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Objective: This study examined children's representations of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as well as their pandemic experiences against the backdrop of the world having transitioned to normalcy. Design: Mixed-methods approach encompassing both qualitative and quantitative analysis. Setting: Two middle schools in Hefei city in mid-eastern China. Method: Data were collected using a qualitative task which elicited children's drawings, commentaries, answers to questions related to their pandemic experiences, followed by small-group interviews. Content analysis and emergent coding techniques were employed to analyse the data, the extracted themes of which were then quantified to reveal their incidence and distribution. Results: Analysis of the multimodal data set revealed children not only depicted viral morphology but also evoked emotions. The pandemic had brought about changes in children's lives, marked by a shift towards more academic activities, rest and relaxation and screen time. These changes also raised psychological, physical and social development concerns warranting mitigation. Multifaceted sources were identified as contributing to children's unhappiness, including restricted social interactions, educational challenges, emotional and psychological issues. Notably, children reported enhanced pre- to post-pandemic hygiene and sanitisation practices. Unsubstantiated beliefs relating to processes of recovery suggest the need for clearer communication in this regard. Conclusion: The study highlights the necessity for health education to support children in physical and psychological coping during a pandemic and build their resilience against future epidemics. Actively listening to children's account of the SARS-CoV-2 coronavirus, and their pandemic experiences paves the way for making health education initiatives more relatable and attuned to their needs.

Abstract Background Adipsin (complement factor D, CFD), as the first described adipokine, is well-known for its regulatory effects in diabetic cardiovascular complications. However, its role in diabetic hind-limb ischemia was not clarified. This study aimed to evaluate the possible therapeutic effect of Adipsin in hind-limb ischemia in type 2 diabetic mice and to elucidate the molecular mechanisms involved. Methods A high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mouse model, and a transgenic mouse model with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg) were employed. Hindlimb ischemia was established by femoral artery ligation, and blood flow recovery was monitored using Laser Doppler perfusion imaging. Molecular mechanisms underlying Adipsin-potentiated angiogenesis were examined using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses. Results Adipsin expression was upregulated in non-diabetic mice following HLI, while suppressed in diabetic mice, indicating its potential role in ischemic recovery which is impaired in diabetes. Adipsin-Tg mice exhibited significantly improved blood flow recovery, increased capillary density, and enhanced muscle regeneration in comparison with non-transgenic (NTg) diabetic mice. Adipsin facilitated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) under hyperglycemic and hypoxic conditions. Additionally, it enhanced phosphorylation of AKT, ERK, and eNOS pathways both in vivo and in vitro. RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses identified that Adipsin promoted angiogenesis by interacting with SERBP1, which disrupted the binding of SERBP1 to SERPINE1 mRNA, resulting in reduced SERPINE1 expression and the subsequent activation of the VEGFR2 signaling cascade. Conclusions Adipsin promotes angiogenesis and facilitates blood perfusion recovery in diabetic mice with HLI by downregulating SERPINE1 through interaction with SERBP1. These findings elucidate a novel therapeutic potential for Adipsin in the management of PAD in diabetic patients, highlighting its role in enhancing angiogenesis and tissue repair.

Abstract Background and objective Positron emission tomography/computed tomography (PET/CT) is recommended as the standard imaging modality for diffuse large B-cell lymphoma (DLBCL) staging. However, many studies have neglected the role of patients' prognostic factors with respect to imaging PET/CT of quantitative features. In this paper, a multi-view learning (MVL) model is established to make full use of both clinical and imaging data to predict the prognosis of DLBCL patients and thereby assist doctors in decision-making. Methods Feature engineering, including feature extraction, feature screening by recursive feature elimination, and dimensionality reduction by principal component analysis, are successively performed on the clinical data and imaging data of the research subjects to obtain the study data. After dividing the data into training and test sets, an instance weighting method is applied to the training data. Subsequently, kernel mapping is performed on the imaging features and clinical features separately, and this kernel mapping is processed in the new kernel feature space using kernel canonical correlation analysis (KCCA). Lastly, model training is performed on the obtained common kernel subspace using a support vector machine (SVM). The final overall model, named SVM-2view-KCCA (SVM-2 K), was compared with three other multi-view models (Ensemble-SVM, Multi-view maximum entropy discrimination, and canonical correlation analysis). The performance of the model was evaluated on the test data with respect to several dichotomous metrics: accuracy, sensitivity, F1 score, the area under the curve (AUC), and G-mean. Results The SVM model improved AUC by 10.5%, sensitivity by 11.9%, accuracy by 9.8%, F1 score by 9.2%, and G-mean by 7.8% for the DLBCL test data after feature engineering based on dimensionality reduction and instance weighting. In the performance comparison of single-view learning models, the SVM-based integration of clinical and imaging features achieved the best overall performance (AUC = 86.3%, accuracy = 91.6%, sensitivity = 83.2%, F1 = 85.7%, and G-mean = 86.1%). In the comparison of MVL models, SVM-2 K achieved the best overall performance (AUC = 92.1%, accuracy = 96.9%, sensitivity = 90.9%, F1 = 92.8%, and G-mean = 91.4%), and the performance of each MVL model was better than that of the best single-view learning model. Conclusions MVL models outperformed single-view learning models. Of the MVL models, the proposed SVM-2 K achieved the best overall performance and could accurately predict patient prognosis.

Abstract The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and further reveal the structural basis of the sustained role of GPR156. We present the cryo-EM structures of human apo GPR156 and the GPR156–Gi3 complex, unveiling a small extracellular region formed by extracellular loop 2 (ECL2) and the N-terminus. The GPR156 dimer in both apo state and Gi3 protein-coupled state adopt a transmembrane (TM)5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. Furthermore, C-terminus in G-bound subunit of GPR156 plays a dual role in promoting G protein binding within G-bound subunit while preventing the G-free subunit from binding to additional G protein. Together, these results explain how GPR156 constitutive activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function.

Abstract β-Hydroxybutyrate (β-OHB), the primary ketone body, is a bioactive metabolite that acts as both an energy substrate and a signaling molecule. Recent studies found that β-OHB inhibits the production of pro-inflammatory cytokines in macrophages, but its underlying molecular mechanisms have not yet been fully elucidated. Lysine β-hydroxybutyrylation (Kbhb), a post-translational modification mediated by β-OHB, plays a key role in regulating the expression and activity of modified proteins. However, whether macrophages undergo protein Kbhb and whether Kbhb modification regulates macrophage polarization remains largely unknown. In this study, treatment with β-OHB and ketone ester significantly decreased the lipopolysaccharide (LPS)-induced enhancement of the M1 phenotype of mouse bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and peritoneal macrophages (PMs) in vitro and in vivo. Moreover, β-OHB treatment induced global protein Kbhb, which is associated with the regulation of macrophage M1 polarization. Proteome-wide Kbhb analysis in β-OHB-treated BMDMs revealed 3469 Kbhb modification sites within 1549 proteins, among which interleukin-12-responding proteins were significantly upregulated. Our results indicated that β-OHB regulated M1 macrophage polarization by inducing Kbhb modification of the signal transducer and activator of transcription 1 (STAT1) K679 site, which inhibited its LPS-induced phosphorylation and transcription. Altogether, our study demonstrated the presence of a widespread Kbhb landscape in the β-OHB-treated macrophages and provided novel insights into the anti-inflammatory effects of β-OHB.

Spectral gamma-ray logging stands out as an efficacious methodology in the exploration of uranium(U). In order to address the challenges associated with low statistical efficacy in spectral analysis and mitigate the impact of spectral drift, machine learning algorithms such as Back Propagation (BP) neural network, Generalized Regression Neural Network (GRNN), and Support Vector Machine (SVM) have been employed for the quantitative interpretation of uranium. A method rooted in machine learning algorithms for energy spectral analysis has been proposed, catering to the analysis of high-speed spectra logging and gamma-ray spectra characterized by spectral drift. Examinations conducted on standard model wells containing uranium revealed that the BP neural network exhibited commendable accuracy in uranium interpretation, achieving quantification accuracy rates of 86.986 % and 93.478 % for low-grade and medium-high-grade uranium ores in the Testing Set, respectively. Notably, marginal variations in the model's quantification errors were observed under diverse logging speeds and spectral drift conditions, underscoring the capacity of gamma-ray spectral quantitative interpretation through machine learning algorithms to effectively surmount the impacts of logging speed and spectral drift. This machine learning-based approach to energy spectral analysis proved instrumental in enhancing traditional logging speeds to 6 m/min, presenting a novel perspective for the quantitative interpretation of uranium spectral gamma-ray logging at heightened logging speeds.

Objective Skeletal muscle growth is an important economic trait for meat production, with notable differences between Tibetan pigs (TIBPs, a slow-growing breed) and Large White pigs (LWPs, a fast-growing breed). However, the genetic underpinnings of this disparity remain unclear. Methods In the current study, we integrated differentially expressed genes (DEGs) and proteins (DEPs) from 60-day-old embryonic muscle tissue, along with whole-genome single nucleotide polymorphisms (SNPs) displaying absolute allele frequency differences (ΔAF) of 0.5 or more between the TIBP and LWP breeds, to unravel the genetic factors influencing skeletal muscle growth. Results Our analysis revealed 3,499 DEGs and 628 DEPs with SNPs having a ΔAF equal to or greater than 0.5. Further functional analysis identified 145 DEGs and 23 DEPs involved in biological processes related to skeletal muscle development, and 22 DEGs and 3 DEPs implicated in the mechanistic target of rapamycin kinase signaling pathway, which is known for positively regulating protein synthesis. Among these genes, several DEGs and DEPs, enriched with TIPB-specific SNPs in regulatory or/and coding regions, showed marked ΔAF between the TIBP and LWP breeds, including MYF5, MYOF, ASB2, PDE9A, SDC1, PDGFRA, MYOM2, ACVR1, ZIC3, COL11A1, TGFBR1, EDNRA, TGFB2, PDE4D, PGAM2, GRK2, SCN4B, CACNA1S, MYL4, IGF1, and FOXO1. Additionally, genes such as CAPN3, MYOM2, and PGAM2, identified as both DEPs and DEGs related to skeletal muscle development, contained multiple TIBP-specific and LWP-predominant SNPs in regulatory and/or coding regions, underscoring significant ΔAF differences between the two breeds. Conclusion This comprehensive investigation of SNPs in DEGs and DEPs identified a significant number of SNPs and genes related to skeletal muscle development during the prenatal stage. These findings not only shed light on potential causal genes for muscle divergence between the TIBP and LWP breeds but also offer valuable insights for pig breeding strategies aimed at enhancing meat production.

Carrier phase measurement plays a crucial role in achieving rapid and high-precision positioning within a global navigation satellite system (Global navigation satellite system, GNSS). A pivotal aspect of this process is the accurate resolution of the integer ambiguity. Although the particle swarm optimization algorithm (Particle swarm optimization, PSO) demonstrates quick convergence, it tends to become trapped in local optima, showing a relatively weak ability to fix ambiguity. Conversely, the artificial fish school algorithm (Artificial fish swarm algorithm, AFSA) excels the global optimization performance. However, its natural selection mode, which operates without a “leader,” renders the integer ambiguity resolution process more time-consuming. By integrating the strengths of PSA and AFSA, we propose an improved hybrid algorithm, termed the particle swarm and artificial fish swarm (PSOAF) algorithms, to efficiently search for integer ambiguity solutions in GNSS. The process begins by solving the floating-point solution and its corresponding covariance matrix using the carrier phase double-difference equation. Then, to address the correlation issue, the inverse integer Cholesky algorithm is used to effectively decorrelate them. Recognizing the limitations inherent in integer least squares estimation, we further refine the effectiveness of the PSOAF algorithm by optimizing the fitness function. This optimization significantly enhances the convergence speed and search performance of the algorithm, resulting in a precise resolution of the integer ambiguity. In the initial stage of integer ambiguity search, the PSO’s characteristic of rapid convergence facilitates a coarse search, yielding a suboptimal solution. This solution serves as foundational data for the AFSA, guiding the fine search required for integer ambiguity resolution. To verify the PSOAF algorithm’s effectiveness and practicality, we conducted both three-dimensional and twelve-dimensional simulation analyses based on a classical example. The results demonstrate that the PSOAF algorithm not only converges to the optimal solution at an unprecedented rate but also exhibits markedly superior search efficiency compared to single algorithms. Further validation of the PSOAF algorithm’s real-world applicability and effectiveness was sought through experiments utilizing actual Beidou data. The results from these experiments were promising, showing that the baseline resolution error mainly remained within a 10-mm range. This finding confirms the correctness of the double-difference integer ambiguity search conducted using the PSOAF algorithm. The applicability and effectiveness of the PSOAF algorithm in real scenarios are verified. In conclusion, this study underscores the PSOAF algorithm’s significant potential for practical applications, particularly in scenarios involving short baselines.

The modification of stereoregulated functionalized polymers on the surface of natural rubber (NR) is a challenging task. This work provided a practicable grafting method to design photochromic polymer brushes on the NR surfaces using surface-initiated ring-opening metathesis polymerization (SI-ROMP). The designed photochromic polymer brushes were based on norbornenes with spiropyrin (SP) pendents, and grew from the surface of NR films in the presence of Grubbs 2nd catalyst. The results showed that the grafting rate of polymer brushes with photoisomerization structure reached up to 44.91 %. The modified natural rubber (NR-SP) films exhibited rapid coloring/decolorization property under UV irradiation and visible light. This photochromic property initiated by the light-induced isomerisation of the spiropyran structure and the increased surface energy under light stimuli. NR-SP films exhibited stable photochromic characteristics and outstanding anti-fatigue properties after exposing to over six cycles of consecutive UV/Vis irradiation. A simple and practical strategy for the preparation of highly sensitive photochromic natural rubber materials is proposed and provides a potential application in the fields of information storage and anti-counterfeiting.

ABSTRACT: To effectively assess the extent of the mycotoxin contamination of grapes, a method was developed to analyze 22 mycotoxins by ultra-high-performance liquid chromatography coupled with quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS). Samples were extracted and purified using the QuEChERS (quick, easy, cheap, effective, rugged, and safe) procedure. The extracts were separated on a BEH Shield C18 column (100 mm × 2.1 mm, 1.7 μm), using methanol and water with 0.1% formic acid solution and 2 mmol/L ammonium acetate as the mobile phases. The quantification was performed according to a matrix-matched external standard method. There was a good linear relationship within the respective mass concentration ranges of 22 mycotoxins; the correlation coefficients were not less than 0.998 1. The limit of quantification was 0.3–10.0 μg/kg. Mycotoxin recovery ranged from 68.6% to 109.0%, with a relative standard deviation of 1.28%–12.80%. The method is simple, rapid, highly sensitive, and accurate, making it useful for screening grapes for common and emerging mycotoxins.

Abstract In the evolution landscape of HIV, the coexistence of multiple subtypes has led to new, complex recombinants, posing public health challenges. CRF55_01B, first identified among MSM in Shenzhen, China, has spread rapidly across China. In this study, 47 plasma samples from newly diagnosed HIV-1 CRF55_01B patients in Shenzhen, of which the genotype was only identified by the routine HIV drug resistance test, were collected. Multiple gene regions were acquired using Sanger and next-generation sequencing methods, followed by the phylogenetic reconstruction, recombination breakpoint scanning, Bayesian molecular clock, and the prediction of coreceptors. From 47 samples, we found seven new unique recombinants formed by CRF55_01B and CRF07_BC, which shared similar breakpoints in certain gene regions and primarily utilized CCR5 receptors. All of the most recent common ancestors of subregions for these recombinants were estimated to be later than CRF55_01B and CRF07_BC, potentially suggesting they are the third-generation recombinants formed by CRF55_01B and CRF07_BC as parents. The continuous emergence of new recombinants highlights the increasing complexity of circulating strains in Shenzhen, and also suggests that subtype analysis using partial pol gene may lead to an overestimation of the major subtype strains and an underestimation of new complex HIV recombinants. Consequently, to effectively address and mitigate the complex HIV epidemic, there is an urgent need for expanded monitoring and the optimization of testing methodologies.

Abstract Antimicrobial peptides (AMPs) have caught the attention of researchers over the last couple of years due to their unique membrane lytic mechanism for combating antibiotic resistance, which differs from the molecular targets of traditional antibiotics. Although natural AMPs exhibit potential antimicrobial activity against a wide range of microorganisms, some drawbacks, such as toxicity, low antibacterial activity, and high production costs limit their clinical application. To enhance the antimicrobial activity of a series of HSP peptides derived from the natural peptide HSP-1, this study optimized them using a variety of strategies, including net charge, hydrophobic moment, hydrophobicity, and helicity. Optimizing the antimicrobial action of HSP peptides depended mostly on net charge, hydrophobic moment, and hydrophobicity rather than helicity. HSP-M4 may be designed to combat microbial infections because the antimicrobial activity and cytotoxicity assays showed that they exhibited low cytotoxicity and prominent antimicrobial activity, respectively.

Abstract The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric GPCRs important for the fine tuning of many synapses. Heterodimeric mGlu receptors with specific allosteric properties have been identified in the brain. Here we report four cryo-electron microscopy structures of mGlu2-4 heterodimer in different states: an inactive state bound to antagonists, two intermediate states bound to either mGlu2 or mGlu4 agonist only and an active state bound to both glutamate and a mGlu4 positive allosteric modulator (PAM) in complex with Gi protein. In addition to revealing a unique PAM binding pocket among mGlu receptors, our data bring important information for the asymmetric activation of mGlu heterodimers. First, we show that agonist binding to a single subunit in the extracellular domain is not sufficient to stabilize an active dimer conformation. Single-molecule FRET data show that the monoliganded mGlu2-4 can be found in both intermediate states and an active one. Second, we provide a detailed view of the asymmetric interface in seven-transmembrane (7TM) domains and identified key residues within the mGlu2 7TM that limits its activation leaving mGlu4 as the only subunit activating G proteins.

With the acceleration of industrialization, heavy metal pollution has become increasingly severe, posing a significant threat to human health. In recent years, various biosensors have been widely used for heavy metal detection. Among them, electrochemiluminescence (ECL) sensors have garnered attention due to their high sensitivity, rapid response, and real-time detection capability. Noble-metal nanocomposite materials play an important role in enhancing sensor performance due to their unique physicochemical properties. This paper summarizes the latest research progress on ECL sensors based on noble-metal nanocomposite materials in heavy metal detection. It emphasizes the role of the nanocomposite materials in improving sensor sensitivity and discusses their performance in heavy metal detection, as well as the design principles and specificity of ECL sensors. Furthermore, it discusses future prospects for improving sensor performance and optimizing the application of microfluidic platforms through technological advancements. We hope that this review will provide more effective solutions for challenges in food safety testing.

Abstract Using 7.33 fb −1 of e + e − collision data samples collected with the BESIII detector at center-of-mass energies between 4.128 and 4.226 GeV, we search for the radiative decay D s + → γρ 770 + $$ {D}_s^{+}\to \gamma \rho {(770)}^{+} $$ for the first time. A hint of D s + → γρ 770 + $$ {D}_s^{+}\to \gamma \rho {(770)}^{+} $$ is observed with a statistical significance of 2.5σ. The branching fraction of D s + → γρ 770 + $$ {D}_s^{+}\to \gamma \rho {(770)}^{+} $$ is measured to be (2.2 ± 0.9stat. ± 0.2syst. ) × 10 −4, corresponding to an upper limit of 6.1 × 10 −4 at the 90% confidence level.

Abstract The protection and restoration of existing buildings requires accurate acquisition of the characteristics of the building facade. The complex, diverse, and irregular distribution characteristics of the building facade components of ethnic minorities have led to a huge workload of field research, surveying, mapping, and calculation, and it is more difficult to extract its facade characteristics accurately. This study proposes a visual model based on the Swin Transformer and applies it to the graphic recognition of ethnic building elevations. The model combines the advantages of the migration learning method and deep neural network technology and is further enriched by layer normalization to improve the stability and extraction ability of model training. In the field survey of ethnic minority buildings in Kangba, Sichuan, 1100 images of local buildings were collected, including 8 different types of ethnic minority buildings. The experimental results show that compared with other mainstream deep neural network models, the Swin Transformer visual model shows excellent predictive performance to prove the effectiveness of the proposed method. This study also uses the t-sne dimension reduction method to verify the feature extraction ability of the Swin Transformer, which contributes to the protection and restoration of ethnic minority buildings, active exploration of energy conservation, digital archiving, and more. Provide theoretical and practical reference in the fields of architectural style and cultural research.

Abstract Driving pressure (DP) is a marker of severity of lung injury in patients with acute respiratory distress syndrome (ARDS) and has a strong association with outcome. However, it is uncertain whether limiting DP can reduce the mortality of patients with acute hypoxemic respiratory failure (AHRF). Therefore, this study aimed to determine the correlation between the initial DP setting and the clinical outcomes of patients with AHRF upon their initial admission to the intensive care unit (ICU). The Medical Information Mart for Intensive Care IV (MIMIC-IV) database was used to search the data of patients with AHRF, with 180-day mortality representing the primary outcome. Multiple regression analysis was subsequently performed to evaluate the initial DP and 180-day mortality association. The reliability of the results was validated using restricted cubic splines and interaction studies. This study retrospectively analyzed data from 907 patients—581 (64.06%) in the survival group and 326 (35.94%) in the nonsurvival group (NSG)—who were followed up 180 days after admission. The results revealed that an elevated initial DP was significantly correlated with 180-day mortality (HR 1.071 (95% CI 1.040, 1.102)), especially when the initial DP exceeded 12 cmH2O. AHRF patients with an initial DP > 12 cmH2O had significantly greater mortality at 28 days (p = 0.0082), 90 days (p = 0.0083), and 180 days (p = 0.0039) than those with an initial DP ≤ 12 cmH2O. Among severe patients with AHRF, 180-day mortality was significantly greater in the group with an initial DP > 12 cmH2O than in the group with an initial DP ≤ 12 cmH2O (p = 0.029). The hospital length of stay (LOS) for patients with an initial DP 12 cmH2O (p = 0.029). Among patients with AHRF and an initial DP > 12 cmH2O, the survival group had a significantly longer LOS in the ICU than the NSG (p = 0.00026). The initial DP settings were correlated with 180-day mortality among patients with AHRF admitted to the ICU. Particularly for patients with AHRF, it is crucial to consider implementing early restrictive DP ventilation as a potential means to mitigate mortality, and close monitoring is essential to evaluate its impact.

Abstract Objectives To explore the impact of hepatic steatosis measured by MRI-proton density fat fraction (MRI-PDFF) on liver stiffness measurement (LSM) value and its diagnostic performance for staging liver fibrosis in patients with chronic hepatitis B (CHB). Methods A total of 914 patients with CHB who underwent liver biopsy and MRI-PDFF were retrospectively reviewed. The influence of MRI-PDFF on LSM value was assessed using univariate and multivariate linear analyses. To assess the influence of liver steatosis on the diagnostic performance of LSM, a series of ROC analyses were performed and compared by stratifying patients into non-steatosis (PDFF

Abstract Objective Many investigation have sought to identify therapeutic targets and treatment strategies for skin cutaneous melanoma (SKCM). Numb, an endocytic adaptor protein, is known to act as a tumor suppressor in various human cancers. However, the roles of Numb and its homolog NumbL in immune microenvironment, and their effect on melanoma remain largely unexplored. Methods We analyzed the expression levels of Numb and NumbL, as well as immune signatures of SKCM patients by UCSCXenaShiny v1 database. We also constructed animal model using Numb and NumbL conditional knockout (cKO) mice. Distribution analysis of immune cells in tumors was performed by flow cytometry and pathology staining. Results Numb and NumbL were found to be consistently expressed at low levels in SKCM patients. In addition, alterations in tumor immune microenvironment were identified. The CD8+ T, CD19+ B, and NK1.1+ CD49+ cells were decreased in tumors of Numb and NumbL cKO mice, confirming previous bioinformatics analysis of immune signatures. Additionally, we observed CD68+ macrophages to be increased as judged by tumor pathology staining. Conclusion Numb and NumbL were found to inhibit melanoma cell growth by modulating immune cell activity. These results suggested that Numb and NumbL may be potential therapeutic targets for SKCM patient immunotherapy.

Abstract A complete goat (Capra hircus) reference genome enhances analyses of genetic variation, thus providing insights into domestication and selection in goats and related species. Here, we assemble a telomere-to-telomere (T2T) gap-free genome (2.86 Gb) from a cashmere goat (T2T-goat1.0), including a Y chromosome of 20.96 Mb. With a base accuracy of >99.999%, T2T-goat1.0 corrects numerous genome-wide structural and base errors in previous assemblies and adds 288.5 Mb of previously unresolved regions and 446 newly assembled genes to the reference genome. We sequence the genomes of five representative goat breeds for PacBio reads, and use T2T-goat1.0 as a reference to identify a total of 63,417 structural variations (SVs) with up to 4711 (7.42%) in the previously unresolved regions. T2T-goat1.0 was applied in population analyses of global wild and domestic goats, which revealed 32,419 SVs and 25,397,794 SNPs, including 870 SVs and 545,026 SNPs in the previously unresolved regions. Also, our analyses reveal a set of selective variants and genes associated with domestication (e.g., NKG2D and ABCC4) and cashmere traits (e.g., ABCC4 and ASIP).

Abstract In allotetraploid common carp, protein-coding homoeologs presented divergent expression levels between the two subgenomes. However, whether subgenome dominance occurs in other transcriptional and post-transcriptional events remains unknown. Using Illumina RNA sequencing and PacBio full-length sequencing, we refined the common carp transcriptome annotation and explored differences in four transcriptional and post-transcriptional events between the two subgenomes. The results revealed that the B subgenome presented more alternative splicing events, as did lncRNAs and circRNAs. However, the expression levels, tissue specificity, sequence features, and functions of lncRNAs and circRNAs did not significantly differ between the two subgenomes, suggesting a common regulatory mechanism shared by the two subgenomes. Furthermore, both the number and base substitution frequency of RNA editing events were greater in the B subgenome. Functional analyses of these transcriptional events also revealed subgenome bias. Genes that undergo alternative splicing in the A subgenome participate in more biological processes, and lncRNA targets show a preference between subgenomes. CircRNA host genes in the B subgenome were associated with more biological functions, and RNA editing preferentially occurred in noncoding regions or led to nonsynonymous mutations in the B subgenome. Taken together, the refined transcriptome annotation revealed complicated and imbalanced expression strategies in allotetraploid common carp.

Abstract Objective We evaluated the interaction of urinary protein-to-creatinine ratio (UPCR) with diabetes on the risk of cardiovascular events in a cohort study. Methods The study population consisted of 639 participants with chronic kidney disease (CKD) stages 2–5, enrolled between 2010 and 2011 in Japan. Cox proportional hazards models were used to evaluate the independent and combined effects of the UPCR and diabetes on cardiovascular events. Results During a median follow-up of 3 years, 59 participants developed cardiovascular events during follow-up. A notably higher risk of cardiovascular events was found in participants with proteinuria [hazards ratio (HR): 2.16, 95% confidence interval (95% CI): 1.17–3.97] compared to those without proteinuria at UPCR levels. In addition, the participants with diabetes had a higher risk of cardiovascular events (HR: 2.53, 95% CI: 1.49–4.30) than those without diabetes. Moreover, an interaction was found between UPCR and diabetes on cardiovascular events (P for interaction = 0.04). Participants with both proteinuria (UPCR ≥ 0.5 g/gCr) and diabetes had a 4.09 times higher risk of cardiovascular events (HR: 4.09, 95% CI: 1.97–8.47) compared with those without proteinuria (UPCR

Abstract Background Glycated albumin (GA) levels have been considered as a promising biomarker for estimating glycemic control during pregnancy, but the relationship between GA levels and the incidence of adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains unclear. Our study aimed to investigate the relationship between GA levels during the third trimester and 13 different adverse pregnancy-related outcomes among women with GDM in China. Methods We retrospectively extracted clinical data from the medical records of 819 pregnant women with GDM who underwent prenatal examinations and child delivery at the Affiliated Hospital of Qingdao University between January 2022 and October 2022. The cohort was divided into GA-high (GA-H) and GA-low (GA-L) groups based on the median GA level of 10.6%. Then, the incidence rates of 13 specific adverse pregnancy outcomes were compared between the two groups. Furthermore, we estimated the mean GA levels in pregnant GDM women with or without specific adverse outcomes. Multivariate logistic regression analysis was performed to assess whether the GA levels (high or low) were independent risk factors for specific adverse outcomes in pregnant women with GDM. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of GA levels for the adverse pregnant outcomes in women with GDM. E-value for sensitivity analysis was performed to assess the robustness of the findings to unmeasured confoundings. Results We included 819 pregnant women with GDM, whose average age was 33.09 ± 4.47 years, average pre-pregnancy BMI was 23.51 ± 3.67 kg/m2, and the average gestational week in which GDM diagnosed was 24.80 ± 1.79 weeks. The analysis showed that 80.71% (661/819) pregnant women with GDM were associated with adverse pregnancy-related outcomes. Pregnant women in the GA-L group showed higher incidence of the premature rupture of membranes (PROM), whereas those in the GA-H group showed higher incidence of neonatal hypoglycemia. The GA levels showed acceptable clinical performance for predicting neonatal hypoglycemia with an area under the ROC curve (AUC) value of 0.700 (P = 0.010), sensitivity of 71.4%, and specificity of 70.2%. The optimal cut off value for GA was 11.55%. Conclusions This study demonstrated that GA levels were significantly associated with specific adverse pregnancy outcomes, especially PROM and neonatal hypoglycemia. Furthermore, GA levels in the third trimester showed acceptable clinical performance for predicting neonatal hypoglycemia among pregnant women with GDM. In the future, the potential role of GA as a predictor of adverse pregnancy outcomes need to be further confirmed and explored in GDM women.

Abstract Objectives We elucidate the impact of the coronavirus disease 2019 (COVID-19) pandemic on assisted reproductive technology (ART) services and birth outcomes and establish an evidence-based framework to maintain the high quality of ART healthcare services and ensure continuous improvement of birth outcomes. Methods A total of 19,170 pregnant women from Sichuan, Guizhou and Chongqing in Southwest China between 2018 and 2021 were included in this study. The log-binomial regression model was employed to analyse the changes in the probability of adverse birth outcomes, such as low birth weight (LBW), preterm birth (PTB), Apgar score

Abstract Background LncRNAs play essential roles in multiple tumors. However, research on genome-wide lncRNA alterations and their functions in cervical cancer (CC) is limited. This study aims to explore key lncRNAs in CC progression and uncover the molecular mechanisms involved in the development of CC. Methods In this study, we analyzed 30 tissues from CC, cervical intraepithelial neoplasia (CIN), and normal (NOR) using transcriptome sequencing and weighted gene co-expression network analysis to establish gene modules related to the NOR-CIN-CC transition. Machine learning diagnostic models were employed to investigate the role of lncRNAs in this transition. Molecular biological experiments were conducted to elucidate the potential mechanisms of CARMN in CC, with a particular focus on its transcriptional and post-transcriptional regulation of abnormal expression in CC. Results CARMN was identified as a hub gene in two modules significantly associated with the NOR-CIN-CC transition. Analysis using ten machine learning models confirmed its critical role in this progression. The results of RNA-seq, qPCR and RNAScope performed in another cohort of 83 cervical tissues all showed that CARMN was significantly downregulated in CC. CARMN significantly enhanced the interaction between Keap1 and Nrf2, leading to increased ROS levels. The elevated ROS levels suppressed the Akt/mTOR signaling pathway, leading to autophagy arrest via autophagic flux blockade. Additionally, CARMN interacted with TFAP2α to repress MAPK13 transcription, further inhibiting the MAPK cascade. A promoter SNP (rs12517403) was found to increase CC risk (OR = 1.34, 95% CI = 1.11–1.61) and reduce CARMN expression by decreasing SP1 binding. Furthermore, the RNA binding proteins that could modulate CARMN RNA stability were also determined using RNA-pulldown assay. The results demonstrated that YBX1, a component of the coding region instability determinant (CRD)-mediated mRNA stabilization complex, promoted CARMN RNA stability. DHX9, another component of complex, acted as a scaffold to bridge YBX1 and CARMN. Conclusions CARMN exerts an anti-cancer effect in CC progression by inhibiting the Akt-mTOR and MAPK signaling pathways. rs12517403 and the YBX1/DHX9 complex are key mechanisms influencing its transcription and stability in CC cells. CARMN represents a promising biomarker for CC diagnosis and therapeutic target.

Semen Lepidii is the dried and mature seeds of the cruciferous plant of Descurainia Sophia or Lepidium Apetalum, being a widely-used traditional Chinese medicine for various pharmacological effects, such as antibacterial, antitumor, diuretic and improving immune function. However, the chemical components of Semen Ledidii from different regions have not been clear, limiting the further application of this herb medicine in clinic. Therefore, in this study, a method of ultra-performance liquid chromatography-electrostatic Orbital ion trap tandem mass spectrometry (UPLC-Orbitrap-MS/MS) was developed to identify the chemical components of the three Semen Lepidii, namely Descurainia Sophia 1 (DS1), Descurainia Sophia 2 (DS2) and Lepidium Apetalum (LA) from different regions, and to study the fragmentation pathways of the identified components. The methanol-water (70:30, V/V) extract of the three mashed powder samples was separated on an ACQUITY UPLC BEH C18 column (100 mm×2.1 mm×1.7 μm), and infused into high mass resolution Orbitrap mass spectrometer for analyzing under positive and negative ion modes. MS/MS data were acquired with a Full MS/dd-MS2 mode, and the chromatographic peaks were aligned and extracted by using Compound Discoverer (CD) software. Then, the accurate mass informations of the precursor and fragment ions were matched to the databases in the CD platform for identification of components in the samples, and studied the fragmentation pathways of identified compounds. A total of 39 compounds are identified in DS1, including alkaloids, flavonoids, cardiac glycosides, amides, organic acids, amino acids, and others. This method was used to analyze methanol-water extract of DS2 and LA, 37 compounds are identified in DS2, including 10 compounds which are not identified in DS1, and 42 compounds are identified in LA, including 7 compounds which are not identified in both DS1 and DS2. The results indicated that the chemical components of Semen Lepidii originated from different regions are remarkably different and may act as medicine in various ways. This study provides a fundamental for further studying the molecular mechanism of pharmacological effects of Semen Lepdii, which can promote its clinical application.

Abstract To explore the relationship between morphological and hemodynamic parameters, baseline characteristics, and long-term outcomes in patients with moyamoya disease (MMD) using a computational fluid dynamics model. We retrospectively reviewed 129 patients at Beijing Tiantan hospital between July 2020 and December 2021. Perioperative clinical variables and Suzuki stage were recorded. Logistic regression analysis was employed to identify the risk factors for unfavorable long-term outcomes. The association between morphological, CT perfusion parameters, hemodynamic parameters and the Suzuki stage, clinical variables of MMD was also analyzed. Patients with high relative Wall Shear Stress (rWSS) were older and had more cases with higher Suzuki stage and worse follow-up mRS scores (p

Abstract The multifunctional proteins of class 2 CRISPR systems such as Cas9, have been employed to activate cryptic biosynthetic gene clusters (BGCs) in Streptomyces, which represent a large and hidden reservoir of natural products. However, such approaches are not applicable to most Streptomyces strains with reasons to be comprehended. Inspired by the prevalence of the class 1 subtype especially the type I-E CRISPR system in Streptomyces, here we report the development of the type I-E CRISPR system into a series of transcriptional regulation tools. We further demonstrate the effectiveness of such activators in nine phylogenetically distant Streptomyces strains. Using these tools, we successfully activate 13 out of 21 BGCs and lead to the identification and characterization of one polyketide, one Ripp and three alkaloid products. Our work is expected to have a profound impact and to facilitate the discovery of numerous structurally diverse compounds from Streptomyces.

Abstract Objective To assess the characteristics, molecular classification, and role of adjuvant treatment in patients with endometrioid endometrial cancer (EEC) and microcystic elongated and fragmented (MELF) myometrial invasion pattern. Methods This study included patients who were diagnosed with EEC with a MELF invasion pattern and underwent surgery from January 2019 to December 2023. We analyzed molecular classification, clinicopathological characteristics, and prognostic outcomes, including recurrence and adjuvant therapy. Results Out of 529 patients, 84 (15.9%) exhibited the MELF pattern, with 1 (1.2%) classified as POLE-mutation, 19 (22.6%) as mismatch repair deficient, 53 (63.1%) as no specific molecular profile, and 11 (13.1%) as p53-mutant subtype. Fifty (59.5%) patients with MELF invasion pattern received adjuvant chemotherapy (CT) ± external beam radiation therapy (EBRT), 19 (22.6%) received EBRT only, and 15 (17.9%) received no adjuvant treatment. Receiving adjuvant therapy was significantly associated with the risk level defined by the ESMO guideline for endometrial cancer (p = 0.002). With a median follow-up of 26 months (range: 1–59), the progression-free survival at 3-years for the MELF invasion patients was 91%. Seven patients with the MELF pattern experienced recurrence, of whom one was in stage IA (low risk, local recurrence) and did not receive any additional treatment, two were in stage IB (intermediate / high-intermediate risk, distant recurrence) and received EBRT only and the remaining four were in stage III to IV and had distant recurrence despite receiving adjuvant chemotherapy with or without EBRT. Among 43 intermediate- and high-intermediate-risk EEC patients, receiving CT ± EBRT was significantly associated with better DFS than without CT (p = 0.047). Conclusion The presence of the MELF pattern in EEC should be incorporated into decision-making regarding adjuvant therapy. The use of adjuvant treatment should be tailored based on histology and molecular type.

Abstract Autophagy has both protective and pathogenetic effects on injury caused by cerebral ischemia/reperfusion (I/R). Our previous research has indicated that stimulator of interferon genes (STING) could orchestrate microglia polarization following middle cerebral artery occlusion. However, it remains largely unexplored whether STING balances microglial polarization by regulating autophagy in brain I/R injury. Here, STING was observed to show an up-regulation in the microglia from mice subjected to experimental ischemic stroke. Strikingly, the deletion of STING led to the significant skewness of microglia activated by ischemia from a pro- to anti-inflammatory state and substantially alleviated ischemia-induced infarction and neuronal injury. In addition, STING-null mice can restore long-term neurobehavioral function. Then, the crosstalk between neuroinflammation and microglia autophagy was analyzed. The differential activity of autophagy in wild-type and STING-knockout (KO) mice or primary microglia was largely reversed when STING was restored in microglia. Irritating autophagy by rapamycin skewed the anti‑inflammatory state induced by STING-KO to a pro‑inflammatory state in microglia. Furthermore, microtubule-associated protein light-chain-3 (LC3) was identified as the key factor in the STING regulation of autophagy by glutathione-S-transferase (GST) pull-down analysis. Mechanically, STING can directly interact with LC3 through the STING transmembrane domain (1-139aa). Herein, current data determine the pivotal role of autophagy, specifically via LC3 protein, in the regulation of microglial phenotypic transformation by STING. These findings may provide a possible treatment target for delaying the progression of ischemic stroke.

Abstract Objective This study aimed to investigate the associations between physical activity (PA) intensity, occupational PA engagement, and sarcopenia in younger adults. Methods Data from the National Health and Nutrition Examination Survey (NHANES) (from 2011 to 2018) were used for the study. PA data were extracted for the Global Physical Activity Questionnaire, and the ratio of limb muscle mass (ALM) to body mass index (BMI) was used to determine sarcopenia. Multiple logistic regression was performed, and dose-response curves were drawn to evaluate the associations. Results Of the 8802 adults aged 20 to 59 years, 770 (8.7%) were identified as having sarcopenia. Compared to those in the reference group, the participants in the “low”, “moderate”, and “high” total METs groups had lower risks of sarcopenia (low: OR = 0.730, 95% CI = 0.583; 0.915; moderate: OR = 0.643, 95% CI = 0.485; 0.853; high: OR = 0.560, 95% CI = 0.457; 0.687). The risk of sarcopenia decreased in the high-intensity recreational PA group; however, such a significant association was observed only in the high-intensity occupational PA group. The relationship between total METs and sarcopenia showed a nonlinear U-shaped trend. Conclusions A greater intensity of PA is associated with a lower risk of sarcopenia among younger adults, regardless of whether moderate or vigorous PA is performed. Moreover, recreational PA may particularly advantageously contrast with occupational PA in lowering the risk of sarcopenia.

Abstract Using e + e − collision data collected by the BESIII detector at BEPCII corresponding to an integrated luminosity of 30 fb −1, we measure Born cross sections and effective form factors for the process e + e − → Ξ 0 Ξ ¯ 0 $$ {e}^{+}{e}^{-}\to {\Xi}^0{\overline{\Xi}}^0 $$ at forty-five center-of-mass energies between 3.51 and 4.95 GeV. The dressed cross section is fitted, assuming a power-law function plus a charmonium(-like) state, i.e., ψ(3770), ψ(4040), ψ(4160), ψ(4230), ψ(4360), ψ(4415) or ψ(4660). No significant charmonium(-like) state decaying into Ξ 0 Ξ ¯ 0 $$ {\Xi}^0{\overline{\Xi}}^0 $$ is observed. Upper limits at the 90% confidence level on the product of the branching fraction and the electronic partial width are provided for each decay. In addition, ratios of the Born cross sections and the effective form factors for e + e − → Ξ 0 Ξ ¯ 0 $$ {e}^{+}{e}^{-}\to {\Xi}^0{\overline{\Xi}}^0 $$ and e + e − → Ξ − Ξ ¯ + $$ {e}^{+}{e}^{-}\to {\Xi}^{-}{\overline{\Xi}}^{+} $$ are also presented to test isospin symmetry and the vector meson dominance model.

Abstract Background Community-based participatory research (CBPR) is a collaborative research approach that engages academic researchers and community stakeholders as equal partners in all research steps to address community concerns and achieve health equity. The CBPR approach has been widely used in vaccination promotion programmes. However, the elements and steps of CBPR-based programmes varied among studies. The purpose of this scoping review was to synthesize the elements and steps, and establish an implementation framework to guide the utilisation of CBPR approaches in vaccination promotion. Methods This scoping review was performed in accordance with Arksey and O’Malley’s five-stage framework. A systematic search was conducted on a set of electronic databases and grey literature sources. The retrieved articles were screened according to the criteria of CBPR and vaccination promotion, and data were extracted and recorded on a calibrated and predefined form in terms of study characteristics and CBPR components. Two authors worked independently to complete literature search, study selection, and data extraction. A narrative summary was used in categorising characteristics, and the contents of the included studies were summarised through qualitative analysis. Results A total of 8557 publications were initially screened, and 23 articles were finally included. According to the CBPR conceptual model, the elements in each CBPR component specifically for vaccination promotion included (1) the establishment of community–academic partnership (CAP)s, (2) community capacity building by partner training vaccination knowledge, research literacy, and service abilities and skills, (3) development and implementation of community-based intervention and (4) Outcome evaluation. A CAP was established between academic researchers or institutes and eight types of partners, including community service organisation–related non-government organisations (NGOs), health service institution–related NGOs, religious organisations, government agencies, educational institutions, media agencies, business agencies, and community representatives. The maintenance of CAP was achieved with four key strategies, namely, strengthening communication, forming management groups, sharing resources and information, and providing incentives. Twelve studies provided comprehensive insights into the strategies employed for intervention development, utilising either quantitative surveys, qualitative methods or a combination of both approaches. The contents of interventions included health service supports, health education activities, social marketing campaigns, community mobilisation, interactive discussions, vaccination reminders and incentives. As for outcome evaluation, vaccination rate and the effectiveness of interventions were assessed. A considerable increase was observed in 95.7% of the included studies (22/23), and the highest increase (92.9%) was attained after the intervention. An implementation framework was generated to summarise the elements and steps of CBPR approaches for vaccination promotion. Conclusions This review summarised current evidence and generated an implementation framework to elucidate the elements and steps in the development and application of CBPR approaches in vaccination promotion. CBPR approaches are recommended for future vaccination promotion programmes, involving community stakeholders and research professionals, to ensure equitable access to vaccinations across diverse populations.

Abstract Prenatal stress exerts long-term impact on neurodevelopment in the offspring, with consequences such as increasing the offspring’s risk of depression in adolescence and early adulthood. S-ketamine can produce rapid and robust antidepressant effects, but it is not clear yet whether and how S-ketamine alleviates depression in prenatally stressed offspring. The current study incestigated the preliminary anti-depression mechanism of S-ketamine in prenatally stressed offspring, particularly with regard to neuroplasticity. The pregnant females were given chronic unpredictable mild stress on the 7th-20th day of pregnancy and their male offspring were intraperitoneally injected with a single dose of S-ketamine (10 mg/kg) on postnatal day 42. Our findings showed that S-ketamine treatment counteracted the development of depression-like behaviors in prenatally stressed offspring. At the cellular level, S-ketamine markedly enhanced neuroplasticity in the CA1 hippocampus: Golgi-Cox staining showed that S-ketamine alleviated the reduction of neuronal complexity and dendritic spine density; Transmission electron microscopy indicated that S-ketamine reversed synaptic morphology alterations. At the molecular level, by western blot and RT-PCR we detected that S-ketamine significantly upregulated the expression of BDNF and PSD95 and activated AKT and mTOR in the hippocampus. In conclusion, prenatal stress induced by chronic unpredictable mild stress leads to depressive-like behaviors and hippocampal neuroplasticity impairments in male offspring. S-ketamine can produce antidepressant effects by enhancing hippocampal neuroplasticity via the BDNF/AKT/mTOR signaling pathway.

Abstract Introduction Sarcomas with muscle differentiation (for example, rhabdomyosarcoma, leiomyosarcoma, and pleomorphic sarcoma) are uncommon in the adult bladder. Case presentation In this case report, we describe a 69-year-old Chinese male patient who presented to the urology outpatient clinic because of intermittent full-course macroscopic hematuria for 10 days. A B ultrasound indicated hypoechoic nodules in the right upper wall of the bladder. Transurethral resection of the bladder tumor and cystoscopic multipoint random biopsy was performed. Postoperative pathological findings showed pleomorphic rhabdomyosarcoma of the adult bladder. Later, he was transferred to the Department of Medical Oncology of our hospital for further postoperative chemotherapy. The chemotherapy regimen used was intravenous chemotherapy of dacarbazine with doxorubicin. The patient in this case has survived for 12 months postoperatively. Conclusion From this case, our elderly patient with early pleomorphic rhabdomyosarcoma of the urinary bladder received transurethral resection of bladder tumor and postoperative chemotherapy, and there had been no recurrence 12 months postoperatively. The aforementioned treatment modality may offer a favorable prognosis.

Abstract Cytosine base editing is a powerful tool for making precise single nucleotide changes in cells and model organisms like zebrafish, which are valuable for studying human diseases. However, current base editors struggle to edit cytosines in certain DNA contexts, particularly those with GC and CC pairs, limiting their use in modelling disease-related mutations. Here we show the development of zevoCDA1, an optimized cytosine base editor for zebrafish that improves editing efficiency across various DNA contexts and reduces restrictions imposed by the protospacer adjacent motif. We also create zevoCDA1-198, a more precise editor with a narrower editing window of five nucleotides, minimizing off-target effects. Using these advanced tools, we successfully generate zebrafish models of diseases that were previously challenging to create due to sequence limitations. This work enhances the ability to introduce human pathogenic mutations in zebrafish, broadening the scope for genomic research with improved precision and efficiency.

Abstract Background Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder caused by variants in PKHD1. Currently, aberrant splicing has been reported to play important roles in genetic disease. Our goal is to analyze intronic variants in PKHD1 at the mRNA level. Results The 12 candidate variants were introduced into the corresponding minigene and functionally assayed in HEK 293T and Hela cells. We identified 11 variants that induce splicing alterations, resulting in various consequences such as skipping of exons, intron retention and protein truncation. Conclusions This underlined the importance of mRNA-level assessment for genetic diagnostics in related genetic disorders.

Abstract Background Systemic lupus erythematosus (SLE) is linked to host gut dysbiosis. Here we performed faecal gut microbiome sequencing to investigate SLE-pathogenic gut microbes and their potential mechanisms. Methods There were 134 healthy controls (HCs) and 114 SLE cases for 16 S ribosomal RNA (rRNA) sequencing and 97 HCs and 124 SLE cases for shotgun metagenomics. Faecal microbial changes and associations with clinical phenotypes were evaluated, and SLE-associated microbial genera were identified in amplicon analysis. Next, metagenomic sequencing was applied for accurate identification of microbial species and discovery of their metabolic pathways and immunogenic peptides both relevant to SLE. Finally, contribution of specific taxa to disease development was confirmed by oral gavage into lupus-prone MRL/lpr mice. Results SLE patients had gut microbiota richness reduction and composition alteration, particularly lupus nephritis and active patients. Proteobacteria/Bacteroidetes (P/B) ratio was remarkably up-regulated, and Escherichia was identified as the dominantly expanded genus in SLE, followed by metagenomics accurately located Escherichia coli and Escherichia unclassified species. Significant associations primarily appeared among Escherichia coli, metabolic pathways of purine nucleotide salvage or peptidoglycan maturation and SLE disease activity index (SLEDAI), and between multiple epitopes from Escherichia coli and disease activity or renal involvement phenotype. Finally, gavage with faecal Escherichia revealed that it upregulated lupus-associated serum traits and aggravated glomerular lesions in MRL/lpr mice. Conclusion We characterize a novel SLE exacerbating Escherichia outgrowth and suggest its contribution to SLE procession may be partially associated with metabolite changes and cross-reactivity of gut microbiota-associated epitopes and host autoantigens. The findings could provide a deeper insight into gut Escherichia in the procession of SLE.

Abstract Background Both anti-aging protein α-Klotho and the triglyceride-glucose (TyG) index hold predictive value for the incidence, progression, and outcomes of cardiovascular disease, diabetes and many other diseases. However, their relationship remains unclear. Methods We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Weighted multivariate linear regression models and subgroup analysis were constructed to assess the association between TyG index and α-Klotho levels. Nonlinear correlations were explored using restricted cubic splines (RCS), generalized additive models (GAM) and smooth curve fitting. Segmented regression model was conducted to explore potential threshold effects and identify the inflection point. Results A total of 2568 participants satisfied the predetermined criteria were enrolled in the final analysis. After fully adjusting for covariates, TyG index was shown to be markedly negatively correlated with α-Klotho [β=-74.07, 95%CI (-100.29,-47.85), p

Noise-induced hearing loss (NIHL) is primarily driven by inflammatory processes within the cochlea, where noise exposure triggers the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, leading to an inflammatory cascade. The interaction between increased NLRP3 expression and NF-κB activity can further amplify cochlear inflammation. Our findings reveal that (R)-PFI-2 hydrochloride, a selective inhibitor of the SETD7 enzyme, effectively inhibits the activation of the cochlear NF-κB pathway, suppresses the release of pro-inflammatory factors, and prevents inflammasome assembly. This intervention disrupts the perpetuating cycle of inflammation, thereby alleviating damage to cochlear hair cells attributed to acoustic trauma. Consequently, (R)-PFI-2 hydrochloride emerges as a promising pharmacological candidate for NIHL, targeting and moderating the excessive immune and inflammatory responses implicated in the pathology of hearing loss.