Population-based genetic analysis in infertile men reveals novel mutations of ADAD family members in patients with impaired spermatogenesis.

The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole-exome sequencing was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM_001159285.2:c.1408G > T (p.V470F) and NM_001159285.2:c.1418A > G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM_001145400.2:c.1381C > T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29 (1/337) and 0.59% (2/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype-phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility.

Role of 8-hydroxyguanine DNA glycosidase 1 deficiency in exacerbating diabetic cardiomyopathy through the regulation of insulin resistance.

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance.

Integrative Multianalytical Model Based on Novel Plasma Protein Biomarkers for Distinguishing Lung Adenocarcinoma and Benign Pulmonary Nodules.

Given the pressing clinical problem of making a decision in diagnosis for subjects with pulmonary nodules, we aimed to discover novel plasma protein biomarkers for lung adenocarcinoma (LUAD) and benign pulmonary nodules (BPNs) and then develop an integrative multianalytical model to guide the clinical management of LUAD and BPN patients. Through label-free quantitative plasma proteomic analysis (data are available via ProteomeXchange with identifier PXD046731), 12 differentially expressed proteins (DEPs) in LUAD and BPN were screened. The diagnostic abilities of DEPs were validated in two independent validation cohorts. The results showed that the levels of three candidate proteins (PRDX2, PON1, and APOC3) were lower in the plasma of LUAD than in BPN. The three candidate proteins were combined with three promising computed tomography indicators (spiculation, vascular notch sign, and lobulation) and three traditional markers (CEA, CA125, and CYFRA21-1) to construct an integrative multianalytical model, which was effective in distinguishing LUAD from BPN, with an AUC of 0.904, a sensitivity of 81.44%, and a specificity of 90.14%. Moreover, the model possessed impressive diagnostic performance between early LUADs and BPNs, with the AUC, sensitivity, specificity, and accuracy of 0.868, 65.63%, 90.14%, and 82.52%, respectively. This model may be a useful auxiliary diagnostic tool for LUAD and BPN by achieving a better balance of sensitivity and specificity.

SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration.

BACKGROUND: Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. METHODS: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. RESULTS: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models. CONCLUSIONS: This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

Harnessing the potential of HLA-G in cancer therapy: advances, challenges, and prospects.

Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells.

Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved housekeeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multifaceted physiological and pathological processes. However, the in vivo function of FAM122A is largely unknown. In this study, we observed that Fam122 deletion resulted in embryonic lethality with severe defects of cardiovascular developments and significantly attenuated cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impaired mesendodermal specification and cardiac differentiation from mouse embryonic stem cells but showed no influence on pluripotent identity. Mechanical investigation revealed that the impaired differentiation potential was caused by the dysregulation of histone modification and Wnt and Hippo signaling pathways through modulation of PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This research not only significantly extends our understanding of the regulatory network of mesendodermal/cardiac differentiation but also proposes the potential significance of FAM122A in cardiac regeneration.

Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cells.

BACKGROUND: Osteosarcoma (OS) is one of the most common aggressive bone malignancy tumors in adolescents. With the application of new chemotherapy regimens, finding new and effective anti-OS drugs to coordinate program implementation is urgent for the patients of OS. Oridonin had been proved to mediate anti-tumor effect on OS cells, but its mechanism has not been fully elucidated. METHODS: The effects of oridonin on the viability, clonal formation and migration of 143B and U2OS cells were detected by CCK-8, colony formation assays and wound-healing test. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the mechanism of oridonin on OS. Western blot (WB), real-time quantitative PCR (qRT-PCR) were used to detect the expression levels of apoptosis and ferroptosis-relative proteins and genes. Annexin V-FITC apoptosis detection kit and flow cytometry examination were used to detect the level of apoptosis. Iron assay kit was used to evaluate the relative Fe2+ content. The levels of mitochondrial membrane potential and lipid peroxidation production was determined by mitochondrial membrane potential detection kit and ROS assay kit. RESULTS: Oridonin could effectively inhibit the survival, clonal formation and metastasis of OS cells. The KEGG results indicated that oridonin is associated with the malignant phenotypic signaling pathways of proliferation, migration, and drug resistance in OS. Oridonin was capable of inhibiting expressions of BAX, cl-caspase3, SLC7A11, GPX4 and FTH1 proteins and mRNA, while promoting the expressions of Bcl-2 and ACSL4 in 143B and U2OS cells. Additionally, we found that oridonin could promote the accumulation of reactive oxygen species (ROS) and Fe2+ in OS cells, as well as reduce mitochondrial membrane potential, and these effects could be significantly reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). CONCLUSION: Oridonin can trigger apoptosis and ferroptosis collaboratively in OS cells, making it a promising and effective agent for OS therapy.

Humoral immune response to tumor-associated antigen Ubiquilin 1 (UBQLN1) and its tumor-promoting potential in lung cancer.

BACKGROUND: This study aims to investigate the expression of UBQLN1 in lung cancer (LC) tissue and the diagnostic capability of autoantibody to UBQLN1 (anti-UBQLN1) in the detection of LC and the discrimination of pulmonary nodules (PNs). METHODS: Sera from 798 participants were used to discover and validate the level of autoantibodies via HuProt microarray and Enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was applied to establish model. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic potential. Immunohistochemistry was performed to detect UBQLN1 expression in 88 LC tissues and 88 para-tumor tissues. qRT-PCR and western blotting were performed to detect the expression of UBQLN1 at the mRNA and protein levels, respectively. Trans-well assay and cell counting kit-8 (CCK-8) was used to investigate the function of UBQLN1. RESULTS: Anti-UBQLN1 was identified with the highest fold change by protein microarray. The level of anti-UBQLN1 in LC patients was obviously higher than that in NC or patients with benign lung disease of validation cohort 1 (P<0.05). The area under the curve (AUC) of anti-UBQLN1 was 0.610 (95%CI: 0.508-0.713) while reached at 0.822 (95%CI: 0.784-0.897) when combining anti-UBQLN1 with CEA, CYFRA21-1, CA125 and three CT indicators (vascular notch sign, lobulation sign and mediastinal lymph node enlargement) in the discrimination of PNs. UBQLN1 protein was overexpressed in lung adenocarcinoma (LUAD) tissues compared to para-tumor tissues. UBQLN1 knockdown remarkably inhibited the migration, invasion and proliferation of LUAD cell lines. CONCLUSIONS: Anti-UBQLN1 might be a potential biomarker for the diagnosis of LC and the discrimination of PNs.

Clpf encodes pentatricopeptide repeat protein (PPR5) and regulates pink flesh color in watermelon (Citrullus lanatus L.).

KEY MESSAGE: The gene controlling pink flesh in watermelon was finely mapped to a 55.26-kb region on chromosome 6. The prime candidate gene, Cla97C06G122120 (ClPPR5), was identified through forward genetics. Carotenoids offer numerous health benefits; while, they cannot be synthesized by the human body. Watermelon stands out as one of the richest sources of carotenoids. In this study, genetic generations derived from parental lines W15-059 (red flesh) and JQ13-3 (pink flesh) revealed the presence of the recessive gene Clpf responsible for the pink flesh (pf) trait in watermelon. Comparative analysis of pigment components and microstructure indicated that the disparity in flesh color between the parental lines primarily stemmed from variations in lycopene content, as well as differences in chromoplast number and size. Subsequent bulk segregant analysis (BSA-seq) and genetic mapping successfully narrowed down the Clpf locus to a 55.26-kb region on chromosome 6, harboring two candidate genes. Through sequence comparison and gene expression analysis, Cla97C06G122120 (annotated as a pentatricopeptide repeat, PPR) was predicted as the prime candidate gene related to pink flesh trait. To further investigate the role of the PPR gene, its homologous gene in tomato was silenced using a virus-induced system. The resulting silenced fruit lines displayed diminished carotenoid accumulation compared with the wild-type, indicating the potential regulatory function of the PPR gene in pigment accumulation. This study significantly contributes to our understanding of the forward genetics underlying watermelon flesh traits, particularly in relation to carotenoid accumulation. The findings lay essential groundwork for elucidating mechanisms governing pigment synthesis and deposition in watermelon flesh, thereby providing valuable insights for future breeding strategies aimed at enhancing fruit quality and nutritional value.

Radon decay product particle radioactivity and oxidative stress biomarkers in patients with COPD.

Radon decay products include α-radiation emitting radionuclides that attach to airborne particles that have potential to promote oxidative tissue damage after inhalation. To assess associations between α-particle radioactivity (α-PR) with urinary biomarkers of oxidative tissue damage, 140 patients with chronic obstructive pulmonary disease (COPD) had up to four 1-week seasonal assessments (N = 413) of indoor (home) and ambient (central site) PM2.5 and black carbon (BC). Following environmental sampling, urine samples were analyzed for total and free malondialdehyde (MDA), biomarkers of lipid oxidation, and 8-hydroxyl-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage. Particle radioactivity was measured as α-activity on PM2.5 filter samples. Linear mixed-effects regression models adjusted for urinary creatinine and other personal characteristics were used to assess associations. Indoor α-PR was associated with an increase in 8-OhdG (8.53%; 95% CI: 3.12, 14.23); total MDA (5.59%; 95% CI: 0.20, 11.71); and free MDA (2.17%; 95% CI: 2.75, 7.35) per interquartile range (IQR) of α-PR [median 1.25 mBq/m3; IQR 0.64], similar adjusting for PM2.5 or BC. The ratio of indoor/ambient α-PR was positively associated with each biomarker and associations with ambient α-PR were positive but weaker than with indoor concentrations. These findings are consistent with a contribution of radon decay products as measured by α-PR to oxidative stress in patients with COPD, with a greater contribution of indoor radon decay products.

Association between gestational exposure to solar activity and pregnancy loss using live births from a Massachusetts-based medical center.

BACKGROUND: Solar activity has been linked to biological mechanisms important to pregnancy, including folate and melatonin levels and inflammatory markers. Thus, we aimed to investigate the association between gestational solar activity and pregnancy loss. METHODS: Our study included 71,963 singleton births conceived in 2002-2016 and delivered at an academic medical center in Eastern Massachusetts. We studied several solar activity metrics, including sunspot number, Kp index, and ultraviolet radiation, with data from the NASA Goddard Space Flight Center and European Centre for Medium-Range Weather Forecasts. We used a novel time series analytic approach to investigate associations between each metric from conception through 24 weeks of gestation and the number of live birth-identified conceptions (LBICs) -the total number of conceptions in each week that result in a live birth. This approach fits distributed lag models to data on LBICs, adjusted for time trends, and allows us to infer associations between pregnancy exposure and pregnancy loss. RESULTS: Overall, the association between solar activity during pregnancy and pregnancy loss varied by exposure metric. For sunspot number, we found that an interquartile range increase in sunspot number (78·7 sunspots) in all of the first 24 weeks of pregnancy was associated with 14·0 (95% CI: 6·5, 21·3) more pregnancy losses out of the average 92 LBICs in a week, and exposure in weeks ten through thirteen was identified as a critical window. Although not statistically significant, higher exposure to Kp index and to UV radiation across all 24 weeks of pregnancy was associated with more and less pregnancy losses, respectively. CONCLUSION: While exposure to certain metrics of solar activity (i.e., sunspot number) throughout the first 24 weeks of pregnancy may be associated with pregnancy losses, exposure to other metrics were not. Solar activity is a complex phenomenon, and more studies are needed to clarify underlying pathways.

AmCBF1 activates the expression of GhClpR1 to mediate dark-green leaves in cotton (Gossypium hirsutum).

KEY MESSAGE: The transcription factor AmCBF1 deepens the leaf colour of transgenic cotton by binding to the promoter of the chloroplast development-related protein GhClpR1 to promote photosynthesis. The ATP-dependent caseinolytic protease (Clp protease) family plays a crucial role within chloroplasts, comprising several Clp proteins to maintain chloroplast homeostasis. At present, research on Clp proteins mainly focuses on Arabidopsis, leaving its function in other plants, particularly in crops, less explored. In this study, we overexpressed AmCBF1 from Ammopiptanthus mongolicus (A. mongolicus) in wild type (R15), and found a significant darkening of leaf colour in transgenic plants (L28 and L30). RNA-seq analysis showed an enrichment of pathways associated with photosynthesis. Subsequent screening of differentially expressed genes revealed a significant up-regulation of GhClpR1, a gene linked to chloroplast development, in the transgenic strain. In addition, GhClpR1 was consistently expressed in upland cotton, with the highest expression observed in leaves. Subcellular localization analysis revealed that the protein encoded by GhClpR1 was located in chloroplasts. Yeast one hybrid and dual luciferase experiments showed that the AmCBF1 transcription factor positively regulates the expression of GhClpR1. VIGs-mediated silencing of GhClpR1 led to a significant yellowing phenotype in the leaves. This was accompanied by a reduction in chlorophyll content, and microscopic examination of chloroplast ultrastructure revealed severe developmental impairment. Finally, yeast two-hybrid assays showed that GhClpR1 interacts with the Clp protease complex accessory protein GhClpT2. Our study provides a foundation for studying the function of the Clp protease complex and a new strategy for cultivating high-light-efficiency cotton resources.

KLF4 inhibits early neural differentiation of ESCs by coordinating specific 3D chromatin structure.

Neural differentiation of embryonic stem cells (ESCs) requires precisely orchestrated gene regulation, a process governed in part by changes in 3D chromatin structure. How these changes regulate gene expression in this context remains unclear. In this study, we observed enrichment of the transcription factor KLF4 at some poised or closed enhancers at TSS-linked regions of genes associated with neural differentiation. Combination analysis of ChIP, HiChIP and RNA-seq data indicated that KLF4 loss in ESCs induced changes in 3D chromatin structure, including increased chromatin interaction loops between neural differentiation-associated genes and active enhancers, leading to upregulated expression of neural differentiation-associated genes and therefore early neural differentiation. This study suggests KLF4 inhibits early neural differentiation by regulation of 3D chromatin structure, which is a new mechanism of early neural differentiation.

TOPK promotes the development of psoriasis and worenine alleviates psoriasiform dermatitis by inhibiting TOPK activity.

BACKGROUND: Psoriasis is an inflammatory skin disease. The pathogenesis of psoriasis has not been fully elucidated. T-lymphokine-activated killer cell-originated protein kinase (TOPK) activity increases in a proinflammatory environment, and inhibiting TOPK blocks inflammation. However, whether TOPK is involved in the pathogenesis of psoriasis remains to be identified. OBJECTIVES: We aimed to study the role of TOPK in psoriasis and attempted to find a drug targeting TOPK for the prevention and treatment of psoriasis. METHOD: Firstly, the expressions of TOPK in psoriatic patients, psoriatic cell and animal model were analysed by Gene Expression Omnibus database, immunohistochemistry (IHC) staining and western blot (WB). After inhibiting TOPK by chemical or gene knockout, the effect of TOPK on the development of psoriasis was verified in cell and animal model by WB, qRT-PCR, ELISA, haematoxylin-eosin (H&E) and IHC staining. Moreover, phosphoproteomic analysis was performed to explore the signalling pathways regulated by TOPK in the occurrence and development of psoriasis. Then, an in vitro kinase assay was performed to prove TOPK kinase activity was inhibited by worenine. Ultimately, WB, qRT-PCR, ELISA, H&E and IHC staining were used to verify the anti-psoriasis effect of worenine by inhibiting TOPK was in cell and animal model. RESULTS: In this study, we found that TOPK was highly expressed in psoriasis patients, psoriatic cell and animal model, which suggests that TOPK might be associated with psoriasis pathogenesis. Interestingly, chemical or genetic inhibition of TOPK alleviated M5- and imiquimod (IMQ)-induced psoriasis-like dermatitis, which further confirmed the role of TOPK in promoting the development of psoriasis. Moreover, we determined that worenine inhibited TOPK kinase activity. In addition, worenine relieved M5- and IMQ-induced psoriasiform dermatitis by inhibiting TOPK activity. CONCLUSIONS: T-lymphokine-activated killer cell-originated protein kinase promotes the development of psoriasis. Therefore, TOPK might be a promising drug target for the prevention and treatment of psoriasis. Worenine alleviates psoriasiform dermatitis by inhibiting TOPK activity, providing new strategies for clinical intervention.

Machine learning based biomarker discovery for chronic kidney disease-mineral and bone disorder (CKD-MBD).

INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. METHODS: We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. RESULTS: Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. DISCUSSION/CONCLUSION: For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition.

Effects of burnout and work engagement in the relationship between self-efficacy and safety behaviours-A chained mediation modelling analysis.

AIMS: To explore the current situation, influencing factors and pathways of safety behaviour of nurses in tumour specialized hospitals, in order to provide a theoretical basis for managers to manage and train nurses, improve their safety behaviour level and ensure medical safety. DESIGN: An anonymous cross-sectional survey. METHOD: A total of 2147 nurses from Grade A cancer hospitals in 15 provinces of China were selected by a convenient sampling method. Questionnaires were collected through the Questionnaire Star platform. Nurses' safety behaviour was measured using the nurse Safety Behaviour Scale, Self-efficacy by the General Self-efficacy Scale, and nurses' occupational burnout was measured by the occupational Burnout Scale, and work engagement through the the Work Engagement Scale. Structural equation modelling was used to test the relationship among nurses' safety behaviour, general self-efficacy, occupational burnout and work engagement. SPSS25.0 software was used to test the relationship among the safety behaviour of nurses, general self-efficacy, occupational burnout and work engagement. RESULTS: The total score of safety behaviour of nurses was 55.45 ± 6.879, the total score of general self-efficacy was 31.39 ± 5.729, the total score of occupational burnout was 44.99 ± 26.587, and the total score of work engagement was 38.48 ± 13.433; the scores of the Nurse Safety Behaviour Scale, Self-Efficacy Scale, and Work Engagement Scale were positively correlated (all p < .001); the occupational burnout scale was negatively correlated with the scores of self-efficacy scale, work engagement scale and nurse safety behaviour scale (all p < .001); Structural equation model analysis shows that self-efficacy and work engagement have a direct positive impact on nurse safety behaviour(ß = .103, ß = .096, all p < .001); Occupational burnout has a direct negative impact on self-efficacy, work engagement and nurse safety behaviour(ß = -.371, ß = -.413, ß = -.328 all p < .001). Bootstrap analysis showed that occupational burnout and job involvement had a significant chain mediating effect between self-efficacy and the safety behaviour of nurses (95% CI: 0.148-0.21). The total effect of self-efficacy on the safety behaviour of nurses was 0.283 (p < .001, 95% CI: 0.225-0.301), the direct effect was 0.096 (p < .001, 95% CI: 0.042-0.15), and the indirect effect was 0.179 (p < .001, 95% CI: 0.085-0.215), The mediating effect accounted for 63.3% of the total effect size. CONCLUSION: Occupational burnout and work engagement play a partial mediating role between self-efficacy and nurse safety behaviour. It is necessary to strengthen training on nurse safety culture awareness, improve the nurse self-efficacy and work engagement, reduce nurse occupational burnout, and thereby improve the level of nurses' safety behaviour.

Effectiveness of shared decision-making for mode of delivery after caesarean section: A systematic review and meta-analysis of randomized controlled trials.

AIM: To review the content, format and effectiveness of shared decision-making interventions for mode of delivery after caesarean section for pregnant women. DESIGN: Systematic review and meta-analysis. METHODS: Six databases (PubMed, Web of science Core Collection, Cochrance Network, Embase, CINAHL, PsycINFO) were searched starting at the time of establishment of the database to May 2023. Following the PRISMAs and use Review Manager 5.3 software for meta-analysis. Two review authors independently assessed the quality of the studies using the risk of bias 2 tool. The protocol was registered in PROSPERO (CRD42023410536). RESULTS: The search strategy obtained 1675 references. After abstract and full text screening, a total of seven studies were included. Shared decision-making interventions include decision aids and counselling that can help pregnant women analyse the pros and cons of various options and help them make decisions that are consistent with their values. The pooled results showed that shared decision-making intervention alleviated decisional conflicts regarding mode of delivery after caesarean section, but had no effect on knowledge and informed choice. CONCLUSION: The results of our review suggest that shared decision-making is an effective intervention to improve the quality of decision-making about the mode of delivery of pregnant women after caesarean section. However, due to the low quality of the evidence, it is recommended that more studies be conducted in the future to improve the quality of the evidence. CORRELATION WITH CLINICAL PRACTICE: This systematic review and meta-analysis provides evidence for the effectiveness of shared decision-making for mode of delivery after cesarean section and may provide a basis for the development of intervention to promote the participation of pregnant women in the decision-making process.

AtRKD5 inhibits the parthenogenic potential mediated by AtBBM.

Parthenogenesis, the development of unfertilized egg cells into embryos, is a key component of apomixis. AtBBM (BABY BOOM), a crucial regulator of embryogenesis in Arabidopsis, possesses the capacity to shift nutritional growth toward reproductive growth. However, the mechanisms underlying AtBBM-induced parthenogenesis remain largely unexplored in dicot plants. Our findings revealed that in order to uphold the order of sexual reproduction, the embryo-specific promoter activity of AtBBM as well as repressors that inhibit its expression in egg cells combine to limiting its ability to induce parthenogenesis. Notably, AtRKD5, a RWP-RK domain-containing (RKD) transcription factor, binds to the 3' end of AtBBM and is identified as one of the inhibitory factors for AtBBM expression in the egg cell. In the atrkd5 mutant, we successfully achieved enhanced ectopic expression of AtBBM in egg cells, resulting in the generation of haploid offspring via parthenogenesis at a rate of 0.28%. Furthermore, by introducing chimeric Arabidopsis and rice BBM genes into the egg cell, we achieved a significant 4.6-fold enhancement in haploid induction through the atdmp8/9 mutant. These findings lay a strong foundation for further exploration of the BBM-mediated parthenogenesis mechanism and the improvement of haploid breeding efficiency mediated by the dmp8/9 mutant.

Career adaptability among new oncology nurses: A longitudinal exploration.

AIM: This study aims to explore the longitudinal predictive effect of self-awareness on career adaptability in new nurses at a tumor specialty hospital and the mediating mechanisms of work readiness and transition shock. BACKGROUND: Career adaptability is crucial for the personal development of nurses and also intricately linked to the retention rates among newcomers in oncology nursing. Inadequate career adaptability contributes to higher turnover, which in turn exacerbates the shortage of qualified nursing personnel in this field. There is a pressing need for dedicated research and interventions that support new nurses, especially in specialized areas like oncology, to promote their well-being and career advancement. Comprehending these challenges is essential for devising effective strategies that will retain nursing talent and ensure the sustainability of a robust healthcare workforce. METHODS: Longitudinal data from four follow-up surveys were collected from 248 new clinical nurses at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Mediation analyses using R 4.1.2 were conducted to examine the pathways between self-awareness, work readiness, transition shock, and career adaptability. CONCLUSIONS: Self-awareness not only directly predicts career adaptability but also influences it through the bidirectional and chained mediating pathways of work readiness and transition shock. IMPLICATIONS FOR NURSING AND HEALTH POLICY: These findings equip nursing managers with flexible strategies to foster and enhance nurses' career adaptability, providing targeted support as nurses assimilate into their clinical roles. This not only strengthens workforce stability but also mitigates turnover, ultimately reinforcing the healthcare workforce.