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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 Cancer cells encounter unavoidable stress during tumor growth. The stress-induced transcription factor, activating transcription factor 4 (ATF4), has been reported to upregulate various adaptive genes involved in salvage pathways to alleviate stress and promote tumor progression. However, this effect is unknown in clear cell renal cell carcinoma (ccRCC). In this study, we found that ATF4 expression was remarkably upregulated in tumor tissues and associated with poor ccRCC outcomes. ATF4 depletion significantly impaired ccRCC cell proliferation, migration, and invasion in vitro and in vivo by inhibiting the AKT/mTOR and epithelial–mesenchymal transition (EMT)-related signaling pathway. RNA sequencing and functional studies identified nuclear protein 1 (NUPR1) as a key downstream target of ATF4 for repressing ferroptosis and promoting ccRCC cell survival. In addition, targeting ATF4 or pharmacological inhibition using NUPR1 inhibitor ZZW115 promoted antitumor immunity in syngeneic graft mouse models, represented by increased infiltration of CD4+ and CD8+ T cells. Furthermore, ZZW115 could improve the response to the PD-1 immune checkpoint blockade. The results demonstrate that the ATF4/NUPR1 signaling axis promotes ccRCC survival and facilitates tumor-mediated immunosuppression, providing a set of potential targets and prognostic indicators for ccRCC patients. Graphical abstract

Abstract For the multistage progression of prostate cancer (PCa) and resistance to immunotherapy, tumour‐associated macrophage is an essential contributor. Although immunotherapy is an important and promising treatment modality for cancer, most patients with PCa are not responsive towards it. In addition to exploring new therapeutic targets, it is imperative to identify highly immunotherapy‐sensitive individuals. This research aimed to establish a signature risk model, which derived from the macrophage, to assess immunotherapeutic responses and predict prognosis. Data from the UCSC‐XENA, GEO and TISCH databases were extracted for analysis. Based on both single‐cell datasets and bulk transcriptome profiles, a macrophage‐related score (MRS) consisting of the 10‐gene panel was constructed using the gene set variation analysis. MRS was highly correlated with hypoxia, angiogenesis, and epithelial‐mesenchymal transition, suggesting its potential as a risk indicator. Moreover, poor immunotherapy responses and worse prognostic performance were observed in the high‐MRS group of various immunotherapy cohorts. Additionally, APOE, one of the constituent genes of the MRS, affected the polarisation of macrophages. In particular, the reduced level of M2 macrophage and tumour progression suppression were observed in PCa xenografts which implanted in Apolipoprotein E‐knockout mice. The constructed MRS has the potential as a robust prognostic prediction tool, and can aid in the treatment selection of PCa, especially immunotherapy options.

Abstract Plant tissue culture is extensively employed in plant functional genomics research and crop genetic improvement breeding. The callus induction ability is critical for utilizing Agrobacterium-mediated genetic transformation. In this study, we conducted a genome-wide association study (GWAS) utilizing 368 rice accessions to identify traits associated with callus induction rate (CIR), resulting in the identification of a total of 104 significant SNP loci. Integrated with gene function annotation and transcriptome analysis, 13 high-confidence candidate genes involved in auxin-related, CYC cyclins, and histone H3K9-specific methyltransferase were identified in significant loci. Furthermore, we also verified a candidate gene, Os05g0493500 (OsCycB1;5), and employed the CRISPR/Cas9 system to generate OsCycB1;5 knockout mutants in rice (Oryza sativa L.). The OscycB1;5 mutant displays significantly reduced callus induction and proliferation capacity, this result indicating OsCycB1;5 is required for the callus formation in rice. Overall, this study provides several reliable loci and high-confidence candidate genes that may significantly affect callus formation in rice. This information will offer valuable insights into the mechanisms underlying callus formation not only in rice but also in other plants.

Abstract Background Surgeries for treating pelvic organ prolapse involving the utilization of synthetic mesh have been associated with complications such as mesh erosion, postoperative pain, and dyspareunia. This work aimed to reduce the surgical implantation-associated complications by nanofibrous membranes on the surface of the polypropylene mesh. The nanofiber of the nanofibrous membrane, which was fabricated by co-axial electrospinning, was composed of polyurethane as fiber core and gelatin as the fiber out layer. The biocompatibility of the modified mesh was evaluated in vitro by cell proliferation assay, immunofluorescence stain, hematoxylin-eosin (HE) staining, and mRNA sequencing. Polypropylene mesh and modified mesh were implanted in a rat pelvic organ prolapse model. Mesh-associated complications were documented. HE and Picro-Sirius red staining, immunohistochemistry, and western blotting were conducted to assess the interactions between the modified mesh and vaginal tissues. Results The modified mesh significantly enhanced the proliferation of fibroblasts and exerted a positive regulatory effect on the extracellular matrix anabolism in vitro. When evaluated in vivo, no instances of mesh exposure were observed in the modified mesh group. The modified mesh maintained a relatively stable histological position without penetrating the muscle layer or breaching the epidermis. The collagen content in the vaginal wall of rats with modified mesh was significantly higher, and the collagen I/III ratio was lower, indicating better tissue elasticity. The expression of metalloproteinase was decreased while the expression levels of tissue inhibitor of metalloproteinase were increased in the modified mesh group, suggesting an inhibition of collagen catabolism. The expression of TGF-β1 and the phosphorylation levels of Smad3, p38 and ERK1/2 were significantly increased in the modified mesh group. NM significantly improved the biocompatibility of PP mesh, as evidenced by a reduction in macrophage count, decreased expression levels of TNF-α, and an increase in microvascular density. Conclusions The nanofibrous membrane-coated PP mesh effectively reduced the surgical implantation complications by inhibiting the catabolism of collagen in tissues and improving the biocampibility of PP mesh. The incorporation of co-axial fibers composed of polyurethane and gelatin with polypropylene mesh holds promise for the development of enhanced surgical materials for pelvic organ prolapse in clinical applications.

Abstract Autophagosome-lysosome fusion defects play a critical role in driving autolysosomal dysfunction, leading to autophagic/lysosomal impairment in neurons following ischemic stroke. However, the mechanisms hindering autophagosome-lysosome fusion remain unclear. Soluble N-ethylmaleimide-sensitive factor (NSF) is an essential ATPase to reactivate STX17 and VAMP8, which are the paired molecules to mediate fusion between autophagosomes and lysosomes. However, NSF is frequently inactivated to inhibit the reactivation of STX17 and VAMP8 in ischemic neurons. Herein, we investigated whether autophagosome-lysosome fusion could be facilitated to alleviate autophagic/lysosomal impairment in ischemic neurons by over-expressing NSF. Rat model of middle cerebral artery occlusion (MCAO) and HT22 neuron ischemia model of oxygen-glucose deprivation (OGD) were prepared, respectively. The results demonstrated that NSF activity was significantly suppressed, accompanied by reduced expressions of STX17 and VAMP8 in penumbral neurons 48 h post-MCAO and in HT22 neurons 2 h post-OGD. Moreover, the attenuated autolysosome formation accompanied by autophagic/lysosomal dysfunction was observed. Thereafter, NSF activity in HT22 neurons was altered by over-expression and siRNA knockdown, respectively. After transfection with recombinant NSF-overexpressing lentiviruses, both STX17 and VAMP8 expressions were concurrently elevated to boost autophagosome-lysosome fusion, as shown by enhanced immunofluorescence intensity co-staining with LC3 and LAMP-1. Consequently, the OGD-created autophagic/lysosomal dysfunction was prominently ameliorated, as reflected by augmented autolysosomal functions and decreased autophagic substrates. By contrast, NSF knockdown conversely aggravated the autophagic/lysosomal impairment, and thereby exacerbated neurological damage. Our study indicates that NSF over-expression induces neuroprotection against ischemic neuronal injury by restoring autophagic/lysosomal dysfunction via the facilitation of autophagosome-lysosome fusion. Over-expression of NSF promotes fusion by reactivating STX17 and VAMP8. Black arrows represent the pathological process after cerebral ischemia, green arrows represent the mechanism of remission after NSF over-expression, and red arrows represent the effect on the pathological process after NSF knockdown.

Abstract Purpose This research evaluates the effect of balloon pulmonary angioplasty (BPA) on cardiac electrophysiological changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods Involving a retrospective analysis of 39 CTEPH patients (average age 61 ± 11), who had at least two BPAs and paired ECGs pre- and post-surgery, we examined changes in ECG indicators of right ventricular hypertrophy and their correlation with hemodynamic results. Results BPA yielded marked improvements in cardiac function and hemodynamics. ECG parameters, specifically the Lewis criteria and Butler-Leggett score, correlated strongly with hemodynamics and were predictive of a mean pulmonary arterial pressure (mPAP) ≥ 35mmHg. Notably, QRS complex axis normalization was observed in 25 patients, with 14 fully normalizing (range − 30° to + 90°). The qR pattern in V1 vanished in 9 cases, and 75% of the patients in qR pattern in V1 group had QRS complex electrical axis completely returned to normal range. The qR V1 group had higher mPAP and pulmonary vascular resistance (PVR), and lower cardiac output and index compared to the non-qR V1 group, alongside a higher Butler-Leggett score. Conclusions BPA enhances cardiac function and hemodynamics in CTEPH patients, with certain ECG measures such as Lewis criteria and Butler-Leggett score reflecting the severity of hemodynamic impairment. The reversal of QRS axis deviation and the disappearance of the qR pattern in lead V1 may serve as valuable indicators for assessing post-BPA satisfaction in CTEPH patients.

Abstract Cutting-edge humanoid machine vision merely mimics human systems and lacks polarimetric functionalities that convey the information of navigation and authentic images. Interspecies-chimera vision reserving multiple hosts’ capacities will lead to advanced machine vision. However, implementing the visual functions of multiple species (human and non-human) in one optoelectronic device is still elusive. Here, we develop an optically-controlled polarimetry memtransistor based on a van der Waals heterostructure (ReS2/GeSe2). The device provides polarization sensitivity, nonvolatility, and positive/negative photoconductance simultaneously. The polarimetric measurement can identify celestial polarizations for real-time navigation like a honeybee. Meanwhile, cognitive tasks can be completed like a human by sensing, memory, and synaptic functions. Particularly, the anti-glare recognition with polarimetry saves an order of magnitude energy compared to the traditional humanoid counterpart. This technique promotes the concept of interspecies-chimera visual systems that will leverage the advances of autonomous vehicles, medical diagnoses, intelligent robotics, etc.

Abstract Parkinson’s disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.

Abstract Background Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM. Methods and results The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 naïve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets. Conclusions The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance.

Abstract Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear. Methods Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression. Results RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway. Conclusions Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.

Abstract A substantial body of research has shown that introducing lexical information in Chinese Named Entity Recognition (NER) tasks can enhance the semantic and boundary information of Chinese words. However, in most methods, the introduction of lexical information occurs at the model architecture level, which cannot fully leverage the lexicon learning capability of pre-trained models. Therefore, we propose seamless integration of external Lexicon knowledge into the Transformer layer of BERT. Additionally, we have observed that in span-based recognition, adjacent spans have special spatial relationships. To capture this relationship, we extend the work after Biaffine and use Convolutional Neural Networks (CNN) to treat the score matrix as an image, allowing us to interact with the spatial relationships of spans. Our proposed LB-BMBC model was experimented on four publicly available Chinese NER datasets: Resume, Weibo, OntoNotes v4, and MSRA. In particular, during ablation experiments, we found that CNN can significantly improve performance.

Abstract Background Dysregulation of zinc homeostasis is widely recognized as a hallmark feature of prostate cancer (PCa) based on the compelling clinical and experimental evidence. Nevertheless, the implications of zinc dyshomeostasis in PCa remains largely unexplored. Methods In this research, the zinc homeostasis pattern subtype (ZHPS) was constructed according to the profile of zinc homeostasis genes. The identified subtypes were assessed for their immune functions, mutational landscapes, biological peculiarities and drug susceptibility. Subsequently, we developed the optimal signature, known as the zinc homeostasis-related risk score (ZHRRS), using the approach won out in multifariously machine learning algorithms. Eventually, clinical specimens, Bayesian network inference and single-cell sequencing were used to excavate the underlying mechanisms of MT1A in PCa. Results The zinc dyshomeostasis subgroup, ZHPS2, possessed a markedly worse prognosis than ZHPS1. Moreover, ZHPS2 demonstrated a more conspicuous genomic instability and better therapeutic responses to docetaxel and olaparib than ZHPS1. Compared with traditional clinicopathological characteristics and 35 published signatures, ZHRRS displayed a significantly improved accuracy in prognosis prediction. The diagnostic value of MT1A in PCa was substantiated through analysis of clinical samples. Additionally, we inferred and established the regulatory network of MT1A to elucidate its biological mechanisms. Conclusions The ZHPS classifier and ZHRRS model hold great potential as clinical applications for improving outcomes of PCa patients.

Cell counting is a common and fundamental cell measurement technique that plays a crucial role in the development and quality control of cell therapy products. However, accurate and reliable cell counting can be challenging owing to the complexity of cell preparations, diverse counting purposes, and various counting methods. This review summarizes the challenges encountered in cell counting for cell therapy products and provides strategies to improve the cell counting accuracy, thereby guiding the counting process and ensuring the quality of cell therapy products.

Background: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. Methods: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. Results: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+ T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. Conclusion: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

Quasi-static and high-rate tension and compression properties of an extruded AZ80 Mg alloy rod were investigated at loading rates of 0.001 and 500 s−1. Acquired stress – strain results show that tension and compression plastic deformations of AZ80 rod are asymmetric, and such strength differential effect is dependent of strain rate and loading orientation. Strength differential effect is weakened at 500 s−1 when the sample was loaded along the extrusion direction. Crystal plasticity simulations on the basis of the visco-plastic self-consistent method were performed. Numerical results indicate that the rate and orientation dependency of strength differential effect in AZ80 alloy is related to {101‾2} extension twinning. High-rate tests for pretension, unloading and reverse compression were realized to investigate the dynamic Bauschinger effect. Experimental results show that Bauschinger effect of AZ80 alloy is anisotropic and sensitive to the strain rate. A Bauschinger effect parameter considering strength differential effect was proposed, and it was found that the Bauchinger effect in the extrusion direction is reduced significantly at 500 s−1.

Abstract Background Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) hold great therapeutic potential in regenerative medicine. Therefore, it is crucial to establish a Good Manufacturing Practice (GMP)-compliant methodology for the isolation and culture of WJ-MSCs. Through comprehensive research, encompassing laboratory-scale experiments to pilot-scale studies, we aimed to develop standardized protocols ensuring the high yield and quality of WJ-MSCs manufacturing. Methods Firstly, optimization of parameters for the enzymatic digestion method used to isolate WJ-MSCs was conducted. These parameters included enzyme concentrations, digestion times, seeding densities, and culture media. Additionally, a comparative analysis between the explant method and the enzymatic digestion method was performed. Subsequently, the consecutive passaging of WJ-MSCs, specifically up to passage 9, was evaluated using the optimized method. Finally, manufacturing processes were developed and scaled up, starting from laboratory-scale flask-based production and progressing to pilot-scale cell factory-based production. Furthermore, a stability study was carried out to assess the storage and use of drug products (DPs). Results The optimal parameters for the enzymatic digestion method were a concentration of 0.4 PZ U/mL Collagenase NB6 and a digestion time of 3 h, resulting in a higher yield of P0 WJ-MSCs. In addition, a positive correlation between the weight of umbilical cord tissue and the quantities of P0 WJ-MSCs has been observed. Evaluation of different concentrations of human platelet lysate revealed that 2% and 5% concentrations resulted in similar levels of cell expansion. Comparative analysis revealed that the enzymatic digestion method exhibited faster outgrowth of WJ-MSCs compared to the explant method during the initial passage. Passages 2 to 5 exhibited higher viability and proliferation ability throughout consecutive passaging. Moreover, scalable manufacturing processes from the laboratory scale to the pilot scale were successfully developed, ensuring the production of high-quality WJ-MSCs. Multiple freeze-thaw cycles of the DPs led to reduced cell viability and viable cell concentration. Subsequent thawing and dilution of the DPs resulted in a significant decrease in both metrics, especially when stored at 20–27 °C. Conclusion This study offers valuable insights into optimizing the isolation and culture of WJ-MSCs. Our scalable manufacturing processes facilitate the large-scale production of high-quality WJ-MSCs. These findings contribute to the advancement of WJ-MSCs-based therapies in regenerative medicine.

Abstract The quality of rice (Oryza sativa L) is determined by a combination of appearance, flavor, aroma, texture, storage characteristics, and nutritional composition. Rice quality directly influences acceptance by consumers and commercial value. The genetic mechanism underlying rice quality is highly complex, and is influenced by genotype, environment, and chemical factors such as starch type, protein content, and amino acid composition. Minor variations in these chemical components may lead to substantial differences in rice quality. Among these components, starch is the most crucial and influential factor in determining rice quality. In this study, quantitative trait loci (QTLs) associated with eight physicochemical properties related to the rapid viscosity analysis (RVA) profile were identified using a high-density sequence map constructed using recombinant inbred lines (RILs). Fifty-nine QTLs were identified across three environments, among which qGT6.4 was a novel locus co-located across all three environments. By integrating RNA-seq data, we identified the differentially expressed candidate gene OsCRLK2 within the qGT6.4 interval. osclrk2 mutants exhibited decreased gelatinization temperature (GT), apparent amylose content (AAC) and viscosity, and increased chalkiness. Furthermore, osclrk2 mutants exhibited downregulated expression of the majority of starch biosynthesis-related genes compared to wild type (WT) plants. In summary, OsCRLK2, which encodes a receptor-like protein kinase, appears to consistently influence rice quality across different environments. This discovery provides a new genetic resource for use in the molecular breeding of rice cultivars with improved quality.

Abstract Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Abstract Brain structural changes in Parkinson’s disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson’s Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

Abstract Background Spontaneous intracerebral hemorrhage (sICH) is associated with significant mortality and morbidity. Predicting the prognosis of patients with sICH remains an important issue, which significantly affects treatment decisions. Utilizing readily available clinical parameters to anticipate the unfavorable prognosis of sICH patients holds notable clinical significance. This study employs five machine learning algorithms to establish a practical platform for the prediction of short-term prognostic outcomes in individuals afflicted with sICH. Methods Within the framework of this retrospective analysis, the model underwent training utilizing data gleaned from 413 cases from the training center, with subsequent validation employing data from external validation center. Comprehensive clinical information, laboratory analysis results, and imaging features pertaining to sICH patients were harnessed as training features for machine learning. We developed and validated the model efficacy using all the selected features of the patients using five models: Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), XGboost and LightGBM, respectively. The process of Recursive Feature Elimination (RFE) was executed for optimal feature screening. An internal five-fold cross-validation was employed to pinpoint the most suitable hyperparameters for the model, while an external five-fold cross-validation was implemented to discern the machine learning model demonstrating the superior average performance. Finally, the machine learning model with the best average performance is selected as our final model while using it for external validation. Evaluation of the machine learning model’s performance was comprehensively conducted through the utilization of the ROC curve, accuracy, and other relevant indicators. The SHAP diagram was utilized to elucidate the variable importance within the model, culminating in the amalgamation of the above metrics to discern the most succinct features and establish a practical prognostic prediction platform. Results A total of 413 patients with sICH patients were collected in the training center, of which 180 were patients with poor prognosis. A total of 74 patients with sICH were collected in the external validation center, of which 26 were patients with poor prognosis. Within the training set, the test set AUC values for SVM, LR, RF, XGBoost, and LightGBM models were recorded as 0.87, 0.896, 0.916, 0.885, and 0.912, respectively. The best average performance of the machine learning models in the training set was the RF model (average AUC: 0.906 ± 0.029, P

Understanding the settling behaviour of particles and the interactions between fluid and particles in channelled fluids is crucial for various natural and industrial processes. The research presented in this study focuses on elucidating the sedimentation modes of dual particles within finite-width channels, employing the Arbitrary Lagrangian-Eulerian (ALE) method in conjunction with Hertz contact theory. We aim to understand how the initial relative position affects the dynamic characteristics of particle settlement. The threshold values of α = 35° and gap ratio (the distance between particles relative to their diameter) L/D = 3.5 are deemed critical. The phenomenon of particles ‘kissing’ does not manifest when the initial angle α ≤ 35°. As the α increases, the DKT (Drafting-Kissing-Tumbling) process recurs at earlier stage. In all cases where dual-particle are arranged in a vertically aligned pattern (DP1 = DP2 or DP1> DP2), the settling behaviour of particles will eventually achieve a steady state characterized by the DKT process when L/D ≤ 4.0. As the gap ratio (L/D) increases, the time taken for the kissing phenomenon is prolonged. Additionally, the two particles exchange positions and the larger particle taking the lead in the settling process. In scenarios where dual particles are arranged side by side, the kissing phenomenon does not occur. Instead, the trajectory of the particles deviates from the centreline and shifts towards the channel wall due to the Magnus effect when L/D ≤ 2.0. When L/D ≥ 3.0, particles settle as though they were a single particle. In cases involving multiple particles, the hindering effect of the wall becomes significant and can not be ignored, leading to the observation of Rayleigh-Taylor instability development. As a result, the overall settlement pattern tends to be ‘concave’.

Understanding the differences in ubiquitination-modified proteins between Duroc pigs and Tibetan fragrant pigs is crucial for comprehending the growth and development of their skeletal muscles. In this study, skeletal muscle samples from 30-day-old Duroc pigs and Tibetan fragrant pigs were collected. Using ubiquitination 4D-Label free quantitative proteomics, we analyzed and identified ubiquitination-modified peptides, screening out 109 differentially expressed ubiquitination-modified peptides. Further enrichment analysis was conducted on the proteins associated with these differential peptides. GO analysis results indicated that the differential genes were primarily enriched in processes such as regulation of protein transport, motor activity, myosin complex, and actin cytoskeleton. KEGG pathway analysis revealed significant enrichment in pathways such as Glycolysis/Gluconeogenesis and Hippo signaling pathway. The differentially expressed key ubiquitinated proteins, including MYL1, MYH3, TNNC2, TNNI1, MYLPF, MYH1, MYH7, TNNT2, TTN, and TNNC1, were further identified. Our analysis demonstrates that these genes play significant roles in skeletal muscle protein synthesis and degradation, providing new insights into the molecular mechanisms of muscle development in Duroc pigs and Tibetan fragrant pigs, and offering theoretical support for breeding improvements in the swine industry.

Objective: The effects of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-exos) on serum metabolites and intestinal microbiota in rats after liver trauma were discussed. Methods: Adult Wistar Albino rats were assigned into control, model (liver trauma), MSCs, and MSC-exos groups (n = 6). The study examined changes in the inflammatory environment in liver tissues were analyzed by histological examination and analysis of macrophage phenotypes. Alterations in serum metabolites were determined by untargeted metabonomics, and gut microbiota composition was characterized by 16S rDNA sequencing. Correlations between specific gut microbiota, metabolites, and inflammatory response were calculated using Spearman correlation analysis. Results: Rats with liver trauma after MSCs and MSC-exos treatment exhibited attenuated inflammatory infiltration and necrosis in liver tissues. MSCs and MSC-exos treatment reduced the proportion of M1 macrophages, accompanied by a decrease in inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) levels. Furthermore, MSCs and MSC-exos treatment expanded the proportion of M2 macrophages, accompanied by an increase in arginase-1 (Arg-1) and interleukin-10 (IL-10) levels. The beneficial effects of MSC-exo treatment on rats with liver trauma were superior to those of MSC treatment. The composition and abundance of the gut microbiota and metabolites were altered in pathological rats, whereas MSC and MSC-exo intervention partially restored specific gut microbiota and metabolite alterations. At the phylum level, alterations in Bacteroidota, Proteobacteria, and Verrucomicrobiota were observed after MSC and MSC-exo intervention. At the genus level, Intestinimonas, Alistipes, Aerococcus, Faecalibaculum, and Lachnospiraceae_ND3007_group were the main differential microbiota. 6-Methylnicotinamide, N-Methylnicotinamide, Glutathione, oxidized, ISOBUTYRATE, ASCORBATE, EICOSAPENTAENOATE, GLYCEROL 3-PHOSPHATE, and Ascorbate radical were selected as important differential metabolites. There was a clear correlation between Ascorbate, Intestinimonas/Faecalibaculum and inflammatory cytokines. Conclusion: MSC-exos promoted the repair of tissue damage in rats with liver trauma by regulating serum metabolites and intestinal microbiota, providing new insights into how MSC-exos reduced inflammation in rats with liver trauma.

Purpose – This study aims to reduce the redundant weight of the anti-roll torsion bar brought by the traditional empirical design and improving its strength and stiffness. Design/methodology/approach – Based on the finite element approach coupled with the improved beluga whale optimization (IBWO) algorithm, a collaborative optimization method is suggested to optimize the design of the anti-roll torsion bar structure and weight. The dimensions and material properties of the torsion bar were defined as random variables, and the torsion bar's mass and strength were investigated using finite elements. Then, chaotic mapping and differential evolution (DE) operators are introduced to improve the beluga whale optimization (BWO) algorithm and run case studies. Findings – The findings demonstrate that the IBWO has superior solution set distribution uniformity, convergence speed, solution correctness and stability than the BWO. The IBWO algorithm is used to optimize the anti-roll torsion bar design. The error between the optimization and finite element simulation results was less than 1%. The weight of the optimized anti-roll torsion bar was lessened by 4%, the maximum stress was reduced by 35% and the stiffness was increased by 1.9%. Originality/value – The study provides a methodological reference for the simulation optimization process of the lateral anti-roll torsion bar.

ObjectiveIn order to improve the safety of ship navigation, this study focuses on virtually aided ship navigation strategies.MethodsTwo different inland river routes are chosen for the simulation of virtually aided ship navigation models based on the fluid-structure interaction mechanism, while taking the navigation rules and flow details of the rivers into consideration. The simulation of the ship sailing process on a typical inland river route under specific current conditions provides the corresponding virtually aided navigation plan in which the ship's velocity, location and course are obtained in a timely manner. ResultsIt is found that the simulation method established on the basis of Fluent can be used to solve the problems of multi-degree-of-freedom motion and fluid-structure interaction. When sailing through bends or branches, steering with a small rudder angle over long distances ensures safe navigation and prevents speed reduction and significant lateral displacement.ConclusionThe proposed method can be effectively combined with the flow field information of digital channels to simulate the ship sailing process, thereby providing data support for the decision-making of intelligent navigation on inland river routes.

Abstract Landslide in reservoirs imposes challenges to reservoir operation and dam safety management practices. The understanding of the landside mechanism during reservoir operation is crucial to landslide‐related risk migration. During the reservoir operation from 2018 to 2021, a massive landslide occurred with over 107 m3 in total volume on the bank of the NE reservoir. The surface movement characteristics before and after the occurrence of landslides in the NE reservoir in the region scale were detected and interpreted by Sentinel‐2 time series images. Experimental studies were conducted to investigate the geotechnical properties of the fine‐grained soil. The slope stability was evaluated for a typical slope profile considering the rising water level using the extended Bishop's simplified method, which was implemented in the code STAB‐UNSAT. It can be found that the landslide in the fine‐grained soil occurred simultaneously when the water level rose. The cumulative area of soil slope failure on the left bank of the NE reservoir increased continuously during the reservoir operation from 2018 to 2020, especially had a remarkable increment from August to October in 2019. The extended Bishop's simplified method provides a more rational method to evaluate the soil slope stability. The slope failure mechanism of the studied soil, that is, collapse–erosion–slide upon the rising reservoir water has been proposed.

Abstract Background Vulvar and vaginal melanoma (VuM & VaM) is a rare gynecologic malignancy with high mortality but low effectiveness to checkpoint immunotherapy compared to cutaneous melanoma. This article aims to elucidate the role of the disordered immune microenvironment in cancer progression in VuM. Methods At first, this article applied single-cell RNA sequencing (scRNA-seq) to the VuM obtained from a 68-year-old female patient, and constructed a single-cell atlas of VuM consist of 12,243 single cells. Then this article explores the genomic complexity and core signal channel in VuM microenvironment. Results This article provides new insights about the pathogenesis of VuM based on single-cell resolution data. It was found that the activation of CD8+ T cell contributed to induce tumor angiogenesis and immune escape, and the activation of the antigen-presenting molecular function participated in melanoma metastasis. Conclusion This article provided new insights into underlining VuM molecular regulation and potential signaling involved in immunotherapy, which would benefit the clinical practice and administration.

Abstract Purpose There is no report about the direct relationship between m6A modification and androgen receptor (AR)-related genes in prostate cancer (PC). We aimed to study the mechanisms of m6A methylation in regulating the pathogenesis of PC from the perspective of AR-related genes. Methods qRT-PCR was applied to detect the expression of m6A-related genes in PC cell with or without AR inhibitor. The effects of YTHDF1 knockdown on PC cell viability, apoptosis, migration and invasion were investigated using flow cytometry, wound healing and transwell assays, respectively. The mechanism of YTHDF1 action was investigated using m6A RNA immunoprecipitation (MeRIP) sequencing. The biological functions of YTHDF1 were also explored through in vivo experiments. Results YTHDF1 was significantly down-regulated in AR inhibitor group. YTHDF1 knockdown significantly decreased AR level, viability and m6A methylation level of PC cells. TRIM68 was identified as a direct target of YTHDF1. Both YTHDF1 and TRIM68 knockdown increased apoptosis, and decreased cell viability, migration, and invasion of PC cells, while TRIM68 overexpression reversed the effects of YTHDF1 knockdown on PC cells. In addition, knockdown of YTHDF1 or TRIM68 significantly decreased the m6A methylation level, and mRNA and protein levels of YTHDF1, TRIM68 and AR in PC cells, while TRIM68 overexpression increased the expression levels above. Furthermore, subcutaneous xenografts of nude mice also revealed that TRIM68 could reverse the effects of YTHDF1 knockdown in PC in vivo. Conclusion This study suggested the key role of YTHDF1-mediated m6A modification in PC progression by regulating androgen function-related gene TRIM68 in PC.

This trial was performed to determine the effects of dietary supplementation of dry dandelion (Taraxacum mongolicum Hand. -Mazz.) on carcase traits, breast meat quality, muscle fatty and amino acid composition and antioxidant capacity of broiler chickens. A total of 120 Arbour Acres broiler chickens were randomly allotted to three groups and fed basal diet (CON), basal diet supplemented with 0.5 g/kg (LD) or 1.0 g/kg (HD) of dandelion. The results showed that compared with LD group, the eviscerated percentage of HD group tended to be higher (p = 0.090), while the abdominal fat yield tended to be lower (p = 0.078). In addition, dandelion quadratically increased redness, water loss rate, the proportion of C20:2, C20:4n-6, C22:6n-3 and the sum of n-3 PUFA and decreased cooking loss of Pectoralis major (PA) muscle (p

Considering its Venturi effect, long corridor terrain is considered as one of the outstanding wind-energy resources, but has not been developed due to unclear inflow turbulence effects on wind turbines. To advance the wind-power technology in long corridors and reveal the physics behind it, we conducted a series of data-fusion analyses combining field measurements in the Hexi Corridor, Gansu, China, and numerical simulations and summarize the effort here. In this study, the classical spectrum for the atmospheric boundary layer for wind-energy research, the IEC Kaimal spectrum (also known as IECKwind, International Elector technical Commission 61400-1) cannot describe the wind profile in corridors. Here, we proposed a new spectrum to describe the wind in the Hexi Corridor by modifying the IEC Kaimal spectrum, and we call it the IECK-HX spectrum. The results demonstrate that it preferentially resides at lower frequencies (larger spatial scales) compared with IECKwind. Large-scale motions (LSMs) and very large-scale motions (VLSMs) coexist in the Hexi Corridor atmospheric boundary layer, which can be well described by the IECK-HX spectrum, and these two dominate the large fluctuations in the power, thrust, and blade root flapwise moment of wind turbines, while the high-frequency small-scale coherent structures mainly cause high-frequency fluctuations in wind-turbine load. Furthermore, IEC Kaimal spectrum can not describe the VLSMs, and the generated flow presents significant fluctuations and thereby reduces the power output in high wind-speed regions. This study provides fundamental support for wind-energy scientists and engineers who are interested in wind energy in corridor terrains.

Submergence stress challenges direct seeding in rice cultivation. In this study, we identified a heat shock protein, NAL11, with a DnaJ domain, which can regulate the length of rice coleoptiles under flooded conditions. Through bioinformatics analyses, we identified cis-regulatory elements in its promoter, making it responsive to abiotic stresses, such as hypoxia or anoxia. Expression of NAL11 was higher in the basal regions of shoots and coleoptiles during flooding. NAL11 knockout triggered the rapid accumulation of abscisic acid (ABA) and reduction of Gibberellin (GA), stimulating rice coleoptile elongation and contributes to flooding stress management. In addition, NAL11 mutants were found to be more sensitive to ABA treatments. Such knockout lines exhibited enhanced cell elongation for coleoptile extension. Quantitative RT-PCR analysis revealed that NAL11 mediated the gluconeogenic pathway, essential for the energy needed in cell expansion. Furthermore, NAL11 mutants reduced the accumulation of reactive oxygen species (ROS) and malondialdehyde under submerged stress, attributed to an improved antioxidant enzyme system compared to the wild-type. In conclusion, our findings underscore the pivotal role of NAL11 knockout in enhancing the tolerance of rice to submergence stress by elucidating its mechanisms. This insight offers a new strategy for improving resilience against flooding in rice cultivation.

Background: Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. Objectives: We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. Methods: This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. Results: PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. Conclusions: Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

In general, carriers are designed to deliver pharmaceutical (featuring small drug‐molecules) and biopharmaceutical (featuring large‐molecule drugs, e.g., antibodies, proteins, etc.) active ingredients and platform that is capable of transporting nanoparticles is rare. Herein, the fabrication of a supramolecular carrier with a nano‐grid structure for the entrapment of liposomes and exosomes is reported. The nano‐grid particles (NGP) are made of cyclodextrins as elementary units which are widely used to load drugs through host–guest inclusion complexes, whilst its secondary structure further formed the NGP tertiary architectures, enabling the entrapment of nanoparticles. The NGP features stimuli responsiveness, tunable surface charge, and good biocompatibility. The entrapped liposomes in NGP present enhanced distribution in lungs and extended duration of action in mice. And elongated release profiles for over 14 days is obtained for exosomes—making one‐of‐its‐kind unique platform to load and deliver nanoparticles.

Summary: The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Background: Poly (ADP-ribose) polymerase (PARP) inhibitor and antiangiogenic agent monotherapy have shown to be effective as maintenance treatment in patients with ovarian cancer (OC). However, there is currently a lack of evidence-based study to directly compare the effects of combination therapy with these two drugs. Therefore, this study aimed to compare the efficacy and safety of combination therapy with PARP inhibitors and antiangiogenic agents in women with OC using a meta-analysis.Methods: An exhaustive search of literature was undertaken using multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library to identify pertinent randomized controlled trials (RCTs) published up until 17 December 2023. The data on progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were pooled. We computed the pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for PFS and OS, along with the relative risks (RRs) and 95% CIs for AEs. Trial sequential analysis, heterogeneity test, sensitivity analysis, and publication bias assessment were performed. Stata 12.0 and Software R 4.3.1 were utilized for all analyses.Results: This meta-analysis included 7 RCTs with a total of 3,388 participants. The overall analysis revealed that combination therapy of PARP inhibitors and antiangiogenic agents significantly improved PFS (HR = 0.615, 95% CI = 0.517–0.731; 95% PI = 0.379–0.999), but also increased the risk of AEs, including urinary tract infection (RR = 1.500, 95% CI = 1.114–2.021; 95% PI = 0.218–10.346), fatigue (RR = 1.264, 95% CI = 1.141–1.400; 95% PI = 1.012–1.552), headache (RR = 1.868, 95% CI = 1.036–3.369; 95% PI = 0.154–22.642), anorexia (RR = 1.718, 95% CI = 1.320–2.235; 95% PI = 0.050–65.480), and hypertension (RR = 5.009, 95% CI = 1.103–22.744; 95% PI = 0.016–1580.021) compared with PARP inhibitor or antiangiogenic agent monotherapy. Our study has not yet confirmed the benefit of combination therapy on OS in OC patients (HR = 0.885, 95% CI = 0.737–1.063). Additionally, subgroup analyses further showed that combination therapy resulted in an increased risk of AEs, encompassing thrombocytopenia, vomiting, abdominal pain, proteinuria, fatigue, headache, anorexia, and hypertension (all p < 0.05).Conclusion: Our study demonstrated the PFS benefit of combination therapy with PARP inhibitors and antiangiogenic agents in patients with OC. The OS result need to be updated after the original trial data is mature. Clinicians should be vigilant of AEs when administering the combination therapy in clinical practice.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023494482.

ABSTRACTAlthough vaginitis is closely related to vaginal microecology in females, the precise composition and functional potential of different types of vaginitis remain unclear. Here, metagenomic sequencing was applied to analyze the vaginal flora in patients with various forms of vaginitis, including cases with a clue cell proportion ranging from 1% to 20% (Clue1_20), bacterial vaginitis (BV), vulvovaginal candidiasis (VVC), and BV combined with VVC (VVC_BV). Our results identified Prevotella as an important biomarker between BV and Clue1_20. Moreover, a gradual decrease was observed in the relative abundance of shikimic acid metabolism associated with bacteria producing indole as well as a decline in the abundance of Gardnerella vaginalis in patients with BV, Clue1_20, and healthy women. Interestingly, the vaginal flora of patients in the VVC_BV group exhibited structural similarities to that of the VVC group, and its potentially functional characteristics resembled those of the BV and VVC groups. Finally, Lactobacillus crispatus was found in high abundance in healthy samples, greatly contributing to the stability of the vaginal environment. For the further study of L. crispatus, we isolated five strains of L. crispatus from healthy samples and evaluated their capacity to inhibit G. vaginalis biofilms and produce lactic acid in vitro to select the potential probiotic candidate for improving vaginitis in future clinical studies. Overall, we successfully identified bacterial biomarkers of different vaginitis and characterized the dynamic shifts in vaginal flora between patients with BV and healthy females. This research advances our understanding and holds great promise in enhancing clinical approaches for the treatment of vaginitis.IMPORTANCEVaginitis is one of the most common gynecological diseases, mostly caused by infections of pathogens such as Candida albicans and Gardnerella vaginalis. In recent years, it has been found that the stability of the vaginal flora plays an important role in vaginitis. Furthermore, the abundant Lactobacillus-producing rich lactic acid in the vagina provides a healthy acidic environment such as Lactobacillus crispatus. The metabolites of Lactobacillus can inhibit the colonization of pathogens. Here, we collected the vaginal samples of patients with bacterial vaginitis (BV), vulvovaginal candidiasis (VVC), and BV combined with VVC to discover the differences and relationships among the different kinds of vaginitis by metagenomic sequencing. Furthermore, because of the importance of L. crispatus in promoting vaginal health, we isolated multiple strains from vaginal samples of healthy females and chose the most promising strain with potential probiotic benefits to provide clinical implications for treatment strategies.

We reported a novel method to prepare Al–Si/SiC composites infiltrated under super-gravity field without Mg addition. Noted that centrifugal force acted as the main driving force to overcome the penetration resistance, making it feasible to obtain the Al–Si/SiC composite with high relative density (≥99.3 %). The interfacial reaction between Al and SiC was retarded by Si addition under super-gravity field. Interestingly, the rod-like eutectic Si was detected at Al–SiC interface with semi-continuous distribution, leading to the excellent bending strength (342.6 ± 1.0 MPa), enhanced thermal conductivity (173 W/m K at 373 K), and relatively low coefficient of thermal expansion (8.90 × 10−6 K−1 ranged from 323 to 373 K). The interfacial regulation and fracture mechanism were discussed in details.

Abstract Background To explore the relationship between changes in salivary cytokine levels and the occurrence of white spot lesions in adolescents receiving clear aligner orthodontic treatment and investigate the predictive value of various factors for lesion occurrence. Methods We retrospectively analyzed sixthy eight adolescent in the permanent dentition period, who received clear aligner orthodontics in our hospital were randomly divided into two groups according to the occurrence or aggravation of white spot lesions after treatment. The general condition of the oral cavity was analyzed, saliva was collected, and inflammation-related cytokines with varying transcription levels between groups were screened by transcriptome analysis. The expression levels of inflammatory cytokines in the saliva of the patients in the two groups were measured, and the risk factors for white spot lesions were screened by correlation analysis and binary logistic regression analysis. The value of the independent and combined application of risk factors for predicting the occurrence of white spot lesions in adolescent patients after invisible orthodontic treatment was analyzed by receiver operating characteristic (ROC) curve analysis. Results Transcriptome and GO and KEGG pathway analyses showed that there were differences in the transcription levels of inflammatory cytokines such as CXCL1, CXCL2, CXCL8, CCL3, CCL4, IL-1β and IL-2 between groups. The levels of CXCL8, CCL3, CCL4, IL-1β and IL-2 in the saliva of patients with white spot lesions were significantly higher in patients after invisible orthodontic treatment (P

Abstract Direct seeding of rice is a lightweight and simple cultivation method, which can effectively promote rice production. Anaerobic germination tolerance is one of the main traits of rice adaptability to direct seeding. The mining of related genetic loci, analysis of anaerobic traits and screening of tolerance genes provided valuable genetic resources for improving the anaerobic germination ability of direct seeding rice. This study conducted a dynamic genome-wide association study (GWAS) based on coleoptile-related traits of 591 rice natural populations, and a total of 317 SNP sites were detected. Integrated dynamic widely targeted metabolomics analysis, we found that xanthine, l-alanine and GABA may be key biomarkers that are sensitive and respond strongly to hypoxic stress perception. By WGCNA analysis of targeted metabolomics and transcriptomics, a total of 3 modules were obtained that were significantly correlated with the above three marker metabolites, namely dark green, dark gray and light green modules, respectively, and several key structural genes of OsAlaAT1, OsGAD4, OsAAH and Os09g0424600 that may affect hypoxic germination were screened from the 3 modules. Among them, OsAlaAT1 (Os10g0390500), located in Chr10-12877840, which is within the GWAS location range of CVAN3d, is considered to be a more reliable candidate gene. Overall, in addition to providing new insight into the metabolic regulation of l-alanine, GABA and xanthine during hypoxic germination of rice. This study also provided a reference for the basic theoretical research and breeding application research on the related traits of anaerobic germination in direct-seeding rice.

Abstract Microalgae as the photosynthetic organisms offer enormous promise in a variety of industries, such as the generation of high-value byproducts, biofuels, pharmaceuticals, environmental remediation, and others. With the rapid advancement of gene editing technology, CRISPR/Cas system has evolved into an effective tool that revolutionised the genetic engineering of microalgae due to its robustness, high target specificity, and programmability. However, due to the lack of robust delivery system, the efficacy of gene editing is significantly impaired, limiting its application in microalgae. Nanomaterials have become a potential delivery platform for CRISPR/Cas systems due to their advantages of precise targeting, high stability, safety, and improved immune system. Notably, algal-mediated nanoparticles (AMNPs), especially the microalgae-derived nanoparticles, are appealing as a sustainable delivery platform because of their biocompatibility and low toxicity in a homologous relationship. In addition, living microalgae demonstrated effective and regulated distribution into specified areas as the biohybrid microrobots. This review extensively summarised the uses of CRISPR/Cas systems in microalgae and the recent developments of nanoparticle-based CRISPR/Cas delivery systems. A systematic description of the properties and uses of AMNPs, microalgae-derived nanoparticles, and microalgae microrobots has also been discussed. Finally, this review highlights the challenges and future research directions for the development of gene-edited microalgae. Graphical Abstract

Abstract Electrocatalytic CO2 reduction into value-added multicarbon products offers a means to close the anthropogenic carbon cycle using renewable electricity. However, the unsatisfactory catalytic selectivity for multicarbon products severely hinders the practical application of this technology. In this paper, we report a cascade AgCu single-atom and nanoparticle electrocatalyst, in which Ag nanoparticles produce CO and AgCu single-atom alloys promote C-C coupling kinetics. As a result, a Faradaic efficiency (FE) of 94 ± 4% toward multicarbon products is achieved with the as-prepared AgCu single-atom and nanoparticle catalyst under ~720 mA cm−2 working current density at −0.65 V in a flow cell with alkaline electrolyte. Density functional theory calculations further demonstrate that the high multicarbon product selectivity results from cooperation between AgCu single-atom alloys and Ag nanoparticles, wherein the Ag single-atom doping of Cu nanoparticles increases the adsorption energy of *CO on Cu sites due to the asymmetric bonding of the Cu atom to the adjacent Ag atom with a compressive strain.

Abstract Background Primary liver cancer has significant intratumor genetic heterogeneity (IGH), which drives cancer evolution and prevents effective cancer treatment. CRISPR/Cas9-induced mouse liver cancer models can be used to elucidate how IGH is developed. However, as CRISPR/Cas9 could induce chromothripsis and extrachromosomal DNA in cells in addition to targeted mutations, we wondered whether this effect contributes to the development of IGH in CRISPR/Cas9-induced mouse liver cancer. Methods CRISPR/Cas9-based targeted somatic multiplex-mutagenesis was used to target 34 tumor suppressor genes (TSGs) for induction of primary liver tumors in mice. Target site mutations in tumor cells were analyzed and compared between single-cell clones and their subclones, between different time points of cell proliferation, and between parental clones and single-cell clones derived from mouse subcutaneous allografts. Genomic instability and generation of extrachromosomal circular DNA (eccDNA) was explored as a potential mechanism underlying the oscillation of target site mutations in these liver tumor cells. Results After efficiently inducing autochthonous liver tumors in mice within 30–60 days, analyses of CRISPR/Cas9-induced tumors and single-cell clones derived from tumor nodules revealed multiplexed and heterogeneous mutations at target sites. Many target sites frequently displayed more than two types of allelic variations with varying frequencies in single-cell clones, indicating increased copy number of these target sites. The types and frequencies of targeted TSG mutations continued to change at some target sites between single-cell clones and their subclones. Even the proliferation of a subclone in cell culture and in mouse subcutaneous graft altered the types and frequencies of targeted TSG mutations in the absence of continuing CRISPR/Cas9 genome editing, indicating a new source outside primary chromosomes for the development of IGH in these liver tumors. Karyotyping of tumor cells revealed genomic instability in these cells manifested by high levels of micronuclei and chromosomal aberrations including chromosomal fragments and chromosomal breaks. Sequencing analysis further demonstrated the generation of eccDNA harboring targeted TSG mutations in these tumor cells. Conclusions Small eccDNAs carrying TSG mutations may serve as an important source supporting intratumor heterogeneity and tumor evolution in mouse liver cancer induced by multiplexed CRISPR/Cas9.

Abstract Objective To determine whether white matter hyperintensity (WMH) volumes in specific regions are associated with Parkinson's disease (PD) compared to non‐PD controls, and to assess their impact on motor signs through cross‐sectional and longitudinal analyses. Methods A total of 50 PD participants and 47 age‐ and gender‐matched controls were enrolled. All PD participants were followed up for at least 2 years. To detect regions of greater WMH in the PD, the WMH volume of each region was compared with the corresponding region in the control group. Linear regression and linear mixed effects models were respectively used for cross‐sectional and longitudinal analyses of the impact of increases in WMH volume on motor signs. Results The PD group had greater WMH volume in the occipital region compared with the control group. Cross‐sectional analyses only detected a significant correlation between occipital WMH volume and motor function in PD. Occipital WMH volume positively correlated with the severity of tremor, and gait and posture impairments, in the PD group. During the follow‐up period, the participants' motor signs progressed and the WMH volumes remained stable, no longitudinal association was detected between them. The baseline occipital WMH volume cannot predict the progression of signs after adjustment for baseline disease duration and the presence of vascular risk factors. Interpretation PD participants in this study were characterized by greater WMH at the occipital region, and greater occipital WMH volume had cross‐sectional associations with worse motor signs, while its longitudinal impact on motor signs progression was limited.

Insomnia is the second most prevalent mental illness worldwide. Periostracum cicadae (PC), as an animal traditional Chinese medicine with rich pharmacological effects, has been documented as a treatment for children’s night cries, and later extended to treat insomnia. This study aimed to investigate the effects of PC extract and N-acetyldopamine compounds in ameliorating insomnia. The UPLC-ESI-QTOF-MS analysis determined that PC extract mainly contained N-acetyldopamine components. Previously, we also isolated some acetyldopamine polymers from PC extract, among which acetyldopamine dimer A (NADA) was present in high content. Molecular docking and molecular dynamic simulations demonstrated that NADA could form stable complexes with 5-HT1A, BDNF, and D2R proteins, respectively. The effects of PC extract and NADA on insomnia were evaluated in the PCPA-induced insomnia model. The results indicated that PC extract and NADA could effectively ameliorate hypothalamic pathology of insomnia rats, increase the levels of 5-HT, GABA, and BDNF, and decrease the levels of DA, DOPAC, and HVA. Meanwhile, the PC extract and NADA also could significantly affect the expression of 5-HT1A, BDNF, and DARPP-32 proteins. This study proved that PC extract and acetyldopamine dimer A could effectively improve PCPA-induced insomnia in rats. It is speculated that the main pharmacological substances of PC were acetyldopamine components.

As an economic species widely distributed in the South China Sea (SCS), the purpleback flying squid (Sthenoteuthis oualaniensis) still has a large potential for exploitation, and the variations in its use as a resource are highly correlated with environmental and other factors. In this study, using a generalized additive model (GAM) and gradient forest analysis (GFA), in conjunction with environmental factors, the distribution of purpleback flying squid surrounding the Xisha and Zhongsha islands during the fishing moratorium period was investigated. The results indicated that catch per unit effort (CPUE) had a gradual increase from May to July 2023 in the primary fishing area surrounded the Xisha Islands during May to June, then moved southward towards 13–15° N after July. CPUE is used as an important indicator to reflect the abundance of the fishery, while the GFA results show that CPUE has a better fit than catch in this study. Therefore, the subsequent analysis focused on CPUE. Longitude and sea surface temperature (SST) were of relative higher importance, followed by sea surface salinity (SSS), latitude, chlorophyll a concentration (Chla), sea surface height (SSH), and mixed layer depth (MLD). Longitude and CPUE had a significant, positive correlation. The CPUE gradually increased with latitude within 14–16° N. The CPUE increased slowly as SST increased from 29.5 to 30.5 °C in the primary fishing area. The Chla in this fishing zone was 0–0.2 mg/m3 and displayed a significant positive association with CPUE. Conversely, SSS, SSH, and MLD had negative correlations with CPUE. These findings will promote the sustainable utilization of purpleback flying squid in the SCS.

Wearable thermoelectric generators have great potential to provide power for smart electronic wearable devices and miniature sensors by harnessing the temperature difference between the human body and the environment. However, the Thomson effect, the Joule effect, and heat conduction can cause a decrease in the temperature difference across the thermoelectric generator during operation. In this paper, phase change materials (PCMs) were employed as the heat sink for the thermoelectric generator, and the COMSOL software 6.1 was utilized to simulate and optimize the power generation processes within the heat sink. The results indicated that with a PCM height of 40 mm, phase transition temperature of 293 K, latent heat of 200 kJ/kg, phase transition temperature interval of 5 K, thermal conductivity of 50 W/(m·K), isobaric heat capacity of 2000 J/(Kg·K), density of 1000 kg/m3, and convective heat transfer coefficient of 10 W/(m·K), the device can maintain a temperature difference of 18–10 K for 1930 s when the thermoelectric leg height is 1.6 mm, and 3760 s when the thermoelectric leg height is 2.7 mm. These results demonstrate the correlation between the device’s output performance and the dimensions and performance parameters of the PCM heat sink, thereby validating the feasibility of employing the PCM heat sink and the necessity for systematic investigations.

To develop new energy enhancement energetic materials with great combustion performance and thermal stability, two kinds of ternary thermite, Al/Fe2O3/CuO and Al/Fe2O3/Bi2O3, were prepared and analyzed via mechanical ball milling. The samples were characterized by SEM, XRD, TG-DSC, constant volume and constant pressure combustion experiments. The first exothermic peaks of Al/Fe2O3/CuO and Al/Fe2O3/Bi2O3 appear at 579 °C and 564.5 °C, respectively. The corresponding activation energies are similar. The corresponding mechanism functions are set as G(α)=[−ln(1−α)]3/4 and G(α)=[−ln(1−α)]2/3, respectively, which belong to the Avrami-Erofeev equation. Al/Fe2O3/CuO has better thermal safety. For small dose samples, its critical temperature of thermal explosion is 121.05 °C higher than that of Al/Fe2O3/Bi2O3. During combustion, the flame of Al/Fe2O3/CuO is spherical, and the main products are FeAl2O4 and Cu. The flame of Al/Fe2O3/Bi2O3 is jet-like, and the main products are Al2O3, Bi and Fe. Al/Fe2O3/Bi2O3 has better ignition and gas production performance. Its average ignition energy is 4.2 J lower than that of Al/Fe2O3/CuO. Its average step-up rate is 28.29 MPa/s, which is much higher than 6.84 MPa/s of Al/Fe2O3/CuO. This paper provides a reference for studying the thermal safety and combustion performance of ternary thermite.