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Abstract Background Bladder cancer (BC) is a prevalent malignancy characterized by significant cellular heterogeneity. While single-cell multi-omics studies have provided valuable insights, much of the existing data remains underexplored, limiting our understanding of BC’s molecular mechanisms. Uncovering the pathogenesis of BC and finding new treatment methods are urgent problems to be solved. This study aims to address this gap by re-analyzing available single-cell datasets to uncover novel insights into BC. Methods In this study, we retrieved three single-cell transcriptome datasets by searching the Gene Expression Omnibus (GEO) database, focusing on single-cell sequencing of normal mouse bladder within the past 5 years. Through quality control and batch effect elimination, we obtained a total of 24,930 cells including epithelial, stromal, and immune cells. Subgroup analysis, pseudotemporal analysis, cell–cell communication, and transcription factor analysis were conducted specifically on epithelial cells to identify a transitional state during basal cell differentiation. We further compared the expression profiles of key transcription factors in cancer and normal tissues. In addition, we also performed immunohistochemical staining and survival analysis for key transcription factors. Results Subgroup analysis revealed multiple subtypes of epithelial cells, including basal, umbrella, and intermediate cells. Through pseudotemporal analysis, we discovered the developmental trajectory from basal cells to umbrella cells and further found that Basal_I is a transitional state for basal cell differentiation. Cell-to-cell communication analyses highlighted the pivotal role of Basal_I in cell–cell interactions, and key ligand-receptor pairs associated with cancer progression were also identified. Furthermore, elevated expression levels of key transcription factors in Basal_I were found to be closely associated with the stage and prognosis of BC. Immunohistochemical staining results further confirmed the upregulated expression of these transcription factors in BC. Conclusions Collectively, we found a transitional state of basal cells in normal bladder epithelial cells in mice, which may be related to the occurrence and development of BC, providing important clues for further understanding of the pathogenesis of BC. Our study provided possible molecular mechanisms or target for the research and treatment of BC.

Abstract Purpose The advantages of en bloc resection of bladder tumors (ERBT) over transurethral resection of bladder tumors (TURBT) in terms of patient prognosis are not yet clear, and there are some technical limitations. We aimed to compare the tumor recurrence in non-muscle invasive bladder cancer (NMIBC) patients with tumor diameter ≥ 3 cm undergoing either TURBT or thulium laser ERBT. Methods The patients included were those diagnosed with NMIBC based on pathological confirmation and underwent TURBT or modified thulium laser ERBT in the Department of Urology at Tongji Hospital from 2019 to 2024. The patients’ medical records were meticulously collected and postoperative follow-up was diligently conducted by trained personnel. Recurrence-free survival curves were generated utilizing the Kaplan–Meier method, and group comparisons were performed using the log-rank trend test. To minimize biases, we employed stratified survival analysis, alongside univariate and multivariate Cox regression analysis. Results This study included a total of 396 patients with NMIBC, with 214 undergoing TURBT and 182 undergoing ERBT. For all patients, there was no significant difference (P = 0.180) in RFS between the TURBT and ERBT groups. For patients with tumor diameter ≥ 3 cm, stratified analysis revealed that the RFS of the ERBT group was significantly better than that of the TURBT group (P = 0.033). However, in patients with tumor diameter

Abstract Background Aging of the male prostate is an inevitable process in which the prostate undergoes hyperplasia, and this growth may lead to compression of the urethra, resulting in voiding dysfunction and associated symptoms, and an increased risk of prostate cancer. Despite the significance of prostate aging, the molecular mechanisms involved are still not fully understood. Methods Prostate split by lobes from young (2 months) and aged (24 months) mice were collected for single-cell RNA sequencing (scRNA-seq) analysis. Tissues from both anterior prostate (AP) and ventral/dorsal/lateral prostate (VDLP) were included in the study. Data analysis included unsupervised clustering using the uniform manifold approximation and projection (UMAP) algorithm to identify distinct cell types based on marker gene expression. Differential gene expression analysis was performed to identify age-related changes in gene expression across different cell types. Functional enrichment analysis was conducted to elucidate biological pathways associated with differentially expressed genes. Additionally, cellular interactions and developmental trajectories were analyzed to characterize cellular dynamics during prostate aging. Results The single-cell transcriptome analysis of the mouse prostate during aging revealed heterogeneity across various cell types and their changes during the aging process. We found a significant increase in the proportion of mesenchymal and immune cells in aged mice. Our study unveiled alterations in genes and pathways associated with cellular senescence, oxidative stress, and regeneration in epithelial cells. Furthermore, we observed that basal cells may undergo epithelial-mesenchymal transition (EMT) to become mesenchymal cells, particularly prominent in aged mice. Additionally, immune cells, notably macrophages and T cells, exhibited a heightened inflammatory response in aged mice. Conclusion In summary, our study provides a comparative analysis of the single-cell transcriptome of the aged and young mice prostates, elucidating cellular and molecular changes between the aged and young mice prostates.

Abstract To explore the favorable factors that help slow the progression of disease in patients with mild Cervical Spondylotic Myelopathy (CSM). A retrospective analysis was conducted, involving the enrollment of 115 CSM patients. The categorization of patients into two groups was based on the duration of symptoms, assessments using the mJOA scale and Health Transition (HT) scores: mild-slow group and severe-rapid group. We found that the patients in both groups had similar degrees of spinal cord compression, but mild-slow group were older and had smaller C2–C7 cobb angle (Flexion) (CL(F)), C2–C7 cobb angle (Range of motion) (CL(ROM)), Transverse area (TA), Normal-TA, Compressive spinal canal area (CSCA), Normal-Spinal canal area (Normal-SCA) and lower Spinal cord increased signal intensity (ISI) Grade than the severe-rapid group. A binary logistic regression analysis showed that CL(ROM) and Normal-TA are favorable factors to help slow the progression of disease patients with mild CSM. Through ROC curves, we found that when CL(ROM)

ABSTRACT Background In recent times, the applications of continuous renal replacement therapy (CRRT) beyond kidney‐related conditions have been progressively increasing, and its implementation in randomized controlled trials (RCTs) specifically for acute respiratory distress syndrome (ARDS) has been documented. This meta‐analysis compiles all existing RCTs to assess whether CRRT benefits ARDS. Methods We searched 12 databases in English and Chinese and two clinical trial centers up to November 28, 2023. The main outcome indicator is the mortality rate. Secondary outcome indicators include incidence of ventilator‐associated pneumonia (VAP), ICU length of stay, mechanical ventilation time, oxygenation index (OI) at 24 h (h), OI at 48 h, OI at 72 h, OI at 7 days (d), partial pressure of oxygen (PaO2) at 72 h, Acute Physiology and Chronic Health Evaluation II (APACHE II) score at 24 h, APACHE II score at 48 h, APACHE II score at 72 h, APACHE II score at 7 d, extravascular lung water indexes (EVLWI) at 72 h, TNF‐α at 24 h, TNF‐α at 7 d, IL‐6 at 24 h, IL‐6 at 48 h, IL‐6 at 72 h, and IL‐6 at 7 d. Statistical measures utilized include risk ratios (RR), weighted mean difference (WMD), and 95% confidence intervals (95% CI). Results We summarized 36 studies, including 2123 patients. It was found that for ARDS, using CRRT in addition to conventional therapy can reduce the mortality rate (I2 = 0%; RR: 0.40; 95% CI: 0.30–0.53; p

Under hygrothermal environments, the structural stability and strength of all-fiber composite aircraft are significantly affected during long-term flight use. The wing skin, as a critical structural component, plays a vital role in bearing and transmitting aerodynamic loads. Therefore, it is crucial to investigate the structural compressive stability and strength of the wing skin throughout the aircraft's entire life cycle under these conditions. This study employs a real wing carbon fiber foam sandwich structure to investigate the compressive stability and strength of the wing skin structure of a new energy aircraft under actual flight conditions, specifically during the entire process of the room temperature dry state (RTD) and elevated temperature wet state (ETW). Initially, three-point bending tests were conducted on carbon fiber reinforced polymer (CFRP) laminates, foam cores, and CFRP reinforced foam sandwich structures. The CFRP laminates fully rebounded after bending damage in both the RTD and ETW environments. While CFRP reinforced foam sandwich structures also rebounded fully in the RTD environment, their rebound performance diminished in hygrothermal conditions due to the thermoplastic mobility of the foam cores, resulting in only weak rebound capabilities. In hygrothermal environments, the thermoplastic mobility of the foam core leads to diminished resilience after bending damage, resulting in only weak rebound capabilities. Subsequently, compressive instability tests were conducted on the wing skin foam sandwich structure. The results indicated that the basic test study effectively predicted the structural test outcomes. Structural components in the RTD environment exhibited overall flexural instability under compressive load, with damage morphology resembling a circular curve; the damaged specimens fully rebounded after unloading. Conversely, specimens in the ETW environment displayed localized instability, characterized by a wrinkled damage profile, resulting in only weak rebound capabilities after unloading.

Abstract Background HBP, a novel biomarker released from neutrophils, may induce inflammatory responses and exacerbate vascular permeability, representing the pathophysiological characteristics of sepsis and septic shock. However, it remains uncertain whether the combination of HBP with other biomarkers yields enhanced diagnostic capacity for sepsis. We hypothesized that measurements included IL-6·IL-8·HBP, IL-6·IL-8·HBP/ALB and HBP/ALB which based on HBP will improve its diagnostic efficacy and even better than the traditional infection biomarkers. Methods Between July 2021 and June 2022, we carried out a comprehensive, multi-center, observational cohort study spanning six leading tertiary hospitals located in Heilongjiang Province, China. Patients were stratified into three categories based on the severity of infection: non-sepsis, sepsis, and septic shock. We collected clinical and laboratory data, along with infection and inflammation biomarkers, for analysis. Results A total of 195 patients were enrolled. Among the three groups, patients with septic shock (n = 75, 38.5%) had significantly higher baseline levels of HBP, WBC, Lac, CRP, PCT, IL-6, IL-8, and IL-10 compared to non-sepsis patients (n = 43, 22.0%) and sepsis patients (n = 77, 39.5%), with statistically significant differences (p

Gliomas are the most common malignant intracranial tumors, with no effective treatments. Better understanding and identification of novel targets are urgently warranted. Actin-binding Rho activating C-terminal like (ABRACL) has been reported as an oncogene in several cancer types. However, the potential roles of ABRACL in the tumorigenesis of malignant glioma remain unknown. We discovered that ABRACL is highly expressed in different sub-types of gliomas in both CGGA and TCGA databases, which was further validated in glioblastoma cell lines and normal human astrocyte lines. RT-qPCR, Western blotting and immunohistochemistry demonstrated that ABRACL expression in glioma tissues was upregulated along with the increasing WHO grades. Further survival analysis of glioma patients also revealed that the overall survival of patients in the ABRACL high expression level group were significantly shorter than those in the low expression level group. Knockdown of ABRACL inhibited the proliferation, cell migration, invasion and cytodynamics behaviors in glioma cell lines via activating STAT3 signaling, which also induced apoptosis and cell cycle arrest. Conversely, overexpressing ABRACL promoted cell renewing and migration, enabled more flexible cell deformation, supporting ABRACL being a bona fide oncogene. Intracranial orthotopic xenograft experiment further confirmed that ABRACL downregulation significantly suppressed glioma growth. These results have demonstrated that the tumorigenic effect of ABRACL is partly mediated by STAT3, whose expression also correlates with clinical prognosis. ABRACL facilitates glioma malignancy phenotype through regulating the cytoskeleton by activating STAT3 pathway, suggesting that it may represent a potential therapeutic target for glioblastoma.

Abstract Background Glioblastoma multiforme (GBM) is a fatal malignant primary brain tumor in adults. The therapeutic efficacy of chemotherapeutic drugs is limited due to the blood-brain barrier (BBB), poor drug targeting, and short biological half-lives. Multifunctional biomimetic nanodrugs have great potential to overcome these limitations of chemotherapeutic drugs. Methods We synthesized and characterized a biomimetic nanodrug CMS/PEG-DOX-M. The CMS/PEG-DOX-M effectively and rapidly released DOX in U87 MG cells. Cell proliferation and apoptosis assays were examined by the MTT and TUNEL assays. The penetration of nanodrugs through the BBB and anti-tumor efficacy were investigated in the orthotopic glioblastoma xenograft models. Results We showed that CMS/PEG-DOX-M inhibited cell proliferation of U87 MG cells and effectively induced cell apoptosis of U87 MG cells. Intracranial antitumor experiments showed that free DOX hardly penetrated the BBB, but CMS/PEG-DOX-M effectively reached the orthotopic intracranial tumor through the BBB and significantly inhibited tumor growth. Immunofluorescence staining of orthotopic tumor tissue sections confirmed that nanodrugs promoted apoptosis of tumor cells. This study developed a multimodal nanodrug treatment system with the enhanced abilities of tumor-targeting, BBB penetration, and cancer-specific accumulation of chemotherapeutic drugs by combining chemotherapy and photothermal therapy. It can be used as a flexible and effective GBM treatment system and it may also be used for the treatment of other central nervous systems (CNS) tumors and extracranial tumors.

The replacement of plastic film with biodegradable film is important for reducing plastic film residual pollution in semi-arid regions of northern China. However, information on biodegradable film improvements based on the hydrothermal requirements of major food crops in the typical plastic film mulching area is limited. This study used a combination of field data measurements and curve fitting to assess the spatiotemporal distribution of soil hydrothermal variation and the corresponding maize yield in the field under biodegradable film mulching (BM), polyethylene film mulching (PM), and without mulching (CT). The warming effect of BM was between those of PM and CT and all treatments differed significantly from each other. The duration of the warming effect of BM was shorter than that of PM, and the warming effect of both disappeared at the early jointing stage of maize. The BM soil moisture was significantly lower compared with PM and CT throughout the soil profile (0–180 cm). Moreover, moisture fluctuations were observed in the 0–40 and 40–120 cm soil layers of BM after degradation, and the timing of fluctuations coincided with the filling period of maize. Consequently, the water use efficiency and yield of BM were lower than those of PM. Hence, we suggest that the conservation effect of biodegradable film mulching on soil moisture should persist until the end of the maize filling period, and that the start-up stage of degradation cannot be based solely on the disappearance of the warming effect.

Covalently bonded particles may exhibit extremely high strength, but their performance in the reinforcement of metal alloys crucially depends on the properties of their interfaces with the embedding matrix. Here, density functional theory is used for investigating a range of interface configurations between magnesium and silicon carbide in view of their mechanical properties. Interfaces are analyzed not only in terms of interface energy/work of separation but also in terms of the interfacial shear stresses required to induce interface-parallel displacements. These properties are studied for bilayer systems with different orientations of the Mg and SiC layers and for different terminations of the SiC layer (Si or C atoms located at the interface). The results are discussed in terms of their implication for mechanical behavior of SiC reinforced Mg alloys.

Pendulum mill is a widely used grinding equipment in powder processing industry. Less in-depth studies have been carried out especially for grinding efficiency and wear. Through theoretical analysis, the main influencing parameters were screened, among which spindle speed and spade degree mainly affect the grinding efficiency, but wind velocity mainly causes the main duct wear. The Fluent-DEM co-simulation method is used for the study of the complex physical field of mill operation. The simulation shows that grinding efficiency increases with spindle speed, but the increase from 110 to 120 rev/min is not significant, so the choice of spindle speed should consider both grinding efficiency and energy consumption. The spade degree determines the spade position, the closer the spade is to the grinding roller, the higher the grinding efficiency. Wind velocity has little effect on grinding efficiency, but it does affect the likelihood of particles entering the main duct and causing wear. Multi-objective optimization determines a spindle speed of 110 rev/min and a spade angle of −12° at a wind velocity of 46 m/s to achieve maximum grinding efficiency and minimum wear. This study provides a digital analysis basis for optimizing the operating parameters of the pendulum mill.

Abstract Introduction Chronic inflammation and malnutrition play important roles in muscle loss. Although albumin, globulin and albumin to globulin ratio (AGR) are considered to be useful inflammatory-nutritional biomarkers, their relationship with muscle mass remain unclear. This study aimed to investigate the relationship between them in adults. Methods We utilized data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 for analysis. Data on albumin, globulin, appendicular skeletal muscle mass, body mass index (BMI) and potential confounders (sociodemographic characteristics, medical conditions, laboratory parameters) were extracted and analyzed. We conducted multivariate linear regression models and smooth curve fittings to investigate the association between albumin, globulin, AGR and muscle mass. Subgroup analysis based on gender and muscle mass were performed. Results A total of 4110 participants were included, there were 294 participants with low muscle mass (LMM) and 3816 participants with normal muscle mass (NMM). LMM individuals were older, had greater prevalence of diabetes, higher BMI, globulin and triglycerides, lower albumin and AGR. Albumin was positively correlated to muscle mass in men, but negatively correlated with muscle mass in women. There were negative association between globulin and muscle mass, and positive association between AGR and muscle mass among men, but no significant associations were detected among women. Moreover, a linear relationship between albumin, globulin and muscle mass, as well as a non-linear relationship between AGR and muscle mass in men were identified. Conclusions The relationships between albumin, globulin, AGR and muscle mass were sex-specific. We speculate these indicators may be useful in assessing muscle mass in men.

Abstract The biomass pretreatment strategies using organic acids facilitate lignin removal and enhance the enzymatic digestion of cellulose. However, lignin always suffers a severe and irreversible condensation. The newly generated C–C bonds dramatically affect its further upgrading. In this study, we used a recyclable hydrotrope (p-Toluenessulfonic acid, p-TsOH) to dissolve lignin under mild condition and stabilized lignin with a quenching agent (formaldehyde, FA) during extraction, achieving both value-added lignin extraction and efficient enzymatic saccharification of cellulose. Approximately 63.7% of lignin was dissolved by 80% (wt. %) p-TsOH with 1.5% FA addition at 80 °C, 30 min. The obtained lignin was characterized by FTIR spectroscopy, TGA, 2D HSQC NMR spectroscopy, and GPC. The results indicated that the extracted lignin exhibited excellent properties, such as light color, a low molecular weight (Mw, 5371 g/mol), and a narrow polydispersity (M w/M n, 1.63). The pretreated substrate was converted to ethanol via a quasi-simultaneous saccharification and fermentation process (Q-SSF). After fermentation of 60 h, the ethanol concentration reached 38.7 ± 3.3 g/L which was equivalent to a theoretical ethanol yield of 82.9 ± 2.2% based on the glucan content, while the residual glucose concentration was only 4.69 ± 1.4 g/L. In short, this pretreatment strategy protected lignin to form new C–C linkages and improved the enzymatic saccharification of glucan for high-titer ethanol production. Graphical Abstract

With recent enhancements in vehicle electrification, electric sliding doors have received significant research attention; however, the testing methods for the sliding doors components need to be improved. Herein, according to the durability evaluation index of sliding doors, a miniaturized durability test bench is designed for the electronic lock system and sliding door power output mechanism assembly. The motion trajectory of the electronic lock system can be fitted as a circular arc curve through dynamic characteristics analysis; therefore, a four-bar linkage with a flexible link is used to simulate the trajectory. Through the finite element simulation method, the test-bench stress is calculated at room temperature and a high temperature (75°C); this facilitates the selection of an appropriate material (GCr15). This experimental method is an economical, reliable, and accurate scheme to standardize the durability test of the electronic lock system and power output mechanism assembly.

Abstract Background In this study, we present a novel electromagnetic navigation (EMN) system for percutaneous transforaminal endoscopic discectomy (PTED) procedure. The objective of this study was to investigate the safety and effectiveness of the PTED with the assistance of the EMN system and compare it with the conventional PTED with the assistance of fluoroscopic guidance (C-arm). Methods The clinical data of 79 patients (32 in EMN group and 47 in C-arm group) undergoing PTED for lumbar disc herniation (LDH) from January to September of 2019 were analyzed retrospectively. The radiation time, puncture time, operation time, visual analog scale (VAS), Oswestry disability index (ODI), modified MacNab criteria, and radiological parameters were recorded in both groups. Results Radiation time, puncture time, and operation time were significantly reduced in the EMN group compared with the C-arm group (P 0.05). The satisfaction rates of the EMN and C-arm groups were 90.63 and 87.23%, respectively, but no significant difference was found between the two groups (P > 0.05). There was no significant difference regarding translation and angular motion between the two groups at preoperation and postoperation (P > 0.05). Conclusions The EMN system can be applied to facilitate the PETD procedure. It can significantly reduce the intraoperative radiation time, puncture time, and operation time, and reshape the learning curve of PTED. Due to limitations of a retrospective study, results may need validation with larger prospective randomized clinical trials.

PurposeRecently, the effects of paraspinal muscle degeneration on osteoporotic vertebral fractures (OVFs) have attracted the attention of researchers; however, studies are limited, and their results vary. Hence, this study aimed to determine the role of paraspinal muscle degeneration in the occurrence and recurrence of OVF.MethodsFollowing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guideline, the PubMed, Embase, Web of Science, Wanfang Data, China National Knowledge Infrastructure, and ClinicalTrials.gov databases were comprehensively searched for relevant studies. Studies comparing the cross-sectional area (CSA) or fatty infiltration (FI) of the paraspinal muscles (including the psoas (PS), erector spinae plus multifidus (ES+MF), quadratus lumborum) in patients with and without initial OVF, or with and without recurrent OVF were included and analyzed.ResultsEleven studies were included in the meta-analysis. Seven studies investigated the effects of paraspinal muscles on initial OVF, and the overall results revealed significantly lower CSAES+MF (SMD: -0.575, 95% CI: -0.866 to -0.285) and CSAPS (SMD: -0.750, 95% CI: -1.274 to -0.226), and higher FI (SMD: 0.768, 95% CI: 0.475 to 1.062) in the fracture group. Meanwhile, four studies evaluated the effects of the paraspinal muscles on recurrent OVF, and the pooled results demonstrated significantly higher FI (SMD:0.720, 95% CI: 0.258 to 1.182) in the refracture group, although no significant difference in CSAES+MF (SMD: -0.103, 95% CI: -0.395 to 0.189) was observed between the two groups.ConclusionsParaspinal muscle degeneration plays a role in the occurrence and recurrence of OVF. Assessing the paraspinal muscles may be useful for identifying high-risk populations.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier (CRD42021276681).

Abstract Background Lateral recess stenosis (LRS) is a common degenerative disease in the elderly. Since the rise of comorbidity is associated with increasing age, transforaminal endoscopic lateral recess decompression (TE-LRD) is advocated. The objective of this study was to compare the clinical outcomes of TE-LRD in patients with LRS via visualized drilled foraminoplasty (VDF) or visualized reamed foraminoplasty (VRF) technique. Methods A total of 45 and 42 consecutive patients with limp or unilateral radiculopathy symptoms underwent TE-LRD using the VDF and VRF technique, respectively. The radiation exposure and operation time, time to return to work, and complications were compared between two groups. Their clinical outcomes were evaluated with the visual analogue scale (VAS) leg pain score, VAS back pain score, Oswestry Disability Index (ODI) and modified MacNab’s criteria. Results The average values of radiation exposure and operative time in the VDF group were significantly higher than those in the VRF group (P

BackgroundChicken meat is one of the most consumed meats worldwide and poultry production is increasing at an exponential rate. Reducing antibiotic usage has resulted in the recurrence of subclinical necrotic enteritis again and influenced global poultry production. Probiotics are potential antibiotic substitutes that can be used to prevent subclinical necrotic enteriti. However, the precise mechanism of action of probiotics and information on which gut microbes confer this efficacy remain elusive.Methods and resultsThe subclinical necrotic enteritis animal model was used to reveal the mechanism underlying the effect of probiotics on intestinal health through RNA sequencing and 16S rDNA amplicon sequencing. Bacillus licheniformis H2 feeding significantly reduced the relative abundance of Clostridium perfringens in the ileum and markedly ameliorated the pathological damage in the ileum and liver. In addition, oral administration of B. licheniformis H2 contributed to the enhancement of the intestinal barrier function and epithelial renewal, reducing energy consumption, and improving enteral nutrition absorption. Probiotic B. licheniformis H2 also ameliorated the inflammatory response and increased the immunity of subclinical necrotic enteritis infected broilers. Finally, B. licheniformis H2 feeding regulated liver gene expression to suppress immune response and promoted growth and metabolism depending on the gut microbiota.ConclusionsThese results indicated the mechanism of probiotic action of B. licheniformis H2 in maintaining intestinal health and thus promoting growth and B. licheniformis H2 may serve as an antibiotic substitute to prevent subclinical necrotic enteritis in poultry farming.

Against the backdrop of the fierce competition in the market nowadays, a closed innovation model based on internal knowledge is no longer sufficient to support enterprises in search of high-performance innovation. Instead, corporations are desperately required to search for resources of external knowledge to meet their innovation goals. Existing studies on open innovation in corporate management failed to fully elaborate on the mechanism of how the external knowledge search could impose an impact on sustaining innovation and disruptive innovation. In this study, the external knowledge search was divided into three categories according to the knowledge-based theory, namely, the scientific knowledge search, the market knowledge search, and the supply-chain knowledge search. While taking into account the moderating role of the focus of attention of the manager, we analyzed the statistical results of 485 questionnaires collected from manufacturing enterprises to elaborate on the mechanism of how the specialized knowledge search could impose an impact on sustaining innovation and disruptive innovation. Our research conclusions are expected to enrich existing studies on the factors contributing to corporate innovation, including but not limited to sustaining innovation and disruptive innovation. In addition, the research findings are expected to lay an empirical foundation by summarizing previous theoretical opinions while providing references for subsequent in-depth studies in the meantime. Moreover, the paper has put forward practical management measures and suggestions that could enable enterprises in developing countries to search and effectively transform the external knowledge into innovative outcomes. Last but not least, this study is expected to provide both theoretical and practical guidance for enterprises to further facilitate innovation by means of knowledge search.

ABSTRACTThe Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neonatal abnormalities and other disorders. Antibodies to the ZIKV envelope (E) protein can block infection. In this study, next-generation sequencing (NGS) of immunoglobulin heavy chain (IgH) mRNA transcripts was combined with single-cell PCR cloning of E-binding monoclonal antibodies for analysing antibody response in a patient from the early stages of infection to more than one year after the clearance of the virus. The patient's IgH repertoire 14 and 64 days after symptom onset showed dramatic dominant clonal expansion but low clonal diversity. IgH repertoire 6 months after disease-free status had few dominant clones but increased diversity. E-binding antibodies appeared abundantly in the repertoire during the early stages of infection but quickly declined after clearance of the virus. Certain VH genes such as VH5-10-1 and VH4-39 appeared to be preferentially enlisted for a rapid antibody response to ZIKV infection. Most of these antibodies require relatively few somatic hypermutations to acquire the ability to bind to the E protein, pointing to a possible mechanism for rapid defence against ZIKV infection. This study provides a unique and holistic view of the dynamic changes and characteristics of the antibody response to ZIKV infection.

Lakes are one of the natural reservoirs of antibiotic resistance genes (ARGs) in environments. Long retention times in lakes potentially allow ARGs to persist and may create increased opportunities for the emergence of resistant pathogens. In this study, we investigated the prevalence, source and dissemination risk of ARGs in the sediments of a typical urban lake, Lake Tai (China) which has been a drastic example of water pollution with eutrophication in the world due to its proliferated cyanobacterial blooms. High-throughput profilings of ARGs in the sediments of Lake Tai were characterized with metagenomic assembly, and were compared with those in other global lakes from Australia, Canada, Indonesia, Rwanda and the United States of America. The hosts of ARGs in the sediments of Lake Tai were explored based on the taxonomic annotation of ARG-carrying contigs and network analysis, and a novel recently-discovered crAssphage was employed for source tracking of resistance bacteria. Meanwhile, the potential resistome risk was identified by projecting the co-occurrence of acquired ARGs, mobile genetic elements (MGEs) and human bacterial pathogens into a three-dimensional exposure space. Results showed 321 ARG subtypes belonging to 21 ARG types were detected in the sediments of Lake Tai, dominated by multidrug, macrolide-lincosamide-streptogramin, bacitracin, quinolone, mupirocin and trimethoprim resistance genes. Relatively, the ARG levels in the sediments of Lake Tai were significantly higher than those in other global lakes. Source tracking showed the coverages of detected crAssphage in the sediments of Lake Tai were positively correlated with the total ARG coverage, suggesting the contribution of human fecal contamination to the prevalence of ARGs in this lake. It should be noted that the co-occurrence ratio of ARGs, MGEs and human pathogens in the sediments of Lake Tai was higher than that in other global lakes, likely indicating a higher risk for the resistance dissemination in the China's third largest freshwater lake. Keywords: Antibiotic resistance genes, Metagenomic assembly, Microbial source tracking, CrAssphage, Resistome risk, Lake Tai

ABSTRACTThe Zika virus (ZIKV) outbreak and its link to microcephaly triggered a public health concern. To examine antibody response in a patient infected with ZIKV, we used single-cell PCR to clone 31 heavy and light chain-paired monoclonal antibodies (mAbs) that bind to ZIKV envelope (E) proteins isolated from memory B cells of a ZIKV-infected patient. Three mAbs (7B3, 1C11, and 6A6) that showed the most potent and broad neutralization activities against the African, Asian, and American strains were selected for further analysis. mAb 7B3 showed an IC50 value of 11.6 ng/mL against the circulating American strain GZ02. Epitope mapping revealed that mAbs 7B3 and 1C11 targeted residue K394 of the lateral ridge (LR) epitope of the EDIII domain, but 7B3 has a broader LR epitope footprint and recognizes residues T335, G337, E370, and N371 as well. mAb 6A6 recognized residues D67, K118, and K251 of the EDII domain. Interestingly, although the patient was seronegative for DENV infection, mAb 1C11, originating from the VH3-23 and VK1-5 germline pair, neutralized both ZIKV and DENV1. Administration of the mAbs 7B3, 1C11, and 6A6 protected neonatal SCID mice infected with a lethal dose of ZIKV. This study provides potential therapeutic antibody candidates and insights into the antibody response after ZIKV infection.

Abstract The mechanisms that eliminate activated platelets in inflammation-induced disseminated intravascular coagulation (DIC) in micro-capillary circulation are poorly understood. This study explored an alternate pathway for platelet disposal mediated by endothelial cells (ECs) through phosphatidylserine (PS) and examined the effect of platelet clearance on procoagulant activity (PCA) in sepsis. Platelets in septic patients demonstrated increased levels of surface activation markers and apoptotic vesicle formation, and also formed aggregates with leukocytes. Activated platelets adhered were and ultimately digested by ECs in vivo and in vitro. Blocking PS on platelets or αvβ3 integrin on ECs attenuated platelet clearance resulting in increased platelet count in a mouse model of sepsis. Furthermore, platelet removal by ECs resulted in a corresponding decrease in platelet-leukocyte complex formation and markedly reduced generation of factor Xa and thrombin on platelets. Pretreatment with lactadherin significantly increased phagocytosis of platelets by approximately 2-fold, diminished PCA by 70%, prolonged coagulation time, and attenuated fibrin formation by 50%. Our results suggest that PS-mediated clearance of activated platelets by the endothelium results in an anti-inflammatory, anticoagulant, and antithrombotic effect that contribute to maintaining platelet homeostasis during acute inflammation. These results suggest a new therapeutic target for impeding the development of DIC.