Pancreatic STAT5 activation promotes KrasG12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear. DESIGN: We performed studies with LSL-Kras G12D; Ptf1a-Cre ERT (KCERT) mice or LSL-KrasG12D; LSL-Trp53R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice. RESULTS: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1ß and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation. CONCLUSION: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.

Joint effect of black carbon deriving from wheat straw burning and plastic mulch film debris on the soil biochemical properties, bacterial and fungal communities.

Black carbon (BC) formed after straw burning remains in farmland soil and coexists with plastic mulch film (PMF) debris. It is unclear how BC influences soil multifunctionality in the presence of PMF debris. In this study, we determined the joint effects of BC and PMF debris on soil biochemical properties and microbial communities. We conducted a soil microcosm experiment by adding BC formed by direct burning of wheat straw and PMF debris (polyethylene (PE) and biodegradable PMF (BP)) into soil at the dosages of 1 %, and soils were sampled on the 15th, 30th, and 100th day of soil incubation for high-throughput sequencing. The results showed that the degradation of PMF debris was accompanied by the release of microplastics (MPs). BC decreased NH4+-N (PE: 68.63 %; BP: 58.97 %) and NO3--N (PE: 12.83 %; BP: 51.37 %) and increased available phosphorus (AP) (PE: 79.12 %; BP: 26.09 %) in soil containing PMF debris. There were significant differences in enzyme activity among all the treatments. High-throughput sequencing indicated that BC reduced bacterial and fungal richness and fungal diversity in PMF debris-exposed soil, whereas PMF debris and BC resulted in significant changes in the proportion of dominant phyla and genera of bacteria and fungi, which were affected by incubation time. Furthermore, BC affected microorganisms by influencing soil properties, and pH and N content were the main influencing factors. In addition, FAPRPTAX analysis indicated that BC and PMF debris affected soil C and N cycling. These findings provide new insights into the response of soil multifunctionality to BC and PMF debris.

Transcriptome analysis of Vero cells infected with attenuated vaccine strain CDV-QN-1.

To better understand the interaction between attenuated vaccines and host antiviral responses, we used bioinformatics and public transcriptomics data to analyze the immune response mechanisms of host cells after canine distemper virus (CDV) infection in Vero cells and screened for potential key effector factors. In this study, CDV-QN-1 infect with Vero cells at an MOI of 0.5, and total RNA was extracted from the cells 24 h later and reverse transcribed into cDNA. Transcriptome high-throughput sequencing perform using Illumina. The results showed that 438 differentially expressed genes were screened, of which 409 were significantly up-regulated and 29 were significantly down-regulated. Eight differentially expressed genes were randomly selected for RT-qPCR validation, and the change trend was consistent with the transcriptomics data. GO and KEGG analysis of differentially expressed genes revealed that most of the differentially expressed genes in CDV-QN-1 infection in the early stage were related to immune response and antiviral activity. The enriched signaling pathways mainly included the interaction between cytokines and cytokine receptors, the NF-kappa B signaling pathway, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway. This study provides a foundation for further exploring the pathogenesis of CDV and the innate immune response of host cells in the early stage of infection.

Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk.

Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.

Global evolutionary dynamics of virulence genes in ST11-KL47 carbapenem-resistant Klebsiella pneumoniae.

ST11-KL47 is a hypervirulent carbapenem-resistant Klebsiella pneumoniae (CRKP) that is highly prevalent in China and poses a major public health risk. To investigate the evolutionary dynamics of virulence genes in this subclone, we analysed 78 sequenced isolates obtained from a long-term study across 29 centres from 17 cities in China. Virulence genes were located in large hybrid pNDM-Mar-like plasmids (length: ∼266 kilobases) rather than in classical pK2044-like plasmids. These hybrid plasmids, derived from the fusion of pK2044 and pNDM-Mar plasmids mediated by insertion sequence (IS) elements (such as ISKpn28 and IS26), integrated virulence gene fragments into the chromosome. Analysis of 217 sequences containing the special IncFIB(pNDM-Mar) replicon using public databases indicated that these plasmids typically contained T4SS-related and multiple antimicrobial resistance genes, were present in 24 countries, and were found in humans, animals, and the environment. Notably, the chromosomal integration of virulence genes was observed in strains across five countries across two continents. In vivo and in vitro models showed that the large hybrid plasmid increased the host fitness cost while increasing virulence. Conversely, virulence genes transferred to chromosomes resulted in increased fitness and lower virulence. In conclusion, virulence genes in the plasmids of ST11-KL47 CRKP are evolving, driven by adaptive negative selection, to enable vertical chromosomal inheritance along with conferring a survival advantage and low pathogenicity.

Enhancing Phosphorus Release from Sewage Sludge in Anaerobic Digestion via Thermal Hydrolysis Pretreatment: Insights from Phosphorus Speciation and Molecular Biological Pathways.

This study explores the mechanisms enhancing phosphorus (P) release from sludge in anaerobic digestion (AD) with thermal hydrolysis pretreatment (THP) using sequential chemical extraction, X-ray absorption near-edge structure spectroscopy (XANES), 31P NMR, and multiomics. THP-treated sludge notably increased liquid-phase P by 53.8% over 3 days compared to sewage sludge (SS), identifying solid-phase Fe-P as the primary P source. The THP+AD also provided a higher abundance of bacteria that contributed to P release through multiple pathways (MPRPB), whereas SS+AD enriched some microbial species with single P release pathway. Moreover, species co-occurrence network analysis underlined the pivotal role of P-releasing bacteria in THP+AD, with 8 out of 16 keystones being P-releasers. Among the 63 screened genes that were related to P transformations and release, the poly beta-hydroxybutyrate (PHB) synthesis genes associated with polyphosphate bacteria-mediated P release were more abundant in THP+AD than in SS+AD. Furthermore, the upregulation of genes involved in methyl phosphonate metabolism in the THP-treated sludge enhanced the methane production potential of the AD process. These findings suggested that MPRPB were indeed the main contributors to P release, and enrichment in the THP+AD process enhanced their capability for P liberation.

Targeting KPNB1 with genkwadaphnin suppresses gastric cancer progression through the Nur77-mediated signaling pathway.

Gastric cancer (GC) remains a global challenge due to the lack of early detection and precision therapies. Genkwadaphnin (DD1), a natural diterpene isolated from the bud of Flos GenkWa (Thymelaeaceae), serves as a Karyopherin ß1 (KPNB1) inhibitor. In this study, we investigated the anti-tumor effect of DD1 in both cell culture and animal models. Our findings reveal that KPNB1, a protein involved in nuclear import, was highly expressed in GC tissues and associated with a poor prognosis in patients. We demonstrated that DD1, alongside the established KPNB1 inhibitor importazole (IPZ), inhibited GC cell proliferation and tumor growth by enhancing both genomic and non-genomic activity of Nur77. DD1 and IPZ reduced the interaction between KPNB1 and Nur77, resulting in Nur77 cytoplasmic accumulation and triggering mitochondrial apoptosis. The inhibitors also increased the expression of the Nur77 target apoptotic genes ATF3, RB1CC1 and PMAIP1, inducing apoptosis in GC cell. More importantly, loss of Nur77 effectively rescued the inhibitory effect of DD1 and IPZ on GC cells in both in vitro and in vivo experiments. In this study, we for the first time explored the relationship between KPNB1 and Nur77, and found KPNB1 inhibition could significantly increase the expression of Nur77. Moreover, we investigated the function of KPNB1 in GC for the first time, and the results suggested that KPNB1 could be a potential target for cancer therapy, and DD1 might be a prospective therapeutic candidate.

Antibiotic-Induced Gut Microbial Dysbiosis Reduces the Growth of Weaning Rats via FXR-Mediated Hepatic IGF-2 Inhibition.

The gut microbiota plays a crucial role in postnatal growth, particularly in modulating the development of animals during their growth phase. In this study, we investigated the effects of antibiotic-induced dysbiosis of the gut microbiota on the growth of weaning rats by administering a non-absorbable antibiotic cocktail (ABX) in water for 4 weeks. ABX treatment significantly reduced body weight and feed intake in rats. Concurrently, ABX treatment decreased microbial abundance and diversity in rat ceca, predominantly suppressing microbes associated with bile salt hydrolase (BSH) activity. Furthermore, decreased appetite may be attributed to elevated levels of glucagon-like peptide-1 (GLP-1) in the serum, along with reduced neuropeptide Y (NPY) and increased cocaine and amphetamine-regulated transcript (CART) in the hypothalamus at the mRNA level. Importantly, concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) were decreased in the serum and liver of antibiotic-treated rats. These alterations were associated with significant down-regulation of IGF-2 mRNA in the liver and significantly decreased farnesoid X receptor (FXR) protein expression and binding to the IGF-2 promoter. These results indicate that antibiotic-induced gut microbial dysbiosis not only impacts bile acid metabolism but also diminishes rat growth through the FXR-mediated IGF-2 pathway.

Unveiling the landscape predictors of resilient vegetation in coastal wetlands to inform conservation in the face of climate extremes.

Unveiling spatial variation in vegetation resilience to climate extremes can inform effective conservation planning under climate change. Although many conservation efforts are implemented on landscape scales, they often remain blind to landscape variation in vegetation resilience. We explored the distribution of drought-resilient vegetation (i.e., vegetation that could withstand and quickly recover from drought) and its predictors across a heterogeneous coastal landscape under long-term wetland conversion, through a series of high-resolution satellite image interpretations, spatial analyses, and nonlinear modelling. We found that vegetation varied greatly in drought resilience across the coastal wetland landscape and that drought-resilient vegetation could be predicted with distances to coastline and tidal channel. Specifically, drought-resilient vegetation exhibited a nearly bimodal distribution and had a seaward optimum at ~2 km from coastline (corresponding to an inundation frequency of ~30%), a pattern particularly pronounced in areas further away from tidal channels. Furthermore, we found that areas with drought-resilient vegetation were more likely to be eliminated by wetland conversion. Even in protected areas where wetland conversion was slowed, drought-resilient vegetation was increasingly lost to wetland conversion at its landward optimum in combination with rapid plant invasions at its seaward optimum. Our study highlights that the distribution of drought-resilient vegetation can be predicted using landscape features but without incorporating this predictive understanding, conservation efforts may risk failing in the face of climate extremes.

Polymer-based cascaded waveguide Bragg grating for blood glucose sensing.

Waveguide Bragg grating (WBG) blood glucose sensing, as a biological sensing technology with broad application prospects, plays an important role in the fields of health management and medical treatment. In this work, a polymer-based cascaded WBG is applied to glucose detection. We investigated photonic devices with two different grating structures cascaded-a crossed grating and a bilateral grating-and analyzed the effects of the crossed grating period, bilateral grating period, and number of grating periods on the sensing performance of the glucose sensor. Finally, the spectral reflectance characteristics, response time, and sensing specificity of the cascaded WBG were evaluated. The experimental results showed that the glucose sensor has a sensitivity of 175 nm/RIU in a glucose concentration range of 0-2 mg/ml and has the advantages of high integration, a narrow bandwidth, and low cost.

CK2-HTATSF1-TOPBP1 signaling axis modulates tumor chemotherapy response.

Homologous recombination (HR) plays a key role in maintaining genomic stability, and the efficiency of the HR system is closely associated with tumor response to chemotherapy. Our previous work reported that CK2 kinase phosphorylates HIV Tat-specific factor 1 (HTATSF1) Ser748 to facilitate HTATSF1 interaction with TOPBP1, which in turn, promotes RAD51 recruitment and HR repair. However, the clinical implication of the CK2-HTATSF1-TOPBP1 pathway in tumorigenesis and chemotherapeutic response remains to be elucidated. Here, we report that the CK2-HTATSF1-TOPBP1 axis is generally hyperactivated in multiple malignancies and renders breast tumors less responsive to chemotherapy. In contrast, deletion mutations of each gene in this axis, which also occur in breast and lung tumor samples, predict higher HR deficiency scores, and tumor cells bearing a loss-of-function mutation of HTATSF1 are vulnerable to poly(ADP-ribose) polymerase inhibitors or platinum drugs. Taken together, our study suggests that the integrity of the CK2-HTATSF1-TOPBP1 axis is closely linked to tumorigenesis and serves as an indicator of tumor HR status and modulates chemotherapy response.

Recent advances on greenhouse gas emissions from wetlands: Mechanism, global warming potential, and environmental drivers.

Greenhouse gas (GHG) emissions from wetlands have exacerbated global warming, attracting worldwide attention. However, the research process and development trends in this field remain unknown. Herein, 1865 papers related to wetlands GHG emissions published from January 2000 to December 2023 were selected, and CiteSpace and VOSviewer were used for bibliometric analysis to visually analyze the publications distribution, research authors, organizations and countries, core journal and keywords, and discussed the research progress, trends and hotspots in the fields. Over the past 24 years, the research has gone through three phases: the "embryonic" stage (2000-2006), the accumulation stage (2007-2014), and the acceleration stage (2015-2023). China has played a pivotal role in this domain, publishing the most papers and working closely with the United States, United Kingdom, Canada, Germany, and Australia. In addition, this study synthesized 311 field observations from 123 publications to analyze the variability in GHG emissions and their driving factors in four different types of natural wetlands. The results suggested that the average carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) fluxes in different wetlands were significantly different. River wetlands exhibited the highest GHG fluxes, while marsh wetlands demonstrated greater global warming potential (GWP). The average CO2, CH4 and N2O fluxes were 60.41 mg m-2·h-1, 2.52 mg m-2·h-1 and 0.05 mg m-2·h-1, respectively. The GWP of Chinese natural wetlands was estimated as 648.72 Tg·CO2-eq·yr-1, and CH4 contributed the largest warming effect, accounting for 57.43%. Correlation analysis showed that geographical location, climate factors, and soil conditions collectively regulated GHG emissions from wetlands. The findings provide a new perspective on sustainable wetland management and reducing GHG emissions.

Sulfadiazine proliferated antibiotic resistance genes in the phycosphere of Chlorella pyrenoidosa: Insights from bacterial communities and microalgal metabolites.

The phycosphere is an essential ecological niche for the proliferation of antibiotic resistance genes (ARGs). However, how ARGs' potential hosts change and the driving mechanism of metabolites under antibiotic stress in the phycosphere have seldom been researched. We investigated the response of Chlorella pyrenoidosa and the structure and abundance of free-living (FL) and particle-attached (PA) bacteria, ARGs, and metabolites under sulfadiazine by using real-time quantitative PCR, 16 S rRNA high-throughput. The linkage of key bacterial communities, ARGs, and metabolites through correlations was established. Through analysis of physiological indicators, Chlorella pyrenoidosa displayed a pattern of "low-dose promotion and high-dose inhibition" under antibiotic stress. ARGs were enriched in the PA treatment groups by 117 %. At the phylum level, Proteobacteria, Bacteroidetes, and Actinobacteria as potential hosts for ARGs. At the genus level, potential hosts included Sphingopyxis, SM1A02, Aquimonas, Vitellibacter, and Proteiniphilum. Middle and high antibiotic concentrations induced the secretion of metabolites closely related to potential hosts by algae, such as phytosphingosine, Lysophosphatidylcholine, and α-Linolenic acid. Therefore, changes in bacterial communities indirectly influenced the distribution of ARGs through alterations in metabolic products. These findings offer essential details about the mechanisms behind the spread and proliferation of ARGs in the phycosphere.

Deciphering the Impact of ZnO Nanoparticles and a Sunscreen Product Containing ZnO on Phosphorus Dynamics and Release in Chlorella pyrenoidosa in Aquatic Systems.

Zinc oxide nanoparticles (ZnO NPs) expedite the conversion of organic phosphorus (OP) into PO4-P (Pi), facilitating phosphorus (P) absorption by algae. Our study explored the mechanisms of converting OP (2-aminoethylphosphonic acid (AEP) and ß-glycerol phosphate (ß-GP)) into Pi in Chlorella pyrenoidosa under P deficiency with sunscreen and ZnO NPs. Cell density followed the order of K2HPO4 > ß-GP+ZnO > ß-GP > AEP+ZnO > AEP > P-free. ZnO NPs promoted the conversion of ß-GP, containing C-O-P bonds (0.028-0.041 mg/L), into Pi more efficiently than AEP, which possesses C-P bonds (0.022-0.037 mg/L). Transcriptomics revealed Pi transport/metabolism (phoB (3.99-12.01 fold), phoR (2.20-5.50 fold), ppa (4.49-10.40 fold), and ppk (2.50-5.40 fold)) and phospholipid metabolism (SQD1 (1.85-2.79 fold), SQD2 (2.60-6.53 fold), MGD (2.13-3.21 fold), and DGD (4.08-7.56 fold)) were up-regulated compared to K2HPO4. 31P nuclear magnetic resonance spectroscopy identified intracellular P as polyphosphate, orthophosphate, and pyrophosphate. Synchrotron radiation-based X-ray near-edge structure spectroscopy indicated that K2HPO4 and Zn3(PO4)2 in ß-GP+ZnO were increased by 8.09% and 7.28% compared to AEP+ZnO, suggesting superior P storage in ß-GP+ZnO. Overall, ZnO NPs improved photoinduced electron-hole pair separation and charge separation efficiency and amplified the ·OH and ·O2- levels, promoting OP photoconversion into Pi and algae growth.

Association of gastrointestinal microbiome and obesity with gestational diabetes mellitus-an updated globally based review of the high-quality literatures.

OBJECTIVES: The purpose of this review is to investigate the relationship between gastrointestinal microbiome, obesity, and gestational diabetes mellitus (GDM) in an objective manner. METHODS: We conducted a thorough and comprehensive search of the English language literatures published in PubMed, Web of Science, and the Cochrane Library from the establishment of the library until 12 December 2023. Our search strategy included both keywords and free words searches, and we strictly applied inclusion and exclusion criteria. Meta-analyses and systematic reviews were prepared. RESULTS: Six high-quality literature sources were identified for meta-analysis. However, after detailed study and analysis, a certain degree of heterogeneity was found, and the credibility of the combined analysis results was limited. Therefore, descriptive analyses were conducted. The dysbiosis of intestinal microbiome, specifically the ratio of Firmicutes/Bacteroides, is a significant factor in the development of metabolic diseases such as obesity and gestational diabetes. Patients with intestinal dysbiosis and obesity are at a higher risk of developing GDM. CONCLUSIONS: During pregnancy, gastrointestinal microbiome disorders and obesity may contribute to the development of GDM, with all three factors influencing each other. This finding could aid in the diagnosis and management of patients with GDM through further research on their gastrointestinal microbiome.

The impacts of learning motivation, emotional engagement and psychological capital on academic performance in a blended learning university course.

Introduction: This study aims to explore the relationships among psychological capital, learning motivation, emotional engagement, and academic performance for college students in a blended learning environment. Method: The research consists of two studies: Study 1 primarily focuses on validating, developing, revising, and analyzing the psychometric properties of the scale using factor analysis, while Study 2 employs structural equation modeling (SEM) to test the hypotheses of relationships of included variables and draw conclusions based on 745 data collected in a university in China. Results: Findings revealed that intrinsic motivation, extrinsic motivation, emotional engagement, and psychological capital all impact academic performance. Extrinsic learning motivation has significant positive direct effects on intrinsic learning motivation, emotional engagement, and psychological capital. Intrinsic motivation mediates the relationship between extrinsic motivation and academic performance. Discussion: In future blended learning practices, it is essential to cultivate students' intrinsic learning motivation while maintaining a certain level of external learning motivation. It is also crucial to stimulate and maintain students' emotional engagement, enhance their sense of identity and belonging, and recognize the role of psychological capital in learning to boost students' confidence, resilience, and positive emotions.

Study on the Flow Field Distribution in Microfluidic Cells for Surface Plasmon Resonance Array Detection.

This research is dedicated to optimizing the design of microfluidic cells to minimize mass transfer effects and ensure a uniform flow field distribution, which is essential for accurate SPR array detection. Employing finite element simulations, this study methodically explored the internal flow dynamics within various microfluidic cell designs to assess the impact of different contact angles on flow uniformity. The cells, constructed from Polydimethylsiloxane (PDMS), were subjected to micro-particle image velocimetry to measure flow velocities in targeted sections. The results demonstrate that a contact angle of 135° achieves the most uniform flow distribution, significantly enhancing the capability for high-throughput array detection. While the experimental results generally corroborated the simulations, minor deviations were observed, likely due to fabrication inaccuracies. The microfluidic cells, evaluated using a custom-built SPR system, showed consistent repeatability.

Remote Sensing Monitoring of Grassland Locust Density Based on Machine Learning.

The main aim of this study was to utilize remote sensing data to establish regression models through machine learning to predict locust density in the upcoming year. First, a dataset for monitoring grassland locust density was constructed based on meteorological data and multi-source remote sensing data in the study area. Subsequently, an SVR (support vector regression) model, BP neural network regression model, random forest regression model, BP neural network regression model with the PCA (principal component analysis), and deep belief network regression model were built on the dataset. The experimental results show that the random forest regression model had the best prediction performance among the five models. Specifically, the model achieved a coefficient of determination (R2) of 0.9685 and a root mean square error (RMSE) of 1.0144 on the test set, which were the optimal values achieved among all the models tested. Finally, the locust density in the study area for 2023 was predicted and, by comparing the predicted results with actual measured data, it was found that the prediction accuracy was high. This is of great significance for local grassland ecological management, disaster warning, scientific decision-making support, scientific research progress, and sustainable agricultural development.