptosis contributes to the therapeutic capability of MLT in IDD. Current studies demonstrated that conditioned medium (CM) from the lipopolysaccharide (LPS)-stimulated macrophages caused a series of changes about IDD, including increased intracellular oxidative stress (increased reactive oxygen species and malondialdehyde levels, but decreased glutathione levels), upregulated expression of inflammation-associated factors (IL-1ß, COX-2 and iNOS), increased expression of key matrix catabolic molecules (MMP-13, ADAMTS4 and ADAMTS5), reduced the expression of major matrix anabolic molecules (COL2A1 and ACAN), and increased ferroptosis (downregulated GPX4 and SLC7A11 levels, but upregulated ACSL4 and LPCAT3 levels) in nucleus pulposus (NP) cells. MLT could alleviate CM-induced NP cell injury in a dose-dependent manner. Moreover, the data substantiated that intercellular iron overload was involved in CM-induced ferroptosis in NP cells, and MLT treatment alleviated intercellular iron overload and protected NP cells against ferroptosis, and those protective effects of MLT in NP cells further attenuated with erastin and enhanced with ferrostatin-1(Fer-1). This study demonstrated that CM from the LPS-stimulated RAW264.7 macrophages promoted the NP cell injury. MLT alleviated the CM-induced NP cell injury partly through inhibiting ferroptosis. The findings support the role of ferroptosis in the pathogenesis of IDD, and suggest that MLT may serve as a potential therapeutic approach for clinical treatment of IDD.

Identification of a novel cuproptosis-related gene signature for rheumatoid arthritis-A prospective study.

BACKGROUND: Rheumatoid arthritis (RA) is a multifactorial systemic autoimmune disease characterized by ongoing synovial inflammation, leading to the degradation of cartilage. Cuproptosis, as a newly characterized form of cell death, may influence RA progression by regulating immune cells and chondrocytes. This study sets out to identify the hub cuproptosis-related gene (CRG) associated with the pathogenesis of RA. METHODS: A series of bioinformatic analyses were performed to evaluate the expression score of CRGs and the immune infiltration landscape between RA and normal samples. The hub gene was screened through the correlation analysis of CRGs, and the interaction network between the hub gene and transcription factors (TFs) was constructed. Finally, the hub gene was validated through quantitative real-time polymerase chain reaction (qRT-PCR) of patient samples and cell experiments. RESULTS: Drolipoamide S-acetyltransferase (DLAT) was screened as the hub gene. Correlation analysis between the hub gene and immune microenvironment demonstrated that DLAT had the highest correlation with T follicular helper cells. Eight pairs of DLAT-TF interaction networks were constructed. Single-cell sequencing showed that CRGs were highly expressed in RA chondrocytes, and chondrocytes could be classified into three different subsets. qRT-PCR was used to validate the above results. Dlat knockdown in immortalized human chondrocytes led to significantly improved mitochondrial membrane potentials and reduced levels of intracellular reactive oxygen species (ROS), mitochondrial ROS and apoptosis. CONCLUSIONS: This study rudimentarily demonstrates the correlation between CRGs and immune cell infiltration in RA. The biomarker DLAT may provide comprehensive insights into the pathogenesis and drug targets of RA.

Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's disease.

Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild-moderate Alzheimer's disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.

CaO2nanomedicines: a review of their emerging roles in cancer therapy.

Metal peroxide-based nanomedicines have emerged as promising theranostic agents for cancer due to their multifunctional properties, including the generation of bioactive small molecules such as metal ions, H2O2, O2, and OH-. Among these metal peroxides, calcium peroxide (CaO2) nanomedicines have attracted significant attention due to their facile synthesis and good biocompatibility. CaO2nanoparticles have been explored for cancer treatment through three main mechanisms: (1) the release of O2, which helps alleviate tumor hypoxia and enhances oxygen-dependent therapies such as chemotherapy, photodynamic therapy, and immunotherapy; (2) the generation of H2O2, a precursor for ·OH generation, which enables cancer chemodynamic therapy; and (3) the release of Ca2+ions, which induce calcium overload and promote cell apoptosis (called ion-interference therapy). This review provides a comprehensive summary of recent examples of CaO2nanoparticle-based cancer therapeutic strategies, as well as discusses the challenges and future directions in the development of CaO2nanomedicines for cancer treatment.