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We conducted ab initio molecular dynamics simulations to investigate the dynamic properties of the liquid Ti–Al–Ni ternary alloy system at 2033 K. Through simulations across the entire composition range, we revealed the complex compositional dependence of self-diffusion coefficients and viscosity. The self-diffusion coefficients of Ti, Al, and Ni exhibit nonlinear distribution characteristics, while viscosity shows non-monotonic compositional dependence, with lower viscosity in Al-rich regions and higher viscosity in Ni-rich regions. To understand the structural origins of these behaviors, we analyzed chemical short-range order and local fivefold symmetry structures using Warren-Cowley parameters and fivefold symmetry parameters, uncovering a close correlation between atomic-scale structural features and dynamic properties. Evaluation of the Stokes-Einstein relation revealed varying degrees of deviation from its predicted viscosity values across composition regions. We observed a negative correlation between free volume fraction and viscosity, with varying strengths in different regions. These findings provide new perspectives for understanding the complex dynamic properties of Ti–Al–Ni liquid alloys.

It has been widely accepted that resistant starch (RS) provides numerous health benefits for human. In this research, we aimed at evaluating the performance of novel starch-lipid complexes, RS5, in comparison with RS2 on physical features, glucolipids metabolism, inflammation, and gut microbiota profiles of type 2 diabetes mellitus (T2DM) rats. The T2DM model was established by streptozotocin injection to the high-fat-sugar fed rats. According to a serial of biochemical analyses, we found that RS5 diets were strongly correlated with enhanced homeostatic model assessment for insulin secretion (HOMA-IS), high-density lipoprotein cholesterol (HDL-C), adiponectin (ADP), insulin action index (IAI), glucagon-like peptide-1 (GLP1), and short-chain fatty acids (SCFAs) in T2DM rats whilst negatively associated with the low-density lipoprotein (LDL-C) and inflammatory cytokines, showing the capabilities to ameliorate T2DM symptoms by regulation of glucolipid metabolism, gut metabolites, and inflammation. On the other hand, RS2-enriched supplementations were influential in the mediation of insulin secretion to improve glucose metabolism. The increasing evidence collected herein suggested that intestinal microbiota could mediate glucolipids metabolism and alleviate inflammation after certain microflora nourished by RS. In addition, RS intake made an impact on phosphoinositide 3-kinase/protein kinase B signaling pathway that might contribute to the improvement of glucose metabolism, insulin resistance, and inflammatory responses.

BackgroundThe high-quality development of manufacturing in China has spurred industrial transformation and upgrading, placing higher demands on the skills of employees in the electronic manufacturing industry. This situation may induce psychological health problems such as job burnout and depressive symptoms in the employees, and also lead to insomnia, which has become a public health problem that urgently needs attention and solution. ObjectiveTo investigate the relationship between job burnout, depressive symptoms, and insomnia among employees in the electronic manufacturing industry. MethodsA total of 3034 employees from four electronic manufacturing companies in Beijing City, Shanghai City, and Guangdong Province were selected using judgment sampling from September to November 2019. The Maslach Burnout Inventory-General Survey, Patient Health Questionnaire-9, and Self-Administered Sleep Questionnaire were used to collect data. The correlation between job burnout, depressive symptoms, and insomnia was evaluated by hierarchical regression. ResultsA total of 3034 survey questionnaires were distributed, and 2614 valid questionnaires were collected, with a response effectiveness rate of 86.2%. The reporting rates of job burnout, depressive symptoms, and insomnia among employees in the electronic manufacturing industry were 47.2%, 19.5%, and 29.1%, respectively. The reporting rates of insomnia of employees in the job burnout group and depressive symptoms group were higher than those in the non-job burnout group and non-depressive symptoms group (35.3% vs. 23.6%, 47.2% vs. 24.7%, P＜0.001). The results of hierarchical regression showed that job burnout explained 2.8% of the variation of insomnia (P

Scanning electron microscopy (SEM) enables microstructure characterization at multi-scale, having potential to quantify strain distribution across multiple fields of view (FOVs) and exploring coordinated relationships among the deformations of multi-scale microstructures. Optimizing distribution of multi-scale speckles is crucial for achieving high precision and efficiency in digital image correlation (DIC) computations. In this work, a multi-scale strain measurement method is proposed for in-situ SEM mechanical experiments, which relies on an uncomplicated multi-scale speckle preparation method. Multi-scale speckle preparation can be achieved by the combination of spin-coating and magnetron sputtering. By using micro- and macro-speckle, multi-scale strain calculations can be achieved during the in-situ SEM mechanical loading. The InSn macro-speckle is composed of controllable-sized InSn nanoscale speckles, ensuring that the accuracy of DIC measurements in the microscopic regions are not compromised by the coverage of macro-speckles in the testing region. In regions covered exclusively by SiO2 nano-speckles, in-situ SEM mechanical loading allows for the acquisition of high-resolution DIC (HR-DIC) and electron backscatter diffraction (EBSD) data from the same region and under the same deformation state. Experiments are conducted to illustrate the functionality and utility of the multi-scale speckles. Such experimental analyses offer an opportunity to further explore multi-scale strain heterogeneity in some advanced structural materials and provide reliable experimental verification for material mechanics simulations.

Abstract The lack of a chemical platform with high spatial dimensional diversity, coupled with the elusive multi-scale amorphous physics, significantly hinder advancements in amorphous electromagnetic wave absorption (EWA) materials. Herein, we present a synergistic engineering of phenolic multiple kinetic dynamics and discrete crystallization thermodynamics, to elucidate the origin of the dielectric properties in amorphous carbon and the cascade effect during EWA. Leveraging the scalability of phenolic synthesis, we design dozens of morphologies from the bottom up and combine with in-situ pyrolysis to establish a nanomaterial ecosystem of hundreds of amorphous carbon materials. Based on controlled discrete crystallization, nano-curvature regulation of spatial inversion symmetry-breaking structures, and surface electric field enhancement from multi-shell structures, the multi-scale charge imbalance triggers intense polarization. Both experiments and theories show that each scale is essential, which collectively drives broadband absorption (8.46 GHz) and efficient dissipation (−54.77 dB) of EWA performance. Our work on the amorphous nanostructure platform and the cascade effect can contribute to uncovering the missing pieces in amorphous physics and EWA research.

Abstract Soft magnetic materials (SMMs) are indispensable for electromechanical energy conversion in high-efficiency applications, but they are exposed to increasing mechanical loading conditions in electric motors due to higher rotational speeds. Enhancing the yield strength of SMMs is essential to prevent the degradation in magnetic performance and failure from plastic deformation, yet most SMMs have yield strengths far below one gigapascal. Here, we present a multicomponent nanostructuring strategy that doubles the yield strength of SMMs while maintaining ductility. We introduce morphologically anisotropic nanoprecipitates through dislocation-driven precipitation induced by preceding deformation during heat treatment in an iron–nickel–cobalt–tantalum material. With all dimensions of the precipitates below the magnetic domain wall width, we achieve a high precipitate number density with a large specific surface area, small interprecipitate spacing, and high lattice mismatch, which impede dislocation glide and strengthen the material. Both the matrix and precipitates are ferromagnetic, yielding a high magnetic moment. This nanostructuring approach offers a pathway to two-gigapascal-strong ductile SMMs with moderately increased coercivity that can be tolerated in exchange for significantly improved mechanical performance for sustainable electrification.

Abstract We propose that the thermodynamics and the kinetics of state switching for the asymptotically flat black hole enclosed by a cavity can be studied in terms of the free energy landscape formalism. The generalized free energy for the black hole enclosed by a cavity in the canonical ensemble is derived by using the York’s approach, where the temperature on the cavity and the charges inside the cavity are kept as the fixed parameters. By quantifying the corresponding free energy landscape, we obtain the phase diagrams for the black hole in cavity, which reveal a Hawking–Page type transition for the uncharged black hole and a Van der Waals type transition for the charged black hole. We further assume that the dynamics of black hole state switching is mutually determined by the gradient force and the stochastic force arising from the free energy landscape and the thermal noises respectively. We then derive a recurrence relation for the n-momentum of the first passage time distribution function, which enables the calculation of the kinetic times characterized by the mean first passage time and its relative fluctuation. Our analysis illustrates that the kinetics of black hole state switching is determined by the ensemble temperature and the barrier height on the free energy landscape.

Abstract Background Diabetes-associated cognitive dysfunction, characterized by hippocampal synaptic loss as an early pathological feature, seriously threatens patients’ quality of life. Synapses are dynamic structures, and hormones play important roles in modulating the formation and elimination of synapses. The pituitary, the master gland of the body, releases several hormones with multiple roles in hippocampal synaptic regulation. In this study, we aimed to explore the relationship between pituitary hormones and cognitive decline in diabetes. Methods A total of 744 patients with type 2 diabetes (T2DM) (445 men and 299 postmenopausal women) who underwent serum pituitary hormone level assessments, comprehensive cognitive evaluations and MRI scans were enrolled. Dynamic diet interventions were applied in both chow diet-fed mice and high-fat diet (HFD)-fed diabetic mice. The cognitive performance and hippocampal pathology of prolactin (PRL)-knockout mice, neuronal prolactin receptor (PRLR)-specific knockout mice and microglial PRLR-specific knockout mice were assessed. Microglial PRLR-specific knockout mice were fed an HFD to model diabetes. Diabetic mice received an intracerebroventricular infusion of recombinant PRL protein or vehicle. Results This clinical study revealed that decreased PRL levels were associated with cognitive impairment and hippocampal damage in T2DM patients. In diabetic mice, PRL levels diminished before hippocampal synaptic loss and cognitive decline occurred. PRL loss could directly cause cognitive dysfunction and decreased hippocampal synaptic density. Knockout of PRLR in microglia, rather than neurons, induced hippocampal synaptic loss and cognitive impairment. Furthermore, blockade of PRL/PRLR signaling in microglia exacerbated abnormal microglial phagocytosis of synapses, further aggravating hippocampal synaptic loss and cognitive impairment in diabetic mice. Moreover, PRL infusion reduced microglia-mediated synaptic loss, thereby alleviating cognitive impairment in diabetic mice. Conclusion PRL is associated with cognitive dysfunction and hippocampal damage in T2DM patients. In diabetes, a decrease in PRL level drives hippocampal synaptic loss and cognitive impairment by increasing microglia-mediated synapse engulfment. Restoration of PRL levels ameliorates cognitive dysfunction and hippocampal synaptic loss in diabetic mice.

Abstract Prior literature has debated whether syntax is separable from semantics in the brain. Using functional magnetic resonance imaging and multi-voxel pattern analysis, our previous studies investigated brain activity during morpho-syntactic versus semantic processing. These studies only detected semantic specialization in activation patterns and no syntactic specialization in 5- to 6-year-old and 7- to 8-year-old children. To examine if older children who have mastered morpho-syntactic skills would show specialization for syntax, the current study examined 64 9- to 10-year-old children using the same design and analyses. We observed that only the left IFG pars opercularis was sensitive to syntactic but not semantic information, supporting the hypothesis that this region serves as a core region for syntax. In addition, the left STG which has been implicated in the integration of semantics and syntax, as well as the left MTG and IFG pars triangularis which have been implicated in semantics, were sensitive to both semantic and syntactic information with no evidence of specialization. These findings suggest a lexicalized view of syntax, which argues that semantically sensitive regions are also critical regions for syntactic processing during language comprehension.

Abstract Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments. One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser, which employs narrow laser beams to stimulate dermal collagen deposition. Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes. Here, we examine the efficacy and safety of a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors, referred to as combined therapy, for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors, referred to as monotherapy. Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy), which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data. Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P

Abstract The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Abstract This was a multicenter, single-arm, open-label, phase Ib/II study (NCT04255576), aimed to evaluate the efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone (GCTB). JMT103 (2 mg/kg) was administered subcutaneously every four weeks, with loading doses on days 8 and 15. The primary endpoint was the objective tumor response rate (OTR) based on best response, defined as the proportion of patients who achieved elimination of at least 90% of the giant cells or radiologic complete or partial response per the modified Inverse Choi density/size (mICDS) or modified European Organization for Research and Treatment of Cancer (mEORTC) within 12 weeks. Secondary endpoints included objective response rate (ORR) per mICDS and mEORTC, and safety. A total of 139 patients were enrolled, and 135 were analyzed for efficacy. OTR, determined by the independent review committee (IRC) was 93.3% (95% CI 87.7-96.9). Treatment-related adverse events occurred in 90 (64.7%) patients, with hypophosphatemia and hypocalcemia being the most common. No serious treatment-related adverse events were observed. Thus, JMT103 demonstrates potential as a therapeutic option for GCTB.

Abstract The interaction between diet and the immune system has garnered considerable attention, especially regarding the immunomodulatory effects of food‐derived peptides. These peptides, derived from dietary proteins, exhibit diverse mechanisms of action, influencing cytokine production, immune cell function, and gut barrier integrity. Although there are numerous in vitro and animal studies supporting its therapeutic potential in immune‐related diseases, clinical relevance requires further investigation. This review synthesizes current knowledge on food‐derived peptides as immunomodulators, highlighting clinical insights and discussing challenges in their application. Additionally, it expands beyond peptides to encompass various dietary compounds influencing immune function. By integrating structural and functional diversity, this review provides a comprehensive understanding of how nutrition shapes immune responses, offering insights for personalized health strategies.

Background: Colon cancer is a malignant tumor with high malignancy and a low survival rate whose heterogeneity limits systemic immunotherapy. Transforming growth factor-β (TGF-β) signaling pathway-related genes are associated with multiple tumors, but their role in prognosis prediction and tumor microenvironment (TME) regulation in colon cancer is poorly understood. Using bioinformatics, this study aimed to construct a risk prediction signature for colon cancer, which may provide a means for developing new effective treatment strategies. Methods: Using consensus clustering, patients in The Cancer Genome Atlas (TCGA) with colon adenocarcinoma were classified into several subtypes based on the expression of TGF-β signaling pathway-related genes, and differences in survival, molecular, and immunological TME characteristics and drug sensitivity were examined in each subtype. Ten genes that make up a TGF-β-related predictive signature were found by least absolute shrinkage and selector operation (LASSO) regression using colon cancer data from the TCGA database and confirmed using a Gene Expression Omnibus (GEO) dataset. A nomogram incorporating risk scores and clinicopathologic factors was developed to stratify the prognosis of patients with colon cancer for accurate clinical diagnosis and therapy. Results: Two TGF-β subtypes were identified, with the TGF-β-high subtype being associated with a poorer prognosis and superior sensitivity to immunotherapy. Mutation analyses showed a high incidence of gene mutations in the TGF-β-high subtype. After completing signature construction, patients with colon cancer were categorized into high- and low-risk subgroups based on the median risk score of the TGF-β-related predictive signature. The risk score exhibited superior predictive performance relative to age, gender, and stage, as evidenced by its AUC of 0.686. Patients in the high-risk subgroup had higher levels of immunosuppressive cell infiltration and immune checkpoints in the TME, suggesting that these patients had better responses to immunotherapy. Conclusions: Patients with colon cancer were divided into two subtypes with different survival and immune characteristics using consensus clustering analysis based on TGF-β signaling pathway-related genes. The constructed risk prediction signature may show promise as a biomarker for evaluating the prognosis of colon cancer, with potential utility for screening individuals for immunotherapy.

Abstract Resection of thoracic wall tumors results in significant defects in the chest wall, leading to various complications. In recent years, the use of three-dimensional (3D) printed titanium alloy prostheses in clinical practice has demonstrated enhanced outcomes in chest wall reconstruction surgery. A cohort of seven patients with sternal tumors was identified for this study. Following a helical CT scan, a digital model was generated for the design of the prosthesis. Subsequently, the tumors were then removed together with the affected sternum and ribs. The chest wall was then reconstructed using 3D-printed titanium alloy prosthesis for bone reconstruction, mesh for pleural reconstruction, and flap for soft tissue reconstruction. Patients were monitored for a period of one year post-surgery. In the seven cases examined, the tumors were found in various locations with varying degrees of invasion. Based on the scope of surgical resection and the size of the defect, 3D-printed titanium alloy prosthesis was custom-designed for chest wall reconstruction. Prior to bone reconstruction, pleural reconstruction was achieved with Bard Composix E/X Mesh, while soft tissue repair involved muscle flap and musculocutaneous flap procedures. A one-year follow-up assessment revealed that the utilization of the 3D-printed titanium alloy prosthesis led to secure fixation, favorable histocompatibility, and enhanced lung function. The findings demonstrate that the utilization of 3D printed titanium alloy prostheses represents a significant advancement in the field of chest wall reconstruction and thoracic surgical procedures.

Objective To analyze genetic variation in two cases of autosomal recessive polycystic kidney disease （ARPKD） and provide theoretical rationales for its early diagnosis， treatment， genetic counseling and prenatal diagnosis. Methods Fetal tissues and parental peripheral blood samples of two children were collected for whole exon sequencing， pedigree analysis and site verification. Results Whole exome and Sanger sequencing revealed compound heterozygous mutations in c.3436C＞T （p.Q1146X） and c.1981A＞C （p.T661P） in fetal PKHD1 gene in family 1. And one ARPKD child of family 2 previously died of heart failure at the age of 1 year. In this case， c.9719G＞A （p.R3240Q）， c.10057C＞T （p.L3353F） and c.7237C＞T （p.R2413C） compound heterozygous mutations were detected in fetal PKHD1 gene. Conclusion Both families had perinatal stage ARPKD caused by variants in PKHD1 gene and 5 genetic variant loci， including 2 new missense variants of c.10057C＞T and c.1981A＞C. In light of a great complexity of ARPKD genotype and phenotype， early genetic counselling of the pedigree may facilitate genetic diagnosis and early prenatal diagnosis.

Abstract The educational landscape of toxicology is increasingly integrating computational methodologies due to ethical concerns about animal testing and advancements in biotechnological and data analysis tools. This paper examines the evolution and significance of the Toxicology in the 21st century (Tox21) initiative and its impact on computational toxicology education. It contrasts computational toxicology with traditional methods, highlighting the limitations of conventional approaches and the new perspectives offered by computational techniques. The study emphasizes the importance of incorporating computational toxicology into curricula, including case studies that demonstrate how this integration enhances students’ problem-solving abilities, real-time data analysis skills, and innovation capabilities. Furthermore, it outlines effective teaching content and methods, including software tools, online resources, and academic literature. The paper also addresses the challenges and limitations faced in this educational shift and explores prospects for advancing computational toxicology education. By documenting these developments, the study aims to clarify the current advancements in toxicology education and the preparedness of students to address global chemical safety challenges with innovative solutions.

Abstract Background Dormancy survival regulator (DosR) and resuscitation-promoting factor (Rpf) antigens of Mycobacterium tuberculosis are activated during dormant phase of tuberculosis (TB). This study evaluates the differential immunogenicity potentials of DosR and Rpf antigens in individuals with latent tuberculosis infection (LTBI) and active TB patients. Methods After a literature search in electronic databases, studies were selected by following precise eligibility criteria. Outcomes were synthesized systematically, and meta-analyses were performed to estimate standardized mean differences (SMDs) in interferon-gamma (IFNγ) levels, and IFNγ positive immune cells between individuals with LTBI and active TB patients. Results Twenty-six studies (1278 individuals with LTBI and 1189 active TB patients) were included. DosR antigens Rv0569 (Standardized mean difference; SMD 2.44 [95%CI: 1.21, 3.66]; p

Abstract Maximizing materials utilization efficiency via enhancing their reconfigurability and multifunctionality offers a promising avenue in addressing the global challenges in sustainability. To this end, significant efforts have been made in developing reconfigurable multifunctional smart materials, which can exhibit remarkable behaviors such as morphing and self-healing. However, the difficulty in efficiently manipulating and controlling matter at the building block level with manageable cost and complexity, which is crucial to achieving superior responsiveness to environmental clues and stimuli, has significantly hindered the further development of such smart materials. Here we introduce a concept of Robo-Matter, which can be activated and controlled through external information exchange at the building block level, to enable a high-level of controllability, mutability and versatility for reconfigurable multifunctional smart materials. Using specially designed micro-robot building blocks with symmetry-breaking active motion modes, tunable anisotropic interactions, and interactive coupling with a programmable spatial-temporal dynamic light field, we demonstrate an emergent Robot-Matter duality, which enables a spectrum of desirable behaviors spanning from matter-like properties such as ultra-fast self-assembly and adaptivity, to robot-like properties including active force output, smart healing, smart morphing and infiltration. Our work demonstrates a promising direction for designing next-generation smart materials and large-scale robotic swarms.

Abstract Recent advancements in bacterial two-component systems (TCS) have spurred research into TCS-based biosensors, notably for their signal amplification and broad input responsiveness. The CusRS system in Escherichia coli (E. coli), comprising cusS and cusR genes, is a copper-sensing module in E. coli. However, due to insufficient sensing performance, CusRS-based biosensors often cannot meet practical requirements. To address this issue, we made improvements and innovation from several aspects. CusR and CusS expression were adjusted to enhance the Cu(II) biosensor’s performance. A copy-number inducible plasmid was used for signal amplification, while removing copper detox genes cueO and cusCFBA improved sensitivity and lowered detection limits. Ultimately, in the optimized biosensor of Cu26, the fold-change (I/I0) increased from 1.5-fold to 18-fold at 1 μM, rising to 100-fold after optimizing the cell culture procedure. The biosensor’s high fluorescence enabled rapid, instrument-free detection and an improved analysis strategy reduced the detection limit to 0.01 μM, surpassing traditional methods.

Abstract P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor’s ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3’s physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3 +/+, but not in P2rx3 −/−, mice, indicating that the 1α3β, a “tunable” region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

Abstract Background Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising avenue for hepatocellular carcinoma (HCC) intervention due to its tumor susceptibility. RNA N6-methyladenosine (m6A) modification has been involved in several types of regulated cell death. However, the roles and molecular mechanisms of m6A-related regulators in HCC cell ferroptosis remain unclear. Methods By examining a series of m6A modification enzymes upon ferroptosis induction or inhibition, we identified METTL16 as a novel ferroptotic repressor in HCC cells. The roles of METTL16 on ferroptosis and HCC development were investigated in multiple cell lines, human HCC organoids, subcutaneous xenografts and MYC/Trp53−/− HCC model in hepatocyte-specific Mettl16 knockout and overexpression mice. The underlying mechanism was elucidated with MeRIP/RIP-qPCR, luciferase assay, Co-IP assay and Mass Spectrometry. The clinical significance and relevance were evaluated in human samples. Results High METTL16 expression confers ferroptosis resistance in HCC cells and mouse models, and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner, and the latter impedes the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates the chelation of free iron and reduces liable iron pool level. SENP3 and LTF are implicated in METTL16-mediated HCC progression and anti-ferroptotic effects both in vivo and in vitro. Clinically, METTL16 and SENP3 expression were positively correlated, and high METTL16 and SENP3 expression predicts poor prognosis in human HCC samples. Conclusions Our study reveals a new METTL16-SENP3-LTF signaling axis regulating ferroptosis and driving HCC development. Targeting this axis is a promising strategy for sensitizing ferroptosis and against HCC.

Abstract Background The WD40 domain, one of the most abundant in eukaryotic genomes, is widely involved in plant growth and development, secondary metabolic biosynthesis, and mediating responses to biotic and abiotic stresses. WD40 repeat (WD40) protein has been systematically studied in several model plants but has not been reported in the Capsicum annuum (pepper) genome. Results Herein, 269, 237, and 257 CaWD40 genes were identified in the Zunla, CM334, and Zhangshugang genomes, respectively. CaWD40 sequences from the Zunla genome were selected for subsequent analysis, including chromosomal localization, phylogenetic relationships, sequence characteristics, motif compositions, and expression profiling. CaWD40 proteins were unevenly distributed on 12 chromosomes, encompassing 19 tandem duplicate gene pairs. The 269 CaWD40s were divided into six main branches (A to F) with 17 different types of domain distribution. The CaWD40 gene family exhibited diverse expression patterns, and several genes were specifically expressed in flowers and seeds. Yeast two-hybrid (Y2H) and dual-luciferase assay indicated that CaWD40-91 could interact with CaAN1 and CaDYT1, suggesting its involvement in anthocyanin biosynthesis and male sterility in pepper. Conclusions In summary, we systematically characterized the phylogeny, classification, structure, and expression of the CaWD40 gene family in pepper. Our findings provide a valuable foundation for further functional investigations on WD40 genes in pepper.

Abstract Background Limited supply of certain nutrients and deregulation of nucleus pulposus (NP) plays a key role in the pathogenesis of intervertebral disc degeneration (IVDD). However, whether nutrient deprivation-induced cell death, particularly disulfidptosis, contributes to the depletion of NP cells and the development of IVDD, is unknown. Methods RNA-seq, single-cell RNA-seq, and Genome-wide DNA methylation datasets of nucleus pulposus tissue were collected for bioinformatic analysis. Predictive models of disulfidptosis related genes in IVDD were constructed by machine learning and their differential expression was analyzed. In addition, we performed cell subsets identification analysis, cell-cell communications analysis, and functional enrichment analysis of key genes in the core subset based on single-cell RNA-seq data of NP tissues isolated from one normal sample and one IVDD sample. Finally, glucose deprivation-induced disulfidptosis in human NP cells (HNPCs) was verified by various cell death inhibitors and disulfidptosis-related molecular markers. Results We found the disulfidptosis signal was significantly activated in the IVDD group. Using single-cell RNA-seq analysis, we focused on the chondrocytes and found that disulfidptosis-related genes significantly highly expressed in the IVDD C4 chondrocyte subset, which was identified as a new disulfidptosis-associated cell subset. Correlation analysis revealed the negative correlation between SLC7A11 (driving gene of disulfidptosis) and the glucose transporter GLUTs (SLC2A1-4) family genes (suppressing genes of disulfidptosis) in the IVDD group. We also found obvious cell death in HNPC upon glucose starvation, while employment of various cell death inhibitors could not inhibit glucose starvation-induced death in HNPCs. Moreover, the accumulation of disulfide bonds in cytoskeletal proteins was indicated by slowed migration in non-reducible protein blotting experiments. 2-DG, a key disulfidptosis inhibitor, significantly rescued cell death caused by glucose starvation through lowering the NADP+/NADPH ratio. Conclusions We validated the occurrence of disulfidptosis in HPNCs and identified a novel disulfidptosis-associated cell subset, followed by experimental verification of disulfidptosis in a glucose-limited context to mimic a fall in nutrient supply during the development disc degeneration. These findings provided new insights into the pathological mechanisms of IVDD and encourage us to explore potential therapeutic targets involved in the regulation of disulfidptosis for the prevention of intervertebral disc degeneration. Graphical Abstract

Abstract BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.

Abstract Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7–78.9%) and the DCR was 76% (95% CI: 54.9–90.6%). The mPFS was 6.0 months (95% CI: 5.4–9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

Abstract Background Frailty is one of the most significant issues related to human aging. Although studies have confirmed the association of mental and cognitive disorders with frailty, the association might be influenced by age, since oldest-old adults are more likely to have adverse health outcomes. Thus, this study aimed to examine independent and combined associations of mental health and cognitive function with frailty in oldest-old adults using data from the Chinese Longitudinal Healthy Longevity Survey in 2018. Methods A sum of 6,891 and 3,171 older adults aged 80 and older were included in this study when analyzing the association of depression and cognitive impairment with frailty, respectively. Frailty was measured by the Study of Osteoporotic Fractures frailty index, depression was assessed by the Center for Epidemiologic Studies Depression Scale, and cognitive impairment was evaluated by the Chinese version of modified Mini-Mental State Examination. Independent sample t-test, Chi-square tests, and logistic regression analyses were used to examine the associations of depression and cognitive impairment with frailty. Results Older persons with depression or cognitive impairment had a higher chance of frailty. The adjusted odds ratio (OR) of frailty was 1.27 (95% CI: 1.01, 1.59, p = 0.044) in those with depression, and 1.85 (95% CI: 1.14, 3.01, p = 0.013) in those with cognitive impairment. Compared to adults who had neither depression nor cognitive impairment, those with either depression or cognitive impairment, and those with both depression and cognitive impairment had a significantly higher likelihood of frailty (adjusted OR: 1.61, 95% CI: 1.07, 2.41; and adjusted OR: 4.03, 95% CI: 2.05, 7.94). Conclusions The findings suggest that depression and cognitive impairment are associated with frailty. The concurrence of depression and cognitive impairment has an additive effect on frailty in oldest-old population.

Abstract Background With the development of novel anti-HER2 targeted drugs, such as ADCs, it has become increasingly important to accurately interpret HER2 expression in breast cancer. Previous studies have demonstrated high intra-observer and inter-observer variabilities in evaluating HER2 staining by human eyes. There exists a strong requirement to develop artificial intelligence (AI) systems to achieve high-precision HER2 expression scoring for better clinical therapy. Methods In the present study, we collected breast cancer tissue samples and stained consecutive sections with anti-Calponin and anti-HER2 antibodies. High-quality digital images were selected from immunohistochemical slides and interpreted as HER2 3+, 2+, 1+, and 0. AI models were trained and assessed using annotated training and testing sets. The AI model was trained to automatically identify ductal carcinoma in situ (DCIS) by Calponin staining and myoepithelial annotation and filter out DCIS components in HER2-stained slides using image-overlapping techniques. Furthermore, we organized two-phase validation studies. In phase one, pathologists interpreted 112 HER2 whole-slide images (WSIs) without AI assistance, whereas in phase two, pathologists read the same slides using the AI system after a washing period of 2 weeks. Results Our AI model greatly improved the accuracy of reading (0.902 vs. 0.710). The number of HER2 1 + patients misdiagnosed as HER2 0 was significantly reduced (32/279 vs. 65/279), and they benefitted from ADC drugs. In addition, the AI algorithm improved the intra-group consistency of HER2 readings by pathologists with different years of experience (intra-class correlation coefficient [ICC]: 0.872–0.926 vs. 0.818–0.908), with the improvement most pronounced among junior pathologists (0.885 vs. 0.818). Conclusions We proposed a high-precision AI system to identify and filter out DCIS components and automatically evaluate HER2 expression in invasive breast cancer.

BackgroundNeonatal hyperbilirubinemia frequently leads to severe neurological damage. Although cranial ultrasound (CUS) is crucial for assessing neonatal brain injury, the association between red blood cell distribution width-coefficient of variation (RDW-CV), a marker of red blood cell size variability, and cranial ultrasound abnormalities (CUAs) remains unclear.ObjectiveThe primary aim of this study was to explore the impact of RDW-CV on CUAs in neonatal hyperbilirubinemia and to elucidate the potential clinical implications of this relationship.MethodsThis retrospective cross-sectional study included 503 cases of neonatal hyperbilirubinemia at gestational age ≥35 weeks with available RDW-CV and CUS screening data at Nanjing Lishui People's Hospital. Multivariate logistic regression analysis and smooth curve fitting were used to estimate the association between RDW-CV and the risk of CUAs in neonatal hyperbilirubinemia.ResultsThis study found that the overall prevalence of CUAs in ultrasound images was 26.0%. Multivariate logistic regression analysis adjusted for risk factors revealed that a one-percent increase in RDW-CV increased the risk of CUAs by 23.0%. After conducting a sensitivity analysis of the three RDW-CV quantiles, the findings remained robust and consistent.ConclusionsThe study concluded that a higher RDW-CV was associated with a proportional increase in the risk of CUAs. These results demonstrate the importance of RDW-CV in neonatal hyperbilirubinemia. Clinicians should consider this association when managing patients with high RDW-CV.

BackgroundPlasma beta-amyloid (Aβ) are important biomarkers for Alzheimer’s disease and cognitive impairment (CI), but results are controversial. It remains unclear whether hypertension modulates their relationship. This cross-sectional study investigates whether hypertension moderates the relationship between plasma Aβ and cognitive impairment (CI).MethodsThis cross-sectional study included 1488 subjects ≥ 40 years from rural areas of northwestern China. CI was defined as a Mini-Mental State Examination score lower than the cutoff. Firstly, plasma Aβ40, Aβ42, Aβ42/Aβ40 were analyzed as restricted cubic spline. Then, categories of combined plasma Aβ were created by making bisection of plasma Aβ according to average and combining them as L-Aβ40 and L-Aβ42, H-Aβ40 and L-Aβ42, L-Aβ40 and H-Aβ42, H-Aβ40 and H-Aβ42. Decreased plasma Aβ40 was defined as < 25th percentile. Multivariate logistic regression examined the relationship between plasma Aβ and CI in total population, the hypertension subgroup and the non-hypertension subgroup.Results737 participants (49.5%) had hypertension and 189 participants (12.7%) had CI. Simultaneously elevated plasma Aβ40 and Aβ42 was associated with CI in hypertension (H-Aβ40 and H-Aβ42 vs. L-Aβ40 and L-Aβ42, 21.1% vs.10.7%, P = 0.033; OR = 1.984 [95% CI, 1.067–3.691], P = 0.030) but not in the non-hypertension. Decreased plasma Aβ40 was associated with CI in the non-hypertension (14.9% vs. 9.2%, P = 0.026; OR = 1.728 [95% CI, 1.018–2.931], P = 0.043) but not in the hypertension.ConclusionHypertension is an important modulator in the relationship between plasma Aβ and CI. Simultaneously elevated plasma Aβ40 and Aβ42 in the hypertension, and decreased plasma Aβ40 in the non-hypertension, may be risk factors for CI. These findings emphasize the need to consider hypertension in CI detection.

Objectives The goal of the current study was to assess the effectiveness of a peer integrated collaborative care intervention for postinjury outcomes.Methods Injury survivors ≥18 years of age were screened for post-traumatic stress disorder (PTSD) symptoms and severe postinjury concerns; screen-positive patients were randomized to the intervention versus enhanced usual care control conditions. The collaborative care intervention included peer support and care management. The intervention also included evidence-based pharmacotherapy and psychotherapeutic elements targeting PTSD. The COVID-19 pandemic interrupted recruitment between March and June 2020; in response to the COVID-19 pandemic, the peer component of the intervention went from in-person to virtual delivery. The primary outcomes were PTSD symptoms assessed with the Diagnostic and Statistical Manual of Mental Disorders fourth edition PTSD checklist, any severe postinjury concerns, and emergency department/inpatient utilization followed over the 12 months postinjury. Secondary outcomes included patient satisfaction with emotional healthcare.Results A total of 450 patients were randomized to the intervention (n=225) and control (n=225) conditions; 124 patients (28%) were recruited and completed all study assessments prior to the onset of the COVID-19 pandemic, while 326 patients (72%) were recruited after and/or had one or more study follow-ups occur postpandemic onset. Mixed model regression revealed no statistically significant comparisons for any of the primary outcomes. In exploratory models that examined the impact of COVID-19, significantly improved PTSD symptoms were present at 3 months pre-COVID-19 relative to post-COVID-19. Intervention patients consistently demonstrated higher satisfaction with emotional aspects of healthcare (F(5,1652)=2.87, p=0.01).Conclusions The intervention demonstrated no significant improvements in primary outcomes in the intent-to-treat sample. The peer integrated collaborative care intervention contributed to higher patient satisfaction with the emotional aspects of healthcare.Level of evidence Level II, randomized clinical trial.Trial registration number NCT03569878.

This case report presents a patient with metastatic adenocarcinoma of unclear primary focus at initial presentation and revealed lung adenocarcinoma in subsequent follow-up. The patient has been surviving for more than 10 years after pemetrexed-based treatment and local radiotherapy. Sequential gene tests showed kirsten rat sarcoma viral oncogene homolog (KRAS) G13D mutation and epidermal growth factor receptor (EGFR) 19ins. To further investigate the correlation between pemetrexed efficacy and genetic polymorphisms, genotyping tests on folate-metabolism-related genes [methylenetetrahydrofolate reductase (MTHFR) (C677T) and MTHFR (A1298C)] were performed, revealing that the patient exhibited the T/T genotype for MTHFR (C677T) and the A/A genotype for MTHFR (A1298C). The clinical data and gene analysis were discussed with literature review to explain the underlying explanation for the long survival.

IntroductionA growing group of young and middle-aged lecturers in universities, during a time of increasing career aspirations, not only bears the significant responsibility of teaching but also serves as the backbone for promoting the high-quality development of higher education in our country. Simultaneously, they are experiencing varying degrees of workplace anxiety.MethodsThis paper adopts the mixed-methods of questionnaire analysis and semi-structured interview. Firstly, it presents a questionnaire designed to assess perceptions of workplace anxiety, job performance, and job burnout. Secondly, data were collected from 506 young and middle-aged lecturers across 10 colleges and universities in the four provinces of Chongqing, Anhui, Beijing, and Hebei in China through online questionnaires. A total of 449 valid questionnaires and 56 interview transcripts were obtained. Subsequently, SPSSAU online data analysis software was employed to test the hypotheses derived from the questionnaire data using confirmatory factor analysis, correlation analysis, and Bootstrap sampling analysis. Additionally, qualitative analysis was conducted in conjunction with the interview transcripts.ResultsThe results indicate that, on one hand, there is a significant positive relationship between the perception of workplace anxiety and the career growth expectations of young and middle-aged university lecturers. This is evidenced by a negative correlation with their perception of job performance and a positive correlation with their perception of competitive pressure. On the other hand, self-efficacy plays a moderating role in alleviating workplace anxiety and burnout among young and middle-aged university lecturers. As their sense of self-efficacy increases, their feelings of workplace anxiety diminish.ConclusionThe increasing competition among peers has posed significant challenges to the physical and mental health of young and middle-aged university lecturers. Reforming competitive mechanisms and establishing a career support system are essential, evidence-based strategies for alleviating workplace anxiety and enhancing professional efficacy. This article explores the relationship between workplace anxiety and job burnout among young and middle-aged university lecturers, while also proposing strategies for mitigation. These insights are crucial for promoting the career development of university lecturers and safeguarding their physical and mental well-being.

Abstract Cancer involves tumor cells and tumor‐specific immunity. The ability to accurately quantify tumor‐specific immunity is limited. Most immunotherapies function by activating new effector tumor antigen‐specific T cells (ETASTs) or reactivating the pre‐existing ETASTs repertoire. Therefore, the amount of ETASTs can be used to characterize immunotherapy efficacy. Tumor antigens are highly heterogeneous and detecting most ETASTs is challenging. Therefore, nanoparticles loading whole‐cell tumor antigens are used to activate and detect pan‐clones ETASTs in the blood. The differences between ETASTs and other T cells are transformed into activated and non‐activated states. By measuring markers of the activated status and cytotoxic function of ETASTs, it can distinguish ETASTs from other T cells. ETASTs in patients with lung cancer are higher than those in healthy individuals and those with benign pulmonary nodules. Therapeutic efficacy positively correlated with the number of ETASTs in the blood. ETATS levels increase only in the blood of patients who respond to immunotherapy. Single‐cell sequencing studies validated these findings. This study provides a highly accurate, specific, non‐invasive, and efficient biomarker for predicting immunotherapy efficacy in lung and other cancers. This method can also be applied to evaluate the efficacy of other treatments, such as radiotherapy, oncolytic viruses, and nanomedicine‐based therapies.

Abstract The high heterogeneity and severe side effects of chemotherapy are major factors contributing to the failure of osteosarcoma treatment. Herein, a comprehensive genomic analysis is conducted, and identified two prominent characteristics of osteosarcoma: significant cyclin‐dependent kinases 4 (CDK4) amplification and homologous recombination repair deficiency. Based on these findings, a co‐delivery system loaded with CDK4/6 inhibitors and poly ADP‐ribose polymerase (PARP) inhibitors is designed. By employing metal–organic frameworks (MOFs) as carriers, issue of drug insolubility is effectively addressed, while also enabling controlled release in response to the tumor microenvironment. To enhance targeting capability and biocompatibility, the MOFs are further coated with a bio‐membrane targeting B7H3. This targeted biomimetic co‐delivery system possesses several key features: 1) it can precisely target osteosarcoma with high B7H3 expression; 2) the combination of CDK4/6 inhibitors and PARP inhibitors exhibits synergistic effects, significantly impairing tumor's DNA repair capacity; and 3) the system has the potential for combination with photodynamic therapy, amplifying DNA repair defects to maximize tumor cell eradication. Furthermore, it is observed that this co‐delivery system can activate immune microenvironment, increasing CD8+ T cell infiltration and converting osteosarcoma from an immune‐cold to an immune‐hot tumor. In summary, the co‐delivery system is an effective therapeutic strategy and holds promise as a novel approach for osteosarcoma treatment.