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Background: Annual influenza vaccination is crucially recommended for the elderly to maintain humoral immunity. Insufficient coverage requires us to understand the determinants of their influenza behaviors and how these patterns impact vaccination choices. Methods: Data from 540 Beijing residents aged over 65 were collected through interviews, capturing vaccination history and sociodemographic details. Individual influenza vaccination records from 2016 to 2020 were obtained from China’s Immunization Information Systems. A latent class model identified three vaccination patterns. Multinomial logistic regression assessed relative risk ratios (RRRs) for vaccination based on sociodemographic factors. Vaccination patterns were used to predict future vaccination likelihood. Results: The analysis revealed three groups: sporadically vaccinated (63.33%), occasionally vaccinated (18.71%), and frequently vaccinated (17.96%). Factors associated with frequent vaccination included age over 70 (RRR = 2.81), lower income (RRR = 0.39), higher vaccine hesitancy (RRR = 3.10), multiple chronic conditions (RRR = 2.72), and rural residence (RRR = 2.48). The frequently vaccinated group was more likely to sustain regular vaccination habits in subsequent years compared to the occasionally vaccinated group. Conclusions: Only 17.96% of Beijing’s older population exhibited a consistent influenza vaccination pattern. Older age, rural residency, and chronic diseases correlated with repeated influenza vaccination. Segmenting the population based on past vaccination behavior can aid in designing targeted interventions to improve vaccination rates.

Background: Osteoporosis is one of the most common bone diseases in middle-aged and elderly populations worldwide. The development of new drugs to treat the disease is a key focus of research. Current treatments for osteoporosis are mainly directed at promoting osteoblasts and inhibiting osteoclasts. However, there is currently no ideal approach for osteoporosis treatment. l-arginine is a semi-essential amino acid involved in a number of cellular processes, including nitric production, protein biosynthesis, and immune responses. We previously reported that l-arginine-derived compounds can play a regulatory role in bone homeostasis. Purpose: To investigate the specific effect of l-arginine on bone homeostasis. Methods: Mildly aged and ovariectomized mouse models were used to study the effects of l-arginine on osteogenesis and angiogenesis, assessed by micro-computed tomography and immunostaining of bone tissue. The effect of l-arginine on osteogenesis, angiogenesis, and adipogenesis was further studied in vitro using osteoblasts obtained from cranial cap bone, endothelial cells, and an adipogenic cell line. Specific methods to assess these processes included lipid staining, cell migration, tube-forming, and wound-healing assays. Protein and mRNA expression was determined for select biomarkers. Results: We found that l-arginine attenuated bone loss and promoted osteogenesis and angiogenesis. l-arginine increased the activity of vascular endothelial cells, whereas it inhibited adipogenesis in vitro. In addition, we found that l-arginine altered the expression of PINK1/Parkin and Bnip3 in the mitochondria of osteoblast-lineage and endothelial cells, thereby promoting mitophagy and protecting cells from ROS. Similarly, l-arginine treatment effectively ameliorated osteoporosis in an ovariectomized mouse model. Conclusion: l-arginine promotes angio-osteogenesis, and inhibits adipogenesis, effects mediated by the PINK1/Parkin- and Bnip3-mediated mitophagy. The Translational Potential of this Article: L-arginine supplementation may be an effective adjunct therapy in the treatment of osteoporosis.

Stress corrosion cracking (SCC) of welded joints is a significant issue that affects the widespread application of multimetal welded structures in aerospace, transportation, and other fields. This paper investigates the effect of laser shock peening (LSP) on the SCC of TC4/2A14 friction stir welded (FSW) joints with dissimilar metals. The microstructural evolution, mechanical properties, and corrosion behavior with and without LSP treatment were investigated using optical microscopy, transmission electron microscopy, X-ray analysis, electrochemical testing, and slow strain rate tensile testing (SSRT). The results showed that the LSP significantly refined the grains and induced work-hardening on the near-surface of the material. After LSP, the compressive residual stresses on the surface of the titanium and aluminium sides were −817.6 MPa and −153.6 MPa for the joint, respectively. Corrosion resistance was also improved, with the self-corrosion current density on the Al side of the joints reduced by 77% and the SCC susceptibility index (Issrt) reduced from 0.140 to 0.121. The enhanced SCC resistance of the LSP-treated TC4/2A14 dissimilar metal FSW joints is primarily due to grain refinement, work-hardening effect, and high-level compressive residual stress. These factors not only enhance the material strength and improve the pitting resistance of the joints but also prevent the initiation and propagation of SCC.

Existing studies have focused on the behavior of the retaining wall equipped with expanded polystyrene (EPS) geofoam inclusions under semi-infinite surcharge loading rather than limited surcharge loading. In this paper, the failure mode and the earth pressure acting on the rigid retaining wall with EPS geofoam inclusions and granular backfills (henceforth referred to as EPS-wall), under limited surcharge loading are investigated through two- and three-dimensional model tests. The testing results show that different from the sliding of almost all the backfill in the EPS-wall under semi-infinite surcharge loading, only an approximately triangular backfill slides in the wall under limited surcharge loading. The distribution of the lateral earth pressure on the EPS-wall under limited surcharge loading is non-linear, and the distribution changes from the increase of the wall depth to the decrease with the increase of the limited surcharge loading. An approach based on the force equilibrium of a differential element is developed to predict the lateral earth pressure behind the EPS-wall subjected to limited surcharge loading, and its performance was fully validated by the three-dimensional model tests.

To achieve all-organic polymer with high dielectric performances, we have designed a novel side-chain liquid crystalline polymer (P7) with strong polar mesogen of (Z)-4-(2-cyano-2-phenylvinyl)benzonitrile (CSCN) attached to polycyclooctene backbone. The bis-cyano-substituted CSCN is board-shaped and exhibits a large dipole moment (8.54 D) which tilts ∼34.2° away from its molecular long axis. Consequently, CSCN shows unique dual molecular anisotropy: one from biaxial shape anisotropy and the other from polarization anisotropy. The complex phase behaviors of P7 were investigated employing mainly the techniques of differential scanning calorimetry and X-ray diffraction. Four liquid crystal (LC) phases are identified as K0, K1, K2 and K3, which are SmA, highly-ordered biaxial SmA, B5-like and B7-like, respectively, with the thermal stability increased in sequence. The experimental results indicate that the different LC phases are arisen from the competition and balance between π-π stacking and dipole-dipole interaction. While the face-to-face π-π stacking is dominant in K0 and K1, optimizing the dipole-dipole interaction causes the CSCN mesogens within the smectic layer to tilt and rotate, resulting in K2 and K3. We further investigated the dielectric properties of P7 films using polarization-electric field loops test. The dielectric constant (εr) of P7 is found to be LC structure dependent, which is increased when the LC phase is varied from K0 to K3. With an average εr of 9.7 achieved in K3 and the low dielectric loss (tan δ = 0.001), P7 film offers a promising material in advanced applications like energy storage and electronic devices.

Background: Chronic pelvic pain (CPP) in women is a critical challenge. Due to the complex etiology and difficulties in diagnosis, it has a greatly negative impact on women's physical and mental health and the healthcare system. At present, there is still a lack of research on the related factors and predictive models of chronic pelvic pain in women. Our study aims to identify risk factors associated with chronic pelvic pain in women and develop a predictive nomogram specifically tailored to high-risk women with CPP. Materials and methods: From May to October 2022, trained interviewers conducted face-to-face questionnaire surveys and pelvic floor surface electromyography assessments on women from community hospitals in Nanjing. We constructed a multivariate logistic regression-based predictive model using CPP-related factors to assess the risk of chronic pelvic pain and create a predictive nomogram. Both internal and external validations were conducted, affirming the model's performance through assessments of discrimination, calibration, and practical applicability using area under the curve, calibration plots, and decision curve analysis. Results: 1108 women were recruited in total (survey response rate:1108/1200), with 169 (15.3 %) being diagnosed as chronic pelvic pain. Factors contributing to CPP included weight, dysmenorrhea, sexual dysfunction, urinary incontinence, a history of pelvic inflammatory disease, and the surface electromyography value of post-baseline rest. In both the training and validation sets, the nomogram exhibited strong discrimination abilities with areas under the curve of 0.85 (95 % CI: 0.81–0.88) and 0.85 (95 % CI: 0.79–0.92), respectively. The examination of the decision curve and calibration plot showed that this model fit well and would be useful in clinical settings. Conclusions: Weight, dysmenorrhea, sexual dysfunction, history of urinary incontinence and pelvic inflammatory disease, and surface electromyography value of post-baseline rest are independent predictors of chronic pelvic pain. The nomogram developed in this study serves as a valuable and straightforward tool for predicting chronic pelvic pain in women.

Background: Ultrafine particle (UFP) has been linked with higher risks of cardiovascular diseases; however, the biological mechanisms remain to be fully elucidated. Objectives: This study aims to investigate the cardiovascular responses to short-term UFP exposure and the biological pathways involved. Methods: A longitudinal panel study was conducted among 32 healthy, non-smoking young adults in Shanghai, China, who were engaged in five rounds of follow-ups between December 2020 and November 2021. Individual exposures were calculated based on the indoor and outdoor real-time measurements. Blood pressure, arterial stiffness, targeted biomarkers, and untargeted proteomics and metabolomics were examined during each follow-up. Linear mixed-effect models were applied to analyze the exposure and health data. The differential proteins and metabolites were used for pathway enrichment analyses. Results: Short-term UFP exposure was associated with significant increases in blood pressure and arterial stiffness. For example, systolic blood pressure increased by 2.10 % (95 % confidence interval: 0.63 %, 3.59 %) corresponding to each interquartile increase in UFP concentrations at lag 0–3 h, while pulse wave velocity increased by 2.26 % (95 % confidence interval: 0.52 %, 4.04 %) at lag 7–12 h. In addition, dozens of molecular biomarkers altered significantly. These effects were generally present within 24 h after UFP exposure, and were robust to the adjustment of co-pollutants. Molecular changes detected in proteomics and metabolomics analyses were mainly involved in systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and disturbance in lipid transport and metabolism. Discussion: This study provides novel and compelling evidence on the detrimental subclinical cardiovascular effects in response to short-term UFP exposure. The multi-omics profiling further offers holistic insights into the underlying biological pathways.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients’ poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

Background: Ovarian cancer, as a highly malignant tumor, features the critical involvement of tumor-associated fibroblasts in the ovarian cancer tissue microenvironment. However, due to the apparent heterogeneity within fibroblast subpopulations, the specific functions of these subpopulations in the ovarian cancer tissue microenvironment remain insufficiently elucidated. Methods: In this study, we integrated single-cell sequencing data from 32 ovarian cancer samples derived from four distinct cohorts and 3226 bulk RNA-seq data from GEO and TCGA-OV cohorts. Utilizing computational frameworks such as Seurat, Monocle 2, Cellchat, and others, we analyzed the characteristics of the ovarian cancer tissue microenvironment, focusing particularly on fibroblast subpopulations and their differentiation trajectories. Employing the CIBERSORTX computational framework, we assessed various cellular components within the ovarian cancer tissue microenvironment and evaluated their associations with ovarian cancer prognosis. Additionally, we conducted Mendelian randomization analysis based on cis-eQTL to investigate causal relationships between gene expression and ovarian cancer. Results: Through integrative analysis, we identified 13 major cell types present in ovarian cancer tissues, including CD8+ T cells, malignant cells, and fibroblasts. Analysis of the tumor microenvironment (TME) cell proportions revealed a significant increase in the proportion of CD8+ T cells and CD4+ T cells in tumor tissues compared to normal tissues, while fibroblasts predominated in normal tissues. Further subgroup analysis of fibroblasts identified seven subgroups, with the MMP11+Fib subgroup showing the highest activity in the TGFβ signaling pathway. Single-cell analysis suggested that oxidative phosphorylation could be a key pathway driving fibroblast differentiation, and the ATRNL1+KCN + Fib subgroup exhibited chromosomal copy number variations. Prognostic analysis using a large sample size indicated that high infiltration of MMP11+ fibroblasts was associated with poor prognosis in ovarian cancer. SMR analysis identified 132 fibroblast differentiation-related genes, which were linked to pathways such as platinum drug resistance. Conclusions: In the context of ovarian cancer, fibroblasts expressing MMP11 emerge as the primary drivers of the TGF-beta signaling pathway. Their presence correlates with an increased risk of adverse ovarian prognoses. Additionally, the genetic regulation governing the differentiation of fibroblasts associated with ovarian cancer correlates with the emergence of drug resistance.

Land-sea atmosphere interaction (LSAI) is one of the important processes affecting ozone (O3) pollution in coastal areas. The effects of small-scale LSAIs like sea-land breezes have been widely studied. However, it is not fully clear how and to what extent the large-scale LSAIs affect O3 pollution. Here we explored an O3 episode to illuminate the role of large-scale LSAIs in O3 pollution over the Bohai–Yellow Seas and adjacent areas through observations and model simulations. The results show that the northern Bohai Sea's coastal region, influenced by the Mongolian High, initially experienced a typical unimodal diurnal O3 variation for three days, when O3 precursors from Beijing–Tianjin–Hebei, Shandong, and Northeast China were transported to the Bohai–Yellow Seas. Photochemical reactions generated O3 within marine air masses, causing higher O3 levels over the seas than coastal regions. As the Mongolian High shifted eastward and expanded, southerly winds on its western edge transported O3-rich marine air masses toward the coast, prolonging pollution for an additional three days and weakening diurnal variations. Subsequently, emissions from the Korean Peninsula and marine shipping significantly affected O3 levels in the northern Bohai Sea (10.7% and 13.7%, respectively). Notably, Shandong's emissions played a substantial role in both phases (27.5% and 26.1%, respectively). These findings underscore the substantial impact of large-scale LSAIs driven by the Mongolian High on O3 formation and pollution duration in coastal cities. This insight helps understand and manage O3 pollution in northern Bohai Sea cities and broadly applies to temperate coastal cities worldwide.

Summary: Eosinophilic chronic rhinosinusitis (ECRS) is a distinct subset of chronic rhinosinusitis characterized by heightened eosinophilic infiltration and increased symptom severity, often resisting standard treatments. Traditional diagnosis requires invasive histological evaluation. This study aims to develop predictive models for ECRS based on patient clinical parameters, eliminating the need for invasive biopsy. Utilizing logistic regression with lasso regularization, random forest (RF), gradient-boosted decision tree (GBDT), and deep neural network (DNN), we trained models on common clinical data. The predictive performance was evaluated using metrics such as area under the curve (AUC) for receiver operator characteristics, decision curves, and feature ranking analysis. In a cohort of 437 eligible patients, the models identified peripheral blood eosinophil ratio, absolute peripheral blood eosinophil, and the ethmoidal/maxillary sinus density ratio (E/M) on computed tomography as crucial predictors for ECRS. This predictive model offers a valuable tool for identifying ECRS without resorting to histological biopsy, enhancing clinical decision-making.

Background: There is currently no consensus regarding the optimal perioperative antiplatelet strategy for carotid artery surgery. This multicentre study aimed to analyse the association between preoperative aspirin monotherapy following postoperative dual antiplatelet therapy (DAPT) and the risk for stroke and death after carotid endarterectomy (CEA). Methods: This cohort study included 821 patients with carotid artery stenosis who underwent CEA. Primary outcomes included any stroke or death up to the one-month postoperative follow-up. Multilevel multivariate regression analyses and descriptive statistics were performed. Results: Patients were predominantly male (53 %), with a mean age of 66.2 years. The primary outcome occurred in 1.6 % of patients. Univariate and multivariate analyses revealed that patients with chronic obstructive pulmonary disease (COPD) exhibited a high risk for stroke or death (P = 0.011). The occurrence of any local complications in the neck was accompanied by an increase in diastolic blood pressure (DBP) (P = 0.007). Patients with a high systolic blood pressure (SBP) (P = 0.002) experienced a longer operative duration. The length of hospital stay was longer in the patients with COPD (P = 0.020), minor stroke (P = 0.011), and major stroke (P = 0.001). A positive linear correlation was found between SBP and operative duration in the overall population (β 0.4 [95 % confidence interval (CI) 0.1–0.7]; P = 0.002). The resultant curve for DBP and any local complications in the neck exhibited a two-stage change and one breakpoint in the entire population (k = 68 mmHg,

Objective: Our study aimed to elucidate the effect of PAI-1 (Plasminogen Activator Inhibitor-1) and t-PA (Tissue-type Plasminogen Activator) in tissue remodeling in nasal polyps patients. Methods: Samples were streamed as early Nasal Polyps (eNP, n = 10) and inferior tissue from the same patient, mature Nasal Polyps (mNP, n = 14), and Control group (n = 15), respectively. Immunohistochemistry and immunofluorescence were applied to detect localization. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot were used to measure different levels among three groups. The mNP tissue was cultured in vitro and treated with TGF-β1 (Transforming Growth Factor-beta 1) activator, TGF-β1 inhibitor (SB431542), and PAI-1 inhibitor (TM5275); then Western blot, qRT-PCR, and ELISA were used to assess changes. Results: The immunohistochemistry and immunofluorescence showed that PAI-1 expression decreased in eNP and mNP, mainly in epithelium and glands. The transcriptional expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 were lower in eNP than IT while mNP group demonstrated lower mRNA expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 than Control group. In mNP tissue culture in vitro, TGF-β1 activator elevated t-PA, PAI-1, and Collagen1 with higher release of PAI-1 and Collagen1 in supernatant, whereas SB431542 suppressed above reactions; TM5275 lowered transcriptional and protein level of Collagen1 in supernatant. Conclusion: Early Nasal polyps’ formation in middle meatus mucous is related with fibrillation system PAI-1/t-PA and tissue remodeling; moreover, nasal polyps’ development is regulated by TGF-β1-mediated PAI-1 reduction. Level of evidence: 3b.

Background: Coronavirus disease 2019(COVID-19) caused a large number of infections worldwide. Although some patients recovered from the disease, some of the other problems that accompanied it, such as cardiac injury, could affect the patient's subsequent quality of life and prognosis. Objectives: To clarify the molecular mechanism of cardiac injury in SARS-CoV-2 Infection. Methods: The RNA-Seq dataset (GSE184715) comparing expression profiling of Mock human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and SARS-CoV-2-infected hiPSC-CMs was downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes(DEGs) were performed by the R software. Degs were analyzed by enrichment analysis to clarify the affected pathways. Hub genes were screened out by a PPI network constructed from Degs. Finally, Connectivity Map was used to screen for the treatment of COVID-19 induced cardiac injury. Results: 2705 differentially expressed genes were identified. Enrichment analysis confirmed that mitochondrial dysfunction was caused by SARS-CoV-2, meanwhile, cardiac muscle contraction was suppressed and NF-κB was activated. Based on the PPI network, 15 hub genes were identified. These 15 down-regulated hub genes were mainly involved in the reduced activity of complexes in the mitochondrial respiratory chain associated with mitochondrial dysfunction. Moreover, 5 candidate drugs were identified to treat cardiac injury. Conclusion: In conclusion, SARS-CoV-2 infection of cardiomyocytes causes mitochondrial dysfunction, including reduced mitochondrial respiratory chain complex activity and decreased ATP synthesis, leading to cardiomyocyte apoptosis, while the activated NF-κB also induced cytokine storms, ultimately resulting in cardiac injury.

As a crucial external capital force of enterprises, common institutional ownership plays an essential role in enterprise innovation and development. However, few studies have focused on the impact and underlying impact mechanisms of common institutional ownership on the digital transformation of enterprises. Hence, this study uses Python to analyse the annual reports of listed companies from 2007 to 2021 and constructs measures of enterprise digital transformation. Then, based on panel fixed effects Poisson regression, this study examines the influence of common institutional ownership on enterprise digital transformation by using theoretical logic and empirical evidence. The results reveal that common institutional ownership significantly inhibits enterprise digital transformation; this result remains valid after a series of endogeneity and robustness tests, thereby indicating that common institutional ownership exerts a collusion fraud effect. The mechanism analysis shows that common institutional ownership hampers enterprise digital transformation mainly by increasing monopoly power within the market, aggravating information asymmetry between enterprise insiders and outsiders, and intensifying executive self-dealing. Further analysis reveals that the inhibitory effect of common institutional ownership on digital transformation is more significantly negative in the case of non-state-owned enterprises versus state-owned enterprises. This study expands the research on the factors influencing enterprise digital transformation. The results provide a helpful reference for further improving institutional investors’ ownership structures and promoting high-quality enterprise development.

This article reports a case of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) misdiagnosed as Kawasaki disease and summarizes the clinical features and therapeutic progress of TRAPS and the relationship between its clinical manifestations and gene mutations. We retrospectively analyzed a patient with tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) -mutated auto-inflammatory disease who was misdiagnosed with Kawasaki disease in another hospital. The clinical features and therapeutic progress of TRAPS were analyzed by combining clinical features and gene reports of this case and literature review. TRAPS onset occurred in a female pediatric patient at the age of 4 months. The child and in his father at the age of 6 years, both of whom manifested periodic fever, and recurrent rash, as well as elevated leukocytes, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during episodes but normal between episodes. This child carried a heterozygous mutation in TNFRSF1A located in the region 6442923–6442931 on chromosome 12. The nucleic acid alteration was: c.298 (exon3) _c.306 (exon3) 291 delCTCAGCTGC, resulting in a 3 amino acid deletion p.L100_C 102del 292 (p.Leu100_Cys102del) (NM_001065). After etanercept treatment, the symptoms of fever and rash disappeared, and the levels of ESR, CRP, interleukin (IL)-1, IL-6, and TNF-α levels were normal. Subsequently, no liver, kidney, or cardiac amyloidosis and severe etanercept-related adverse events were observed at 1-year follow-up. TRAPS pathogenesis is associated with TNFRSF1A mutation, which is characterized by periodic episodes of fever, mostly accompanied by recurrent rashes, periorbital edema, abdominal pain, and serious complications of organ amyloidosis. Moreover, etanercept can effectively alleviate the clinical symptoms and high inflammation level of TRAPS.

Summary: Hotspots in electronic devices can cause overheating and reduce performance. Enhancing the thermal spreading ability is critical for reducing device temperature to improve the reliability. However, as devices shrink, phonon ballistic effects can increase thermal resistance, making conventional optimization methods less effective. This paper presents a topology optimization method that combines the phonon Boltzmann transport equation with solid isotropic material with penalization method to optimize high thermal conductivity (HTC) material distributions for thermal spreading problems. Results show that the contraction-expansion structure can effectively reduce thermal resistance. Optimal distributions differ from that based on Fourier’s heat conduction law, and only the trunk structure appears in optimized layouts due to the size effect. Additionally, HTC material with longer mean free paths tends to be filled around the heat source with a gap in a ballistic-diffusive regime. This work deepens understanding of thermal spreading and aids in thermal optimization of microelectronic chips.

Intelligent manufacturing offers opportunities for green technology innovation at a low cost, helps eliminate outdated equipment, and improves pollution efficiency, which is essential for environmental protection. From the perspective of the industrial sector, based on the data of 269 Chinese cities, this study empirically examines the impacts of intelligent manufacturing on ecological environment using the fixed effect model and unconditional quantile model. The research results show that intelligent manufacturing can significantly reduce the concentration of PM2.5 in the air and environmental pollution by optimizing resource allocation during production and operation. The results of the external mechanism show that green technological innovation plays a positive mediating role in the impact mechanism of intelligent manufacturing to improve air quality. The marginal impact of intelligent manufacturing on environmental pollution is nonlinear, and the main trend is the M-type distribution trend of increasing first, then decreasing, and then rising. In particular, intelligent manufacturing has a greater welfare effect on the ecological environment at the lower quantiles. The results provide a viable path for the government to actively plan a strategic layout to improve the ecological environment and achieving the goal of high-quality economic development.

Based on the first principles calculation method, we explored the impacts of p-type doping on the electronic characteristics of Al0.5Ga0.5N nanowire. Firstly, Al0.5Ga0.5N nanowires are simulated with different doping elements (Be, Mg and Zn), as well as different doping strategies (interstitial doping and substitutional doping). The estimated formation energies show that the p-type doping of Al0.5Ga0.5N nanowire is an endothermic process. Also, in the substitutional doping process, it is easier for dopant atoms to replace Ga atoms than Al atoms. The substitutional doping of Mg atom drops the nanowire electron affinity obviously, which promotes the transition of surface photoelectrons. Furthermore, it can be concluded that the substitutional doping contributes to the Fermi level cross the valence band and causing the nanowires to exhibit distinct p-type properties. Also, the charge density maps show that for Be and Mg substitutional doping system, the electron density around the dopant significantly decreases, which further verifies the p-type conductivity. Meanwhile, the p-type characteristic of Mg atom substitution doping is the most obvious. This work not only thoroughly explored the impacts of different doping schemes on the electronic characteristics of Al0.5Ga0.5N nanowires but also serves as a significant resource for developing high-quality p-type AlxGa1-xN nanowire photocathodes.

Abaqus is a commercial software suite for numerical simulation and ParaView is an open-source software application for 3D scientific data visualization. While the Abaqus suite provides Abaqus/Viewer for post-processing, it is not open-source, and custom visualization features can only be implemented using Abaqus official APIs (e.g., Python APIs). ParaView has a robust rendering pipeline, such that complicated post-processing operations can be implemented using filters. Due to ParaView’s openness and plugin architectures, highly tailored data processing and visualization are made possible. However, visualizing Abaqus output database (.odb extension) in ParaView is a nontrivial task. ODB files are proprietary binary files that can only be read by Abaqus. Without reverse engineering, the option is to extract data from ODB files using Abaqus’ official APIs (C++ or Python) and write them to a file format compatible with ParaView. There have been some efforts to achieve this, but none of them are satisfactory in terms of extensibility and generality. Our converter is designed to address this issue by providing a compact, robust, and extensible solution for converting Abaqus ODB files to a format that can be read by ParaView. Our converter stands out due to the following benefits: (1) It can handle a variety of element types, including linear elements, high-order elements, and elements with multiple integration or section points; (2) It extracts data at integration and section points; (3) It includes a separate script that utilizes Python multiprocessing; (4) A C++ version is also provided, which offers a significant increase in speed compared to the Python version.

In our previous paper, we derived a new single bubble model including the effect of bulk viscosity. To confront it to experiments, single bubble dynamics was measured here in 30% (v/v) glycerol-water mixture under different acoustic amplitudes and compared to models including or not the effect of bulk viscosity. The results showed that calculated bubble dynamics were not significantly affected by the bulk viscosity within the experimental conditions used in this study. However, there was a noticeable delay for the first rebound when bulk viscosity was considered. The corresponding sonoluminescence intensities were collected and compared with theoretical predictions. The results did not allow to discriminate between the two models (one includes the effect of bulk viscosity, the other does not), confirming the negligible effect of bulk viscosity in this condition (30% (v/v) glycerol-water mixture). Due to the instability of a single bubble in higher viscosity solutions, we could not implement experiments that can discriminate between the two models.

Although fine particulate matter (PM2.5) is a neurotoxicant, little is known about whether early-life PM2.5 exposure is associated with an increased risk of developmental coordination disorder (DCD). We conducted a cohort study of 109 731 children aged 3–5 years from 551 county-level cities in China between April 2018 and December 2019. Residential PM2.5 exposure was estimated using a hybrid satellite-based exposure model. Children’s motor performance was assessed using the Little DCD Questionnaire (LDCDQ). Linear mixed-effect models and generalized linear mixed models with a binomial distribution were used to examine the associations of PM2.5 exposure with LDCDQ scores and risk of DCD, respectively. Both prenatal and postnatal exposure to a higher level of PM2.5 was significantly associated with reduced total LDCDQ score, and the impacts were evident on subscales of control during movement and general coordination function but not fine motor function. For example, an interquartile range increase in PM2.5 exposure in ages 0–3 was associated with a 0.19 (95% confidence interval [CI]: 0.05, 0.33) decrement in the total score. Additionally, higher PM2.5 exposure was associated with increased risk of DCD, and the adjusted odds ratios were 1.06 (95% CI: 1.01, 1.10) and 1.06 (95% CI: 1.01, 1.13) for each interquartile range increase in PM2.5 exposure during the first trimester and the first 3 years, respectively. Children who were from rural areas, had neonatal intensive care unit admission, or were exclusively breastfed for less than 6 months appeared to be more susceptible to PM2.5 exposure than their counterparts. Our findings provide robust evidence that early-life PM2.5 exposure contributes to an elevated risk of DCD.

Background: Biometric parameters play an important role in studies on myopia. This study aimed to explore the application of a commercially available two-dimensional visualized swept-source optical coherence tomography (OCT) system, for in vivo biometric measurement in multiple myopia model species. Methods: In this study, chickens, guinea pigs, and C57BL/6 mice underwent eye imaging with the commercially available OCT (CASIA2), and the original images were used to calculate the central corneal thickness, anterior chamber depth (ACD), lens thickness (LT), vitreous chamber depth (VCD), and axial length (AL). The retinal thickness and choroidal thickness were also calculated in chicken eyes. The repeatability of the biometric measurement outcomes was analyzed. Results: Excellent repeatable AL measurements were obtained for all three species, with an intraclass correlation coefficient (ICC) of ≥0.941 and a within-subject standard deviation of ≤0.055. Excellent repeatability was found in chicken eyes for ACD, LT, and VCD, with an ICC of ≥0.932; in guinea pig eyes for ACD and VCD, with an ICC of ≥0.934; and in mouse eyes for LT, with an ICC of ≥0.941. Conclusions: It is effective to use commercially available OCT to measure biometric parameters in chickens, guinea pigs, and C57BL/6 mice. This methodology could potentially increase the accuracy and efficiency of future myopia animal experiments.

The incidence rate of human uterine leiomyomas is over 70% in the women of childbearing age, which has caused serious health and financial burden. Our previous study confirmed that Bisphenol A (BPA)，representative environmental estrogen, promoted the proliferation of human uterine leiomyomas and up-regulated the expression of cell proliferation-related genes. In this study, by combining ChIP-seq and RNA-seq, it was shown that after BPA intervention, H3K27ac modification levels and gene expression levels were altered in uterine leiomyomas cells. Moreover experimental verification found that BPA can regulate ITGA2 through the transcription factor XBP1, activate the downstream PI3K/AKT signaling pathway, eventually promote the proliferation of uterine leiomyomas. The present study provides new insights into the pathogenesis associated with exposure to BPA and other endocrine disruptors with similar effects by defining XBP1 as an important regulator, and which may act as an intervention and treatment target for uterine leiomyomas.

Breast cancer metastases to the bone can lead to a series of bone-related events that seriously affect the quality of life. Pexmetinib, a novel p38 mitogen-activated protein kinase (p38) inhibitor that has been evaluated in phase I clinical trials for myelodysplastic syndrome, but the effects of Pexmetinib on breast cancer induced osteolysis haven’t been explored. Here, we found that Pexmetinib inhibited receptor activator of nuclear factor-κB ligand-induced osteoclast formation and bone resorption in vitro. Pexmetinib suppressed p38-mediated signal transducer and activator of transcription 3 (STAT3), which direct regulated transcription of the nuclear factor of activated T cells 1 (NFATc1), leading to reduced osteoclast formation. Moreover, Pexmetinib exerted anti-tumor effects in breast cancer cells in vitro via suppressing p38-mediated STAT3 activation and matrix metalloproteinases (MMPs) expression. Furthermore, Pexmetinib suppressed breast cancer-associated osteolysis in vivo. These results suggest that Pexmetinib may be a promising drug for the treatment of breast cancer-induced osteolysis.

While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population remains affected by HIV-associated neurocognitive disorder (HAND). C-C chemokine receptor 5 (CCR5) has been well studied in immune response and as a co-receptor for HIV infection. HIV-infected (HIV+) patients experienced mild to significant amelioration of cognitive function when treated with different CCR5 antagonists, including maraviroc and cenicriviroc. Consistent with clinical results, Ccr5 knockout or knockdown rescued cognitive deficits in HIV animal models, with mechanisms of reduced microgliosis and neuroinflammation. Pharmacologic inhibition of CCR5 directly improved cerebral and hippocampal neuronal plasticity and cognitive function. By summarizing the animal and human studies of CCR5 in HIV-associated cognitive deficits, this review aims to provide an overview of the mechanistic role of CCR5 in HAND pathophysiology. This review also discusses the addition of CCR5 antagonists, such as maraviroc, to cART for targeted prevention and treatment of cognitive impairments in patients infected with HIV.

Depolymerization of lignin can yield phenolic monomeric platform molecules, but depolymerization and repolymerization are proposed as concurrent processes, which greatly limit the yield of monomeric products. Molecular-level characterization of heavy intermediates during depolymerization process is crucial for developing efficient methods to depolymerize raw lignin into monomers. In this study, a reactor-integrated negative-ion electrospray ionization high-resolution mass spectrometry was used to real-time analyze the lignin depolymerization process under operando conditions. Elemental composition, structural information as well as time-resolved evolution of a series of dimers and oligomers were obtained, which is hard to achieve with traditional GC-MS methods. The real-time evolution profiles of monomers, dimers, and oligomers reveals a possible repolymerization process during lignin depolymerization. These results provide insight into the complex lignin depolymerization process.

A model of cavitation bubbles is derived in liquid confined in an elastic sealed vessel driven by ultrasound. In this model, an assumption that the pressure acting on the sealed vessel due to bubble pulsations is proportional to total volume change of bubbles is made. Numerical simulations are carried out for a single bubble and for bubbles. The results show that the pulsation of a single bubble can be suppressed to a large extent in sealed vessel, and that of two matched bubbles with same ambient radius can be further suppressed. However, when two mismatched bubbles have the same ambient radii, an interesting breathing phenomenon takes place, where one bubble pulsates inversely with the other one. Due to this breathing phenomenon the suppression effect becomes weak, so the maximum radii of two mismatched bubbles can be larger than that of a single bubble or that of two matched bubbles in sealed vessel. Besides that, for two mismatched bubbles with different ambient radii, the small one in sealed vessel under some certain parameters can pulsate as strong as or even stronger than that of a single bubble in an open vessel.

Background & Objectives: Coagulation test results in clinical laboratories are released after manual verification, which increases the laboratory turnaround time (TAT). The purpose of this study was to establish auto-verification rules for routine coagulation tests that can reduce the laboratory TAT as well as ensure the accuracy of results. Methods: Auto-verification rules were established for six routine coagulation tests, i.e., prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen (FIB), fibrin/fibrinogen degradation product, and D-Dimer. Data were collected from nine centers and the auto-verification rules were designed with reference to CLSI Auto 10A guidelines, which included quality control (QC) status check, consistency check (checking whether sample test assays match the medical order or if results are in correct numerical form), sample quality check, alarm check, critical value check, delta check, limit range check, and logical rules check. The auto-verification rules were then assessed based on passing rate, true-positive rate, true-negative rate, false-positive rate, and false-negative rate. The efficiency of the auto-verification rules was evaluated by TAT. Results: From January 2020 to March 2020, 22,072 coagulation results were collected from nine hospitals for establishing auto-verification rules. The preliminary evaluation of the rules was a simulation validation with data from the rule-generating group, and the passing rate was 69.5% with no false-negative cases. In phase I evaluation, a total of 32,743 results were randomly collected from four hospitals. The overall auto-verification rate was 66.7% (true-positive rate 100.0%; true-negative rate 82.5%; false-positive rate 17.6%; false-negative rate 0%). The phase II evaluation was based on validation of results of actual samples. Auto-verification rules were configured in a middleware (HemoHub) and 14,642 samples results were verified by the auto-verification rules. The overall passing rate was 69.5%. Auto-verification significantly decreased the mean laboratory TAT from 90.8 min to 71.8 min (P = 0.006). Conclusion: This study established auto-verification rules for routine coagulation tests based on Werfen coagulation instrument. Use of auto-verification rules significantly improved the laboratory TAT and workflow. This study provides insights and methods for establishing auto-verification rules.

Understanding the interface effect in dielectric nanocomposites is crucial to the enhancement of their performance. In this work, a data-driven interface design strategy based on high-throughput phase-field simulations is developed to study the interface effect and then optimize the permittivity and breakdown strength of nanocomposites. Here, we use two microscopic features that are closely related to the macroscopic dielectric properties, the thickness and permittivity of the interface phases, to evaluate the role of interfaces in experimental configuration, and thus provide quantitative design schemes for the interfacial phases. Taking the polyvinyl difluoride (PVDF)BaTiO3 nanocomposite as an example, the calculation results demonstrate that the interfacial polarization could account for up to 83.6% of the increase in the experimentally measured effective permittivity of the nanocomposite. Based on the interface optimized strategy, a maximum enhancement of ∼156% in the energy density could be achieved by introducing an interface phase with d/r = 0.55 and εinterface/εfiller=0.036, compared to the pristine nanocomposite. Overall, the present work not only provides fundamental understanding of the interface effect in dielectric nanocomposites, but also establishes a powerful data-driven interface design framework for such materials that could also be easily generalized and applied to study interface issues in other functional nanocomposites, such as solid electrolytes and thermoelectrics.

A combined dam structure using different concrete materials offers many practical benefits. There are several real-world cases where large-volume heterogeneous concrete materials have been used together. From the engineering design standpoint, it is crucial to understand the deformation coordination characteristics and mechanical properties of large-volume heterogeneous concrete, which affect dam safety and stability. In this study, a large dam facility was selected for a case study, and various design schemes of the combined dam structure were developed by changing the configurations of material zoning and material types for a given dam shape. Elastoplastic analysis of the dam-foundation-reservoir system for six schemes was carried out under dynamic conditions, in which the concrete damaged plasticity (CDP) model, the Lagrangian finite element formulation, and a surface-to-surface contact model were utilized. To evaluate the mechanical properties of zoning interfaces and coordination characteristics, the vertical distribution of the first principal stress at the longitudinal joint was used as the critical index of deformation coordination control, and the overall deformation and damage characteristics of the dam were also investigated. Through a comparative study of the design schemes, an optimal scheme of the combined dam structure was identified: large-volume roller-compacted concrete (RCC) is recommended for the dam body upstream of the longitudinal joint, and high-volume fly ash conventional concrete (CC) for the dam body downstream of the longitudinal joint. This study provides engineers with a reference basis for combined dam structure design.

This research aims to analyze the differences in bone healing rate, cytokines content, and growth factor content in rats with fracture and traumatic brain injury. In this study, rat models of tibial fracture (fracture group) and tibial fracture combined with brain injury (combined group) were first constructed. Callus and brain tissue sections of the two groups of rat models were made, and the pathological changes were analyzed by hematoxylin – eosin staining. Tissue sections were made to compare the differences in callus volume, trabecular width, and trabecular bone ratio between the two groups of rats. Taking normal rats as controls, serum samples were collected from rats in the control group, fracture group, and combined group. The differences of levels in nerve growth factor (NGF), insulin-like growth factor 1 (IGF1), bone morphogenetic protein 7 (BMP7), and transforming growth factor β1 (TGFβ1) in serum of different groups of rats were detected by enzyme-linked immunosorbent assay, and the expression of NGF, IGF 1, BMPR7, and TGFβR1 in rat callus was detected by Western-Blot. It was found that the rate of bone healing in the combined group was faster than that in the fracture group. The bone callus volume, trabecular width, and trabecular proportion of the rats in the combined group were significantly higher than those in the fracture group (P

Bulk-type all-solid-state batteries (ASSBs) using sulfide solid electrolyte are considered as a promising alternative to commercial lithium-ion batteries owing to their high energy density and safety. However, cell energy density is often comparatively low due to use of a thick solid electrolyte separator and a lithium alloy as anode. For achieving high-performance ASSBs, creating a thin free-standing electrolyte with high-conductivity and good cycling stability against lithium anode is essential. In this work, we present Li6PS5Cl/poly(vinylidene difluoride) (LPSCl/PVDF) composite electrolytes prepared by a slurry method. The influence of the PVDF content on the microstructure, morphology, ionic conductivity and activation energy of the LPSCl/PVDF electrolytes is systematically investigated. Free-standing LPSCl/PVDF membranes with a thickness of 100–120 μm and a high ionic conductivity of about 1·10−3 S cm−1 at 25 °C are obtained. After adding PVDF to the LPSCl electrolyte, the cycling stability of the LPSCl electrolyte against lithium metal improves significantly. Therefore, LPSCl/PVDF composite electrolytes are promising candidates to be used in ASSBs. Keywords: Composite solid electrolyte, Li6PS5Cl, Poly(vinylidene difluoride)

Osteosarcoma frequently presents as recurrence and metastasis, even if the primary lesion was eradicated and/or radiotherapy and chemotherapy were administered. Osteosarcoma cancer stem cells (CSCs) are one of the key factors for the recurrence and metastasis of osteosarcoma. We have shown that interleukin-24 (IL-24) inhibits osteosarcoma cell proliferation, migration and invasion in vitro. In the current study, we investigated the role of IL-24 in inhibiting the growth of osteosarcoma CSCs. IL-24 inhibited proliferation and invasion and decreased the stemness of osteosarcoma CSCs in vitro. In a nude mouse xenograft model, IL-24 significantly inhibited the growth of tumors originating from osteosarcoma CSCs. Moreover, we found that IL-24 was able to inactivate both Notch and Wnt/β-Catenin signaling, which are important for the development of the biological characteristics of CSCs. These data demonstrate that IL-24 is able to kill not only cancer cells but also CSCs in osteosarcoma, suggesting that IL-24 might eradicate osteosarcoma and enhance long-term cure rates in patients with osteosarcoma.

Using a model that with or without considering the interaction between bubbles through the radiated pressure waves, numerical simulations of cavitation bubbles have been performed in order to study the effect of the bubble–bubble interaction on radial pulsations of bubbles. Comparing the results obtained by with or without considering the bubble–bubble interaction, it is suggested that the suppression or enlargement property of expansion ratios of bubbles due to the bubble–bubble interaction largely depends on the ultrasound parameters, the ambient bubble radii, the distances between bubbles and the number of bubbles (in multi-bubble environment, the last two aspects can be expressed using the coupling strength). The frequency response curve of expansion ratio decreases and shifts to left due to the bubble–bubble interaction and the larger the coupling strength is, the more the left-shifting is.

Through the modulation of the dipolar entropy under an applied electric field (E), a reversible temperature change (ΔT) could be achieved in a dielectric material, which is known as the electrocaloric (EC) effect. Among all EC materials, ferroelectric terpolymer P(VDF-TrFE-CFE) has been regarded as one of the most promising EC materials owing to its large EC effect and superior thermal stability. Yet, the low EC strength limits the application of terpolymers in realistic cooling devices. In this work, using the thermal treatment of quenching and low-temperature annealing, the terpolymers with significantly decreased crystalline size are prepared with their EC performances investigated. Compared to the normal ones, the terpolymers with smaller crystalline size exhibit substantially enhanced EC strength. The better EC performance may be mainly attributed to the lower energy barriers for dipole orientation, which gives rise to higher polarization at low electric fields. This work emphasizes the critical role of crystalline size on the macroscopic properties of EC polymers. Keywords: Electrocaloric effect, P(VDF-TrFE-CFE), Crystalline size

Foam sandwich structures reinforced with the fiber column arrays are proposed to achieve broadband absorption at microwave frequencies as well as good mechanical properties. To achieve the microwave absorption, two layers of resistive films are embedded into the sandwich structures. The results show that the proposed sandwich structure with the whole thickness of 9.73 mm can achieve broadband absorption with the reflection less than −10 dB in the frequency range of 2.6–21 GHz. The absorption mechanism has been discussed by using the equivalent circuit model. It is further indicated that introduction of the fiber column array in the sandwich structure has little influence on the absorption performance, but can remarkably enhance the mechanical properties. This has been well demonstrated experimentally by three-point bending experiment. Compared with the ordinary sandwich absorbing structures, enhanced mechanical properties make the designed structure suitable in some loading applications. It is expected that the proposed multifunctional structure may find great potentials in the applications of stealth technology, electromagnetic interferences and so on. Keywords: Sandwich structure, Broadband absorption, Mechanical properties, Equivalent circuit model

Immune checkpoint inhibitors (ICPI) have shown considerable promise in the treatment of tumors. However, immune-related adverse events (irAEs) caused by ICPI have been reported in nearly every organ system. Whilst this represents a new challenge in the field of cancer treatment, traditional Chinese medicine (TCM) provides benefits in the treatment of irAEs. This article reviews the studies of the treatment of immune-related gastrointestinal diseases and dermatosis with TCM and introduces the collaborative efforts between China and France in the implementation of TCM for the treatment of irAEs. Keywords: Immune-related adverse events, Traditional Chinese medicine, Cancer immunotherapy, Immune checkpoint inhibitors

Objective: The study aimed to recognize potential molecular targets and signal pathways whereby phenolic environmental estrogen promotes the proliferation of uterine leiomyoma cells. Methods: Primary cultured cell lines of uterine leiomyoma were treated with 0.1% DMSO, 10.0μmol/L Bisphenol A (BPA), and 32.0μmol/L Nonylphenol (NP) for 48 h before RNA-seq was performed. Those genes affected by BPA and NP were identified. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Protein-protein Interaction (PPI) analysis were performed. Quantitative real-time polymerase chain reaction (q-PCR) and western blot were used to verify the differentially expressed gene and protein. Results: Compared to with the control group, 739 differentially expressed genes were identified in both the BPA group and the NP group. GO enrichment analysis showed that the most enriched GO terms were connective tissue development and G1/S transition of mitotic cell cycle, and extracellular matrix. The results of KEGG enrichment analysis showed that differentially expressed mRNA were enriched mainly in three primary pathways, including environmental information processing, human diseases, and cellular processes. The cell cycle, PI3K-Akt signaling pathway are significantly enriched. The q-PCR and western blot verified the cell cycle associated genes and proteins were upregulated in both BPA group and NP group. Both BPA and NP activated the PI3K-AKT signaling pathway. Conclusion: Phenolic environmental estrogens may promote the proliferation and cell cycle progression of uterine leiomyoma cells through rapid non-genomic ER signaling, which leads to disordered cell cycle regulation and accelerates the transition of the cell cycle from G0/G1 phase to S phase. In addition, as an external stimulant, phenolic estrogen promotes the upregulation of inflammatory factors in uterine leiomyomas.

Background: The high heterogeneity of acute myeloid leukaemia (AML) reflected in the patient- and disease-related factors accounts for the unsatisfactory prognosis despite the introduction of novel therapeutic approaches and drugs in recent years. Methods: In the development set (n = 412), parameters including age, hematopoietic cell transplantation-comorbidity index, white blood cell count, hemoglobin, biallelic CEBPA mutations, DNMT3A mutations, FLT3-ITD/NPM1 status, and ELN cytogenetic risk status were identified as independent prognostic factors for overall survival (OS) in the multivariable Cox regression analysis. A nomogram combining these predictors for individual risk estimation was established thereby. Findings: The prognostic model demonstrated promising performance in the development cohort. The calibration plot, C-index (0.74), along with the 1-, 2- and 3-year area under the receiver operating characteristic curve (AUC, 0.76, 0.79, and 0.74, respectively) in the validation set (n = 238) substantiated the robustness of the model. In addition to stratifying young (age ≤ 60 years) and elderly patients (age > 60 years) into three and two risk groups with significant distinct outcomes, the prognostic model succeeded in distinguishing eligible candidates for hematopoietic stem cell transplantation. Interpretation: The prognostic model is capable of survival prediction, risk stratification and helping with therapeutic decision-making with the use of easily acquired variables in daily clinical routine. Funding: This work was supported in part by grants from the National Natural Science Foundation of China (81770141), the National Key R&D Program of China (2016YFE0202800), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161406).

The cell wall polymers wall teichoic acid (WTA) and lipoteichoic acid (LTA) are often modified with glycosyl and D-alanine residues. Recent studies have shown that a three-component glycosylation system is used for the modification of LTA in several Gram-positive bacteria including Bacillus subtilis and Listeria monocytogenes. In the L. monocytogenes 1/2a strain 10403S, the cytoplasmic glycosyltransferase GtlA is thought to use UDP-galactose to produce the C55-P-galactose lipid intermediate, which is transported across the membrane by an unknown flippase. Next, the galactose residue is transferred onto the LTA backbone on the outside of the cell by the glycosyltransferase GtlB. Here we show that GtcA is necessary for the glycosylation of LTA in L. monocytogenes 10403S and B. subtilis 168 and we hypothesize that these proteins act as C55-P-sugar flippases. With this we revealed that GtcA is involved in the glycosylation of both teichoic acid polymers in L. monocytogenes 10403S, namely WTA with N-acetylglucosamine and LTA with galactose residues. These findings indicate that the L. monocytogenes GtcA protein can act on different C55-P-sugar intermediates. Further characterization of GtcA in L. monocytogenes led to the identification of residues essential for its overall function as well as residues, which predominately impact WTA or LTA glycosylation.

Previous studies have demonstrated that polypeptides extracted from fish protein possess potential anti-inflammatory effects, but few studies have reported the underlying anti-inflammatory mechanism of sturgeon peptides. Hence, the goal of this study was to explore the peptide sequences with potential anti-inflammatory activity derived from sturgeon muscle protein in the lipopolysaccharide (LPS)-induced RAW264.7 inflammatory model. Fourteen novel peptides were identified in major muscle proteins by mass spectrometry, and three synthetic peptides – KIWHHTF, VHYAGTVDY, and HLDDALRGQE - decreased the release of inflammatory mediators and inflammatory cytokines (NO, IL-6, and IL-1β), while increasing SOD activity significantly in the LPS-induced RAW264.7 inflammatory model. Western blotting analysis revealed that these peptides suppressed the phosphorylation levels of MAPKs, indicating that these peptides exerted anti-inflammatory effects by inhibiting the MAPK pathway. The novel peptides potentially have application prospects as functional food ingredients.

Summary: Cyclin E is a key factor for S phase entry, and deregulation of Cyclin E results in developmental defects and tumors. Therefore, proper cycling of Cyclin E is crucial for normal growth. Here we found that transcription factors Apontic (Apt) and E2f1 cooperate to induce cyclin E in Drosophila. Functional binding motifs of Apt and E2f1 are clustered in the first intron of Drosophila cyclin E and directly contribute to the cyclin E transcription. Knockout of apt and e2f1 together abolished Cyclin E expression. Furthermore, Apt up-regulates Retinoblastoma family protein 1 (Rbf1) for proper chromatin compaction, which is known to repress cyclin E. Notably, Apt-dependent up-regulation of Cyclin E and Rbf1 is evolutionarily conserved in mammalian cells. Our findings reveal a unique mechanism underlying the induction and subsequent decline of Cyclin E expression.

Efficacy and safety are fundamental qualities to uphold and improve when developing an extended-release carrier system for local anesthetics (LAs). This is especially true as diverse analgesics are applied in multimodal analgesia regimens and interactions between drugs may lead to adverse events. Here we propose a new formulation of LA carrier delivery: a PLGA nanomembrane produced by electrospinning technique that allows improved analgesia and better compatibility with combination analgesia regimen. In vitro release profile of this nanomembrane exhibited prolonged release profile (~35 days) compared to other extended-release systems of LAs studied so far. In vivo bupivacaine delivered through nanomembrane showed superior and prolonged analgesia compared to lidocaine infiltration in rat model of postoperative pain. Furthermore, in vivo safety profile of nanomembrane in single or combined use was confirmed by symptomatic, histological and pharmacokinetic analysis. These results indicate a novel formula of extended-release system that may potentiate better safety and analgesia of LAs compared to available extended-release products of LAs.

Handwriting verification represents an important area in forensic science. Herein, handwritings based on different types and brands pen ink samples made in China were investigated by non-invasive micro-identification methods. Scanning electron microscopy and energy spectrum (SEM-ES) were employed to measure the micro elements and component analysis of the written traces, and spectral mapping (surface scanning) function was focused. The exact assessments of elements in handwriting traces can distinguish the microcosmic differences between different types and brands ink in handwriting, which provides a new means of analysis and research methods of pen handwriting detection in forensic science.

Summary: Bacteriophages provide excellent tools for diagnostics, remediation, and targeted microbiome manipulation, yet isolating viruses with suitable host specificity remains challenging. Using Listeria phage PSA, we present a synthetic biology blueprint for host-range engineering through targeted modification of serovar-specific receptor binding proteins (RBPs). We identify Gp15 as the PSA RBP and construct a synthetic phage library featuring sequence-randomized RBPs, from which host range mutants are isolated and subsequently integrated into a synthetic, polyvalent phage with extended host range. To enable rational design of chimeric RBPs, we determine the crystal structure of the Gp15 receptor-binding carboxyl terminus at 1.7-Å resolution and employ bioinformatics to identify compatible, prophage-encoded RBPs targeting different Listeria serovars. Structure-guided design enables exchange of heterologous RBP head, neck, or shoulder domains to generate chimeric phages with predictable and extended host ranges. These strategies will facilitate the development of phage biologics based on standardized virus scaffolds with tunable host specificities. : Receptor binding proteins (RBPs) are key determinants of bacteriophage host range. Dunne et al. solve the RBP crystal structure of Listeria phage PSA and combine synthetic biology with structure-guided approaches to re-program RBP specificity. Using the temperate, narrow host range PSA scaffold, they construct virulent phages with extended and defined host specificities. Keywords: bacteriophage, listeria, phage engineering, tail spike, receptor binding protein, X-ray crystallography, host range, directed evolution, synthetic biology, chimeric phage

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p = 0.019 and p = 0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

Hippocampal synaptic plasticity is modulated by neuropeptides, the disruption of which might contribute to cognitive deficits observed in Alzheimer’s disease (AD). Although pro-opiomelanocortin (POMC)-derived neuropeptides and melanocortin 4 receptor (MC4R) are implicated in hippocampus-dependent synaptic plasticity, how the POMC/MC4R system functions in the hippocampus and its role in synaptic dysfunction in AD are largely unknown. Here, we mapped a functional POMC circuit in the mouse hippocampus, wherein POMC neurons in the cornu ammonis 3 (CA3) activate MC4R in the CA1. Suppression of hippocampal MC4R activity in the APP/PS1 transgenic mouse model of AD exacerbates long-term potentiation impairment, which is alleviated by the replenishment of hippocampal POMC/MC4R activity or activation of hippocampal MC4R-coupled Gs signaling. Importantly, MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP)/PKA/cAMP-response element binding protein (CREB)-dependent mechanism. Hence, disruption of this hippocampal POMC/MC4R circuit might contribute to synaptic dysfunction observed in AD, revealing a potential therapeutic target for the disease.

Summary: DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. : Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores. Keywords: The Cancer Genome Atlas PanCanAtlas project, DNA damage repair, somatic mutations, somatic copy-number alterations, epigenetic silencing, DNA damage footprints, mutational signatures, integrative statistical analysis, protein structure analysis