Reduction of Ketones and Coupling of Ketyls by a Zn-Zn-Bonded Compound.

The α-diimine-ligated Zn-Zn-bonded compound [K(THF)2]2[LZn-ZnL] (1, L = [(2,6-iPr2C6H3)NC(Me)]22-) displays diverse reactivities toward a variety of ketones. In the reaction of 1 with benzophenone or 4,4'-di-tert-butylbenzophenone, a multielectron transfer process was observed to give bimetallic (Zn/K) complexes with both ketyl radical fragments and C-C coupled pinacolate moieties (products 2 and 3). In contrast, treating 1 with 9-fluorenone only afforded pinacolate complex 5. Moreover, the reactions of 1 with N- or O-heterocycle-functionalized ketones, i.e., di(2-pyridyl)ketone, 2,2-pyrrolidinone, 9-xanthenone, or 10-methyl-9(10H)-acridone, were also carried out. Besides different transformations of the ketone moiety, the heteroatoms (nitrogen or oxygen) are also involved in coordination with zinc or potassium ions, yielding discrete aggregates or polymeric structures of products 6-9.

Establishment and Application of a Novel Genetic Detection Panel for SNPs in Mongolian Gerbils.

The Mongolian gerbil is a distinctive experimental animal in China, as its genetic qualities possess significant value in the field of medical biology research. Here, we aimed to establish an economical and efficient panel for genetic quality detection in Mongolian gerbils using single-nucleotide polymorphism (SNP) markers. To search for SNPs, we conducted whole-genome sequencing (WGS) in 40 Mongolian gerbils from outbred populations. Reliable screening criteria were established to preliminarily select SNPs with a wide genome distribution and high levels of polymorphism. Subsequently, a multiple-target regional capture detection system based on second-generation sequencing was developed for SNP genotyping. Based on the results of WGS, 219 SNPs were preliminarily selected, and they were established and optimized in a multiple-amplification system that included 206 SNP loci by genotyping three outbred populations. PopGen.32 analysis revealed that the average effective allele number, Shannon index, observed heterozygosity, expected heterozygosity, average heterozygosity, polymorphism information content, and other population genetic parameters of the Capital Medical University (CMU) gerbils were the highest, followed by those of Zhejiang gerbils and Dalian gerbils. Through scientific screening and optimization, we successfully established a novel, robust, and cost-effective genetic detection system for Mongolian gerbils by utilizing SNP markers for the first time.

Monoterpene-chalcone conjugates and diarylheptanoids isolated from the seeds of Alpinia katsumadai Hayata with cytotoxic activity.

Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7-8), and fourteen known compounds (9-22) were isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3-8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC50 values ranging from 3.59 to 21.78 µM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking.

Accelerating human-computer interaction through convergent conditions for LLM explanation.

The article addresses the accelerating human-machine interaction using the large language model (LLM). It goes beyond the traditional logical paradigms of explainable artificial intelligence (XAI) by considering poor-formalizable cognitive semantical interpretations of LLM. XAI is immersed in a hybrid space, where humans and machines have crucial distinctions during the digitisation of the interaction process. The author's convergent methodology ensures the conditions for making XAI purposeful and sustainable. This methodology is based on the inverse problem-solving method, cognitive modeling, genetic algorithm, neural network, causal loop dynamics, and eigenform realization. It has been shown that decision-makers need to create unique structural conditions for information processes, using LLM to accelerate the convergence of collective problem solving. The implementations have been carried out during the collective strategic planning in situational centers. The study is helpful for the advancement of explainable LLM in many branches of economy, science and technology.

Effect of obstructive sleep apnea on postoperative delirium: a system review and meta-analysis.

PURPOSE: To investigate the impact of obstructive sleep apnea (OSA) on postoperative delirium (PD), and evaluate the effectiveness of positive airway pressure (PAP) therapy on PD among OSA patients. METHODS: We systematically searched Embase, Cochrane Library and PubMed databases from their establishment to November 27, 2022. A random-effects approach was employed to determine aggregated results. Subgroup and sensitivity analyses were carried out to investigate heterogeneity. RESULTS: Sixteen eligible studies were included in the analysis. Thirteen studies revealed that OSA significantly elevated the likelihood of developing PD (OR = 1.71; 95%CI = 1.17 to 2.49; p = 0.005). Subgroup analysis according to delirium assessment scales showed that OSA did not exhibit an association with the incidence of PD assessed by the Confusion Assessment Method-Intensive Care Unit (OR = 1.14; 95%CI = 0.77 to 1.67; p = 0.51) but enhanced the likelihood of developing PD evaluated with other measurement scales (OR = 2.15; 95%CI = 1.44 to 3.19; p = 0.0002). Three additional studies explored the impact of PAP treatment on PD among OSA individuals, indicating no significant reduction in PD incidence with PAP use (OR = 0.58; 95%CI = 0.13 to 2.47; p = 0.46). CONCLUSIONS: OSA may not be a risk factor for PD in critically ill patients in the intensive care unit, but may increase the likelihood of developing PD among individuals receiving regular care in the ward postoperatively. The efficacy of PAP therapy in decreasing PD incidence among OSA patients remains debatable.

Generative learning facilitated discovery of high-entropy ceramic dielectrics for capacitive energy storage.

Dielectric capacitors offer great potential for advanced electronics due to their high power densities, but their energy density still needs to be further improved. High-entropy strategy has emerged as an effective method for improving energy storage performance, however, discovering new high-entropy systems within a high-dimensional composition space is a daunting challenge for traditional trial-and-error experiments. Here, based on phase-field simulations and limited experimental data, we propose a generative learning approach to accelerate the discovery of high-entropy dielectrics in a practically infinite exploration space of over 1011 combinations. By encoding-decoding latent space regularities to facilitate data sampling and forward inference, we employ inverse design to screen out the most promising combinations via a ranking strategy. Through only 5 sets of targeted experiments, we successfully obtain a Bi(Mg0.5Ti0.5)O3-based high-entropy dielectric film with a significantly improved energy density of 156 J cm-3 at an electric field of 5104 kV cm-1, surpassing the pristine film by more than eight-fold. This work introduces an effective and innovative avenue for designing high-entropy dielectrics with drastically reduced experimental cycles, which could be also extended to expedite the design of other multicomponent material systems with desired properties.

Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review.

Exosomes are 30-150 nm small extracellular vesicles (sEVs) which are highly stable and encapsulated by a phospholipid bilayer. Exosomes contain proteins, lipids, RNAs (mRNAs, microRNAs/miRNAs, long non-coding RNAs/lncRNAs), and DNA of their parent cell. In pathological conditions, the composition of exosomes is altered, making exosomes a potential source of biomarkers for disease diagnosis. Exosomes can cross the blood-brain barrier (BBB), which is an advantage for using exosomes in the diagnosis of central nervous system (CNS) diseases. Neuropsychiatric diseases belong to the CNS diseases, and many potential diagnostic markers have been identified for neuropsychiatric diseases. Here, we review the potential diagnostic markers of exosomes in neuropsychiatric diseases and discuss the potential application of exosomal biomarkers in the early and accurate diagnosis of these diseases. Additionally, we outline the limitations and future directions of exosomes in the diagnosis of neuropsychiatric diseases.

Hydroxyl Group as the 'Bridge' to Enhance the Single-Molecule Conductance by Hyperconjugation.

For designing single-molecule devices that have both conjugation systems and structural flexibility, a hyperconjugated molecule with a σ-π bond interaction is considered an ideal candidate. In the investigation of conductance at the single-molecule level, since few hyperconjugation systems have been involved, the strategy of building hyperconjugation systems and the mechanism of electron transport within this system remain unexplored. Based on the skipped-conjugated structure, we present a rational approach to construct a hyperconjugation molecule using a hydroxyl group, which serves as a bridge to interact with the conjugated fragments. The measurement of single-molecule conductance reveals a two-fold conductance enhancement of the hyperconjugation system having the 'bridging' hydroxyl group compared to hydroxyl-free derivatives. Theoretical studies demonstrate that the hydroxyl group in the hyperconjugation system connects the LUMO of the two conjugated fragments and opens a through-space channel for electron transport to enhance the conductance.

Iodine(III)-Mediated Trifluoroacetylation of a C(sp2)-H or C(sp)-H Bond with Masked Trifluoroacyl Reagents.

A novel strategy for incorporating a trifluoroacetyl functionality into a range of structurally varied unsaturated bonds was developed by using PhI(OCOMe)2 as an oxidant with a masked trifluoroacyl reagent as a trifluoroacetyl radical precursor. The oxidative decarboxylation of the masked trifluoroacyl precursor followed by a tandem radical process provides versatile access to 5-exo-trig cyclization of N-arylacrylamides, direct C(sp2)-H trifluoroacetylation of quinolines, isoquinoline, 2H-indazole, and quinoxalin-2(1H)-ones, and C(sp)-H trifluoroacetylation of alkynes. This protocol is characterized by mild reaction conditions, operational simplicity, and broad functional group compatibility.

Enhanced degradation and methane production of food waste anaerobic digestate using an integrated system of anaerobic digestion and microbial electrolysis cells for long-term operation.

The integrated system of anaerobic digestion and microbial electrolysis cells (AD-MEC) was a novel approach to enhance the degradation of food waste anaerobic digestate and recover methane. Through long-term operation, the start-up method, organic loading, and methane production mechanism of the digestate have been investigated. At an organic loading rate of 4000 mg/L, AD-MEC increased methane production by 3-4 times and soluble chemical oxygen demand (SCOD) removal by 20.3% compared with anaerobic digestion (AD). The abundance of bacteria Fastidiosipila and Geobacter, which participated in the acid degradation and direct electron transfer in the AD-MEC, increased dramatically compared to that in the AD. The dominant methanogenic archaea in the AD-MEC and AD were Methanobacterium (44.4-56.3%) and Methanocalculus (70.05%), respectively. Geobacter and Methanobacterium were dominant in the AD-MEC by direct electron transfer of organic matter into synthetic methane intermediates. AD-MEC showed a perfect SCOD removal efficiency of the digestate, while methane as clean energy was obtained. Therefore, AD-MEC was a promising technology for deep energy transformation from digestate.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.

Porcine deltacoronavirus nucleocapsid protein antagonizes JAK-STAT signaling pathway by targeting STAT1 through KPNA2 degradation.

Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.

Hypoxia exacerbates the malignant transformation of gastric epithelial cells induced by long-term H. pylori infection.

Helicobacter pylori is a microaerophilic Gram-negative bacterium that resides in the human stomach and is classified as a class I carcinogen for gastric cancer. Numerous studies have demonstrated that H. pylori infection plays a role in regulating the function of host cells, thereby contributing to the malignant transformation of these cells. However, H. pylori infection is a chronic process, and short-term cellular experiments may not provide a comprehensive understanding of the in vivo situation, especially when considering the lower oxygen levels in the human stomach. In this study, we aimed to investigate the mechanisms underlying gastric cell dysfunction after prolonged exposure to H. pylori under hypoxic conditions. We conducted a co-culture experiment using the gastric cell line GES-1 and H. pylori for 30 generations under intermittent hypoxic conditions. By closely monitoring cell proliferation, migration, invasion, autophagy, and apoptosis, we revealed that sustained H. pylori stimulation under hypoxic conditions significantly influences the function of GES-1 cells. This stimulation induces epithelial-mesenchymal transition and contributes to the propensity for malignant transformation of gastric cells. To confirm the in vitro results, we conducted an experiment involving Mongolian gerbils infected with H. pylori for 85 weeks. All the results strongly suggest that the Nod1 receptor signaling pathway plays a crucial role in H. pylori-related apoptosis and autophagy. In summary, continuous stimulation by H. pylori affects the functioning of gastric cells through the Nod1 receptor signaling pathway, increasing the likelihood of cell carcinogenesis. The presence of hypoxic conditions further exacerbates this process.IMPORTANCEDeciphering the collaborative effects of Helicobacter pylori infection on gastric epithelial cell function is key to unraveling the development mechanisms of gastric cancer. Prior research has solely examined the outcomes of short-term H. pylori stimulation on gastric epithelial cells under aerobic conditions, neglecting the bacterium's nature as a microaerophilic organism that leads to cancer following prolonged stomach colonization. This study mimics a more genuine in vivo infection scenario by repeatedly exposing gastric epithelial cells to H. pylori under hypoxic conditions for up to 30 generations. The results show that chronic exposure to H. pylori in hypoxia substantially increases cell migration, invasion, and epithelial-mesenchymal transition, while suppressing autophagy and apoptosis. This highlights the significance of hypoxic conditions in intensifying the carcinogenic impact of H. pylori infection. By accurately replicating the in vivo gastric environment, this study enhances our comprehension of H. pylori's pathogenic mechanisms in gastric cancer.

Tannic acid protects against colitis by regulating the IL17 - NFκB and microbiota - methylation pathways.

Tannic acid, a bioactive polyphenol found in various phytogenic foods and medicinal plants, has potential prevention effects on colitis, though more evidence and mechanistic studies are required to substantiate this. In this study, we investigated the effects of different doses from 0 to 3 mg/mL of tannic acid on mice, ultimately selecting a dose of 3 mg/mL for the anti-colitis trial based on growth and intestinal morphology assessments. Using the DSS-induced colitis model, we found that tannic acid may alleviate colitis by inhibiting the IL-17 - NF-κB p65 signaling pathway and modulating epigenetic pathways, particularly methylation modifications. Additionally, tannic acid altered the gut microbiota, increasing the abundances of Prevotella, Eubacterium_siraeum_group, and Enterorhabdus in the colon. Supplementation with Eubacterium siraeum via gavage also inhibited colitis, accompanied by increased folate and methylation regulators in the colon. These findings suggest that tannic acid may inhibit colitis through the suppression of the IL-17 - NF-κB pathway and the enhancement of microbiota-mediated methylation pathways.

Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis.

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

Rare Earth Single-Atom Catalysis for High-Performance Li-S Full Battery with Ultrahigh Capacity.

Lithium-sulfur (Li-S) batteries have many advantages but still face problems such as retarded polysulfides redox kinetics and Li dendrite growth. Most reported single atom catalysts (SACs) for Li-S batteries are based on d-band transition metals whose d orbital constitutes active valence band, which is inclined to occur catalyst passivation. SACs based on 4f inner valence orbital of rare earth metals are challenging for their great difficulty to be activated. In this work, we design and synthesize the first rare earth metal Sm SACs which has electron-rich 4f inner orbital to promote catalytic conversion of polysulfides and uniform deposition of Li. Sm SACs enhance the catalysis by the activated 4f orbital through an f-d-p orbital hybridization. Using Sm-N3C3 modified separators, the half cells deliver a high capacity over 600 mAh g-1 and a retention rate of 84.3 % after 2000 cycles. The fabricated Sm-N3C3-Li|Sm-N3C3@PP|S/CNTs full batteries can provide an ultra-stable cycling performance of a retention rate of 80.6 % at 0.2 C after 100 cycles, one of the best full Li-S batteries. This work provides a new perspective for the development of rare earth metal single atom catalysis in electrochemical reactions of Li-S batteries and other electrochemical systems for next-generation energy storage.

Endovascular treatment versus standard medical treatment in patients with established large infarct: a cohort study.

BACKGROUND: Previous trials confirmed the benefit of endovascular treatment (EVT) in acute large core stroke, but the effect of EVT on outcomes in these patients based on non-contrast computed tomography (NCCT) in real-world clinical practice was unclear. The aim of this study was to explore the effect of EVT versus standard medical treatment (SMT) in patients with large ischemic core stroke defined as Alberta Stroke Program Early CT Score (ASPECTS)≤5 based on NCCT alone. MATERIALS AND METHODS: Patients with acute large core stroke at 38 Chinese centers between November 2021 and February 2023 were reviewed from prospectively maintained databases. The primary outcome was favorable functional outcome (modified Rankin Scale score [mRS], 0-3) at 90 days. Safety outcomes included 48-hour symptomatic intracerebral hemorrhage (sICH) and 90-day mortality. RESULTS: Of 745 eligible patients recruited at 38 stroke centers between November 2021 and February 2023, 490 were treated with EVT and 255 with SMT alone. One hundred and eighty-one (36.9%) in the EVT group achieved favorable functional independence versus 48 (18.8%) treated with SMT only (adjusted risk ratio [RR], 1.86; 95% CI, 1.43 to 2.42, P<0.001; adjusted risk difference [RD], 13.77; 95% CI, 7.40 to 20.15, P<0.001). The proportion of sICH was significantly higher in patients undergoing EVT (13.3% vs. 2.4%; adjusted RR, 5.17; 95% CI, 2.17 to 12.32, P<0.001; adjusted RD, 10.10; 95% CI, 6.12 to 14.09, P<0.001). No significant difference of mortality between the groups was observed (41.8% vs. 49.0%; adjusted RR, 0.91; 95% CI, 0.77 to 1.07, P=0.24; adjusted RD, -5.91; 95% CI, -12.91 to 1.09, P=0.1). CONCLUSION: Among patients with acute large core stroke based on NCCT in real world, EVT is associated with better functional outcomes at 90 days despite of higher risk of sICH. Rates of procedure-related complications were high in the EVT group.

Causal relationship between circulating cytokines and follicular lymphoma: a two-sample Mendelian randomization study.

Follicular lymphoma (FL), derived from germinal centre (GC) B cells, is a kind of systemic neoplasm. Even though FL is indolent, it remains an incurable haematology Neoplasm. Accumulating evidence has suggested that the circulating cytokine is associated with the development of FL, yet the causal relationship between FL and circulating cytokines remains undetermined. Therefore, we conducted a two-sample Mendelian randomization (MR) to confirm the causal link between FL and levels of circulating cytokines with the use of summary data on circulating cytokines and FL. All these data from genome-wide association study were derived from the Genome-wide pQTL mapping which contains 14,824 individuals. FL data were acquired exclusively from FinnGen, where 218,792 individuals (522 cases vs. 218,270 controls) were involved. Various statistical methods, including the inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model (WM) and MR-Egger, were used to evaluate the potential causal connection between circulating cytokines and FL. Sensitivity analysis, which involves the examination of the heterogeneity, pleiotropy, and leave-one-out method, was also performed to ensure more trustworthy results. A bidirectional MR test was performed to evaluate the direction of causal association between circulating cytokines and FL. Combining all the steps of MR analysis, we revealed four causal cytokines: C-X-C motif chemokine ligand 5 (CXCL5), interleukin-15 receptor A (IL15RA), interleukin-20 (IL20), and neurotrophin-3 (NT-3). The risk of FL may be inversely linked to CXCL5 (OR=0.73, CI: 0.545-0.979, P=0.036), IL-15RA (OR=0.669, CI: 0.451-0.993, P=0.046), and IL-20 (OR=0.565, CI: 0.325-0.981, P=0.043) but positively linked to NT-3 (OR=1.872, CI: 1.063-3.297, P=0.03). In addition, in our study, no causal effect of FL on cytokines was demonstrated and no significant heterogeneity and pleiotropy were found. Our research revealed the causal relationship between cytokines and FL, along with both the anti-protective effect of CXCL5, IL-15RA, and IL-20 and the protective effect of neurotrophin-3 on FL. These findings aim to provide new clues regarding the pathogenesis of FL and to extend the potential of circulating cytokines to therapeutic interventions.

Unraveling pancreatic ductal adenocarcinoma immune prognostic signature through a naive B cell gene set.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality, has a complex pathogenesis involving various immune cells, including B cells and their subpopulations. Despite emerging research on the role of these cells within the tumor microenvironment (TME), the detailed molecular interactions with tumor-infiltrating immune cells (TIICs) are not fully understood. METHODS: We applied CIBERSORT to quantify TIICs and naive B cells, which are prognostic for PDAC. Marker genes from scRNA-seq and modular genes from weighted gene co-expression network analysis (WGCNA) were integrated to identify naive B cell-related genes. A prognostic signature was constructed utilizing ten machine-learning algorithms, with validation in external cohorts. We further assessed the immune cell diversity, ESTIMATE scores, and immune checkpoint genes (ICGs) between patient groups stratified by risk to clarify the immune landscape in PDAC. RESULTS: Our analysis identified 994 naive B cell-related genes across single-cell and bulk transcriptomes, with 247 linked to overall survival. We developed a 12-gene prognostic signature using Lasso and plsRcox algorithms, which was confirmed by 10-fold cross-validation and showed robust predictive power in training and real-world cohorts. Notably, we observed substantial differences in immune infiltration between patients with high and low risk. CONCLUSION: Our study presents a robust prognostic signature that effectively maps the complex immune interactions in PDAC, emphasizing the critical function of naive B cells and suggesting new avenues for immunotherapeutic interventions. This signature has potential clinical applications in personalizing PDAC treatment, enhancing the understanding of immune dynamics, and guiding immunotherapy strategies.

VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane.

Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.