Extracellular pH sensing by plant cell-surface peptide-receptor complexes.

The extracellular pH is a vital regulator of various biological processes in plants. However, how plants perceive extracellular pH remains obscure. Here, we report that plant cell-surface peptide-receptor complexes can function as extracellular pH sensors. We found that pattern-triggered immunity (PTI) dramatically alkalinizes the acidic extracellular pH in root apical meristem (RAM) region, which is essential for root meristem growth factor 1 (RGF1)-mediated RAM growth. The extracellular alkalinization progressively inhibits the acidic-dependent interaction between RGF1 and its receptors (RGFRs) through the pH sensor sulfotyrosine. Conversely, extracellular alkalinization promotes the alkaline-dependent binding of plant elicitor peptides (Peps) to its receptors (PEPRs) through the pH sensor Glu/Asp, thereby promoting immunity. A domain swap between RGFR and PEPR switches the pH dependency of RAM growth. Thus, our results reveal a mechanism of extracellular pH sensing by plant peptide-receptor complexes and provide insights into the extracellular pH-mediated regulation of growth and immunity in the RAM.

TIR domains of plant immune receptors are 2',3'-cAMP/cGMP synthetases mediating cell death.

2',3'-cAMP is a positional isomer of the well-established second messenger 3',5'-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2',3'-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2',3'-cAMP/cGMP but not 3',5'-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2',3'-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.

Substrate-induced condensation activates plant TIR domain proteins.

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain mediate recognition of strain-specific pathogen effectors, typically via their C-terminal ligand-sensing domains1. Effector binding enables TIR-encoded enzymatic activities that are required for TIR-NLR (TNL)-mediated immunity2,3. Many truncated TNL proteins lack effector-sensing domains but retain similar enzymatic and immune activities4,5. The mechanism underlying the activation of these TIR domain proteins remain unclear. Here we show that binding of the TIR substrates NAD+ and ATP induces phase separation of TIR domain proteins in vitro. A similar condensation occurs with a TIR domain protein expressed via its native promoter in response to pathogen inoculation in planta. The formation of TIR condensates is mediated by conserved self-association interfaces and a predicted intrinsically disordered loop region of TIRs. Mutations that disrupt TIR condensates impair the cell death activity of TIR domain proteins. Our data reveal phase separation as a mechanism for the activation of TIR domain proteins and provide insight into substrate-induced autonomous activation of TIR signalling to confer plant immunity.

Expansion of Anticomplement Therapy Indications from Rare Genetic Disorders to Common Kidney Diseases.

Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.

To assemble or not to assemble: metagenomic profiling of microbially mediated biogeochemical pathways in complex communities.

High-throughput profiling of microbial functional traits involved in various biogeochemical cycling pathways using shotgun metagenomic sequencing has been routinely applied in microbial ecology and environmental science. Multiple bioinformatics data processing approaches are available, including assembly-based (single-sample assembly and multi-sample assembly) and read-based (merged reads and raw data). However, it remains not clear how these different approaches may differ in data analyses and affect result interpretation. In this study, using two typical shotgun metagenome datasets recovered from geographically distant coastal sediments, the performance of different data processing approaches was comparatively investigated from both technical and biological/ecological perspectives. Microbially mediated biogeochemical cycling pathways, including nitrogen cycling, sulfur cycling and B12 biosynthesis, were analyzed. As a result, multi-sample assembly provided the most amount of usable information for targeted functional traits, at a high cost of computational resources and running time. Single-sample assembly and read-based analysis were comparable in obtaining usable information, but the former was much more time- and resource-consuming. Critically, different approaches introduced much stronger variations in microbial profiles than biological differences. However, community-level differences between the two sampling sites could be consistently observed despite the approaches being used. In choosing an appropriate approach, researchers shall balance the trade-offs between multiple factors, including the scientific question, the amount of usable information, computational resources and time cost. This study is expected to provide valuable technical insights and guidelines for the various approaches used for metagenomic data analysis.

MASP3 Deficiency in Mice Reduces but Does Not Abrogate Alternative Pathway Complement Activity Due to Intrinsic Profactor D Activity.

Complement factor D (FD) is a rate-limiting enzyme of the alternative pathway (AP). Recent studies have suggested that it is synthesized as an inactive precursor and that its conversion to enzymatically active FD is catalyzed by mannan-binding lectin-associated serine protease 3 (MASP3). However, whether MASP3 is essential for AP complement activity remains uncertain. It has been shown that Masp1/3 gene knockout did not prevent AP complement overactivation in a factor H-knockout mouse, and a human patient lacking MASP3 still retained AP complement activity. In this study, we have assessed AP complement activity in a Masp3-knockout mouse generated by CRISPR/Cas9 editing of the Masp1/3 gene. We confirmed specific Masp3 gene inactivation by showing intact MASP1 protein expression and absence of mature FD in the mutant mice. Using several assays, including LPS- and zymosan-induced C3b deposition and rabbit RBC lysis tests, we detected plasma concentration-dependent AP complement activity in Masp3 gene-inactivated mice. Thus, although not measurable in 5% plasma, significant AP complement activity was detected in 20-50% plasma of Masp3 gene-inactivated mice. Furthermore, whereas FD gene deletion provided more than 90% protection of CD55/Crry-deficient RBCs from AP complement-mediated extravascular hemolysis, Masp3 gene deletion only provided 30% protection in the same study. We also found pro-FD to possess intrinsic catalytic activity, albeit at a much lower level than mature FD. Our data suggest that MASP3 deficiency reduces but does not abrogate AP complement activity and that this is explained by intrinsic pro-FD activity, which can be physiologically relevant in vivo.

Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.

Phytophthora sojae Effector PsCRN108 Targets CAMTA2 to Suppress HSP40 Expression and ROS Burst.

Oomycete pathogens secrete numerous crinkling and necrosis proteins (CRNs) to manipulate plant immunity and promote infection. However, the functional mechanism of CRN effectors is still poorly understood. Previous research has shown that the Phytophthora sojae effector PsCRN108 binds to the promoter of HSP90s and inhibits their expression, resulting in impaired plant immunity. In this study, we found that in addition to HSP90, PsCRN108 also suppressed other Heat Shock Protein (HSP) family genes, including HSP40. Interestingly, PsCRN108 inhibited the expression of NbHSP40 through its promoter, but did not directly bind to its promoter. Instead, PsCRN108 interacted with NbCAMTA2, a negative regulator of plant immunity. NbCAMTA2 was a negative regulator of NbHSP40 expression, and PsCRN108 could promote such inhibition activity of NbCAMTA2. Our results elucidated the multiple roles of PsCRN108 in the suppression of plant immunity and revealed a new mechanism by which the CRN effector hijacked transcription factors to affect immunity. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

RHC genotyping in Chinese Han population.

BACKGROUND: The Rh blood group system is characterized by its complexity and polymorphism, encompassing 56 different antigens. Accurately predicting the presence of the C antigen using genotyping methods has been challenging. The objective of this study was to evaluate the accuracy of various genotyping methods for predicting the Rh C and to identify a suitable method for the Chinese Han population. METHODS: In total, 317 donors, consisting 223 D+ (including 20 with the Del phenotype) and 94 D- were randomly selected. For RHC genotyping, 48C and 109bp insertion were detected on the Real-time PCR platform and -292 substitution was analyzed via restriction fragment length polymorphism (RFLP). Moreover, the promoter region of the RHCE gene was sequenced to search for other nucleotide substitutions between RHC and RHc. Agreement between prediction methods was evaluated using the Kappa statistic, and comparisons between methods were conducted via the χ2 test. RESULTS: The analysis revealed that the 48C allele, 109bp insertion, a specific pattern observed in RFLP results, and wild-type alleles of seven single nucleotide polymorphisms (SNPs) were in strong agreement with the Rh C, with Kappa coefficients exceeding 0.8. However, there were instances of false positives or false negatives (0.6% false negative rate for 109bp insertion and 5.4-8.2% false positive rates for other methods). The 109bp insertion method exhibited the highest accuracy in predicting the Rh C, at 99.4%, compared to other methods (P values≤0.001). Although no statistical differences were found among other methods for predicting Rh C (P values>0.05), the accuracies in descending order were 48C (94.6%) > rs586178 (92.7%) > rs4649082, rs2375313, rs2281179, rs2072933, rs2072932, and RFLP (92.4%) > rs2072931 (91.8%). CONCLUSIONS: None of the methods examined can independently and accurately predict the Rh C. However, the 109bp insertion test demonstrated the highest accuracy for predicting the Rh C in the Chinese Han population. Utilizing the 109bp insertion test in combination with other methods may enhance the accuracy of Rh C prediction.

High-Performance Composite Membranes: Embedding Yttria-Stabilized Zirconia in Polyphenylene Sulfide Fabric for Enhanced Alkaline Water Electrolysis Efficiency.

Due to their excellent alkali resistance and chemical stability, polyphenylene sulfide (PPS) fabric membranes are widely used in alkaline water electrolysis (AWE) for hydrogen production. However, traditional PPS membranes suffer from poor hydrophilicity, low airtightness, and high area resistance, resulting in high energy consumption and reduced safety in industrial applications. This study addresses the aforementioned issues by coupling 3-(2,3-epoxy propoxy) propyl trimethoxy silane (KH560) via self-condensation to the PPS membrane and blending it with self-synthesized yttrium-stabilized zirconia nanoparticles (YSZNPs). The YSZNPs are loaded onto the modified PPS fiber surface through dip-coating and hot-pressing processes, forming a micro-mechanical interlocking structure that enhances the overall performance of the membrane in practical hydrogen production applications. The findings indicate that the developed composite membrane demonstrate outstanding hydrophilicity, minimal area resistance (0.21 Ω cm2), and elevated bubble point pressure (2.93224 bar). Significantly, tests on gas purity indicate that the produced hydrogen and oxygen attain purities of 99.90% and 99.75%, respectively, when evaluated at a current density of 1.5 A cm-2. Moreover, after 500 h of electrolysis testing in a simulated industrial environment, minimal decline in membrane performance is observed, highlighting the competitive edge of this composite membrane in the current AWE market.

Unraveling the distribution pattern and driving forces of soil microorganisms under geographic barriers.

The Altai Mountains (ALE) and the Greater Khingan Mountains (GKM) in northern China are forest regions dominated by coniferous trees. These geographically isolated regions provide an ideal setting for studying microbial biogeographic patterns. In this study, we employed high-throughput techniques to obtain DNA sequences of soil myxomycetes, bacteria, and fungi and explored the mechanisms underlying the assembly of both local and cross-regional microbial communities in relation to environmental factors. Our investigation revealed that the environmental heterogeneity in ALE and GKM significantly affected the succession and assembly of soil bacterial communities at cross-regional scales. Specifically, the optimal environmental factors affecting bacterial Bray-Curtis similarity were elevation and temperature seasonality. The spatial factors and climate change impact on bacterial communities under the geographical barriers surpassed that of local soil microenvironments. The assembly pattern of bacterial communities transitions from local drift to cross-regional heterogeneous selection. Environmental factors had a relatively weak influence on myxomycetes and fungi. Both soil myxomycetes and fungi faced considerable dispersal limitation at local and cross-regional scales, ultimately leading to weak geographical distribution patterns.IMPORTANCEThe impact of environmental selection and dispersal on the soil microbial spatial distribution is a key concern in microbial biogeography, particularly in large-scale geographical patterns. However, our current understanding remains limited. Our study found that soil bacteria displayed a distinct cross-regional geographical distribution pattern, primarily influenced by environmental selection. Conversely, the cross-regional geographical distribution patterns of soil myxomycetes and fungi were relatively weak. Their composition exhibited a weak association with the environment at local and cross-regional scales, with assembly primarily driven by dispersal limitation.

The Phytophthora sojae effector PsFYVE1 modulates immunity-related gene expression by targeting host RZ-1A protein.

Oomycete pathogens secrete numerous effectors to manipulate plant immunity and promote infection. However, relatively few effector types have been well characterized. In this study, members of an FYVE domain-containing protein family that are highly expanded in oomycetes were systematically identified, and one secreted protein, PsFYVE1, was selected for further study. PsFYVE1 enhanced Phytophthora capsici infection in Nicotiana benthamiana and was necessary for Phytophthora sojae virulence. The FYVE domain of PsFYVE1 had PI3P-binding activity that depended on four conserved amino acid residues. Furthermore, PsFYVE1 targeted RNA-binding proteins RZ-1A/1B/1C in N. benthamiana and soybean (Glycine max), and silencing of NbRZ-1A/1B/1C genes attenuated plant immunity. NbRZ-1A was associated with the spliceosome complex that included three important components, glycine-rich RNA-binding protein 7 (NbGRP7), glycine-rich RNA-binding protein 8 (NbGRP8), and a specific component of the U1 small nuclear ribonucleoprotein complex (NbU1-70K). Notably, PsFYVE1 disrupted NbRZ-1A-NbGRP7 interaction. RNA-seq and subsequent experimental analysis demonstrated that PsFYVE1 and NbRZ-1A not only modulated pre-mRNA alternative splicing (AS) of the necrotic spotted lesions 1 (NbNSL1) gene, but also co-regulated transcription of hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (NbHCT), ethylene insensitive 2 (NbEIN2), and sucrose synthase 4 (NbSUS4) genes, which participate in plant immunity. Collectively, these findings indicate that the FYVE domain-containing protein family includes potential uncharacterized effector types and also highlight that plant pathogen effectors can regulate plant immunity-related genes at both AS and transcription levels to promote disease.

Cyclometalated gold(III)-hydride under oriented external electric fields: a new strategy to modulate its reactivity?

Selected gold complexes have been regarded as promising anti-cancer agents because they can bind with protein targets containing thiol or selenol moieties, but their clinical applications were hindered by the unbiased binding towards off-target thiol-proteins. Recently, a novel gold(III)-hydride complex (abbreviated as 1) with visible light-induced thiol reactivity has been reported as potent photo-activated anticancer agents (Angew. Chem. Int. Ed., 2020, 132, 11139). To explore new strategies to stimuli this potential antitumor drug, the effect of oriented external electric fields (OEEFs) on its geometric structure, electronic properties, and chemical reactivity was systematically investigated. Results reveal that imposing external electric fields along the Au-H bond of 1 can effectively activate this bond, which is conducive to its dissociation and the binding of Au site to potential targets. Hence, this study provides a new OEEF-strategy to activate this reported gold(III)-hydride, revealing its potential application in electrochemical therapy. We anticipate this work could promote the development of more electric field-activated anticancer agents. However, further experimental research should be conducted to verify the conclusions obtained in this work.

Thulium laser en bloc resection reduces recurrence rates in NMIBC patients with tumor diameters ≥3cm compared to transurethral resection: a non-randomized controlled study.

PURPOSE: The advantages of en bloc resection of bladder tumors (ERBT) over transurethral resection of bladder tumors (TURBT) in terms of patient prognosis are not yet clear, and there are some technical limitations. We aimed to compare the tumor recurrence in non-muscle invasive bladder cancer (NMIBC) patients with tumor diameter ≥ 3 cm undergoing either TURBT or thulium laser ERBT. METHODS: The patients included were those diagnosed with NMIBC based on pathological confirmation and underwent TURBT or modified thulium laser ERBT in the Department of Urology at Tongji Hospital from 2019 to 2024. The patients' medical records were meticulously collected and postoperative follow-up was diligently conducted by trained personnel. Recurrence-free survival curves were generated utilizing the Kaplan-Meier method, and group comparisons were performed using the log-rank trend test. To minimize biases, we employed stratified survival analysis, alongside univariate and multivariate Cox regression analysis. RESULTS: This study included a total of 396 patients with NMIBC, with 214 undergoing TURBT and 182 undergoing ERBT. For all patients, there was no significant difference (P = 0.180) in RFS between the TURBT and ERBT groups. For patients with tumor diameter ≥ 3 cm, stratified analysis revealed that the RFS of the ERBT group was significantly better than that of the TURBT group (P = 0.033). However, in patients with tumor diameter < 3 cm, there was no significant difference (P = 0.150) between the two groups. Univariate (HR: 0.52, 95% CI 0.28-0.96, P = 0.036) and multivariate (HR: 0.49, 95% CI 0.25-0.93, P = 0.031) Cox analyses revealed that ERBT was an independent protective factor for recurrence in NMIBC patients with tumor diameter ≥3cm. CONCLUSION: This study found that thulium laser ERBT may offer advantages in managing NMIBC patients with tumor diameters ≥ 3 cm. This could potentially drive the clinical application of thulium laser ERBT. TRIAL REGISTRATION: Protocol was registered at Chinese Clinical Trial Register (ChiCTR) with number ChiCTR2000035407 on 12 August 2020.

A novel long noncoding RNA-lncRNA-AABR07066529.3 alleviates inflammation, apoptosis, and pyroptosis by inhibiting MyD88 in lipopolysaccharide-induced myocardial depression.

Sepsis-induced myocardial depression (SIMD) is common in pediatric intensive care units and seriously threatens children's health. Recently, long noncoding RNAs (lncRNAs) have been showed to play important roles in various diseases; however, its role in SIMD is unclear. In this study, we used lipopolysaccharide (LPS)-treated rats and H9c2 cardiomyocytes to mimic SIMD in vivo and in vitro. We found that the expression of a novel lncRNA, we named lncRNA-AABR07066529.3, was elevated in LPS-induced rat heart tissue and H9c2 cardiomyocytes. In addition, LPS-induced inflammation, apoptosis, and pyroptosis were significantly exacerbated after lncRNA-AABR07066529.3 knockdown. Moreover, we found that myeloid differentiation factor 88 (MyD88) was upregulated in LPS-treated groups and was inhibited by lncRNA-AABR07066529.3. Besides, MyD88 knockdown abolished lncRNA-AABR07066529.3 silencing effects on inflammation, apoptosis, and pyroptosis induced by LPS in H9c2 cardiomyocytes. In our study, we found lncRNA-AABR07066529.3 exerted protective effects on LPS-induced cardiomyocytes by regulating MyD88 and might serve as a potential treatment target for SIMD.

Photodynamic Therapy Synergizes CD47 Blockade Strategy for Enhanced Antitumor Therapy.

The antitumor strategies based on innate immunity activation have become favored by researchers in recent years. In particular, strategies targeting antiphagocytic signaling blockade to enhance phagocytosis have been widely reported. For example, the addition of prophagocytic signals such as calreticulin could make the strategy significantly more effective. In this study, an antitumor strategy that combines photodynamic therapy (PDT) with CD47 blockade has been reported. This approach promotes the maturation of dendritic cells and the presentation of tumor antigens by PDT-mediated tumor immunogenic cell death, as well as the enhancement of cytotoxic T lymphocyte infiltration in tumor areas and the phagocytic activity of phagocytes. Furthermore, the downregulation and blockage of CD47 protein could further promote phagocytic activity, strengthen the innate immune system, and ultimately elevate the antitumor efficacy and inhibit tumor metastasis.

Morphological and phylogenetic analyses reveal four species of myxomycetes new to China.

Four species of myxomycetes (Arcyria pseudodenudata, Diderma europaeum, Lycogala irregulare, and Trichia armillata) new to China were observed via light microscope and scanning electron microscope, and detailed descriptions and illustrations are provided, along with comparisons with related species. Among them, A. pseudodenudata was discovered for the first time outside of the type locality, D. europaeum was discovered for the first time outside of Europe, and L. irregulare and T. armillata were reported again after being named. Phylogenetic analyses based on nuclear 18S rDNA and elongation factor-1 alpha sequences or nuclear 18S rDNA and cytochrome oxidase subunit I sequences was performed to provide a molecular basis for morphological identification. These specimens were deposited in the Herbarium of Fungi of Nanjing Normal University.

Electrostatic-Field-Induced Collapse of Nanobubbles in Nanochannels.

The adsorbed nanobubbles inside the nanochannels can cause fluid transport blockages, which will obviously degrade the nanodevice performance and reduce the lifetime. However, due to small-scale effects, the removal of nanobubbles is a huge challenge at the nanoscale. Herein, molecular dynamics simulations are carried out to study the effect of the electrostatic field on underwater nitrogen nanobubbles confined in nanochannels. It is found that the nanobubbles will collapse under an appropriate electrostatic field, thereby unblocking the transport of water in the nanochannels. The formation of ordered water structures induced by electrostatic fields plays an important role in the removal of nanobubbles from the nanochannels. Our findings provide a convenient, controllable, and remote way to address the blockage problem of nanobubbles in nanochannels, which may have potential applications in improving the performance of fuel cells.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Bioinformatic Analysis of the Significance of the KIR2DL4 Gene in Recurrent Implantation Failure.

Related studies have pointed out that Killer immunoglobulin-like receptor 2DL4 (KIR2DL4) was associated with vascular remodeling in early pregnancy, and it might play an important role in immunity. In this study, recurrent implantation failure (RIF)-related GSE58144 dataset was extracted from the Gene Expression Omnibus (GEO) database. Firstly, the immune micro-environment analyses were conducted to analyze the pathogenesis of KIR2DL4 in RIF. Then, the gene set enrichment analysis (GSEA) was performed to investigate the function of KIR2DL4. Moreover, the TF-mRNA-miRNA and the co-expression networks were constructed to reveal the potential regulation of KIR2DL4. Furthermore, the genes that were associated with KIR2DL4 and differentially expressed in RIF were obtained and defined as key genes, and the functions of these genes were further explored. KIR2DL4 could be used for clinical diagnosis of RIF, and it was correlated with the changes in the immune micro-environment in RIF. From the perspective of function, KIR2DL4 was associated with complement and coagulation cascades, natural killer cell-mediated cytotoxicity, etc. Moreover, the TF-mRNA-miRNA regulatory network was constructed with KIR2DL4, 9 TFs, and 29 miRNAs. Furthermore, KIR2DL4, ACSM1, IL2RB, and PTPN11 were screened as key genes, which were associated with immune-related functions. This study deeply analyzed the function of KIR2DL4 and its role in RIF, and we found that STAT1 might up-regulate KIR2DL4 by INF-γ/JAK2/STAT1 signaling pathway. Besides, over-expressed KIR2DL4 in the mid-luteal endometrium might influence embryo implantation by affecting the embryo implantation microenvironment, which might help deepen the understanding of the molecular mechanism of RIF.