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Abstract Background Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. Methods The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. Results High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. Conclusions Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy.

Abstract Background Information on the influences of daily eating frequency (DEF) and nighttime fasting duration (NFD) on biological aging is minimal. Our study investigated the potential associations of DEF and NFD with accelerated aging. Methods Out of 24212 participants in NHANES 2003–2010 and 2015–2018, 4 predicted age metrics [homeostatic dysregulation (HD), Klemera–Doubal method (KDM), phenoAge (PA), and allostatic load (AL)] were computed based on 12 blood chemistry parameters. Utilizing 24-h dietary recall, DEF was measured by the frequency of eating occurrences, while NFD was determined by assessing the timing of the initial and final meals throughout the day. Weighted multivariate linear regression models and restricted cubic spline (RCS) were utilized to examine the associations. Results Compared to DEF of ≤ 3.0 times, subjects with DEF ≥ 4.6 times demonstrated lower KDM residual [β: -0.57, 95% confidence-interval (CI): (-0.97, -0.17)] and PA residual [β: -0.47, 95% CI: (-0.69, -0.25)]. In comparison to NFD between 10.1 and 12.0 h, individuals with NFD ≤ 10.0 h were at higher HD [β: 0.03, 95% CI: (0.01, 0.04)], KDM residual [β: 0.34, 95% CI: (0.05, 0.63)], and PA residual [β: 0.38, 95% CI: (0.18, 0.57)]. Likewise, those with NFD ≥ 14.1 h also had higher HD [β: 0.02, 95% CI: (0.01, 0.04)] and KDM residual [β: 0.33, 95% CI: (0.03, 0.62)]. The results were confirmed by the dose–response relationships of DEF and NFD with predicted age metrics. Lactate dehydrogenase (LDH) and globulin (Glo) were acknowledged as implicated in and mediating the relationships. Conclusions DEF below 3.0 times and NFD less than 10.0 or more than 14.1 h were independently associated with higher predicted age metrics.

Wastewater surveillance (WWS) can leverage its wide coverage, population-based sampling, and high monitoring frequency to capture citywide pandemic trends independent of clinical surveillance. Here we conducted a nine months daily WWS for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 12 wastewater treatment plants (WWTPs), covering approximately 80% of the population, to monitor infection dynamics in Hong Kong, China. We found that the SARS-CoV-2 virus concentration in wastewater was correlated with the daily number of reported cases and reached two pandemic peaks three days earlier during the study period. In addition, two different methods were established to estimate the prevalence/incidence rates from wastewater measurements. The estimated results from wastewater were consistent with findings from two independent citywide clinical surveillance programmes (rapid antigen test (RAT) surveillance and serology surveillance), but higher than the cases number reported by the Centre for Health Protection (CHP) of Hong Kong, China. Moreover, the effective reproductive number (Rt) was estimated from wastewater measurements to reflect both citywide and regional transmission dynamics. Our findings demonstrate that large-scale intensive WWS from WWTPs provides cost-effective and timely public health information, especially when the clinical surveillance is inadequate and costly. This approach also provides insights into pandemic dynamics at higher spatiotemporal resolutions, facilitating the formulation of effective control policies and targeted resource allocation.

Abstract Background Understanding the interactions and dynamics of microbiotas within biological wastewater treatment systems is essential for ensuring their stability and long-term sustainability. In this study, we developed a systematic framework employing multi-omics and Hi-C sequencing to extensively investigate prokaryotic and phage communities within a hybrid biofilm and activated sludge system. Results We uncovered distinct distribution patterns, metabolic capabilities, and activities of functional prokaryotes through the analysis of 454 reconstructed prokaryotic genomes. Additionally, we reconstructed a phage catalog comprising 18,645 viral operational taxonomic units (vOTUs) with high length and contiguity using hybrid assembly, and a distinct distribution of phages was depicted between activated sludge (AS) and biofilm. Importantly, 1340 host-phage pairs were established using Hi-C and conventional in silico methods, unveiling the host-determined phage prevalence. The majority of predicted hosts were found to be involved in various crucial metabolic processes, highlighting the potential vital roles of phages in influencing substance metabolism within this system. Moreover, auxiliary metabolic genes (AMGs) related to various categories (e.g., carbohydrate degradation, sulfur metabolism, transporter) were predicted. Subsequent activity analysis emphasized their potential ability to mediate host metabolism during infection. We also profiled the temporal dynamics of phages and their associated hosts using 13-month time-series metagenomic data, further demonstrating their tight interactions. Notably, we observed lineage-specific infection patterns, such as potentially host abundance- or phage/host ratio-driven phage population changes. Conclusions The insights gained from this research contribute to the growing body of knowledge surrounding interactions and dynamics of host-phage and pave the way for further exploration and potential applications in the field of microbial ecology. Video Abstract

Abstract The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

IntroductionIn recent years, some clinical studies of first-line treatment for advanced-stage urothelial carcinoma (aUC) have reached the main endpoint, showing inconsistent clinical efficacy. We hope to explore the efficacy and safety of first-line treatment for aUC.MethodsThe relevant literature from January 2000 to February 2024 was searched, and the R language (version 4.3.1) was used to perform a network meta-analysis based on the JAGS package and GEMTC package under the Bayesian framework. The main indicators included OS, PFS, ORR and adverse events of grade 3 or higher. This study has been registered in PROSPERO (CRD42024525372).ResultsA total of 8 RCTs involving 5539 patients and 12 treatments were included. Pembrolizumab plus Enfortumab Vedotin (PEM+EV) was significantly better than other groups in OS, PFS and ORR. In terms of OS, PEM+EV was significantly better than nivolumab plus platinum-based chemotherapy (NIVO+platinumCT) (HR=0.60; 95% CI: 0.45-0.81), PEM+platinumCT (HR=0.55; 95%CI: 0.42-0.72), atezolizumab (ATE) + platinumCT (HR=0.57; 95%CI: 0.43-0.75) and platinumCT (HR=0.47; 95%CI: 0.38-0.58). In terms of PFS, PEM+EV was also significantly better than NIVO+platinumCT (HR=0.62; 95%CI: 0.48-0.82), PEM+platinumCT (HR=0.58; 95%CI: 0.45-0.74), ATE+platinumCT (HR=0.55; 95%CI: 0.43-0.69) and platinumCT (HR=0.45; 95%CI: 0.38-0.54). In terms of ORR, PEM+EV had a significant be nefit compared with other treatment measures, which was 2.63 times that of platinumCT (OR=2.63; 95%CI: 2.00-3.45). The adverse events of grade 3 or higher in immunotherapy (ATE, PEM, durvalumab) was significantly lower than other treatment measures.ConclusionsPEM+EV can significantly prolong OS and PFS compared with other treatments, and has a higher ORR. The adverse events of grade 3 or higher of ATE was the lowest.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024525372, identifier CRD42024525372.

Background & Aims: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms. Methods: The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20–75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders. Results: After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44–3.01; p-trend

Objective: Dendrobin A, a typical active ingredient of the traditional Chinese medicine Dendrobium nobile, has potential clinical application in cancer treatment; however, its effect and mechanism in anti-hepatocellular carcinoma (HCC) remain unsolved. Method: The effects of Dendrobin A on the viability, migration, invasion, cycle, apoptosis, and epithelial-mesenchymal transition of HepG2 and SK-HEP-1 cells were verified by in vitro experiments. mRNA sequencing was performed to screen the differentially expressed genes (DEGs) of HCC cells before and after Dendrobin A treatment, following GO enrichment and KEGG signaling pathway analyses. Mechanistically, molecular docking was used to evaluate the binding of Dendrobin A with proteins p65 and p50, before further verifying the activation of nuclear factor kappa-B (NF-κB) signaling. Finally, the antiproliferative effect of Dendrobin A on HCC cells was explored through animal experiments. Results: Dendrobin A arrested cell cycle, induced apoptosis, and inhibited proliferation, migration, invasion, and blocked epithelial-mesenchymal transition in HepG2 and SK-HEP-1 cells. mRNA sequencing identified 830 DEGs, involving various biological processes. KEGG analysis highlighted NF-κB signaling. Molecular docking revealed strong binding of Dendrobin A with p65 and p50 proteins, and western blotting confirmed reduced levels of p-p65 and p-p50 in HCC cells post Dendrobin A treatment. NF-κB agonist PMA reversed Dendrobin A-inhibited cell proliferation migration and invasion. In vivo experiments showed that Dendrobin A inhibited HCC cell growth. Conclusion: Our findings suggest that Dendrobin A exhibits anti-HCC properties by inhibiting the activation of the NF-κB pathway. These results provide a scientific basis for utilizing Dendrobium nobile in anti-HCC therapies.

Abstract TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.

Abstract Background Kidney transplantation stands out as the most effective renal replacement therapy for patients grappling with end-stage renal disease. However, post-transplant renal fibrosis is a prevalent and irreversible consequence, imposing a substantial clinical burden. Unfortunately, the clinical landscape remains devoid of reliable biological markers for diagnosing post-transplant renal interstitial fibrosis. Methods We obtained transcriptome and single-cell sequencing datasets of patients with renal fibrosis from NCBI Gene Expression Omnibus (GEO). Subsequently, we employed Weighted Gene Co-Expression Network Analysis (WGCNA) to identify potential genes by integrating core modules and differential genes. Functional enrichment analysis was conducted to unveil the involvement of potential pathways. To identify key biomarkers for renal fibrosis, we utilized logistic analysis, a LASSO-based tenfold cross-validation approach, and gene topological analysis within Cytoscape. Furthermore, histological staining, Western blotting (WB), and quantitative PCR (qPCR) experiments were performed in a murine model of renal fibrosis to verify the identified hub genes. Moreover, molecular docking and molecular dynamics simulations were conducted to explore possible effective drugs. Results Through WGCNA, the intersection of core modules and differential genes yielded a compendium of 92 potential genes. Logistic analysis, LASSO-based tenfold cross-validation, and gene topological analysis within Cytoscape identified four core genes (CD3G, CORO1A, FCGR2A, and GZMH) associated with renal fibrosis. The expression of these core genes was confirmed through single-cell data analysis and validated using various machine learning methods. Wet experiments also verified the upregulation of these core genes in the murine model of renal fibrosis. A positive correlation was observed between the core genes and immune cells, suggesting their potential role in bolstering immune system activity. Moreover, four potentially effective small molecules (ZINC000003830276-Tessalon, ZINC000003944422-Norvir, ZINC000008214629-Nonoxynol-9, and ZINC000085537014-Cobicistat) were identified through molecular docking and molecular dynamics simulations. Conclusion Four potential hub biomarkers most associated with post-transplant renal fibrosis, as well as four potentially effective small molecules, were identified, providing valuable insights for studying the molecular mechanisms underlying post-transplant renal fibrosis and exploring new targets.

Dynamic changes in daily climatic features may induce a lag in the responses of ecosystems, representing a crucial mechanism in the climate-ecosystem interactions. However, the underlying mechanisms are not fully understood. With help of long term half-hourly data series (from 2006 to 2022) of carbon fluxes and climate from the Inner Mongolia no-grazing grassland ecosystem eddy covariance station, we conducted the following studies: (i) investigation of the lagged mechanisms between carbon flux and climatic factors, (ii) characterization of diurnal variation patterns that demonstrated the hysteresis between carbon flux and climatic factors, and (iii) assessment of the potential mechanisms underlying the diurnal variation in carbon flux. The results indicated that (i) there is a pronounced asynchrony between the carbon flux and climatic factors. Light saturation is crucial in the lagged relationship between net ecosystem exchange (NEE) and climatic factors. The lag times between NEE and climatic factors were separately explained by moisture and temperature conditions. (ii) Non-linear response relationships were observed between carbon flux and climatic factors. Under similar climatic conditions, the increasing stage of NEE consistently remained lower than the decreasing stage, presenting a distinctive hysteresis loop. (iii) Further investigations revealed the collaborative role of gross primary productivity (GPP) and ecosystem respiration (RECO) in the diurnal variation patterns of NEE. Specifically, the difference in light-use efficiency between the increasing and decreasing stages dominated the difference in GPP for both stages, whereas the difference in air temperature between the increasing and decreasing stages dominated the difference in RECO for both stages. The diurnal variation patterns of NEE were similar across the different parts of growing season. Results furthermore allowed to optimize the light-ues efficiency model, which exhibited remarkable accuracy in daily GPP estimation and effectively simulated the diurnal variation patterns between GPP and climatic factors. In summary, this study provides a theoretical basis for understanding lagged effects and diurnal variations in grassland ecosystems in response to climatic factors. These research findings are of great importance for predicting the future ecosystem carbon sink potential.

Summary: Natural silks are renewable proteins with impressive mechanical properties and biocompatibility that are useful in various fields. However, the cellular and spatial organization of silk-secreting organs remains unclear. Here, we combined single-nucleus and spatially resolved transcriptomics to systematically map the cellular and spatial composition of the silk glands (SGs) of mulberry silkworms late in larval development. This approach allowed us to profile SG cell types and cell state dynamics and identify regulatory networks and cell-cell communication related to efficient silk protein synthesis; key markers were validated via transgenic approaches. Notably, we demonstrated the indispensable role of the ecdysone receptor (ultraspiracle) in regulating endoreplication in SG cells. Our atlas presents the results of spatiotemporal analysis of silk-secreting organ architecture late in larval development; this atlas provides a valuable reference for elucidating the mechanism of efficient silk protein synthesis and developing sustainable products made from natural silk.

BackgroundGut microbiota may influence the development of acute pancreatitis (AP), a serious gastrointestinal disease with high morbidity and mortality. This study aimed to identify a causal link by investigating the relationship between gut microbiota and AP.MethodsMendelian randomization (MR) and a nested case–control study were used to explore associations between gut microbiota composition and AP. 16S rRNA sequencing, random forest modelling (RF), support vector machine (SVM), and Kaplan–Meier survival analysis was applied to identify significant gut microbiota and their correlation with hospitalization duration in AP patients.ResultsBidirectional MR results confirmed a causal link between specific gut microbiota and AP (15 and 8 microbial taxa identified via forward and reverse MR, respectively). The 16S rRNA sequencing analysis demonstrated a pronounced difference in gut microbiota composition between cases and controls. Notably, after a comprehensive evaluation of the results of RF and SVM, Bacteroides plebeius (B. plebeius) was found to play a significant role in influencing the hospital status. Using a receiver operating characteristic (ROC) curve, the predictive power (0.757) of B. plebeius. Kaplan–Meier survival analysis offered further insight that patients with an elevated abundance of B. plebeius experienced prolonged hospital stays.ConclusionCombining MR with nested case–control studies provided a detailed characterization of interactions between gut microbiota and AP. B. plebeius was identified as a significant contributor, suggesting its role as both a precursor and consequence of AP dynamics. The findings highlight the multifactorial nature of AP and its complex relationship with the gut microbiota. This study lays the groundwork for future therapeutic interventions targeting microbial dynamics in AP treatment.

BackgroundEmpathy, as one of the fundamental principles of nursing professionalism, plays a pivotal role in the formation and advancement of the nursing team. Nursing interns, as a reserve force within the nursing team, are of significant importance in terms of their ability to empathize. This quality is not only directly related to the degree of harmony in the nurse–patient relationship and the enhancement of patient satisfaction, but also plays a pivotal role in the promotion of the quality of nursing services to a new level.AimThe objective of this study was to gain a deeper understanding of the current state of nursing interns’ empathic abilities. To this end, we sought to examine empathic performance under different profile models and to identify the key factors influencing these profile models.MethodsThe study utilized 444 nursing interns from 11 tertiary general hospitals in Inner Mongolia as research subjects. The study employed a number of research tools, including demographic characteristics, the Jefferson Scale of Empathy, and the Professional Quality of Life Scale. A latent profile model of nursing interns’ empathy ability was analyzed using Mplus 8.3. The test of variability of intergroup variables was performed using the chi-square test. Finally, the influencing factors of each profile model were analyzed by unordered multi-categorical logistic regression analysis.ResultsThe overall level of empathy among nursing interns was found to be low, with 45% belonging to the humanistic care group, 43% exhibiting low empathy, and 12% demonstrating high empathy. The internship duration, empathy satisfaction, secondary traumatic stress, only child, place of birth, and satisfaction with nursing were identified as factors influencing the latent profiles of empathy in nursing interns (p

Federated learning is a distributed learning approach which can protect clients’ privacy. The success of federated learning depends on the participation of high quality clients. However, many works neglect how to incentivize high quality clients to contribute to the model training. Furthermore, in existing works focusing on incentive mechanisms, the communication between the server and clients is unexplored. In this paper, we propose an auction-based incentive mechanism considering communication path finding to incentivize high quality clients’ participation. Specifically, we conduct the multi-criteria path finding to improve the communication between the server and clients. Then we take the communication parameters into the auction between the server and clients to select high quality clients for model training. When clients only have their own information, we design a distributed algorithm for clients to choose their optimal bids. Finally, numerical simulation results have been implemented to evaluate the efficiency of our proposed method.

Abstract Background To explore the relationship between sleep patterns and cardiovascular disease (CVD) incidence and mortality risk in a population with type 2 diabetes through a UK Biobank sample. Methods A total of 6860 patients with type 2 diabetes were included in this study. Five sleep factors (including Chronotype, sleep duration, insomnia, daytime sleepiness, and snoring) were collected as a questionnaire. The calculation generates a sleep score of 0–5, and then three sleep patterns were defined based on the sleep scores: poor sleep pattern (0–2), Intermediate sleep pattern (3–4), and healthy sleep pattern (5). HRs and 95% confidence intervals were calculated by multivariate COX proportional risk model adjustment. Restricted cubic splines were used to validate linear associations between sleep scores CVD events. Results Our results found a reduced risk of CVD events in individuals with healthy sleep patterns compared to participants with poor sleep patterns. CVD Mortality (HR, 0.690; 95% CI 0.519–0.916), ASCVD (Atherosclerosis CVD) (HR, 0.784; 95% CI 0.671–0.915), CAD (Coronary Artery Disease) (HR, 0.737; 95% CI 0.618–0.879), PAD (Peripheral Arterial Disease) (HR, 0.612; 95% CI 0.418–0.896), Heart Failure (HR, 0.653; 95% CI 0.488–0.875). Restricted cubic spline responded to a negative linear correlation between sleep scores and CVD Mortality, ASCVD, CAD, PAD, and Heart Failure. Conclusions Healthy sleep patterns are significantly associated with a reduced risk of CVD Mortality, ASCVD, CAD, PAD, and Heart Failure in the diabetes population.

Abstract Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous in tumor microenvironment (TME). Cross-talk between cancer cells and CAFs results in cancer progression. Here, we demonstrated that a distinct cancer-associated fibroblasts subset with podoplanin (PDPN) positive expression (PDPN+ CAFs) was correlated with poor survival in oral squamous cell carcinoma (OSCC). PDPN+ CAFs promoted the progression of OSCC by transferring exosomal lncRNA FTX to OSCC cells. Mechanically, FTX bound to flap endonuclease-1 (FEN1), forming an RNA‒protein complex. FTX enhanced promoter demethylation of FEN1 by recruiting ten-eleven translocation-2 (TET2). In addition, FTX/FEN1 axis promoted OSCC cells motility by inhibiting ferroptosis. In xenograft experiments, RSL-3, a ferroptosis-inducing agent, suppressed the tumorigenesis potential of FEN1-overexpressed OSCC cells. Furthermore, Acyl-CoA synthetase long-chain family member 4 (ACSL4) was confirmed to participate in the motility promotion induced by FEN1 overexpression. FEN1 could bind to promoter region of ACSL4 and then inhibit ferroptosis in OSCC cells. Our study reveals that PDPN+ CAFs promote the invasiveness of OSCC cells by inhibiting ferroptosis through FTX/FEN1/ACSL4 signaling cascade. PDPN+ CAFs may serve as a novel potential therapeutic target for OSCC.

Agrobacterium sp. are notable for their ability to produce substantial amounts of exopolysaccharides. Our study identified an exopolysaccharide (Galacan, 4982.327 kDa) from Agrobacterium sp. FN01. Galacan is a heteropolysaccharide primarily composed of glucose and galactose at a molar ratio of 25:1. The FT-IR results suggested that Galacan had typical absorption peaks of polysaccharide. The results of periodate oxidation, Smith degradation, and NMR confirmed the presence of structural units, such as β-D-Galp(→, →3)β-D-Galp(1→, →2,3)β-D-Glcp(1→, β-D-Glcp(1→, and →2)β-D-Glcp(1→. Galacan demonstrated significant biological activities. In experiments conducted with zebrafish, it facilitated the proliferation of Lactobacillus brevis in the intestinal tract, suggesting potential prebiotic properties. Moreover, in vivo studies revealed its antihyperglycemic effects, as evidenced by significant reductions in blood glucose levels and enhanced fluorescence intensity of pancreatic β cells in a streptozotocin (STZ)-induced hyperglycemic zebrafish model. Additionally, antiaging assays demonstrated Galacan’s ability to inhibit β-galactosidase activity and enhance telomerase activity in a hydrogen peroxide (HP)-induced aging zebrafish model. These findings emphasized the potential of Galacan as a natural prebiotic with promising applications in diabetes prevention and antiaging interventions.

To enhance the uplift capacity and facilitate the installation of multi-row perfobond connectors at shallow burial depths, this study puts forward a novel notched T-perfobond connector. The design incorporates an integrated flange at the bottom of the connector and a notch at the edge of the hole. Through pull-out model tests on four notched T-perfobond connectors, this research investigates their failure mechanisms and pull-out capacities. Utilizing the explicit dynamics method in ABAQUS, a finite-element model of the pull-out resistance test for notched T-perfobond connectors is established and verified against experimental data. Furthermore, a detailed parametric analysis involving 54 models is conducted, examining crucial parameters such as rib dimensions, hole geometry, flange size, notch width, bar diameter, and material properties. Based on the combined experimental and numerical results, this paper assesses the suitability of current formulas for calculating the pull-out capacity of perfobond connectors and proposes a refined calculation method specifically for notched T-perfobond connectors. All the findings reported in this paper can serve as a reference in the design and construction of composite structures.

Objective: This study aims to explore the impact of research pressure on depression tendency among Chinese doctoral students and analyze the mediating effect of familial financial support in this relationship. Methods: Based on the ecological systems theory, this study employs a mediating effect model and OLS regression model for empirical analysis. Through an online questionnaire, 2815 valid data from Chinese doctoral students were successfully collected. Conclusion: The study finds that research pressure has a significant positive impact on depression tendency among doctoral students (t = 18.347, p < 0.01). Married doctoral students show relatively lower depression tendency, indicating a negative impact of marital status on depression tendency (t = 12.579, p < 0.01). In terms of gender, female doctoral students are more prone to depression compared to their male counterparts (t = −2.921, p < 0.01). Additionally, as the doctoral year progresses, depression tendency also tends to increase (t = 3.690, p < 0.01). Importantly, familial financial support is proven to be a significant mediator between research pressure and depression tendency, explaining 32.116% of the relationship. Suggestion: This study not only provides a multi-dimensional perspective for understanding the mental health issues of doctoral students but also offers a scientific basis for universities and related educational departments to formulate more precise mental health intervention strategies.

Objective In this study, we aimed to establish a new nomogram score to predict the occurrence of surgery-related pressure ulcers (SRPU) in patients undergoing cardiovascular surgery. Methods We conducted a retrospective study among patients who underwent cardiovascular surgery between February 2016 and November 2020. Results We established a prediction model based on a logistic regression model and tested the calibration and discrimination. We included 1163 patients who had undergone cardiovascular surgery. We formulated the logistic regression model, with Logit(P) = −11.745 + 0.024 preoperative hemoglobin value + 0.118 serum sodium value − 0.014 prealbumin value − 0.213 intraoperative mean temperature − 0.058 minimum mean arterial pressure + 0.646 preoperative blood potassium value + 0.264 smoking frequency + 0.760 hypertension history + 0.536 age ≥70 years. In this model ,“+” indicates that the factor is positively related to the occurrence risk of SRPU and “−” indicates that the factor is negatively associated with SRPU risk. The predictive model and nomogram had good accuracy in estimating the risk of SRPU, with a C-index of 0.755 (95% confidence interval: 0.719–0.792). Conclusions The present model can be used to effectively screen patients with a high risk of SRPU to devise targeted nursing intervention strategies and ultimately reduce the incidence rate of SRPU.

Abstract Background Lung cancer is one of the most common malignant cancers worldwide. Previous studies have shown that Afzelin, a flavonoid, possesses anticancer activity. The aim of this study was to explore Afzelin’s effect on lung cancer cells and delineate potential anti-cancer mechanism. Methods The effect of Afzelin on cell viability, proliferation, and apoptosis of lung cancer cells i.e., A549 and H1299 cells, was studied. The targets for Afzelin in lung cancer were predicted using SwissTargetPrediction, Next, the GO analysis and pathway enrichment were analyzed using String. For in vitro studies, the overexpression plasmid of NQO2, the identified target of Afzelin, was transfected into Afzelin-treated cells to verify the regulatory role of Afzelin on its target and signaling pathway. Results In in vitro studies, Afzelin markedly inhibited cell viability, proliferation, and raised apoptotic rate of A549 and H1299 cells. In addition, Afzelin activated endoplasmic reticulum (ER) stress and increased ATP, HMGB1, and CRT levels in lung cancer cells, indicating that Afzelin induced immunogenic cell death (ICD). SwissTargetPrediction identified NQO2 as a target of Afzelin. Further, Afzelin markedly inhibited NQO2 protein expression and in turn, overexpression of NQO2 attenuated the effect of Afzelin on A549 and H1299 cells. Conclusion Afzelin inhibits lung cancer progression by targeting NQO2, in turn, activating ER stress and inducing ICD.

Abstracts Phosphorylation of IRF3 is critical to induce type I interferon (IFN-I) production in antiviral innate response. Here we report that lysine methyltransferase SMYD2 inhibits the expressions of IFN-I and proinflammatory cytokines in macrophages upon viral infections. The Smyd2-deficient mice are more resistant to viral infection by producing more IFN-I and proinflammatory cytokines. Mechanistically, SMYD2 inhibits IRF3 phosphorylation in macrophages in response to viral infection independent of its methyltransferase activity. We found that SMYD2 interacts with the DNA-binding domain (DBD) and IRF association domain (IAD) domains of IRF3 by its insertion SET domain (SETi) and could recruit phosphatase PP1α to enhance its interaction with IRF3, which leads to decreased phosphorylation of IRF3 in the antiviral innate response. Our study identifies SMYD2 as a negative regulator of IFN-I production against virus infection. The new way of regulating IRF3 phosphorylation will provide insight into the understanding of IFN-I production in the innate response and possible intervention of the related immune disorders.

Based on the existing research on connectors, a web-embedded composite shear connector was proposed in this paper. Further, six types of push-out specimens were carried out on static push-out and low-cycle repeated load tests. The failure forms, load–slip curves, and load–strain curves of the tests are analysed. On the basis of the experiment, the finite element analysis is also carried out to enlarge the parameters of the specimens. The results showed that the shear stiffness of the web-embedded composite shear connector was larger than that of pure stud shear connector or perfobond rib shear connector, the slip limit was smaller, and ductility was good. A parameter analysis showed that penetrating steel rebars have the greatest impact on ultimate shear bearing capacity, reaching 43.82% of ultimate shear bearing capacity. Following repeated loading, the ultimate shear bearing capacity of the specimen decreased, the ultimate slip increased, and the ductility decreased. Based on the experimental results of this study, a new calculation equation for the ultimate shear bearing capacity of a web-embedded composite shear connector was proposed with a finite element model for verification.

Abstract Objectives Previous studies have shown that there may be a positive correlation between serum uric acid levels and hyperthyroidism. However, the relationship between thyroid function and serum uric acid in healthy people is unclear. This study analyzed the relationship between impaired thyroid hormone sensitivity and serum uric acid levels, and presented them in quantitative form. Research design and methods This is a cross-sectional study of 4460 adults (male: 2300; female: 2160) who participated in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010. Parameters representing central sensitivity to thyroid hormones were calculated as: thyroid feedback quantile-based index (TFQIFT4), thyroid stimulating hormone index (TSHI), and total thyroxine (T4) resistance index (TT4RI); Peripheral sensitivity to thyroid hormone was evaluated by FT3/FT4 ratio. In addition, we have innovated total triiodothyronine (T3) resistance index (TT3RI) and TFQIFT3 indexes based on FT3 and TSH. Multiple linear regression models were used to evaluate the correlation between thyroid resistance index and serum uric acid, and the results were presented graphically as smooth curve fittings. Results Higher levels of serum uric acid were associated with decreased sensitivity to thyroid hormones in euthyroid individuals. In conjunction with an increase in the thyroid hormone sensitivity index value, uric acid levels gradually increased as well. Furthermore, we found a segmented relationship between TT3RI and serum uric acid changes. The saturation and threshold analyses indicated that 18.85 was the turning point (logarithmic likelihood ratio test = 0.036). When TT3RI 18.85, there was a significant rise in serum uric acid with an increase in TT3RI [β(95% CI) 3.94 (0.94, 6.95), P = 0.010]. A further finding of the interaction test was that impaired thyroid hormone sensitivity and uric acid changes vary among different age groups and BMI levels. Conclusions Decreased sensitivity to thyroid hormones was associated with high levels of serum uric acid in people with normal thyroid function. The interaction test shows that different age groups and BMI groups impact the association between impaired thyroid hormone sensitivity and serum uric acid. Furthermore, smooth curve fitting revealed a segmental relationship between TT3RI and serum uric acid levels.

Over-use or misuse of antibiotics in livestock and poultry production contributes to the rising threat of antibiotic resistance in animals and has negative ecological effects. Exopolysaccharides from lactic acid bacteria (LAB-EPS) are a class of biological macromolecules which are secreted by lactic acid bacteria to the outside of the cell wall during their growth and metabolism. Numerous studies demonstrated that LAB-EPS have anti-inflammatory and antimicrobial activities and are able to regulate intestinal health and the immune system in livestock. They are biodegradable, nontoxic and bio-compatible, which are considered as ideal alternatives to antibiotics. This review aims to discuss and summarize recent research findings of LAB-EPS on regulation of intestinal health and the immune system in animals, and thus provide scientific justification for commercial applications of LAB-EPS in livestock.

Abstract Background There is insufficient evidence for the ability of vitamin K2 to improve type 2 diabetes mellitus symptoms by regulating gut microbial composition. Herein, we aimed to demonstrate the key role of the gut microbiota in the improvement of impaired glycemic homeostasis and insulin sensitivity by vitamin K2 intervention. Methods We first performed a 6-month RCT on 60 T2DM participants with or without MK-7 (a natural form of vitamin K2) intervention. In addition, we conducted a transplantation of the MK-7-regulated microbiota in diet-induced obesity mice for 4 weeks. 16S rRNA sequencing, fecal metabolomics, and transcriptomics in both study phases were used to clarify the potential mechanism. Results After MK-7 intervention, we observed notable 13.4%, 28.3%, and 7.4% reductions in fasting serum glucose (P = 0.048), insulin (P = 0.005), and HbA1c levels (P = 0.019) in type 2 diabetes participants and significant glucose tolerance improvement in diet-induced obesity mice (P = 0.005). Moreover, increased concentrations of secondary bile acids (lithocholic and taurodeoxycholic acid) and short-chain fatty acids (acetic acid, butyric acid, and valeric acid) were found in human and mouse feces accompanied by an increased abundance of the genera that are responsible for the biosynthesis of these metabolites. Finally, we found that 4 weeks of fecal microbiota transplantation significantly improved glucose tolerance in diet-induced obesity mice by activating colon bile acid receptors, improving host immune-inflammatory responses, and increasing circulating GLP-1 concentrations. Conclusions Our gut-derived findings provide evidence for a regulatory role of vitamin K2 on glycemic homeostasis, which may further facilitate the clinical implementation of vitamin K2 intervention for diabetes management. Trial registration The study was registered at https://www.chictr.org.cn (ChiCTR1800019663).

The increased frequency of human infectious disease outbreaks caused by RNA viruses worldwide in recent years calls for enhanced public health surveillance for better future preparedness. Wastewater-based epidemiology (WBE) is emerging as a valuable epidemiological tool for providing timely population-wide surveillance for disease prevention and response complementary to the current clinical surveillance system. Here, we compared the analytical performance and practical applications between predominant molecular detection methods of RT-qPCR and RT-ddPCR on SARS-CoV-2 detection in wastewater surveillance. When pure viral RNA was tested, RT-ddPCR exhibited superior quantification accuracy at higher concentration levels and achieved more sensitive detection with reduced variation at low concentration levels. Furthermore, RT-ddPCR consistently demonstrated more robust and accurate measurement either in the background of the wastewater matrix or with the presence of mismatches in the target regions of the consensus assay. Additionally, by detecting mock variant RNA samples, we found that RT-ddPCR outperformed RT-qPCR in virus genotyping by targeting specific loci with signature mutations in allele-specific (AS) assays, especially at low levels of allele frequencies and concentrations, which increased the possibility for sensitive low-prevalence variant detection in the population. Our study provides insights for detection method selection in the WBE applications for future infectious disease outbreaks.

IntroductionSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Anti-B-cell-activating factor (BAFF) therapy effectively depletes B cells and reduces SLE disease activity. This research aimed to evaluate the effect of BAFF blockade on B cell receptor (BCR) repertoire and gene expression.MethodsThrough next-generation sequencing, we analyzed gene expression and BCR repertoire in MRL/lpr mice that received long-term anti-BAFF therapy. Based on gene expression profiles, we predicted the relative proportion of immune cells using ImmuCellAI-mouse, validating our predictions via flow cytometry and FluoroSpot.ResultsThe loss of BCR repertoire diversity and richness, along with increased clonality and differential frequency distribution of the immunoglobulin heavy chain variable (IGHV) segment gene usage, were observed in BAFF-blockade mice. Meanwhile, the distribution of complementarity-determining region 3 (CDR3) length and CDR3 amino acid usage remained unaffected. BAFF blockade resulted in extensive changes in gene expression, particularly that of genes related to B cells and immunoglobulins. Besides, the tumor necrosis factor (TNF)-α responses and interferon (IFN)-α/γ were downregulated, consistent with the decrease in IFN-γ and TNF-α serum levels following anti-BAFF therapy. In addition, BAFF blockade significantly reduced B cell subpopulations and plasmacytoid dendritic cells, and caused the depletion of antibody-secreting cells.DiscussionOur comparative BCR repertoire and transcriptome analyses of MRL/lpr mice subjected to BAFF blockade provide innovative insights into the molecular pathophysiology of SLE.

ABSTRACT Innate lymphoid cells (ILCs) play a crucial role in mucosal protection and tissue homeostasis. However, the early mucosal defense mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have not been fully understood to date. This knowledge gap has motivated us to develop a coronavirus disease 2019-like mouse model to investigate the interactions between the virus, its receptor, and ILCs. In our study, we conducted intranasal challenges using pseudovirus expressing Spike (PSV-S) to examine the expression patterns of humanized ACE2 (chiACE2) and the transduction of PSV-S in lung and ileum tissues over a specified time period. Within a span of 72 hours, we observed an intense viral transduction induced by the spike protein, which was detected from the central bronchus to the bronchiole and alveolus in the lung (levels 3 to 8). Similarly, we observed the transduction of PSV-S in the villi and crypts of the ileum. Interestingly, our precise three-dimensional colocalization analysis revealed that only 73.74% ± 1.76% of the PSV-S transduction depended on chiACE2. Furthermore, type 2 innate lymphoid cells (ILC2s) exhibited the most pronounced activation in the gut mucosa. This finding indicates the significant role of ILC2s as contributors to the mucosal defense against viral infections. Our data shed light on the critical involvement of ILC2s and their intricate three-dimensional regulatory network in combating SARS-CoV-2 within the mucosa. IMPORTANCE Our study revealed the spatial interaction between humanized ACE2 and pseudovirus expressing Spike, emphasizing the role of type 2 innate lymphoid cells during the initial phase of viral infection. These findings provide a foundation for the development of mucosal vaccines and other treatment approaches for both pre- and post-infection management of coronavirus disease 2019.

Construction joints accelerate concrete carbonation, which is one critical durability concern of concrete infrastructures. However, due to the lack of experimental data, it is still challenging to quantify its negative impact on concrete carbonation resistance. In this study, the carbonation depth of construction joints in the girder of Jinshan Bridge, which was exposed to an urban atmospheric condition in a metropolitan city for 30 years, were examined. Moreover, accelerated carbonation tests were conducted to investigate the effect of the water-cement ratio, compressive stress level, carbonation time, and the surface treatment of the joint on the concrete carbonation. The results showed that the joint influence factor, defined as the ratio between the depth at the joint section and the depth of monolithic concrete, ranged from 1.34 to 3.99 with a mean value of 2.26, and a lognormal distribution represented the random nature of the factor well. Furthermore, a function for predicting the distribution curve of carbonation depth for concrete with a construction joint was proposed, and methods to improve the carbonation resistance at the construction joint were suggested: reducing concrete’s water-cement ratio and applying silane impregnation on both sides of the joint within the range of 2.0 times of cover thickness.

While previous research on cancer biology has focused on genes that code for proteins, in recent years it has been discovered that non-coding RNAs (ncRNAs)play key regulatory roles in cell biological functions. NcRNAs account for more than 95% of human transcripts and are an important entry point for the study of the mechanism of cancer development. An increasing number of studies have demonstrated that ncRNAs can act as tumor suppressor genes or oncogenes to regulate tumor development at the epigenetic level, transcriptional level, as well as post-transcriptional level. Because of the importance of ncRNAs in cancer, most clinical trials have focused on ncRNAs to explore whether ncRNAs can be used as new biomarkers or therapies. In this review, we focus on recent studies of ncRNAs including microRNAs (miRNAs), long ncRNAs (lncRNAs), circle RNAs (circRNAs), PIWI interacting RNAs (piRNAs), and tRNA in different types of cancer and explore the application of these ncRNAs in the development of cancer and the identification of relevant therapeutic targets and tumor biomarkers. Graphical abstract drawn by Fidraw.

Abstract HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Renal fibrosis is a pathological endpoint of maladaptation after ischemia-reperfusion injury (IRI), and despite many attempts, no good treatment has been achieved so far. At the core of renal fibrosis is the differentiation of various types of cells into myofibroblasts. MSCs were once thought to play a protective role after renal IRI. However, growing evidence suggests that MSCs have a two-sided nature. In spite of their protective role, in maladaptive situations, MSCs start to differentiate towards myofibroblasts, increasing the myofibroblast pool and promoting renal fibrosis. Following renal IRI, it has been observed that Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Renal Resident Mesenchymal Stem Cells (RR-MSCs) play important roles. This review presents evidence supporting their involvement, discusses their potential mechanisms of action, and suggests several new targets for future research.

In recent years, traditional antibiotic efficacy outcomes have rapidly diminished due to the advent of drug resistance, and the dose limitation value has increased due to the severe side effect of globalized healthcare. Therefore, novel strategies are required to resensitize resistant pathogens to antibiotics existing in the field and prevent the emergence of drug resistance. In this study, cationic hyperbranched polylysine (HBPL-6) was synthesized using the one-pot polymerization method. HBPL-6 exhibited excellent non-cytotoxicity and bio-solubility properties. The present study also showed that HBPL-6 altered the outer membrane (OM) integrity of Escherichia coli O157:H7, Salmonella typhimurium, and Pseudomonas aeruginosa PAO1 by improving their permeability levels. When administered at a safe dosage, HBPL-6 enhanced the accumulation of rifampicin (RIF) and erythromycin (ERY) in bacteria to restore the efficacy of the antibiotics used. Moreover, the combination of HBPL-6 with colistin (COL) reduced the antibiotic dosage, which was helpful in preventing further drug-resistance outcomes. Therefore, this research provides a new strategy for reducing the dosage of drugs used to combat Gram-negative (G−) bacteria through their synergistic effects.

Summary: The roles of long noncoding RNA (lncRNA) and RNA-binding proteins (RBPs) in antiviral innate response warrant further investigation. Here, we identify an lncRNA, termed lncRNA-BTX (between Tbk1 and Xpot), which is upregulated upon viral infection via an IRF3-type I interferon-independent pathway, promoting viral innate immune escape. Deletion of lncRNA-BTX in cells or mice significantly reduces viral load in vitro or in vivo, respectively. Mechanistically, lncRNA-BTX strengthens the interactions between DHX9 or ILF3 (two RBPs that have opposite functions in regulating the replication of RNA virus) and their respective partner, JMJD6 or ILF2, which regulates intracellular translocations of DHX9 and ILF3 from the nucleus to the cytoplasm. Put simply, lncRNA-BTX facilitates DHX9’s return to the cytoplasm and retains ILF3 within the nucleus, promoting viral replication. This work unveils a strategy developed by the virus to bypass host innate immunity, thus providing a potential target for antiviral therapeutics.

BackgroundThe management of atrial fibrillation (AF) with oral anticoagulants (OAC) is generally recommended to reduce the risk of stroke. However, the decision to prescribe these medications for patients with AF and dementia remains controversial.MethodsA systematic review and meta-analysis of retrospective cohort studies were conducted. The search encompassed PubMed, Cochrane Library, Web of Science, and Embase databases from inception until May 1st, 2023, with language limited to English. Eligible studies included comparisons between exposure to OAC vs. non-OAC in the AF population with dementia or cognitive impairment. Studies that compared the effects of direct oral anticoagulants (DOAC) and vitamin-K antagonists were also included. The primary outcome was all-cause mortality, and the secondary outcomes were ischemic stroke and major bleeding. This study was registered with PROSPERO (No. CRD42023420678).ResultsA total of five studies (N = 21,962 patients) met the eligibility criteria and were included in this review. The follow-up duration ranged from 1 to 4 years. Meta-analysis demonstrated that OAC treatment was associated with a lower risk of all-cause mortality in AF patients with dementia with a hazard ratio (HR) of 0.79 and a 95% confidence interval (CI) ranging from 0.68 to 0.92, compared to non-OAC treatment. No statistical differences were observed in the risk of major bleeding (HR = 1.12, 95% CI: 0.88–1.42) or ischemic stroke (HR = 0.77, 95% CI: 0.58–1.00). Three studies reported comparisons between DOAC and warfarin; however, pooled analysis was not performed due to heterogeneity.ConclusionThe use of OACs in individuals diagnosed with both AF and dementia holds the potential to reduce all-cause mortality rates, thereby improving the overall clinical prognosis within this specific population.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420678, PROSPERO identifier, CRD42023420678.

ABSTRACT Yersinia pestis is the etiological agent of plague. Marmota himalayana of the Qinghai-Tibetan plateau is the primary host of flea-borne Y. pestis. This study is the report of isolation of Mu-like bacteriophages of Y. pestis from M. himalayana. The isolation and characterization of four Mu-like phages of Y. pestis were reported, which were named as vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 according to their morphology. Comparative genome analysis revealed that vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 are phylogenetically closest to Escherichia coli phages Mu, D108 and Shigella flexneri phage SfMu. The role of LPS core structure of Y. pestis in the phages’ receptor was pinpointed. All the phages exhibit “temperature dependent infection,” which is independent of the growth temperature of the host bacteria and dependent of the temperature of phage infection. The phages lyse the host bacteria at 37°C, but enter the lysogenic cycle and become prophages in the chromosome of the host bacteria at 26°C. IMPORTANCE Mu-like bacteriophages of Y. pestis were isolated from M. himalayana of the Qinghai-Tibetan plateau in China. These bacteriophages have a unique temperature dependent life cycle, follow a lytic cycle at the temperature of warm-blooded mammals (37°С), and enter the lysogenic cycle at the temperature of its flea-vector (26°С). A switch from the lysogenic to the lytic cycle occurred when lysogenic bacteria were incubated from lower temperature to higher temperature (initially incubating at 26°C and shifting to 37°C). It is speculated that the temperature dependent lifestyle of bacteriophages may affect the population dynamics and pathogenicity of Y. pestis.

ObjectiveTo objectively evaluate the efficacy of the Zilongjin tablets in non-small cell lung cancer (NSCLC) and to explore its potential mechanism of action against NSCLC and COVID-19 based on network pharmacology.MethodsThe database was searched for randomized controlled trials (RCTs) of the Zilongjin tablets for NSCLC published up to 22 August 2022. The quality of included trials was assessed using Cochrane standard guidelines, and a meta-analysis was performed using Rev Man 5.3. Gene targets for intersections of NSCLC and COVID-19 (the NC) and drugs were obtained from the TCMSP database, HERB database, GeneCards database, and the NCBI database for network pharmacology research.ResultsMeta-analysis included 14 articles with 2,430 patients. The meta-analysis showed that the Zilongjin tablets combined with conventional chemotherapy were significantly more effective than chemotherapy alone in the treatment of NSCLC. A total of 29 drug-disease intersecting targets were identified in the network pharmacology. The “ingredient-target-pathway” diagram component-target-pathway network contained 119 nodes and 429 edges, with the majority of targets associated with inflammatory responses.ConclusionThe efficacy and quality of life of the Zilongjin tablets combined conventional chemotherapy for NSCLC were significantly better than chemotherapy alone, alleviating various adverse effects. At the same time, the Zilongjin tablets may modulate the inflammatory response to alleviate NSCLC and COVID-19.

The convergence of networking and cloud computing leads to an increasing number of cloud based services and applications, which require to be processed by network nodes with enough resources. There are multiple available nodes in the network and network operators need to find paths to forward the traffic to these nodes for processing. In addition, services and application may have diversified requirements on the paths in terms of bandwidth, delay, jitter, etc. Therefore, network operators need to determine the optimal paths considering multiple criteria. However, single-criterion based shortest path algorithms are often used to compute paths from a source node to one target node, which may result in uneven traffic distribution and low resource utilization. Furthermore, the paths obtained are only optimal to this criterion and may not satisfy the Service Level Agreement (SLA) requirements. Therefore, in this paper, we propose a multi-criteria path finding method to obtain all the Pareto-optimal paths from a source node to multiple target nodes (destinations). We extend an existing effective multi-criteria routing algorithm (ParetoBFS), and integrate a multi-queues based bidirectional search mechanism. Additionally, we use a topology sampling technique to accelerate path computation. We evaluate the performance of these path finding methods using various topologies with multiple criteria including bottleneck and additive types. Experimental results demonstrate that our approach can reduce the running time by 54% −89% in different topologies compared to the ParetoBFS algorithm. By employing topology sampling, we further improve our algorithm’s speed while still finding most of the Pareto-optimal paths.

With the widespread use of sensory profiling methods in the food industry and the increasing demands of researchers on analytical techniques, rapid sensory analysis methods have emerged, one of which is projective mapping. projective mapping can quickly collect sensory attributes of products and analyze the similarity or difference of sensory characteristics among products, it can also be combined with preference questionnaires to distinguish people categories and explore the factors affecting consumer preferences. This paper examines the literature related to the projective mapping method in recent years, introduces the experimental procedure, influencing factors and data processing of the method, advantages and limitations, derivative methods and their research in different types of food products, and looks forward to the development of this method, in order to provide reference for researchers and enterprises infields related to food sensory evaluation.

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, immune complex deposition, and tissue/organ damage. In this study, we aimed to identify molecular features and signaling pathways associated with SLE severity using RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and clinical parameters.Methods: We analyzed transcriptome profiles of 45 SLE patients, grouped into mild (mSLE, SLEDAI ≤ 9) and severe (sSLE, SLEDAI > 9) based on SLE Disease Activity Index (SLEDAI) scores. We also collected clinical data on anti-dsDNA, ANA, ESR, CRP, snRNP, AHA, and anti-Smith antibody status for each patient.Results: By comparing gene expression across groups, we identified 12 differentially expressed genes (DEGs), including 7 upregulated (CEACAM6, UCHL1, ARFGEF3, AMPH, SERPINB10, TACSTD2, and OTX1) and 5 downregulated (SORBS2, TRIM64B, SORCS3, DRAXIN, and PCDHGA10) DEGs in sSLE compared to mSLE. Furthermore, using the CIBERSORT algorithm, we found that Treg cells were significantly decreased in sSLE and negatively correlated with AMPH expression, which was mainly expressed in Treg cells from SLE patients according to public scRNA-seq data (GSE135779).Discussion: Overall, our findings shed light on the molecular mechanisms underlying SLE severity and provide insight into potential therapeutic targets.

Glass fiber reinforced polymer (GFRP) bar reinforced ultra-high performance concrete (UHPC) (GFRP-UHPC) members’ tensile performance should be significantly different from that of steel-UHPC members due to differences between GFRP and steel bars in mechanical and bond properties. In this paper, six dog-bone shaped specimens with different types of reinforcement materials, rebar diameters, and quantities of rebars were fabricated and tested under axial tension, and their failure modes, load-displacement curves, and cracking behavior were recorded and investigated. Furthermore, an extensive nonlinear finite element analysis considering the bond behavior between rebars and UHPC was conducted. Finally, formulas were proposed to predict the tensile stiffness and ultimate tensile capacity of GFRP-UHPC members. Results confirmed that bond shear strength (τcs) and stiffness (K) of the GFRP and UHPC interface were the key factors that affected GFRP-UHPC members’ tensile performance: τcs mainly determined the failure mode; increasing K and the reinforcement ratio can improve the post-cracking stiffness and obtain tension hardening behavior; the wedging effect caused the post-cracking curve of the tension member in bond failure mode re-ascend periodically. The proposed formulas could produce accurate and safe predictions after comparing predicted results with experimental and simulation results. This study provides the underlying insights needed to guide the design of GFRP-UHPC members.

ObjectivePost-hepatectomy liver failure (PHLF) remains clinical challenges after major hepatectomy. The aim of this study was to establish and validate a deep learning model to predict PHLF after hemihepatectomy using preoperative contrast-enhancedcomputed tomography with three phases (Non-contrast, arterial phase and venous phase).Methods265 patients undergoing hemihepatectomy in Sir Run Run Shaw Hospital were enrolled in this study. The primary endpoint was PHLF, according to the International Study Group of Liver Surgery’s definition. In this study, to evaluate the proposed method, 5-fold cross-validation technique was used. The dataset was split into 5 folds of equal size, and each fold was used as a test set once, while the other folds were temporarily combined to form a training set. Performance metrics on the test set were then calculated and stored. At the end of the 5-fold cross-validation run, the accuracy, precision, sensitivity and specificity for predicting PHLF with the deep learning model and the area under receiver operating characteristic curve (AUC) were calculated.ResultsOf the 265 patients, 170 patients with left liver resection and 95 patients with right liver resection. The diagnosis had 6 types: hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver metastases, benign tumor, hepatolithiasis, and other liver diseases. Laparoscopic liver resection was performed in 187 patients. The accuracy of prediction was 84.15%. The AUC was 0.7927. In 170 left hemihepatectomy cases, the accuracy was 89.41% (152/170), and the AUC was 82.72%. The accuracy was 77.47% (141/182) with liver mass, 78.33% (47/60) with liver cirrhosis and 80.46% (70/87) with viral hepatitis.ConclusionThe deep learning model showed excellent performance in prediction of PHLF and could be useful for identifying high-risk patients to modify the treatment planning.

Plague caused by Yersinia pestis remains a public health threat worldwide. Because multidrug-resistant Y. pestis strains have been found in both humans and animals, phage therapy has attracted increasing attention as an alternative strategy against plague. However, phage resistance is a potential drawback of phage therapies, and the mechanism of phage resistance in Y. pestis is yet to be investigated. In this study, we obtained a bacteriophage-resistant strain of Y. pestis (S56) by continuously challenging Y. pestis 614F with the bacteriophage Yep-phi. Genome analysis identified three mutations in strain S56: waaA* (9-bp in-frame deletion 249GTCATCGTG257), cmk* (10-bp frameshift deletion 15CCGGTGATAA24), and ail* (1-bp frameshift deletion A538). WaaA (3-deoxy-D-manno-octulosonic acid transferase) is a key enzyme in lipopolysaccharide biosynthesis. The waaA* mutation leads to decreased phage adsorption because of the failure to synthesize the lipopolysaccharide core. The mutation in cmk (encoding cytidine monophosphate kinase) increased phage resistance, independent of phage adsorption, and caused in vitro growth defects in Y. pestis. The mutation in ail inhibited phage adsorption while restoring the growth of the waaA null mutant and accelerating the growth of the cmk null mutant. Our results confirmed that mutations in the WaaA–Cmk–Ail cascade in Y. pestis contribute to resistance against bacteriophage. Our findings help in understanding the interactions between Y. pestis and its phages.

The escalating frequency and severity of extreme climate greatly impact the carbon dynamics of terrestrial ecosystems worldwide. To understand the multi-temporal response of net ecosystem productivity (NEP) to extreme climate, we investigated 11 temperature and precipitation extreme indices across different vegetation types in China. From 1981 to 2019, the results showed that NEP in China increased at a rate of 0.64 g·m−2·a−2. Extreme climate demonstrated a significant warming trend and a non-significant moistening trend; specifically, maximum daily minimum temperature (TNx) exhibited a significant increase at a rate of 0.34 °C/10 a, while maximum 5-day precipitation (Rx5day) showed an insignificant increase at a rate of 1.78 mm/10 a. NEP was significantly impacted by extreme temperature at the annual, seasonal, and monthly scales, but moderately impacted by extreme precipitation. Specifically, extreme temperature had the most significant effect on grassland, with minimal influence on cropland. In contrast, extreme precipitation had the most significant effect on forest, with minimal impact on cropland. Moreover, the lagged time for extreme precipitation was longer than that for extreme temperature. Extreme precipitation exhibited a corresponding lagged time of at least 2 months (p < 0.01), while extreme temperature exhibited a lagged time of at least 1 month (p < 0.01). The maximum lag time observed was 4 months (p < 0.01). Our findings provide valuable insights into the multi-temporal response of NEP to extreme climate in China and inform sustainable development practices in the region.

Abstract Background Repressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer’s disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy. Methods Participants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis. Results The plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02). Conclusion The plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

Background:Dendrobium nobile (D. nobile), a traditional Chinese medicine, has received attention as an anti-tumor drug, but its mechanism is still unclear. In this study, we applied network pharmacology, bioinformatics, and in vitro experiments to explore the effect and mechanism of Dendrobin A, the active ingredient of D. nobile, against pancreatic ductal adenocarcinoma (PDAC).Methods: The databases of SwissTargetPrediction and PharmMapper were used to obtain the potential targets of Dendrobin A, and the differentially expressed genes (DEGs) between PDAC and normal pancreatic tissues were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression databases. The protein-protein interaction (PPI) network for Dendrobin A anti-PDAC targets was constructed based on the STRING database. Molecular docking was used to assess Dendrobin A anti-PDAC targets. PLAU, one of the key targets of Dendrobin A anti-PDAC, was immunohistochemically stained in clinical tissue arrays. Finally, in vitro experiments were used to validate the effects of Dendrobin A on PLAU expression and the proliferation, apoptosis, cell cycle, migration, and invasion of PDAC cells.Results: A total of 90 genes for Dendrobin A anti-PDAC were screened, and a PPI network for Dendrobin A anti-PDAC targets was constructed. Notably, a scale-free module with 19 genes in the PPI indicated that the PPI is highly credible. Among these 19 genes, PLAU was positively correlated with the cachexia status while negatively correlated with the overall survival of PDAC patients. Through molecular docking, Dendrobin A was found to bind to PLAU, and the Dendrobin A treatment led to an attenuated PLAU expression in PDAC cells. Based on clinical tissue arrays, PLAU protein was highly expressed in PDAC cells compared to normal controls, and PLAU protein levels were associated with the differentiation and lymph node metastatic status of PDAC. In vitro experiments further showed that Dendrobin A treatment significantly inhibited the proliferation, migration, and invasion, inducing apoptosis and arresting the cell cycle of PDAC cells at the G2/M phase.Conclusion: Dendrobin A, a representative active ingredient of D. nobile, can effectively fight against PDAC by targeting PLAU. Our results provide the foundation for future PDAC treatment based on D. nobile.

Little is known about the effects of grassland degradation on the carbohydrate-active enzyme (CAZYme) genes responsible for C cycling. Here we used a metagenomic approach to reveal variation in abundance and composition of CAZyme genes in grassland experiencing a range of degradation severity (i.e., non-, light, moderately, and severely degraded) in two soil layers (0–10 cm, 10–20 cm) in a steppe grassland in northern China. We observed a higher CAZyme abundance in severely degraded grassland compared with the other three degradation severities. Glycoside hydrolase (GH) and glycosyltransferase (GT) were identified as the most abundant gene families. The Mantel test and variation partitioning suggested an interactive effect of degradation severity and soil depth with respect to CAZyme gene composition. Structural equation modeling indicated that total soil carbon, microbial biomass carbon and organic carbon were the three soil characteristics most important to CAZyme abundance, which suggests an interaction between degradation and soil carbon fractions in determining CAZyme gene composition. Both above- and below-ground factors linked to soil organic matter play a central role in determining the abundance of CAZyme gene families.

Abstract Background Low-frequency electroacupuncture (EA) has been shown to ameliorate obesity and reproductive dysfunctions in patients with polycystic ovary syndrome (PCOS), and further explorations in PCOS-like rats showed that EA could affect white adipose tissue. However, the function and neuromodulation of brown adipose tissue (BAT) in PCOS and after EA treatment have remained unknown. The present study focused on the role of BAT in PCOS-like rats and its relationship with EA and characterized the three-dimensional (3D) innervation of BAT associated with activation molecules. Methods Female rats (21 days old) were implanted with dihydrotestosterone or fed with a high fat diet to establish PCOS-like and obesity models, respectively, and then EA treatment at “Guilai” (ST 29) and “Sanyinjiao” (SP 6) was carried out for 4 weeks. In the present study, morphological analysis, 3D imaging, molecular biology, and other experimental techniques were used to study the sympathetic nerves and activity of BAT. Results PCOS-like rats showed both obvious weight gain and reproductive dysfunction, similar to what was seen in obese rats except for the absence of reproductive dysfunction. The body weight gain was mainly caused by an increase in white adipose tissue, and there was an abnormal decrease in BAT. Because both the lipid metabolism and reproductive disorders could be improved with bilateral EA at “Guilai” (ST 29) and “Sanyinjiao” (SP 6), especially the restoration of BAT, we further investigated the neuromodulation and inflammation in BAT and identified the sympathetic marker tyrosine hydroxylase as one of the key factors of sympathetic nerves. Modified adipo-clearing technology and 3D high-resolution imaging showed that crooked or dispersed sympathetic nerves, but not the twisted vasculature, were reconstructed and associated with the activation of BAT and are likely to be the functional target for EA treatment. Conclusion Our study highlights the significant role of BAT and its sympathetic innervations in PCOS and in EA therapy.