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Abstract Introduction Sepsis-associated acute kidney injury (SA-AKI) is strongly associated with poor prognosis. We aimed to build a machine learning (ML)-based clinical model to predict 1-year mortality in patients with SA-AKI. Methods Six ML algorithms were included to perform model fitting. Feature selection was based on the feature importance evaluated by the SHapley Additive exPlanations (SHAP) values. Area under the receiver operating characteristic curve (AUROC) was used to evaluate the discriminatory ability of the prediction model. Calibration curve and Brier score were employed to assess the calibrated ability. Our ML-based prediction models were validated both internally and externally. Results A total of 12,750 patients with SA-AKI and 55 features were included to build the prediction models. We identified the top 10 predictors including age, ICU stay and GCS score based on the feature importance. Among the six ML algorithms, the CatBoost showed the best prediction performance with an AUROC of 0.813 and Brier score of 0.119. In the external validation set, the predictive value remained favorable (AUROC = 0.784). Conclusion In this study, we developed and validated a ML-based prediction model based on 10 commonly used clinical features which could accurately and early identify the individuals at high-risk of long-term mortality in patients with SA-AKI.

ObjectiveInjectable skin fillers offer a wider range of options for cutaneous anti-aging and facial rejuvenation. PLLA microspheres are increasingly favored as degradable and long-lasting fillers. The present study focused solely on the effect of PLLA on dermal collagen, without investigating its impact on the epidermis. In this study, we investigated the effects of PLLA microspheres on epidermal stem cells (EpiSCs).MethodsDifferent concentrations of PLLA microspheres on epidermal stem cells (EpiSCs) in vitro through culture, and identification of primary rat EpiSCs. CCK-8 detection, apoptosis staining, flow cytometry, Transwell assay, wound healing assay, q-PCR analysis, and immunofluorescence staining were used to detect the effects of PLLA on EpiSCs. Furthermore, we observed the effect on the epidermis by injecting PLLA into the dermis of the rat skin in vivo.ResultsPLLA microspheres promote cell proliferation and migration while delaying cell senescence and maintaining its stemness. In vitro, Intradermal injection of PLLA microspheres in the rat back skin resulted in delayed aging, as evidenced by histological and immunohistochemical staining of the skin at 2, 4, and 12 weeks of follow-up.ConclusionThis study showed the positive effects of PLLA on rat epidermis and EpiSCs, while providing novel insights into the anti-aging mechanism of PLLA.

Accelerometers play a crucial role in the railway industry, especially in track monitoring. Traditionally, they are placed on the railway tracks or often on bridges to monitor the health and condition of the infrastructure. Recently, there has been an increased focus on using regular trains to monitor the condition of railway infrastructure. Often, the sensors are placed based on certain assumptions without much scientific evidence or support. This paper utilizes the multibody simulation software GENSYS to identify the optimal placement of accelerometers on a passenger train for monitoring railway switch wear. Switch wear profiles were generated systematically and used as input for the simulations, studying acceleration at a total of 93 locations distributed among the wheelsets, bogies, and carbody. Based on both time and frequency domain analyses, optimal sensor locations were identified, generally close to the first bogie or wheelset at the leading carbody. Accelerations generated by the wheelset passing the switch can also be captured in the carbody, but it is important to note that these are several orders lower in magnitude compared to the acceleration on the wheelset. If accelerometers are to be placed in the carbody, correct sensitivity must be chosen, and a high-pass filter should be applied to capture the acceleration signals associated with switch wear. The study confirms that there is a direct correlation between the depth of switch wear and the magnitude of the acceleration. It remains effective even under various curve radii and train speeds.

Abstract Background The stress hyperglycemia ratio (SHR) has been demonstrated as an independent risk factor for acute kidney injury (AKI) in certain populations. However, this relationship in patients with congestive heart failure (CHF) remains unclear. Our study sought to elucidate the relationship between SHR and AKI in patients with CHF. Methods A total of 8268 patients with CHF were included in this study. We categorized SHR into distinct groups and evaluated its association with mortality through logistic or Cox regression analyses. Additionally, we applied the restricted cubic spline (RCS) analysis to explore the relationship between SHR as a continuous variable and the occurrence of AKI. The primary outcome of interest in this investigation was the incidence of AKI during hospitalization. Results Within this patient cohort, a total of 5,221 (63.1%) patients experienced AKI during their hospital stay. Upon adjusting for potential confounding variables, we identified a U-shaped correlation between SHR and the occurrence of AKI, with an inflection point at 0.98. When the SHR exceeded 0.98, for each standard deviation (SD) increase, the risk of AKI was augmented by 1.32-fold (odds ratio [OR]: 1.32, 95% CI: 1.22 to 1.46). Conversely, when SHR was below 0.98, each SD decrease was associated with a pronounced increase in the risk of AKI. Conclusion Our study reveals a U-shaped relationship between SHR and AKI in patients with CHF. Notably, we identified an inflection point at an SHR value of 0.98, signifying a critical threshold for evaluating AKI in this population.

Abstract. Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with a range of symptoms, including palpitations, cognitive impairment, systemic embolism, and increased mortality. It places a significant burden on healthcare systems worldwide. Despite decades of research, the precise mechanisms underlying AF remain elusive. Current understanding suggests that factors like stretch-induced fibrosis, epicardial adipose tissue (EAT), chronic inflammation, autonomic nervous system (ANS) imbalances, and genetic mutations all play significant roles in its development. In recent years, the advent of wearable devices has revolutionized AF diagnosis, enabling timely detection and monitoring. However, balancing early diagnosis with efficient resource utilization presents new challenges for healthcare providers. AF management primarily focuses on stroke prevention and symptom alleviation. Patients at high risk of thromboembolism require anticoagulation therapy, and emerging pipeline drugs, particularly factor XI inhibitors, hold promise for achieving effective anticoagulation with reduced bleeding risks. The scope of indications for catheter ablation in AF has expanded significantly. Pulsed field ablation, as a novel energy source, shows potential for improving success rates while ensuring safety. This review integrates existing knowledge and ongoing research on AF pathophysiology and clinical management, with emphasis on diagnostic devices, next-generation anticoagulants, drugs targeting underlying mechanisms, and interventional therapies. It offers a comprehensive mosaic of AF, providing insights into its complexities.

The discrete element method (DEM) is a vital numerical approach for analyzing the mechanical behavior of elastoplastic wet sand. However, parameter uncertainty persists within the mapping between constitutive relationships and inherent model parameters. We propose a Parameter calibration neural network based on Attention, Retention, and improved Transformer for Sequential data (PartsNet), which effectively captures the nonlinear mechanical behavior of wet sand and obtains the optimal parameter combination for the Edinburgh elasto-plastic adhesion constitutive model. Variational autoencoder-based principal component ordering is employed by PartsNet to reduce the high-dimensional dynamic response and extract critical parameters along with their weights. Gated recurrent units are combined with a novel sparse multi-head attention mechanism to process sequential data. The fusion information is delivered by residual multilayer perceptron, achieving the association between sequential response and model parameters. The errors in response data generated by calibrated parameters are quantified by PartsNet based on adaptive differentiation and Taylor expansion. Remarkable calibration capabilities are exhibited by PartsNet across six evaluation indicators, surpassing seven other deep learning approaches in the ablation test. The calibration accuracy of PartsNet reaches 91.29%, and MSE loss converges to 0.000934. The validation experiments and regression analysis confirmed the generalization capability of PartsNet in the calibration of wet sand. The improved sparse attention mechanism optimizes multi-head attention, resulting in a convergence speed of 21.25%. PartsNet contributes to modeling and simulating the precise mechanical properties of complex elastoplastic systems and offers valuable insights for diverse engineering applications.

Staphylococcus aureus [S. aureus] is a leading cause of sepsis and septic arthritis, conditions that pose significant medical challenges due to their high mortality and morbidity. No studies have used an in vivo imaging system [IVIS] to monitor S. aureus sepsis and septic arthritis. Here, we employed a bioluminescent reporter strain of S. aureus, Newman AH5016, administered intravenously to induce sepsis and intra-articularly to induce local septic arthritis in mice. Disease progression was monitored using IVIS to capture bioluminescent signals from kidneys, joints, and whole mice. Cytokines in the blood and joints were measured. The efficacy of cloxacillin treatment was evaluated. In the sepsis model, bioluminescent signals from kidneys, but not from whole mice, were correlated with kidney bacterial load and abscess formation. Ex vivo kidney imaging detected increased bacterial load and abscess formation from day 3 to day 10. Antibiotic treatment significantly reduced kidney signals, correlating with decreased bacterial counts and IL-6 levels, indicating effective infection control. In the local infection model, early-phase bioluminescent signals from joints were correlated with macroscopic arthritis and bacterial burden. Thus, signal detection from kidneys using IVIS is useful for monitoring S. aureus sepsis and assessing antibiotic efficacy, though it may only be effective for early-phase monitoring of local septic arthritis.

ObjectiveSkin fibrosis is a lesion in the dermis causing to itching, pain, and psychological stress. The gut microbiome plays as an essential role in skin diseases developments. We conducted a Mendelian randomization study to determine the causal association between the gut microbiome and skin fibrosis.MethodsWe retrieved valid instrumental variables from the genome-wide association study (GWAS) files of the gut microbiome (n = 18,340) conducted by the MiBioGen consortium. Skin fibrosis-associated data were downloaded from the GWAS Catalog. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to determine whether the gut microbiome was related to skin fibrosis. A reverse MR analysis was also performed on the bacterial traits which were causally associated with skin fibrosis in the forward MR analysis. In addition, we performed an MR-Pleiotropy Residual Sum and Outlier analysis to remove outliers and a sensitivity analysis to verify our results.ResultsAccording to the inverse variance-weighted estimation, we identified that ten bacterial traits (Class Actinobacteria, Class Bacteroidia, family Bifidobacteriaceae, family Rikenellaceae, genus Lachnospiraceae (UCG004 group), genus Ruminococcaceae (UCG013 group), order Bacteroidales, order Bifidobacteriales, genus Peptococcus and genus Victivallis) were negatively correlated with skin fibrosis while five bacterial traits (genus Olsenella, genus Oscillospira, genus Turicibacter, genus Lachnospiraceae (NK4A136group), and genus Sellimonas) were positively correlated. No results were obtained from reverse MR analysis. No significant heterogeneity or horizontal pleiotropy was observed in MR analysis.Objective conclusionThere is a causal association between the gut microbiome and skin fibrosis, indicating the existence of a gut-skin axis. This provides a new breakthrough point for mechanistic and clinical studies of skin fibrosis.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.

The sample carried back by the Mars Ascent Vehicle (MAV) is a potential flagship mission of deep space exploration in recent years. A low-gravity simulation experiment is an effective method and a necessary stage for verifying the performance of the MAV launch dynamic in Earth’s gravity. In this paper, the uniqueness of low-gravity simulation is illustrated by the classical pulley balance method for the high dynamic process of a test model of the MAV. Its movement direction is the same as the compensation force, which leads to the relaxation of the sling and the failure of the compensation force in traditional cable suspension. Here, three cable suspension schemes including an improved pulley balancing scheme based on a coordinate transformation scheme and based on a dynamic pulley group scheme are proposed. For the actual launch condition of the MAV, the motion state of the ascent under the schemes and the real Mars launch are compared, which proves the feasibility of the schemes. Among them, the improved pulley balancing scheme has the best gravity compensation effect, and the error between the average value and the required value is the smallest, only 1%.

Abstract Aging alters immunoglobulin production, affecting the humoral immune response. Toll-like receptor 2 (TLR2) recognizes Staphylococcus aureus (S. aureus) which causes bacteremia with high mortality in the elderly. To understand how TLR2 and aging affect the humoral immune response in bacteremia, four groups of mice (wild type-young, wild type-old, TLR2−/−-young, and TLR2−/−-old) were used to analyze immunoglobulin levels in healthy conditions as well as 10 days after intravenous injection with S. aureus. We found that aging increased the levels of both IgM and IgG. Increased IgG in aged mice was controlled by TLR2. In bacteremia infection, aged mice failed to mount proper IgM response in both wild-type (WT) and TLR2−/− mice, whereas IgG response was impaired in both aged and TLR2−/− mice. Aged mice displayed reduced IgG1 and IgG2a response irrespective of TLR2 expression. However, impaired IgG2b response was only found in aged WT mice and not in TLR2−/− mice. Both aging and TLR2−/− increased the levels of anti-staphylococcal IgM in bacteremia. Aging increased sialylated IgG in WT mice but not in TLR2−/− mice. IgG sialylation was not affected by the infection in neither of the mice. In summary, aging increases all immunoglobulins except IgG1. However, aged mice fail to mount a proper antibody response to S. aureus bacteremia. TLR2 plays the regulatory role in IgG but not IgM response to infection.

Abstract Background The composite transplantation of a split-thickness skin graft (STSG) combined with an acellular dermal matrix (ADM) is a promising repair method for full-thickness skin defects. Due to delayed vascularization of the ADM, no currently available engineered skin tissue is able to permanently cover full-thickness skin defects via a single-stage procedure. Epidermal stem cells (EpSCs) have been found to promote angiogenesis in the wound bed. Whether EpSCs can induce early angiogenesis of dermal substitutes and promote the survival of single-stage tissue-engineered skin transplantation needs to be further studied. Methods In vitro, rat vascular endothelial cells (RVECs) were treated with the supernatant of EpSCs cultured in ADM and stimulated for 48 h. RVECs were analysed by RNA sequencing and tube formation assays. For the in vivo experiment, 75 rats were randomly divided into five groups: ADM, ADM + EpSCs (AE), STSG, ADM + STSG (AS), and ADM + STSG + EpSCs (ASE) groups. The quality of wound healing was estimated by general observation and H&E and Masson staining. The blood perfusion volume was evaluated using the LDPI system, and the expression of vascular markers was determined by immunohistochemistry (IHC). Results The active substances secreted by EpSCs cultured in ADM promoted angiogenesis, as shown by tube formation experiments and RNA-seq. EpSCs promoted epithelialization of the ADM and vascularization of the ADM implant. The ASE group showed significantly increased skin graft survival, reduced skin contraction, and an improved cosmetic appearance compared with the AS group and the STSG control group. Conclusions In summary, our findings suggest that EpSCs promote the formation of new blood vessels in dermal substitutes and support one-step transplantation of tissue-engineered skin, and thereby provide new ideas for clinical application.

Although the role of FGFs in cardiovascular disease has attracted extensive attention, the potential role of FGF18 in pathological cardiac hypertrophy remains unknown. Here, the authors show the cardioprotective effect of FGF18 is mediated by maintaining redox homeostasis through FYN/Nox4 signaling.

Physics-informed DeepONet (PI_DeepONet) is utilized for the reconstruction task of structural displacement based on measured strain. For beam and plate structures, the PI_DeepONet is built by regularizing the strain–displacement relation and boundary conditions, referred to as geometric differential equations (GDEs) in this paper, and the training datasets are constructed by modeling strain functions with mean-zero Gaussian random fields. For the GDEs with more than one Neumann boundary condition, an algorithm is proposed to balance the interplay between different loss terms. The algorithm updates the weight of each loss term adaptively using the back-propagated gradient statistics during the training process. The trained network essentially serves as a solution operator of GDEs, which directly maps the strain function to the displacement function. We demonstrate the application of the proposed method in the displacement reconstruction of Euler–Bernoulli beams and Kirchhoff plates, without any paired strain–displacement observations. The PI_DeepONet exhibits remarkable precision in the displacement reconstruction, with the reconstructed results achieving a close proximity, surpassing 99%, to the finite element calculations.

Spatiotemporal data visualization is of paramount importance in several applications, especially for analyzing urban mobility data encoded on topologies. This paper introduces a novel solution, called Temporal Topology Density Map (TTDM), to represent 2D discrete spatial data with temporal variations into a 2D continuous spatial space constrained by a topology. The proposed approach combines topological density maps with Change Frequency Heatmap (CFH) to convey visual information regarding temporal changes, leading to a new visualization method. Two case studies related to the analysis of response time associated with emergency services and walkability changes over time in specific areas of interest demonstrated the effectiveness of TTDM in challenging scenarios. The proposed solution provides an intuitive visualization for supporting the accurate analysis of spatiotemporal data changes over time using topology density maps.

Abstract Background C5AR2 is recognized as a proinflammatory molecule and activates the inflammatory response in multiple disorders. However, little has been reported on C5AR2 in glioma. This study sought to explore its expression, biological function, and association with clinical pathological indicators, prognosis, and immune infiltration levels in glioma through glioma cohorts. Methods A cohort of 657 patients was screened from the Chinese Glioma Genome Atlas (CGGA). χ2 test was performed to calculate the difference of classified variables. Cox proportional hazard regression modeling was used to identify independent prognostic indicators of glioma patients. A survival plot was generated by the Kaplan–Meier method. The immune cell infiltration score of glioma patients was calculated by TIMER algorithm. Results We observed that high expression of C5AR2 was strongly associated with malignant clinical indicators in 657 patients with glioma, and patients with high C5AR2 expression had worse prognoses. Multivariate Cox analysis showed that C5AR2 could be a new independent prognostic indicator for glioma patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that C5AR2 overexpression correlated with multiple inflammatory and immune biological processes. Additionally, high C5AR2 expression was strongly associated with higher abundance and marker gene expression of multiple tumor immune cells in low‐grade glioma. Finally, a model was constructed to improve the prognostic evaluation of glioma patients. Conclusions The C5AR2 gene is highly expressed in gliomas and is significantly associated with clinical indicators of malignant progression in glioma patients. In glioma, patients with high C5AR2 expression displayed a worse outcome. In glioma tissues, the expression level of C5AR2 highly correlated with the abundance of tumor immune cell infiltration. Additionally, GO and KEGG enrichment analysis revealed that C5AR2 expression may be involved in a variety of immune and inflammatory biological processes.

Phenol-soluble modulin α and β display divergent roles in staphylococcal infection and its associated septic arthritis - whereas PSMα is a virulence factor for neutrophils that worsens infection, PSMβ protects from the development of septic arthritis.

ABSTRACT Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward the fermentative pathway, as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion, and lactate and malate accumulation than P3C. These observed P2C effects were completely abrogated in monocyte/macrophage-depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease.

Septic arthritis is the most aggressive joint disease associated with high morbidity and mortality. The interplay of the host immune system with the invading pathogens impacts the pathophysiology of septic arthritis. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction. To date, there are no specific predictive biomarkers for septic arthritis. Transcriptome sequencing analysis identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an Staphylococcus aureus septic arthritis mouse model. Importantly, downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The mice infected intra-articularly with the S. aureus arthritogenic strain significantly increased S100a8/a9 protein expression levels in joints over time. Intriguingly, the synthetic bacterial lipopeptide Pam2CSK4 was more potent than Pam3CSK4 in inducing S100a8/a9 release upon intra-articular injection of these lipopeptides into the mouse knee joints. Such an effect was dependent on the presence of monocytes/macrophages. In conclusion, S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies.

Abstract A donor–acceptor (D-A) conjugated polymer PBTFO-T-1 consisting of 2,1,3-benzothiadiazole (BT) as A unit and thiophene (T) as D unit was facilely obtained by a straightforward three-step reaction. The BT unit is attached with a fluorine atom and an alkoxy chain to simultaneously endow the polymer with a deep HOMO energy level and desirable solubility. The alkoxyl chain orientation on the BT unit has been regulated and the polymer PBTFO-T-2 with regio-regularly oriented side chains was also developed to investigate the impact of the alkoxyl chain orientation on their optoelectronic properties. The PBTFO-T-1:Y6-BO polymer solar cells (PSCs) were processed with a non-halogenated solvent and achieved an optimized power conversion efficiency of 14.16%, significantly higher than 9.39% of the PBTFO-T-2:Y6-BO counterpart. It has been demonstrated that the PBTFO-T-1:Y6-BO film exhibits higher and more balanced charge transportation and superior film morphology, resulting in higher exciton generation and dissociation, less recombination and eventually the higher short-circuit current density (J sc) and fill factor. This study provides a possible strategy to develop polymer donors with low cost for future commercial applications of PSCs and gives some insights into regulating optoelectronic properties of polymer donors via rationally modifying their side chain orientation.

Abstract Cardiac hypertrophy occurs initially in response to an increased cardiac load as a compensatory mechanism to maintain cardiac output. However, sustained pathological hypertrophy can develop into heart failure and cause sudden death. Fibroblast growth factor 20 (FGF20) is a member of the fibroblast growth factor family, which involved in apoptosis, aging, inflammation, and autophagy. The precise function of FGF20 in pathological cardiac hypertrophy is unclear. In this study, we demonstrated that FGF20 was significantly decreased in response to hypertrophic stimulation. In contrast, overexpression of FGF20 protected against pressure overload-induced cardiac hypertrophy. Mechanistically, we found that FGF20 upregulates SIRT1 expression, causing deacetylation of FOXO1; this effect promotes the transcription of downstream antioxidant genes, thus inhibits oxidative stress. In content, the anti-hypertrophic effect of FGF20 was largely counteracted in SIRT1-knockout mice, accompanied by an increase in oxidative stress. In summary, our findings reveal a previously unknown protective effect of FGF20 on pathological cardiac hypertrophy by reducing oxidative stress through activation of the SIRT1 signaling pathway. FGF20 is a potential novel molecular target for preventing and treating pressure overload-induced myocardial injury.

The evaluation on prognosis of glioma patients is critical for the individualized treatment. Despite of the widely used mRNA expression level and methylation status of prognostic genes in predicting the patients’ prognosis, the clinical application of high-throughput sequencing technology is still limited. Thus, this study aimed to construct a visual and reliable nomogram based on the common clinicopathological parameters for predicting the prognosis of patients diagnosed with high grade glioma (HGG). Notably, age, histopathology, IDH status, 1p/19q status, radiotherapy status, chemotherapy status, and tumor recurrence were identified as seven independent prognostic factors for HGG patients. A comprehensive nomogram based on the seven identified factors was subsequently constructed with the remarkable C-index of 0.732. Calibrations for nomogram showed great consistency between the predictive values and the actual values in 1-, 3-, and 5-year survival rates. Besides, the areas under the ROC curve (AUC) for predicting 1-, 3-, and 5-year survival rates of patients had the values of 0.796 (95% CI: 0.759-0.833), 0.809 (95% CI: 0.770-0.848), and 0.820 (95% CI: 0.771-0.869), respectively. Furthermore, an external cohort (n=89) was used to validate the nomogram. In conclusion, age, histopathology, IDH status, 1p/19q status, radiotherapy status, chemotherapy status, and tumor progression were identified as independent prognostic factors, on which a visual predictive model was constructed with powerful predictive value.

Abstract As a transcription factor, the role of CASZ1 in different entities is inconsistent. Glioma is one of the leading causes of cancer death worldwide. Its prognostic relevance and biological functions in glioma remain obscure. We focused on the role, mechanism, and prognostic value of CASZ1 in glioma cells. Herein, CASZ1 was identified as a novel potential oncogene in glioma tissues from GEO and TCGA datasets. CASZ1 was highly expressed in glioma tissues, predicting poor prognosis in glioma patients. Knockdown of CASZ1 inhibited proliferation and invasion in vitro, whereas upregulation of CASZ1 presented opposite results. Overexpression of CASZ1 increased transcriptional process of target gene p75NTR. CASZ1 was the potential transcriptional regulators for p75NTR. In addition, the p75NTR expression is essential for CASZ1 to exert its function as an oncogene. Our findings indicate that highly expressed CASZ1 in glioma cells acts as a pro‐oncogene factor in gliomas via regulating transcriptional process of target gene p75NTR, which was identified as an unfavorable prognostic marker in patients with gliomas. CASZ1 is expected to become a novel target for the treatment of gliomas.

Acute myocardial infarction (MI) triggers oxidative stress, which worsen cardiac function, eventually leads to remodeling and heart failure. Unfortunately, effective therapeutic approaches are lacking. Fibroblast growth factor 7 (FGF7) is proved with respect to its proliferative effects and high expression level during embryonic heart development. However, the regulatory role of FGF7 in cardiovascular disease, especially MI, remains unclear. FGF7 expression was significantly decreased in a mouse model at 7 days after MI. Further experiments suggested that FGF7 alleviated MI-induced cell apoptosis and improved cardiac function. Mechanistic studies revealed that FGF7 attenuated MI by inhibiting oxidative stress. Overexpression of FGF7 actives nuclear factor erythroid 2-related factor 2 (Nrf2) and scavenging of reactive oxygen species (ROS), and thereby improved oxidative stress, mainly controlled by the phosphatidylinositol-3-kinase α (PI3Kα)/AKT signaling pathway. The effects of FGF7 were partly abrogated in Nrf2 deficiency mice. In addition, overexpression of FGF7 promoted hexokinase2 (HXK2) and mitochondrial membrane translocation and suppressed mitochondrial superoxide production to decrease oxidative stress. The role of HXK2 in FGF7-mediated improvement of mitochondrial superoxide production and protection against MI was verified using a HXK2 inhibitor (3-BrPA) and a HXKII VDAC binding domain (HXK2VBD) peptide, which competitively inhibits localization of HXK2 on mitochondria. Furthermore, inhibition of PI3Kα/AKT signaling abolished regulation of Nrf2 and HXK2 by FGF7 upon MI. Together, these results indicate that the cardio protection of FGF7 under MI injury is mostly attributable to its role in maintaining redox homeostasis via Nrf2 and HXK2, which is mediated by PI3Kα/AKT signaling.

Background: Hypertrophic scar (HS) is a fibrotic cutaneous disease with few effective therapies. Lycorine is a drug with pro-apoptotic ability and anti-fibrosis potential. This study aimed to test whether lycorine could trigger the apoptosis of hypertrophic scar fibroblasts (HSFs) to inhibit HS formation.Methods: The proapoptotic and anti-fibrosis effects of lycorine on the viability and apoptosis of human primary HSFs and their reactive oxygen species (ROS) production as well as a rabbit ear model of HS were determined by CCK-8, flow cytometry, Western blot, immunofluorescence, transwell migration, collagen gel contraction assays.Results: Lycorine treatment selectively decreased the viability of HSFs, and induced their apoptosis, but not normal fibroblasts (NFs). Lycorine treatment increased the relative levels of Bax and cleaved PARP expression, cytochrome C cytoplasm translocation, but decreased Bcl-2, caspase-3 and caspase-9 expression, the mitochondrial membrane potential (MMP) in HSFs. Lycorine inhibited the migration and contraction of HSFs, and reduced the expression of collagen I, collagen III and α-SMA. Mechanistically, lycorine treatment stimulated high levels of ROS production, leading to apoptosis of HSFs while treatment with NAC, a ROS inhibitor, significantly mitigated or abrogated the pro-apoptotic and antifibrotic activity of lycorine in HSFs. Moreover, lycorine treatment mitigated the severity of HS in rabbit ears by inducing fibroblast apoptosis.Conclusion: These results indicate that lycorine has a potent anti-fibrotic activity and is a potential drug for intervention of HS.

Abstract Background Melon is a very important horticultural crop produced worldwide with high phenotypic diversity. Fruit size is among the most important domestication and differentiation traits in melon. The molecular mechanisms of fruit size in melon are largely unknown. Results Two high-density genetic maps were constructed by whole-genome resequencing with two F2 segregating populations (WAP and MAP) derived from two crosses (cultivated agrestis × wild agrestis and cultivated melo × cultivated agrestis). We obtained 1,871,671 and 1,976,589 high quality SNPs that show differences between parents in WAP and MAP. A total of 5138 and 5839 recombination events generated 954 bins in WAP and 1027 bins in MAP with the average size of 321.3 Kb and 301.4 Kb respectively. All bins were mapped onto 12 linkage groups in WAP and MAP. The total lengths of two linkage maps were 904.4 cM (WAP) and 874.5 cM (MAP), covering 86.6% and 87.4% of the melon genome. Two loci for fruit size were identified on chromosome 11 in WAP and chromosome 5 in MAP, respectively. An auxin response factor and a YABBY transcription factor were inferred to be the candidate genes for both loci. Conclusion The high-resolution genetic maps and QTLs analyses for fruit size described here will provide a better understanding the genetic basis of domestication and differentiation, and provide a valuable tool for map-based cloning and molecular marker assisted breeding.

Abstract Background The mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function. Methods Nrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) –Nrf2–NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules. Results HDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1–Nrf2–Nox4 signaling pathway. Conclusion The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract

Mohammad et al. show that subcutaneous injection of Staphylococcus aureus lipoproteins (Lpp) leads to the infiltration of neutrophils and monocytes/macrophages, inducing skin lesions in mice. They find that S. aureus Lpp promotes abscess formation, which protects bacteria from innate immune killing, suggesting an intriguing bacterial immune evasion mechanism.

Diabetic foot ulcer (DFU) is a complex and devastating complication of diabetes mellitus that are usually stagnant in the inflammatory phase. However, oral wound healing, which is characterized by a rapid and scarless healing process, is regarded an ideal model of wound healing. Thus, we performed a comprehensive bioinformatics analysis of the previously published data regarding oral ulcers and DFUs and found that compared to oral wound healing, the activated pathways of DFUs were enriched in cellular metabolism-related pathways but lacked the activation of inflammatory and immune-related pathways. We also found that CXCL11, DDX60, IFI44, and IFI44L were remarkable nodes since they had the most connections with other members of the module. Meanwhile, CXCL10, IRF7, and DDX58 together formed a closed-loop relationship and occupied central positions in the entire network. The real-time polymerase chain reaction and western blot was applied to validate the gene expression of the hub immune-related genes in the DFU tissues, it was found that CXCL11, IFI44, IFI44L, CXCL10 and IRF7 have a significant difference compared with normal wound tissues. Our research reveals some novel potential immune-related biomarkers and provides new insights into the molecular basis of this debilitating disease.

Septic arthritis, most often caused by Staphylococcus aureus, is a rapidly progressive and destructive joint disease with substantial mortality and morbidity. Staphylococcus aureus lipoproteins (Lpps) are known to induce arthritis and bone destruction. Here, we aimed to investigate the bone resorptive effect of S. aureus Lpps in a murine arthritis model by intra-articular injection of purified S. aureus Lpps, synthetic lipopeptides, and live S. aureus strains. Analyses of the bone mineral density (BMD) of the distal femur bone were performed. Intra-articular injection of both live S. aureus and purified S. aureus Lpps were shown to significantly decrease total- and trabecular BMD. Liquid chromatography–mass spectrometry analyses revealed that the Lpps expressed by S. aureus SA113 strain contain both diacyl and triacyl lipid moieties. Interestingly, synthetic diacylated lipopeptide, Pam2CSK4, was more potent in inducing bone resorption than synthetic triacylated lipopeptide, Pam3CSK4. Modified lipoproteins lacking the lipid moiety were deprived of their bone resorptive abilities. Monocyte depletion by clodronate liposomes fully abrogated the bone resorptive capacity of S. aureus lipoproteins. Our data suggest that S. aureus Lpps induce bone resorption in locally-induced murine arthritis, an effect mediated by their lipid-moiety through monocytes/macrophages.

Abstract Background Full-thickness wounds severely affect patients’ life quality and become challenging problems for clinicians. Stem cells have great prospects in the treatment of wounds. Our previous study confirmed that autologous basal cell suspension could promote wound healing, and epidermal stem cells (ESCs) were detected in the basal cell suspension. Herein, this study aimed to explore the effect of ESCs on full-thickness wounds. Methods Rat ESCs were isolated and expanded and then were transfected with lentivirus to stably express enhanced green fluorescent protein. The experimental rats were randomly divided into 2 groups: in the ESC group, the rat ESCs were sprayed on the full-thickness wounds of rats; in the control group, phosphate-buffered saline was sprayed the on the wounds. Next, wound healing and neovascularization were evaluated. Colonization, division, and differentiation of ESCs on the wound were analyzed by immunofluorescence. Results The rat ESCs colonized, divided, and proliferated in the wound. Additionally, rat ESCs around blood vessels differentiated into vascular endothelial cells and formed a lumen-like structure. Compared with the control group, the ESC group showed enhanced angiogenesis and accelerated wound healing. Conclusions Our study confirmed that rat ESCs are safe and effective for treating full-thickness wounds. Additionally, under certain conditions, ESCs can differentiate into vascular endothelial cells to promote angiogenesis and wound healing.

Narrowband organic photodetectors (OPDs) are attractive for emerging applications. Here, the authors report a simple strategy to produce filter-free narrowband OPDs with outstanding performances by manipulating exciton dissociation with a hierarchical device structure.

Abstract Background Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection. Conclusions Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

Background: Scald burns in the neonate are rare in literature, especially major full-thickness injuries in newborns. However, burns are the third most common cause of accidental death among children in the United States. We hope that this report can provide us a new insight for guiding the timing of surgical treatment and the choice of the surgical scheme in severe burn neonates. Case presentation: In this case report, we demonstrate a case of a three-hour-old neonate, who suffered from severe scald burn injuries of 14% of the total body surface area (TBSA). Nearly two weeks after conservative treatment, the wounds showed no sign of healing. Escharotomy following skin grafting was done after the stabilization of the neonate. The neonate was discharged 32 days after injury. Conclusions: Through the review of this case report, we suggest we should pay attention to the following points. First, we should always pay attention to the blood supply of the extremities of the patient, and appropriately relax the indications for deep fasciotomy to reduce the disability rate. Secondly, we should pay special attention to the respiratory system of the newborn, especially for those after cesarean delivery. Moreover, the early application of broad-spectrum antibiotics should be conducted. Third, we should choose antibiotics with less hepatorenal toxicity, and adjust the dosage according to the body surface area of the neonate. Finally, skin grafting is an appropriate treatment and should be done as soon as possible. Keywords: Scald burns, Neonate

Dry permanent magnetic separators have been widely used in the mineral and coal processing industries due to their simple operation and high separation efficiency. These tools not only discard some amount of bulk gangue from the raw ore, thereby reducing the volume of the grinding operation and cutting energy consumption, but also do not require water in the sorting process, thereby expanding their applicability to arid and cold areas. With the depletion of global iron ore resources, a dry, low-cost processing or pre-sorting prior to the wet separation has received the attention of industrial practitioners as a potential alternative. The performance of dry magnetic separators plays a critical role in dry processing This paper reviews the dry magnetic separators available in the literature and describes their operating principles, separation performance, and applications. A detailed comparison of different separators is also conducted to evaluate the differences in their sorting performance and mechanisms and to provide a reference for the optimization of dry magnetic separators.

Conjugated polyelectrolytes (CPEs) have achieved vast success in organic electronics due to their appealing opt-electrical properties and convenient solution-processability. However, most of the existing n-type CPEs commonly exhibit distinct light capture in visible region. The attainment of novel n-type CPEs possessing both high electron conductivity and high visible light transparency is significant while still challenging. Herein, optimized amount of organic diradicals achieved by benzobisthiadiazo (BBT) unit are intentionally introduced into the backbone of the representative wide-band-gap polyfluorene-based conjugated polyelectrolyte via ternary copolymerization. The incorporation of diradical canonical structure could promote the quinoid resonance of conjugated skeleton, leading to increased self-doping effect. Consequently, the copolymerized CPE exhibits high visible light transmittance (AVT over 85%) and enhanced electron conductivity compared to the referenced CPE. The fabricated organic solar cell devices with the new-designed polyelectrolyte as the cathode interface layer can achieve high power conversion efficiencies of more than 16%, which is not susceptible to the thickness up to 50 nm. This work provides a feasible molecular modification strategy via organic diradicals regulation to obtain high performance n-type self-doped conjugated polyelectrolytes.

BackgroundImmunotherapy is an effective therapeutic approach for multiple human cancer types. However, the correlations between EVA1C and patients’ prognosis as well as immune infiltration remain obscure. Herein, we employed transcriptomic and clinical data extracted from two independent databases to systematically investigate the role of EVA1C in the oncological context.MethodsThe differential expression of EVA1C was analyzed via TCGA and Oncomine databases. We evaluated the influence of EVA1C on clinical prognosis using Kaplan-Meier plotter. We then used the expression profiler to calculate stromal score, immune score, and ESTIMATE score based on the ESTIMATE algorithm. The abundance of infiltrating immune cells was calculated via TIMER. The correlations between EVA1C expression and immune infiltration levels were analyzed in two independent cohorts.ResultsIn patients with World Health Organization (WHO) grade II/III glioma, high EVA1C expression was associated with malignant clinicopathological features and poor overall survival in both cohorts. EVA1C expression was positively associated with immune infiltration levels of B cell, CD4+ T cell, neutrophil, macrophage, and dendritic cells (DCs). Besides, EVA1C expression strongly correlated with diverse immune marker sets. And the predictive power of EVA1C was better than that of other indicators in predicting high immune infiltration levels in glioma.ConclusionsFor the first time, we identified the overexpression of EVA1C in glioma, which was tightly correlated with the high infiltration levels of multiple immune cells as well as poor prognosis. Meanwhile, EVA1C might be a potential biomarker for predicting high immune infiltration in WHO grade II/III gliomas.

Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase β (IKKβC179) and transcription factor p65 (p65C38), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKβC179S and p65C38S mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKβ and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.

Abstract Background Autologous epidermal basal cell suspension therapy has been proven to be one of the most effective treatments for full-thickness wounds. However, we found there remain obvious defects that significantly confined the utilization and function of the epidermal basal cells (EBCs), especially the epidermal stem cells (ESCs) in it. This study investigated whether precoating fibronectin (FN) on the wound bed before spraying EBCs could overcome these defects and further explored its possible mechanisms. Methods In the in vitro study, EBCs were isolated from the donor skin of patients who needed skin grafting. Different concentrations of FN were used to precoat culture dishes before cell culture; the adherent efficiency, proliferation and migration ability of ESCs were analyzed and compared with traditional collagen IV precoating. In the in vivo study, Sprague–Dawley (SD) rats with full-thickness skin wounds were selected as full-thickness wounds’ model. For the experiment groups, 20 μg/ml FN was precoated on the wound bed 10 min before EBC spray. The quality of wound healing was estimated by the residual wound area rate, wound healing time, and hematoxylin and eosin (H&E) staining. Expression of ESC markers, neovascular markers, inflammation markers, and collagen formation and degradation markers was elucidated by immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and RT-qPCR analysis. Results The in vitro study showed that the dishes precoated with 20 μg/ml FN had a similar adherent efficiency and colony formation rate with collagen IV, but it could improve the proliferation and migration of ESCs significantly. Similarly, in the in vivo study, precoating FN on wound bed before EBC spray also significantly promote wound healing by improving ESCs’ utilization efficiency, promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation. Conclusion FN precoating wound bed before EBC spray could significantly promote full-thickness wound healing by improving the utilization and function of the ESCs and further by promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation. Graphical abstract

Summary: Conjugated polymers are emerging as promising organic photocatalysts for hydrogen evolution from water. However, it is still very challenging for conjugated polymers to realize highly efficient photocatalytic hydrogen evolution. Herein, we demonstrate an efficient strategy of hydrophilic side chain functionalization to boost the hydrogen evolution rates of conjugated polymers. By functionalizing conjugated polymers with hydrophilic oligo (ethylene glycol) monomethyl ether (OEG) side chains, a 90-fold improvement in hydrogen evolution rate has been achieved than that of alkyl-functionalized conjugated polymer. It is found that the OEG side chains interact robustly with Pt co-catalysts, resulting in more efficient charge transfer. Moreover, OEG side chains in conjugated polymers can adsorb H+ from water, resulting in significantly lowered energy levels on the surfaces of conjugated polymers, which enables cascade energy levels and enhances charge separation and photocatalytic performance. Our results indicate that rational side-chain engineering could facilitate the design of improved organic photocatalysts for hydrogen evolution. : Polymer Chemistry; Organic Chemistry Methods; Electrochemical Energy Conversion; Polymers Subject Areas: Polymer Chemistry, Organic Chemistry Methods, Electrochemical Energy Conversion, Polymers

We prepared a series of one-dimensional conjugated-material-based nanofibers with different morphologies and donor/acceptor (D/A) compositions by electrospinning for efficient photocatalytic hydrogen evolution. It was found that homogeneous D/A heterojunction nanofibers can be obtained by electrospinning, and the donor/acceptor ratio can be easily controlled. Compared with the single-component-based nanofibers, the D/A-based nanofibers showed a 34-fold increase in photocatalytic efficiency, attributed to the enhanced exciton dissociation in the nanofibrillar body. In addition, the photocatalytic activity of these nanofibers can be easily optimized by modulating the diameter. The results show that the diameter of the nanofibers can be conveniently controlled by the electrospinning feed rate, and the photocatalytic effect increases with decreasing fiber diameter. Consequently, the nanofibers with the smallest diameter exhibit the most efficient photocatalytic hydrogen evolution, with the highest release rate of 24.38 mmol/(gh). This work provides preliminary evidence of the advantages of the electrospinning strategy in the construction of D/A nanofibers with controlled morphology and donor/acceptor composition, enabling efficient hydrogen evolution.

ABSTRACT Septic arthritis, one of the most dangerous joint diseases, is predominantly caused by Staphylococcus aureus. In contrast, coagulase-negative staphylococci are rarely found in septic arthritis. We hypothesize that coagulases released by S. aureus, including coagulase (Coa) and von Willebrand factor-binding protein (vWbp), play potent roles in the induction of septic arthritis. Four isogenic S. aureus strains differing in expression of coagulases (wild-type [WT] Newman, Δcoa, Δvwb, and Δcoa Δvwb) were used to induce septic arthritis in both wild-type and von Willebrand factor (vWF)-deficient mice. Septic arthritis severity was greatly reduced when wild-type mice were infected with the Δcoa Δvwb and Δvwb variants compared to WT or Δcoa strains, suggesting that vWbp rather than Coa is a major virulence factor in S. aureus septic arthritis. vWF-deficient mice were more susceptible to bone damage in septic arthritis, especially when the Δvwb strain was used. Importantly, no difference in arthritis severity between the Δvwb and WT strains was observed in vWF-deficient mice. Collectively, we conclude that vWbp production by S. aureus enhances staphylococcal septic arthritis. IMPORTANCE Septic arthritis remains one of the most dangerous joint diseases with a rapidly progressive disease character. Despite advances in the use of antibiotics, permanent reductions in joint function due to joint deformation and deleterious contractures occur in up to 50% of patients with septic arthritis. So far, it is still largely unknown how S. aureus initiates and establishes joint infection. Here, we demonstrate that von Willebrand factor-binding protein expressed by S. aureus facilitates the initiation of septic arthritis. Such effect might be mediated through its interaction with a host factor (von Willebrand factor). Our finding contributes significantly to the full understanding of septic arthritis etiology and will pave the way for new therapeutic modalities for this devastating disease.

BackgroundComplex hypertrophic scar is a condition that causes multiple joint contractures and deformities after trauma or burn injuries. Three-dimensional (3D) printing technology provides a new evaluation method for this condition. The objective of this study was to print individualized 3D models of complex hypertrophic scars and to assess the accuracy of these models.MethodsTwelve patients with complex hypertrophic scars were included in this study. Before surgery, each patient underwent a computed tomography (CT) scan to obtain cross-sectional information for 3D printing. Mimics software was used to process the CT data and create 3D printed models. The length, width, height, and volume measurements of the physical scars and 3D printed models were compared. Experienced surgeons used the 3D models to plan the operation and simulate the surgical procedure. The hypertrophic scar was completely removed for each patient and covered with skin autografts. The surgical time, bleeding, complications, and skin autograft take rate were recorded. All patients were followed up at 12 months. The surgeons, young doctors, medical students, and patients involved in the study completed questionnaires to assess the use of the 3D printed models.ResultsThe 3D models of the hypertrophic scars were printed successfully. The length, width, height, and volume measurements were significantly smaller for the 3D printed models than for the physical hypertrophic scars. Based on preoperative simulations with the 3D printed models, the surgeries were performed successfully and each hypertrophic scar was completely removed. The surgery time was shortened and the bleeding was decreased. On postoperative day 7, there were two cases of subcutaneous hemorrhage, one case of infection and one case of necrosis. On postoperative day 12, the average take rate of the skin autografts was 97.75%. At the 12-month follow-up, all patients were satisfied with the appearance and function.ConclusionAccurate 3D printed models can help surgeons plan and perform successful operations, help young doctors and medical students learn surgical methods, and enhance patient comprehension and confidence in their surgeons.

This paper focuses on efficiently numerical investigation of two-dimensional heat conduction problems of material subjected to multiple moving Gaussian point heat sources. All heat sources are imposed on the inside of material and assumed to move along some specified straight lines or curves with time-dependent velocities. A simple but efficient moving mesh method, which continuously adjusts the two-dimensional mesh dimension by dimension upon the one-dimensional moving mesh partial differential equation with an appropriate monitor function of the temperature field, has been developed. The physical model problem is then solved on this adaptive moving mesh. Numerical experiments are presented to exhibit the capability of the proposed moving mesh algorithm to efficiently and accurately simulate the moving heat source problems. The transient heat conduction phenomena due to various parameters of the moving heat sources, including the number of heat sources and the types of motion, are well simulated and investigated.

Staphylococcal aureus (S. aureus), a Gram-positive bacteria, is known to cause various infections. Extracellular vesicles (EVs) are a heterogeneous array of membranous structures secreted by cells from all three domains of life, i.e., eukaryotes, bacteria, and archaea. Bacterial EVs are implied to be involved in both bacteria–bacteria and bacteria–host interactions during infections. It is still unclear how S. aureus EVs interact with host cells and induce inflammatory responses. In this study, EVs were isolated from S. aureus and mutant strains deficient in either prelipoprotein lipidation (Δlgt) or major surface proteins (ΔsrtAB). Their immunostimulatory capacities were assessed both in vitro and in vivo. We found that S. aureus EVs induced pro-inflammatory responses both in vitro and in vivo. However, this activity was dependent on lipidated lipoproteins (Lpp), since EVs isolated from the Δlgt showed no stimulation. On the other hand, EVs isolated from the ΔsrtAB mutant showed full immune stimulation, indicating the cell wall anchoring of surface proteins did not play a role in immune stimulation. The immune stimulation of S. aureus EVs was mediated mainly by monocytes/macrophages and was TLR2 dependent. In this study, we demonstrated that not only free Lpp but also EV-imbedded Lpp had high pro-inflammatory activity.

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.

In-silico bitterant prediction received the considerable attention due to the expensive and laborious experimental-screening of the bitterant. In this work, we collect the fully experimental dataset containing 707 bitterants and 592 non-bitterants, which is distinct from the fully or partially hypothetical non-bitterant dataset used in the previous works. Based on this experimental dataset, we harness the consensus votes from the multiple machine-learning methods (e.g., deep learning etc.) combined with the molecular fingerprint to build the bitter/bitterless classification models with five-fold cross-validation, which are further inspected by the Y-randomization test and applicability domain analysis. One of the best consensus models affords the accuracy, precision, specificity, sensitivity, F1-score, and Matthews correlation coefficient (MCC) of 0.929, 0.918, 0.898, 0.954, 0.936, and 0.856 respectively on our test set. For the automatic prediction of bitterant, a graphic program “e-Bitter” is developed for the convenience of users via the simple mouse click. To our best knowledge, it is for the first time to adopt the consensus model for the bitterant prediction and develop the first free stand-alone software for the experimental food scientist.

This paper is concerned about the efficiently numerical simulation of heat conduction problems with multiple heat sources that are allowed to move with different speeds. Based on the dynamical domain decomposition upon the trajectories of moving sources, which are solved by a predictor⁻corrector algorithm, a non-overlapping domain-decomposed moving mesh method is developed. Such a method can not only generate the adaptive mesh efficiently by parallel computing, but also greatly simplify the discretization of the underlying equations without loss of accuracy. Numerical examples for various motions of sources are presented to illustrate the accuracy, the convergence rate and the efficiency of the proposed method. The dependence of the solution on the moving sources such as the types of motion and the distance between sources is numerically investigated. A blow-up phenomenon that occurs at multiple locations simultaneously can also be well observed for the case of symmetrically moving sources.