Endogenous mutant Huntingtin alters the corticogenesis via lowering Golgi recruiting ARF1 in cortical organoid.

Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington's disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.

Potential global distribution of Setaria italica, an important species for dryland agriculture in the context of climate change.

Setaria italica (S. italica, Linnaeus, 1753) is a drought-resistant, barren-tolerant, and widely adapted C-4 crop that plays a vital role in maintaining agricultural and economic stability in arid and barren regions of the world. However, the potential habitat of S. italica under current and future climate scenarios remains to be explored. Predicting the potential global geographic distribution of S. italica and clarifying its ecological requirements can help promote sustainable agriculture, which is crucial for addressing the global food crisis. In this study, we predicted the potential global geographic distribution of S. italica based on 3,154 global distribution records using the Maxent model and ArcGIS software. We assessed the constraints on its potential distribution based on the contribution of environmental factors variables. The predictive accuracy of the Maxent model was evaluated using AUC values, TSS values, and Kappa statistics, respectively. The results showed that the Maxent model had a high prediction accuracy, and the simulation results were also reliable; the total suitable habitats of S. italica is 5.54×107 km2, which mainly included the United States (North America), Brazil (South America), Australia (Oceania), China, India (Asia), and the Russian Federation (Europe). The most suitable habitat of S. italica was 0.52×107 km2, accounting for 9.44% of the total areas, mainly in the United States, India, the Russian Federation, and China. Soil and precipitation (driest monthly precipitation, hottest seasonal precipitation) are the most critical factors limiting the potential distribution of S. italica. Compared with the modern potential distribution, we predict that the four future climate change scenarios will result in varying reductions in the possible geographic ranges of S. italica. Overall, climate change may significantly affect the global distribution of S. italica, altering its worldwide production and trade patterns.

Cistanche phenylethanoid glycosides induce apoptosis and pyroptosis in T-cell lymphoma.

Cistanche deserticola, known for its extensive history in Traditional Chinese Medicine (TCM), is valued for its therapeutic properties. Recent studies have identified its anticancer capabilities, yet the mechanisms underlying these properties remain to be fully elucidated. In this study, we determined that a mixture of four cistanche-derived phenylethanoid glycosides (CPhGs), echinacoside, acteoside, 2-acetylacteoside, and cistanoside A, which are among the main bioactive compounds in C. deserticola, eliminated T-cell lymphoma (TCL) cells by inducing apoptosis and pyroptosis in vitro and attenuated tumor growth in vivo in a xenograft mouse model. At the molecular level, these CPhGs elevated P53 by inhibiting the SIRT2-MDM2/P300 and PI3K/AKT carcinogenic axes and activating PTEN-Bax tumor-suppressing signaling. Moreover, CPhGs activated noncanonical and alternative pathways to trigger pyroptosis. Interestingly, CPhGs did not activate canonical NLRP3-caspase-1 pyroptotic signaling pathway; instead, CPhGs suppressed the inflammasome factor NLRP3 and the maturation of IL-1ß. Treatment with a caspase-1/4 inhibitor and silencing of Gasdermin D (GSDMD) or Gasdermin E (GSDME) partially rescued CPhG-induced cell death. Conversely, forced expression of NLRP3 restored cell proliferation. In summary, our results indicate that CPhGs modulate multiple signaling pathways to achieve their anticancer properties and perform dual roles in pyroptosis and NLRP3-driven proliferation. This study offers experimental support for the potential application of CPhGs in the treatment of TCL.

Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

Diabetic retinopathy (DR) is one of leading causes of vision loss in adults with increasing prevalence worldwide. Increasing evidence has emphasized the importance of gut microbiome in the aetiology and development of DR. However, the causal relationship between gut microbes and DR remains largely unknown. To investigate the causal associations of DR with gut microbes and DR risk factors, we employed two-sample Mendelian Randomization (MR) analyses to estimate the causal effects of 207 gut microbes on DR outcomes. Inputs for MR included Genome-wide Association Study (GWAS) summary statistics of 207 taxa of gut microbes (the Dutch Microbiome Project) and 21 risk factors for DR. The GWAS summary statistics data of DR was from the FinnGen Research Project. Data analysis was performed in May 2023. We identified eight bacterial taxa that exhibited significant causal associations with DR (FDR < 0.05). Among them, genus Collinsella and species Collinsella aerofaciens were associated with increased risk of DR, while the species Bacteroides faecis, Burkholderiales bacterium_1_1_47, Ruminococcus torques, Streptococcus salivarius, genus Burkholderiales_noname and family Burkholderiales_noname showed protective effects against DR. Notably, we found that the causal effect of species Streptococcus salivarius on DR was mediated through the level of host fasting glucose, a well-established risk factor for DR. Our results reveal that specific gut microbes may be causally linked to DR via mediating host metabolic risk factors, highlighting potential novel therapeutic or preventive targets for DR.

Polymerizing M-Series Acceptors for Efficient Polymer Solar Cells: Effect of the Molecular Shape.

Currently, high-performance polymerized small-molecule acceptors (PSMAs) based on ADA-type SMAs are still rare and greatly demanded for polymer solar cells (PSCs). Herein, two novel regioregular PSMAs (PW-Se and PS-Se) are designed and synthesized by using centrosymmetric (linear-shaped) and axisymmetric (banana-shaped) ADA-type SMAs as the main building blocks, respectively. It is demonstrated that photovoltaic performance of the PSMAs can be significantly improved by optimizing the configuration of ADA-type SMAs. Compared to the axisymmetric SMA-based polymer (PS-Se), PW-Se using a centrosymmetric SMA as the main building block exhibits better backbone coplanarity thereby resulting in bathochromically shifted absorption with a higher absorption coefficient, tighter interchain π-π stacking, and more favorable blend film morphology. As a result, enhanced and more-balanced charge transport, better exciton dissociation, and reduced charge recombination are achieved for PW-Se-based devices with PM6 as polymer donor. Benefiting from these positive factors, the optimal PM6:PW-Se-based device exhibits a higher power conversion efficiency (PCE) of 15.65% compared to the PM6:PS-Se-based device (8.90%). Furthermore, incorporation of PW-Se as a third component in the binary active layer of PM6:M36 yields ternary devices with an outstanding PCE of 18.0%, which is the highest value for PSCs based on ADA-type SMAs, to the best of the knowledge.

A Novel Approach Utilizing Domain Adversarial Neural Networks for the Detection and Classification of Selective Sweeps.

The identification and classification of selective sweeps are of great significance for improving the understanding of biological evolution and exploring opportunities for precision medicine and genetic improvement. Here, a domain adaptation sweep detection and classification (DASDC) method is presented to balance the alignment of two domains and the classification performance through a domain-adversarial neural network and its adversarial learning modules. DASDC effectively addresses the issue of mismatch between training data and real genomic data in deep learning models, leading to a significant improvement in its generalization capability, prediction robustness, and accuracy. The DASDC method demonstrates improved identification performance compared to existing methods and excels in classification performance, particularly in scenarios where there is a mismatch between application data and training data. The successful implementation of DASDC in real data of three distinct species highlights its potential as a useful tool for identifying crucial functional genes and investigating adaptive evolutionary mechanisms, particularly with the increasing availability of genomic data.

A high-resolution time-frequency analysis technique based on bi-directional squeezing and its application in fault diagnosis of rotating machinery.

Most of the signals in the field of industrial engineering are nonstationary signals, and the accurate description of the time-frequency (TF) characteristics of nonstationary signals is important for the advancement of industrial engineering. Instantaneous frequency (IF) and group delay (GD) are common TF features used to describe nonstationary signals. Time-reassigned synchrosqueezing transform and synchrosqueezing transform are two TF analysis tools that can accurately characterize the GD and IF of nonstationary signals by squeezing the TF coefficients in the time direction and frequency direction, respectively. However, it is difficult for such two techniques to accurately characterize IF and GD simultaneously. A novel method called time-frequency squeezing transform is introduced in this paper to conquer this drawback. The technique first uses the short-time Fourier transform to calculate the time-frequency representation (TFR) of a signal, and then divides the TFR into two parts according to a chirp rate estimator. The subdivided TFR parts are then squeezed in the frequency and time directions to accurately characterize the IF and GD, respectively, and the two squeezed results are added to form a high-resolution result. The effectiveness of the proposed technique is demonstrated with numerical and experimental signals.

Long-term ecological restoration increased plant diversity and soil total phosphorus content of the alpine flowing sand land in northwest Sichuan, China.

The ecological restoration techniques that combine grazing, sand barriers with willows, fertilization, artificial planting, and continuous management are increasingly adopted in the management of flowing sandy land in high-altitude and cold regions. However, few studies have focused on the long-term ecological restoration effects of such technologies. This study systematically compared the vegetation and soil characteristics under different ecological restoration durations (0 (CK), 3 (F1), 14 (F2), 26 (F3), and 46 (F4) years) in the alpine sandy land of northwest Sichuan. The results showed that, with the increase of ecological restoration durations, (1) the aboveground and underground biomass of plants, and species number significantly increased, while the shannon-wiener index, margalef index, and simpson index dramatically decreased; (2) in the early stage of ecological restoration (0-3 yr), Cyperaceae accounted for the main groups, while in the late stage of ecological restoration (14-46 yr), Leguminosae and Forb groups predominated; (3) ecological restoration durations significantly influenced the total phosphorus (TP) content at a soil depth of 0-60 cm, but soil organic carbon and C/P ratio were only significantly impacted at 40-60 cm; (4) the plant and soil characteristics of F1, F2, and F3 treatments were more similar, and CK and F4 treatments were clearly distinguished on PC1 of principal component analysis; (5) there was no significant correlation between Leguminosae groups and environmental factors. Instead, a correlation between total nitrogen (TN) and Forb groups, Gramineae groups, and Cyperaceae groups was revealed. TN was very significantly positively correlated with species diversity and TP. Long-term ecological restoration improved plants biomass, plant species diversity, functional plant groups, and increased soil TP content in the alpine sandy land of northwest Sichuan.

AGIDB: a versatile database for genotype imputation and variant decoding across species.

The high cost of large-scale, high-coverage whole-genome sequencing has limited its application in genomics and genetics research. The common approach has been to impute whole-genome sequence variants obtained from a few individuals for a larger population of interest individually genotyped using SNP chip. An alternative involves low-coverage whole-genome sequencing (lcWGS) of all individuals in the larger population, followed by imputation to sequence resolution. To overcome limitations of processing lcWGS data and meeting specific genotype imputation requirements, we developed AGIDB (https://agidb.pro), a website comprising tools and database with an unprecedented sample size and comprehensive variant decoding for animals. AGIDB integrates whole-genome sequencing and chip data from 17 360 and 174 945 individuals, respectively, across 89 species to identify over one billion variants, totaling a massive 688.57 TB of processed data. AGIDB focuses on integrating multiple genotype imputation scenarios. It also provides user-friendly searching and data analysis modules that enable comprehensive annotation of genetic variants for specific populations. To meet a wide range of research requirements, AGIDB offers downloadable reference panels for each species in addition to its extensive dataset, variant decoding and utility tools. We hope that AGIDB will become a key foundational resource in genetics and breeding, providing robust support to researchers.

Integration of human organoids single-cell transcriptomic profiles and human genetics repurposes critical cell type-specific drug targets for severe COVID-19.

Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single-cell RNA sequencing (scRNA-seq) technology and genome-wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait-relevant cell types or states. Here, we constructed a computational framework to integrate atlas-level organoid scRNA-seq data, GWAS summary statistics, expression quantitative trait loci, and gene-drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID-19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID-19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID-19-damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID-19, and this cell subset showed a notable increase in cell-to-cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID-19 in a cell-type-specific manner. Overall, our results showcase that host genetic determinants have cellular-specific contribution to COVID-19 severity, and identification of cell type-specific drug targets may facilitate to develop effective therapeutics for treating severe COVID-19 and its complications.

Alterations in gut microbiota and host transcriptome of patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a widespread heart condition caused by atherosclerosis and influences millions of people worldwide. Early detection of CAD is challenging due to the lack of specific biomarkers. The gut microbiota and host-microbiota interactions have been well documented to affect human health. However, investigation that reveals the role of gut microbes in CAD is still limited. This study aims to uncover the synergistic effects of host genes and gut microbes associated with CAD through integrative genomic analyses. RESULTS: Herein, we collected 52 fecal and 50 blood samples from CAD patients and matched controls, and performed amplicon and transcriptomic sequencing on these samples, respectively. By comparing CAD patients with health controls, we found that dysregulated gut microbes were significantly associated with CAD. By leveraging the Random Forest method, we found that combining 20 bacteria and 30 gene biomarkers could distinguish CAD patients from health controls with a high performance (AUC = 0.92). We observed that there existed prominent associations of gut microbes with several clinical indices relevant to heart functions. Integration analysis revealed that CAD-relevant gut microbe genus Fusicatenibacter was associated with expression of CAD-risk genes, such as GBP2, MLKL, and CPR65, which is in line with previous evidence (Tang et al., Nat Rev Cardiol 16:137-154, 2019; Kummen et al., J Am Coll Cardiol 71:1184-1186, 2018). In addition, the upregulation of immune-related pathways in CAD patients were identified to be primarily associated with higher abundance of genus Blautia, Eubacterium, Fusicatenibacter, and Monoglobus. CONCLUSIONS: Our results highlight that dysregulated gut microbes contribute risk to CAD by interacting with host genes. These identified microbes and interacted risk genes may have high potentials as biomarkers for CAD.

Uncovering nutritional metabolites and candidate genes involved in flavonoid metabolism in Houttuynia cordata through combined metabolomic and transcriptomic analyses.

The perennial herb Houttuynia cordata has long been cultivated and used as medicinal and edible plant in Asia. Nowadays, increasing attention is attracted due to its numerous health benefits. Flavonoids are the main chemical constituents exerting pharmacological activities. In the present study, we investigated both metabolome and transcriptome of two H. cordata accessions (6# and 7#) with distinct flavonoids contents. In total 397 metabolites, i.e., 220 flavonoids, 92 amino acids and derivatives, 20 vitamins, and 65 saccharides were abundant in aboveground part. Cyanidin-3-O-rutinoside and quercetin-3-O-galactoside were the most abundant flavonoids, which can be categorized into seven classes, namely anthocyanidins, chalcones, flavanols, flavanones, flavanonols, flavones, and flavonols. Flavonols was the most abundant group. Contents of 112 flavonoids differed significantly between the two accessions, with catechin-(7,8-bc)-4α-(3,4-dihydroxyphenyl)-dihydro-2-(3H)-one, cinchonain Id, and cinchonain Ic being the dominant flavonoid metabolites among them. Pinocembrin-7-O-neohesperidoside, pinocembrin-7-O-rutinoside, and kaempferol-3-O-galactoside-4'-O-glucoside were uniquely abundant in accession 7. Transcriptome data revealed a total of 110 different expressed genes related to flavonoid metabolism, with more highly expressed genes observed in 7#. We annotated a total of 19 differential flavonoid metabolites and 34 differentially expressed genes that are associated with the flavonoid metabolic network. Based on the transcriptome and qPCR data a total of 8 key candidate genes involved in flavonoid metabolism were identified. The ANS gene were found to play an important role in the synthesis of cyanidin-3-O-glucoside, while the CHI, F3'H and FLS genes were mainly responsible for controlling the levels of flavanones, flavones, and flavonols, respectively. Collectively, the present study provides important insights into the molecular mechanism underlying flavonoid metabolism in H. cordata.

Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ T cell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.

The recent progress in the research of extraction and functional applications of basil seed gum.

Basil seed gum (BSG) is a new hydrophilic colloid of natural plant origin. Extracted from basil seeds, it possesses excellent functional characteristics in terms of emulsification, rheology, gelation, stability, and adsorption, which are just as favorable as those of certain commercial gums. Besides, BSG has been widely used in food, medicine, industry, and many other fields for its physiological functions of weight reduction, detoxification, and control of blood sugar and cholesterol as a good dietary fiber. In this paper, we analyzed and discussed the extraction procedures, composition structures, functional characteristics, and modification strategies of BSG. In addition, we summarized the latest research on the applications of BSG in different industries to provide theoretical references for the high-value processing and utilization of BSG.

Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data.

Advances in single-cell RNA sequencing (scRNA-seq) techniques have accelerated functional interpretation of disease-associated variants discovered from genome-wide association studies (GWASs). However, identification of trait-relevant cell populations is often impeded by inherent technical noise and high sparsity in scRNA-seq data. Here, we developed scPagwas, a computational approach that uncovers trait-relevant cellular context by integrating pathway activation transformation of scRNA-seq data and GWAS summary statistics. scPagwas effectively prioritizes trait-relevant genes, which facilitates identification of trait-relevant cell types/populations with high accuracy in extensive simulated and real datasets. Cellular-level association results identified a novel subpopulation of naive CD8+ T cells related to COVID-19 severity and oligodendrocyte progenitor cell and microglia subsets with critical pathways by which genetic variants influence Alzheimer's disease. Overall, our approach provides new insights for the discovery of trait-relevant cell types and improves the mechanistic understanding of disease variants from a pathway perspective.

Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity.

As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.

Development of a Naked Eye CRISPR-Cas12a and -Cas13a Multiplex Point-of-Care Detection of Genetically Modified Swine.

The Rapid Visual CRISPR (RAVI-CRISPR) assay employs Cas12a and Cas13a enzymes for precise gene detection in a sample. However, RAVI-CRISPR is limited in single-tube multiplex detection applications due to the lack of specific single-strand (ss) DNA-fluorescently quenched (ssDNA-FQ) and RNA-fluorescently quenched (ssRNA-FQ) reporter cleavage mechanisms. We report the development of a sensitive and specific dual-gene Cas12a and Cas13a diagnostic system. To optimize the application for field testing, we designed a portable multiplex fluorescence imaging assay that could distinguish test results with the naked eye. Herein, dual gene amplified products from multiplex recombinase polymerase amplification (RPA) were simultaneously detected in a single tube using Cas12a and Cas13a enzymes. The resulting orthogonal DNA and RNA collateral cleavage specifically distinguishes individual and mixed ssDNA-FQ and ssRNA-FQ reporters using the green-red-yellow, fluorescent signal conversion reaction system, detectable with portable blue and ultraviolet (UV) light transilluminators. As a proof-of-concept, reliable multiplex RAVI-CRISPR detection of genome-edited pigs was demonstrated, exhibiting 100% sensitivity and specificity for the analysis of CD163 knockout, lactoferrin (LF) knock-in, and wild-type pig samples. This portable naked-eye multiplex RAVI-CRISPR detection platform can provide accurate point-of-care screening of genetically modified animals and infectious diseases in resource-limited settings.

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.

Association of mitochondrial DNA variation with high myopia in a Han Chinese population.

High myopia (HM), which is characterized by oxidative stress, is one of the leading causes of visual impairment and blindness across the world. Family and population genetic studies have uncovered nuclear-genome variants in proteins functioned in the mitochondria. However, whether mitochondrial DNA mutations are involved in HM remains unexplored. Here, we performed the first large-scale whole-mitochondrial genome study in 9613 HM cases and 9606 control subjects of Han Chinese ancestry for identifying HM-associated mitochondrial variants. The single-variant association analysis identified nine novel genetic variants associated with HM reaching the entire mitochondrial wide significance level, including rs370378529 in ND2 with an odds ratio (OR) of 5.25. Interestingly, eight out of nine variants were predominantly located in related sub-haplogroups, i.e. m.5261G > A in B4b1c, m.12280A > G in G2a4, m.7912G > A in D4a3b, m.94G > A in D4e1, m.14857 T > C in D4e3, m.14280A > G in D5a2, m.16272A > G in G2a4, m.8718A > G in M71 and F1a3, indicating that the sub-haplogroup background can increase the susceptible risk for high myopia. The polygenic risk score analysis of the target and validation cohorts indicated a high accuracy for predicting HM with mtDNA variants (AUC = 0.641). Cumulatively, our findings highlight the critical roles of mitochondrial variants in untangling the genetic etiology of HM.

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.