{"paper_id":"49f72a21-fbbd-42f8-ab1a-e4d2cbd6d78a","body_text":"Exploring the Causal Relationship Between Plasma Proteins and Obstructive Sleep Apnea: A Study Using Genome-Wide Mendelian Randomization, Single-Cell RNA Sequencing Analysis, and Network Pharmacology | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring the Causal Relationship Between Plasma Proteins and Obstructive Sleep Apnea: A Study Using Genome-Wide Mendelian Randomization, Single-Cell RNA Sequencing Analysis, and Network Pharmacology Lingzhi Duan, Yan Wang, Haiqing Jing, Yanqiong Wang, Shuye Ning, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6936975/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology → Version 1 posted 9 You are reading this latest preprint version Abstract Observational studies suggest that plasma proteins play a crucial role in the development and progression of obstructive sleep apnea (OSA); however, the causal relationship between plasma proteins and OSA remains controversial. This study conducted a comprehensive evaluation of the causal relationships between 4,907 plasma proteins and OSA by employing bidirectional Mendelian randomization (MR) analysis, network pharmacology strategies, and single-cell sequencing techniques. The plasma protein data used in this study were derived from Ferkingstad et al.'s research (n=35,559), and OSA-related data were obtained from genome-wide association studies (GWAS) conducted on European populations through Finland's biobank (FinnGen). This study utilized multi-omics integration strategies, including enrichment analysis, protein-protein interaction (PPI) network construction, drug target prediction, molecular docking simulation, and single-cell transcriptome sequencing, to investigate the biological mechanisms of identified targets and evaluate their potential applications in drug development. MR analysis identified 62 plasma proteins significantly associated with OSA risk, including NTN4 (p=0.003, OR=1.076, CI [1.024, 1.129]) and TFF2 (p=0.004, OR=1.098, CI [1.029, 1.174]). Further reverse Mendelian analysis revealed causal relationships between OSA and the CELF2, NTRK3, ANTXR2, and MYOM2 genes. PPI network analysis identified 10 core genes, including IL1β, TGFβ1, EGF, SHH, and SMAD2, which participate in critical pathological processes in OSA, such as oxidative stress, inflammatory responses, and immune regulation. Through drug prediction analysis, this study identified compounds with potential therapeutic effectiveness, including 3,4-DHB, BIM IX, and SB 202190, and molecular docking studies further confirmed their high binding affinity to target proteins. Single-cell sequencing revealed high expression levels of key genes in T cells and dendritic cells, thereby confirming the critical role of these cells in the pathological progression of OSA. A total of 62 candidate therapeutic targets for OSA were identified in this study, with 10 of these targets deemed important candidates for clinical trials. These findings not only enrich the understanding of the molecular pathological mechanisms underlying OSA but also offer new perspectives for developing targeted therapeutic strategies to treat the condition. By facilitating the establishment of more precise and personalized disease management approaches, these results are expected to advance the development of therapeutic drugs for OSA and substantially reduce the economic costs associated with new drug development. Plasma proteins Obstructive sleep apnea Mendelian randomization Single-cell RNA-seq Network pharmacology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 1. Introduction Obstructive Sleep Apnea (OSA) is a disorder characterized by recurrent upper airway obstruction during sleep, leading to intermittent hypoxia, sleep fragmentation, and carbon dioxide retention. This condition results in increased nocturnal oxidative stress and systemic inflammatory responses, inducing abnormal activation of the sympathetic nervous system. Epidemiological studies estimate that approximately 936 million adults worldwide suffer from OSA[ 1] . OSA not only impairs sleep quality but also contributes to a range of serious complications, including cardiovascular diseases, cognitive dysfunction, metabolic disorders, and other systemic conditions[ 2] . The prevalence of OSA varies by age, sex, and body composition, with men demonstrating a higher prevalence rate compared to women[ 3] . Despite advances in the diagnosis of OSA, its complex pathogenesis poses significant challenges to treatment. Therefore, exploring the underlying mechanisms and therapeutic targets of OSA has substantial social significance. Plasma proteins, whether derived from cellular leakage or active secretion, serve as major sources of biomarkers and therapeutic targets, reflecting the metabolic activities and genetic characteristics of biological cells[ 4] . Previous studies have established associations between protein levels and OSA, suggesting their potential significance in the treatment of OSA. In a cross-sectional study involving 1,171 OSA patients, it was demonstrated that HsCRP levels were significantly elevated in OSA patients[ 5] . In a case-control study involving 100 OSA patients and 100 healthy controls, the CRP gene was confirmed to be associated with an increased risk of OSA[ 6] . Moreover, a randomized controlled trial involving 59 OSA patients indicated that interleukin-6 (IL-6) levels were positively correlated with the severity of OSA[ 7] . However, these observational studies are limited by various factors, including small sample sizes, restricted protein diversity, observational study design, and methodological constraints, rendering the causal relationships between these plasma proteins and OSA uncertain. Mendelian Randomization (MR) is a well-established method in genetic epidemiology that uses instrumental variables (IV) in non-experimental designs to infer causal relationships between modifiable exposures and disease outcomes, minimizing confounding and reverse causation [8] . Because traditional observational studies are prone to confounding factors, the causal relationship between OSA and plasma proteins remains unclear. MR utilizes genetic variants as naturally randomized instrumental variables to assess the causality between plasma proteins and OSA [9] . This study intends to employ a research strategy combining single-cell transcriptomics with bulk RNA sequencing to systematically elucidate the molecular mechanisms of plasma proteins in the pathogenesis of OSA. Among these, single-cell transcriptomics, with its high-resolution capability to analyze cellular heterogeneity, can provide essential insights into the molecular interaction networks between plasma proteins and OSA [10][11] . Single-cell transcriptomic analysis possesses high-resolution capabilities for exploring cellular and functional properties, offering critical value for investigating the interaction mechanisms between plasma proteins and OSA. Meanwhile, large-scale RNA sequencing effectively captures comprehensive gene expression profiles, providing empirical support and enriched data for single-cell transcriptomic studies. This study aims to utilize these technological platforms to analyze drugs with potential therapeutic value and explore novel treatment pathways for OSA. By integrating plasma protein regulatory mechanisms with existing drug databases, the study seeks to identify therapeutic candidates and validate their efficacy and safety. The core objective of this study is to accurately quantify the correlation between plasma proteins and OSA, clarify their mechanisms of action, and provide innovative perspectives and strategies for precise OSA treatment. 2. Methods This study employed Mendelian randomization to evaluate the causal relationship between plasma proteins and OSA. Moreover, single-cell RNA sequencing and network pharmacology methods were utilized to explore the biological significance of plasma proteins and their potential in drug development. Figure 1 illustrates the overall framework of this study. 2.1.Data Sources 2.1.1.Data on Plasma Proteins and OSA Building upon the research findings of Ferkingstad et al [12] , this study references the pQTL data for 4,907 proteins documented in the deCODE database (https://www.decode.com). This study utilized GWAS methods to systematically analyze plasma protein levels among 35,559 Icelandic participants, involving a total of 4,907 aptamers. Since the exposure variables and outcome data in the MR analysis were derived from samples of different countries, it effectively minimizes population overlap issues. GWAS data for OSA were obtained from the Finnish FinnGen project (https://r12.finngen.fi/), which integrates genetic information and clinical data from more than 500,000 samples in Finland's biobank. The study utilized the latest OSA dataset from the FinnGen R12 release, which includes 56,885 diagnosed cases and 441,137 healthy controls. 2.1.2 Mendelian Randomization Analysis This study utilized a bidirectional MR framework to evaluate the causal relationship between plasma proteins and OSA [13] . Exposure data for plasma proteins were obtained from preprocessed summary statistics related to pQTL. In the process of selecting instruments, we calculated both the explained variance and the F-statistic for each single nucleotide polymorphism (SNP), ensuring that only those SNPs with an F-statistic greater than 10 were included. Moreover, SNPs that exhibited an effect allele frequency greater than 0.01 were retained in our analysis. To minimize redundant signals, linkage disequilibrium clustering was deliberately disabled. To evaluate the outcomes for OSA, we sourced data from a Finnish database, ensuring to eliminate any duplicate entries. A structured harmonization process was then used to align the exposure and outcome variables, which involved matching chromosome positions, adjusting for allele orientation, and excluding palindromic SNPs. Additionally, SNPs that were directly associated with OSA and had a p-value exceeding 0.05 were excluded to mitigate potential confounding bias in the study. This study employed multiple statistical methods, including the inverse-variance weighted (IVW) method, MR-Egger regression, weighted median method, simple mode method, and weighted mode method, to comprehensively evaluate the causal effects. To quantify the association strength, odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated. To ensure the reliability of the results, a series of sensitivity analyses were conducted, including Cochran's Q test for heterogeneity assessment, MR-Egger intercept tests to identify potential horizontal pleiotropy, leave-one-out analyses to test result stability, and funnel plot analysis for evaluating the balance in data distribution. In cases where the results from IVW demonstrated statistical significance with a p-value lower than 0.05, we generated four diagnostic plots: a scatter plot, a forest plot, a funnel plot, and a leave-one-out plot. The criteria used for final selection necessitated consistent directions of odds ratios across all five statistical methods employed, ensuring either that all odds ratios were greater than one or that all were less than one. Furthermore, we excluded any results from significant MR-Egger intercept tests with p-values below 0.05, while retaining the most significant measurements derived from repeated protein assessments. This rigorous approach was essential for ensuring reliable and interpretable results in our analysis. This study employed a genome-wide significance threshold (p < 5 × 10⁻⁸) as the selection criterion to perform reverse analysis on OSA-associated SNPs. To ensure the independence of instrumental variables, linkage disequilibrium clustering (r² < 0.001) was applied to reduce correlations between variables, and the strength of instrumental variables (F > 10) was further validated to enhance the reliability of causal inference. All data processing and statistical analyses were performed on the R 4.5.0 platform, with Mendelian randomization analysis primarily conducted using the TwoSampleMR package. 2.2 Enrichment Analysis This study utilized enrichment analysis techniques, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), to focus on the biological effects of various potential therapeutic targets. GO enrichment analysis was conducted to explore biological processes (BPs), molecular functions (MFs), and cellular components (CCs) at three core levels. Additionally, KEGG pathway enrichment analysis was performed on the significant genes identified through Mendelian randomization techniques. To facilitate these analyses, the R package ClusterProfiler was utilized, providing a robust framework for examining the functional roles of the selected genes within the context of their biological significance. [14] . Terms with raw p-values less than 0.05 were kept and modified with the Benjamini-Hochberg correction technique. Bubble plots were utilized to enhance the interpretability of the results. 2.3 Construction of Protein–Protein Interaction Network and Screening of Core Genes To further investigate the interaction mechanisms among intracellular proteins, this study constructed a protein-protein interaction (PPI) network utilizing the STRING database (https://cn.string-db.org/). For this analysis, a confidence score threshold of 0.15 was established as the minimum acceptable interaction score necessary for inclusion. Additionally, any disconnected nodes, which do not contribute to the interaction framework, were systematically removed from consideration. All other parameters were maintained at their default settings to ensure consistency in the analysis. Following the construction of this network, the generated data file was subsequently imported into Cytoscape version 3.10.0 for the purposes of visualization. To identify the most significant interactions, the cytoHubba plugin available within Cytoscape was employed to filter and highlight the top 10 genes based on their degree values, thereby designating them as core genes within the network[ 15] . 2.4 Drug Prediction Assessing the interactions between proteins and drugs plays a fundamental role in the process of identifying whether a specific target protein can be considered a promising candidate for therapeutic intervention. This evaluation is essential, as it can provide insights into the binding affinity, specificity, and overall efficacy of potential drug candidates in modulating the activity of the target protein. Understanding these interactions not only informs the likelihood of success in drug development but also aids in the design of more effective and tailored therapeutic strategies.In this study, we utilized the Drug Signatures Database (DSigDB, http://dsigdb.tanlab.org/DSigDBv1.0/) to investigate the relationship between core genes and potential drugs[ 16] . The DSigDB database integrates over 22,500 gene sets, more than 17,000 chemical substances, and nearly 20,000 gene profiles, facilitating the mapping of relationships between drugs and their target genes. This research acts as an important resource for investigating drug targets and facilitating drug discovery. This study submitted the filtered core protein gene data to the DSigDB database for drug target prediction analysis, aiming to identify candidate drug molecules that may interact with these target genes, thus providing a scientific foundation for future research on targeted gene therapies. Subsequently, drug enrichment analysis was conducted using the ClusterProfiler package in R. In this analysis, the significance threshold was set at a p-value and its adjusted value (p.adjust) of 0.05 to identify drugs significantly associated with key genes. During the enrichment analysis, a hypergeometric test was employed to evaluate the enrichment of core genes within the gene clusters affected by target drugs, with a significance level defined as a p-value below 0.05. To depict the ranking of enriched drugs, the distribution of genes, and the connections between core genes and drugs, bar plots and gene-drug interaction network diagrams were created. 2.5 Molecular Docking To thoroughly investigate the efficacy of candidate compounds on their target proteins and evaluate the feasibility of new drug development, this study utilized molecular docking techniques. This technique enabled a scientific evaluation of the binding affinity and diverse interaction mechanisms between candidate drugs and their specific targets. To ensure a focused analysis, we selected the top five candidate drugs based on outcomes from prior drug enrichment analyses. The molecular docking experiments were carried out utilizing the CB-Dock2 platform(https://cadd.labshare.cn/cb-dock2/index.php). Through this method, we aimed to elucidate the mechanisms underlying the interaction between these candidate compounds and their protein targets, thereby contributing to our understanding of their druggability[ 17] . We retrieved the structural data of the corresponding drugs from the PubChem compound database (https://pubchem.ncbi.nlm.nih.gov/) and obtained the structural data for each protein from the PDB protein database (https://www.rcsb.org/). 2.6 Single-Cell Sequencing In order to delve deeper into the expression characteristics and potential functionalities of specific core genes in OSA, we undertook a comprehensive single-cell sequencing analysis. This approach allowed us to closely examine the unique expression profiles of these genes within the context of the disease. For our study, we acquired the single-cell RNA sequencing dataset (SRA550660:SRS2089637), which comprises data from peripheral blood cells. This dataset was sourced from the PanglaoDB platform (https://panglaodb.se/) , an extensive database that provides valuable resources for single-cell RNA sequencing analysis[ 18] . The single-cell sequencing dataset constructed in this study encompasses gene expression data from peripheral blood cell populations. Through integrative analysis of these single-cell data, this study aims to accurately evaluate the expression patterns of core genes in peripheral blood cells, thereby identifying specific cell subsets that may play critical roles in the pathogenesis of OSA. To further elucidate the expression distribution characteristics of core genes in different cell types, the study utilized t-SNE dimensionality reduction technique for visualization of single-cell data. 3. Results 3.1 MR Analysis Results The findings from the MR analysis illustrated in Figure 2 revealed that 62 genetic loci are significantly linked to OSA. For example, the NTN4 gene (p = 0.003, OR = 1.076, CI [1.024, 1.129]) and the TFF2 locus (p = 0.004, OR = 1.098, CI [1.029, 1.174]) showed a positive association with OSA. In contrast, the FBP1 locus (p = 0.004, OR = 0.893, CI [0.828, 0.964]) and the RGS18 locus (p = 0.006, OR = 0.815, CI [0.703, 0.944]) exhibited a negative association with the disorder. Experimental data indicate that the aforementioned proteins may exert protective regulatory effects on OSA through their biological activities. Based on this finding, changes in the expression levels of specific proteins may serve as important molecular indicators for assessing the progression of OSA. 3.2 Enrichment Analysis As shown in Figure 3, significantly enriched BP terms include regulation of carbohydrate biosynthetic processes, response to lipopolysaccharide, and hyaluronan biosynthetic processes. In the CC category, the enrichment of phagocytic cup, platelet alpha granule lumen, and cytoplasmic vesicle lumen suggests the importance of dynamic membrane structures, secretory vesicle compartments, and extracellular matrix microenvironments. Furthermore, in the MF category, significant enrichment of endopeptidase activity, growth factor receptor binding, and D-glucose binding highlights molecular functions such as growth factor signal transduction, regulation of glucose metabolism, and inhibition of protease activity. As shown in Figure 4, the five pathways identified through KEGG enrichment analysis are the MAPK signaling pathway, TNF signaling pathway, AMPK signaling pathway, Neurotrophin signaling pathway, and NOD-like receptor signaling pathway. 3.3 PPI Network and Core Gene Screening The 62 gene proteins were uploaded to the STRING database for network construction. The generated files were imported into Cytoscape 3.1.0 for visualization, and core genes were identified using the cytoNAC plugin. As shown in Figure 5, the PPI network comprises 61 nodes and 243 edges. The identified core genes include IL1β, TGFβ1, EGF, SHH, SMAD2, NTRK3, G6PD, TNFRSF1β, AKT2, and CTSG. Network analysis revealed that these processes are associated with upper airway anatomical abnormalities, inflammation-hypoxia vicious cycles, neuromuscular dysfunction, and systemic metabolic disorders, consistent with the fundamental pathogenesis of OSA[ 19] . 3.4 Prediction of Candidate Drugs In the present study, we employed the Drug Signatures Database (DSigDB) to forecast potential therapeutic agents that may be effective for our research objectives. This database provided a valuable resource for identifying compounds that could be repurposed or developed further as treatments. Furthermore, we conducted a comprehensive drug enrichment analysis using the R package clusterProfiler. This analytical approach allowed us to assess the significance of the identified therapeutic targets and to understand their biological relevance, thereby enhancing the overall rigor of our findings. The results indicated that 3,4-Dihydroxybenzaldehyde (3,4-DHB), bisindolylmaleimide IX (BIM IX), chitosamine (amino sugar), ciprofloxacin, and SB 202190 are key drugs associated with the core genes (Figure 6). 3.5 Molecular Docking In this study, we conducted molecular docking to evaluate the binding affinity of selected candidate drugs to their specific biological targets. This approach also allowed us to assess the druggability of these targets, which is an essential consideration in drug development. To facilitate our analysis, we utilized the CB-Dock2 platform, which is designed specifically for studying molecular interactions. Our focus was on five candidate drugs, and we examined their binding interactions with the respective target proteins, as illustrated in Figure 7.Through our molecular docking analysis, we identified that the binding energy between the candidate drug SB 202190 and the target protein AKT2 was notably the lowest at -8.0 kcal/mol. This result suggests that the interaction between SB 202190 and AKT2 is highly stable, which is a desirable characteristic for effective drug-target interactions. Furthermore, our data revealed that the overall binding energies for the five candidate drugs varied between -4.7 kcal/mol and -8.0 kcal/mol, as highlighted in Table 1. This range indicates that each candidate drug demonstrates a good binding affinity toward its respective target protein, showcasing the potential for successful therapeutic applications. Table 1 Docking results of available proteins with small molecules. 3.6 Single-Cell Sequencing In this research, we made use of the PanglaoDB platform to conduct a comprehensive analysis of the expression levels of core genes within peripheral blood mononuclear cells (PBMCs). Furthermore, we specifically selected datasets associated with PBMCs to perform a detailed single-cell RNA sequencing analysis. This approach allowed us to delve deeper into the gene expression profiles at the single-cell level, enhancing our understanding of the functional roles of these core genes in PBMCs.The results showed that the IL1β gene was significantly expressed in T cells, dendritic cells, Langerhans cells, and gamma delta T cells, with the highest expression in T cells, suggesting that IL1β is involved in immune regulation and inflammatory responses. The TGFβ1 and SHH genes were highly expressed in dendritic cells and T cells, indicating their critical roles in oxidative stress and inflammatory responses. The SMAD2 gene was significantly expressed across various cell types, with the highest expression observed in gamma delta T cells. The AKT2 gene was significantly expressed in platelets and gamma delta T cells, suggesting its potential roles in cellular survival, apoptosis, and metabolic regulation. The TNFRSF1β gene was significantly expressed in all cell types, with the highest level observed in T cells. The G6PD gene was significantly expressed in T cells and platelets, suggesting its involvement in immune regulation and oxidative stress processes (Figures 8, 9, and 10). These results further elucidate the roles of these genes in the pathogenesis of OSA and provide valuable insights and theoretical support. Firstly, most potential targets are highly expressed in T cells and dendritic cells, indicating their critical roles in immune regulation, oxidative stress, inflammatory responses, and metabolic processes, thereby promoting the onset and progression of OSA and its related complications. Meanwhile, some genes are significantly expressed in platelets, suggesting their potential involvement in the development of cardiovascular diseases, which is consistent with previous clinical studies. 4. Discussion Under specific conditions, the plasma proteome demonstrates notable stability, significant variability, and predictability, thus establishing itself as a crucial resource for research concerning obstructive sleep apnea (OSA). Various studies have documented these characteristics, highlighting the plasma proteome’s relevance in understanding the complexities associated with OSA. Despite the inherent individual differences in plasma protein profiles, the application of robust statistical methodologies in extensive studies has effectively reduced variability, which in turn aids in the identification of key proteins that are associated with OSA. This understanding is particularly vital for improving both the diagnosis and the overall comprehension of OSA.In the course of this study, molecular research analysis methods were employed to pinpoint 62 potential therapeutic targets within the plasma proteome related to OSA. To ascertain the biological significance of these identified targets, enrichment analysis and protein-protein interaction (PPI) network analysis were performed, facilitating the identification of core genes associated with OSA. Additionally, drug prediction and molecular docking studies were conducted to explore potential therapeutic options. The validation of the therapeutic potential of these identified genes was further enhanced through single-cell sequencing techniques. The results of these analyses indicated that most of the predicted drugs operate through mechanisms that are anti-inflammatory, antioxidant, and related to immune regulation—key processes that play a fundamental role in the management and treatment of OSA. Consequently, these findings not only broaden the clinical applications of existing pharmaceuticals but also lay a theoretical foundation for their prospective utilization in the treatment of OSA. Among the identified core genes, IL1β, a key pro-inflammatory cytokine, is a core member of the interleukin-1 family and plays a pivotal role in immune regulation and inflammatory responses [ ] . Intermittent hypoxia (IH), a clinical characteristic of OSA, activates the inflammasome (NLRP) via the ROS/TXNIP/NLRP3 pathway, promoting the maturation and release of IL-1β and IL-18. This further stimulates the secretion of other pro-inflammatory cytokines (IL-6, TNF-α, IL-18), exacerbating systemic inflammation. Concurrently, IL-1β acts on neuronal IL-1 receptors, impairing hippocampal synaptic plasticity and leading to cognitive dysfunction [ ][ ] .TGFβ1 is a multifunctional factor that plays a significant role in metabolic disorders, inflammation regulation, and fibrosis associated with OSA. TGFβ1 is closely associated with the occurrence, progression, and prognosis of OSA [ ] . It promotes the generation of reactive oxygen species (ROS) by upregulating NOX4 expression, leading to oxidative stress damage. Meanwhile, elevated levels of TGF-β1 in peripheral blood reduce Treg cells and suppress Foxp3 expression, while increasing Th17 cell counts and associated inflammatory factors (IL-17, IL-6), thereby exacerbating the inflammatory response [ ][ ] .EGF is a small-molecule polypeptide, and intermittent hypoxia (IH) can elevate EGF levels, promoting the release of inflammatory factors (ICAM, IL6) [ ] . SHH primarily participates in the pathophysiological process of OSA-related complications through the activation of the Hedgehog signaling pathway. IH can induce hypoxia-inducible factor-1α (HIF-1α) to further activate SHH, promoting epithelial-mesenchymal transition (EMT) and accelerating disease progression. Moreover, it is positively correlated with liver injury markers (AST, ALT) and fibrosis markers (α-SMA, K7) [ ] .SMAD2 is a transcriptional regulator that promotes the development and progression of OSA complications by participating in metabolic regulation and tissue fibrosis [ ] . Adipocyte-derived exosomes under OSA upregulate long non-coding RNA, suppress miR-455-3p expression, and subsequently activate the SMAD2 signaling pathway. This leads to the accumulation of fat, triglycerides, and cholesterol in hepatocytes, exacerbating liver damage in metabolic-associated steatotic liver disease (MASLD) [ ] .In cardiac perivascular fibrosis, the IH conditions of OSA promote endothelial-to-mesenchymal transition (EndMT) by activating the SMAD2/3 pathway, manifested by enhanced endothelial cell migration and increased collagen secretion, resulting in vascular endothelial remodeling [ ] . NTRK3, a gene encoding tropomyosin receptor kinase, currently has no direct research linking it to OSA. However, NTRK3 regulates pathways related to oxidative stress and inflammatory responses and enhances the activity of antioxidant enzymes, thereby mitigating oxidative stress and inflammation-induced damage [ ] .G6PD is a key enzyme in the pentose phosphate pathway, primarily responsible for producing nicotinamide adenine dinucleotide phosphate (NADPH). NADPH plays a vital role in cellular antioxidant processes, particularly in red blood cells [ ] . Oxidative stress damage is a hallmark of OSA, and G6PD deficiency reduces NADPH production, rendering cells more vulnerable to oxidative damage [ ] . Currently, no studies have directly linked TNFRSF1β, AKT2, or CTSG to OSA. However, these genes are critical regulators involved in oxidative stress, inflammatory responses, and immune modulation. Thus, we hypothesize their relevance to OSA and regard them as potential therapeutic targets for OSA [ ][ ] . 3,4-DHB, BIM IX, and SB 202190 are potential therapeutic agents for OSA that can improve OSA and its complications by modulating inflammatory responses, oxidative stress, and apoptotic processes. 3,4-DHB, a natural phenolic acid compound also known as protocatechuic acid (PCA), can inhibit oxidative stress and inflammatory damage by targeting and regulating the MAPK signaling pathway. Animal studies indicate that PCA scavenges free radicals (DPPH and ABTS) in SD rats, reduces IL-1β levels in the brain, and suppresses excessive microglial activation, thereby alleviating neuroinflammation induced by CIH [ ] . PCA upregulates the expression of brain-derived neurotrophic factor (BDNF) and synapsin (SYN), enhances synaptic function by modulating the MAPK pathway, and repairs synaptic ultrastructural damage caused by CIH [ ] .BIM IX is a protein kinase C (PKC) inhibitor that regulates downstream signaling pathways (MAPK and PI3K/AKT pathways) by inhibiting PKC. Intermittent hypoxia (IH) activates the ERK/PI3K pathways via PKC, promoting IL-8 expression in monocytes and exacerbating inflammatory responses. BIM IX can alleviate OSA-associated systemic inflammation by blocking this pathway [ ][ ] .SB 202190 is a p38 MAPK inhibitor that blocks the activity of p38 MAPK, thereby suppressing the production of inflammatory cytokines [ ] . Although no direct studies have explored the application of SB 202190 in sleep apnea, its ability to suppress inflammation and regulate cellular immunity suggests it might be a potential therapeutic agent for OSA. All three drugs have demonstrated their potential in inhibiting the MAPK signaling pathway, which is consistent with previous KEGG analysis results. The results obtained from molecular docking studies demonstrate that the compounds 3,4-DHB, BIM IX, and SB 202190 exhibit stable interactions with their respective target molecules. The calculated binding energies for these compounds fall within the range of -4.7 to -8.0 kcal/mol. This range of binding energies not only highlights the affinity of these compounds for their targets but also reinforces their potential role in the intervention of obstructive sleep apnea (OSA). This intervention is believed to occur through the modulation of antioxidant and anti-inflammatory pathways, which are crucial in mitigating the effects associated with this condition. To sum up, the drug targets revealed in this research are strongly linked to OSA and show considerable potential for therapeutic applications. These results endorse the creation of OSA therapies that focus on particular molecules and offer essential theoretical and practical groundwork for the advancement of upcoming treatments. While this study has achieved substantial advancements in its findings, it is important to acknowledge specific limitations that still exist. One major limitation is that the study population primarily comprises individuals of European ancestry. This concentration may restrict the extent to which the findings can be generalized to a wider population. To ensure that these results are truly applicable across different demographics, additional research that includes a more diverse array of ethnic groups is essential. Such investigations would help verify the applicability of the findings beyond the current study's demographic scope.This study does not include severity stratification analysis of OSA, which may introduce a certain degree of confounding bias. However, the elevated expression of key genes (IL1β and TGFβ1) in peripheral blood mononuclear cells and their strong association with the MAPK signaling pathway are closely linked to the pathological characteristics of OSA [ ] . These findings indicate that these genes play pivotal roles in the pathological mechanisms of OSA. Future research should validate the specificity of these targets in well-defined patient groups with varying severity and further investigate their regulatory differences across different degrees of OSA. Moreover, although this study did not include severity stratification analysis, single-cell RNA sequencing reveals that the elevated expression of core genes (IL1β, TGFβ1, SHH) in T cells and dendritic cells is closely associated with mechanisms involving inflammatory responses, immune regulation, and oxidative stress [ ][ ] . The findings of this study indicate that the identified genes may collectively contribute to the pathogenic processes underlying OSA, with their influence manifesting in varying degrees of severity across different cases. It is clearly important for future research to incorporate subtype classification data, as doing so will provide a deeper understanding of the specific roles these genes play and the mechanisms through which they operate in distinct pathological scenarios.While significant efforts were undertaken to reduce bias in our analysis, it is important to note that MR analyses are still susceptible to the effects of unmeasured confounding factors or the phenomenon of pleiotropy, where a single gene impacts multiple traits. To address the robustness of our findings, we employed a range of sensitivity analyses. The research strategy employed included MR-Egger regression analysis, weighted median and mode methods, Cochran's Q test, and MR-PRESSO pleiotropy detection techniques. Although these methods have been extensively validated, the study should recognize a limitation, namely the absence of external validation using datasets independent of the current study (UK Biobank data). To enhance the credibility of the study's conclusions, conducting repeated analyses using independent pQTL datasets is crucial. Future research should focus on integrating resource-rich and high-quality datasets to comprehensively validate the preliminary findings of this study. Additionally, the precision of protein-ligand molecular docking relies on the quality of their structural models. While single-cell sequencing offers valuable insights, its inherent limitations—including dataset selection biases and variability in analytical platforms—can lead to an incomplete picture of certain cell types' phenotypic and functional profiles. Although promising drug targets have emerged from this research, their real-world effectiveness remains unproven and must be rigorously tested through both preclinical studies and clinical trials. Additionally, chronic kidney disease (CKD) has been shown to dramatically reshape the plasma proteome's composition, introducing further complexity to biomarker discovery and therapeutic development [ ][ ] . The lack of consideration for CKD during the data filtering process in this study may potentially impact the results. This oversight highlights a significant limitation in the current research framework, as CKD could influence the outcomes related to OSA. To enhance the reliability and validity of future studies, it is essential to address these limitations comprehensively. By doing so, researchers can improve their understanding of OSA, its underlying mechanisms, and the effectiveness of various therapeutic strategies aimed at managing this condition. This approach will ultimately contribute to more accurate conclusions and better clinical practices. Based on the findings and limitations identified in this study, we put forth a series of recommendations aimed at shaping future research endeavors in a more fruitful direction. To begin with, it is crucial to enhance the generalizability of our results by incorporating study populations that represent a variety of ethnic backgrounds and geographic regions. By doing so, we can better validate the applicability of our findings to a wider range of patient groups, allowing for a more comprehensive understanding of the issues at hand.In addition, future research should consider the integration of multi-omics data along with environmental factors. This multidisciplinary approach will enable investigators to delve into the molecular mechanisms of obstructive sleep apnea (OSA) from a more holistic viewpoint. By incorporating various biological data types, researchers can uncover intricate relationships and processes that may not be evident when examining singular aspects of the disease. Furthermore, employing higher-resolution structural biology techniques and molecular dynamics simulations can enhance the precision of molecular docking analyses, thereby producing more reliable and meaningful results.Another promising avenue for future investigations lies in the combination of spatial transcriptomics with single-cell multi-omics technologies. This integration will significantly bolster the comprehensiveness and accuracy of data interpretation, allowing for a finer resolution in depicting the functional characteristics of distinct cellular subpopulations involved in OSA. Such detailed insights are vital for advancing our understanding of how various cells contribute to the overall pathology of the condition.Moreover, it is essential for future studies to validate the targets identified in this research through a variety of approaches, including laboratory settings, animal models, and early-phase clinical trials. This multi-tiered validation process will help determine the clinical applicability and safety of the identified targets, ultimately paving the way for potential therapeutic advancements.Finally, we recommend that future study designs take into account kidney function-related parameters and actively exclude patients with CKD. This step is critical for minimizing potential confounding effects that could skew the results and lead to misleading conclusions. In conclusion, by adopting these proposed strategies, future research efforts are anticipated to deepen our understanding of the pathogenesis of pulmonary fibrosis (PF), broaden the array of possible therapeutic interventions, and, most importantly, enhance patient outcomes. 5. Conclusions This study integrated Mendelian randomization (MR) analyses to identify 62 potential therapeutic targets associated with OSA and to screen core genes, systematically evaluating the causal relationships between plasma proteins and OSA. Furthermore, reverse Mendelian randomization analysis identified four key genes associated with OSA, offering new insights into the bidirectional causal relationship between plasma proteins and OSA. The results indicate that these key genes play vital roles in oxidative stress, inflammatory responses, and immune regulation and are predominantly expressed in T cells and dendritic cells. Through drug enrichment and molecular docking analyses, the study identified candidate drugs, including 3,4-DHB, BIM IX, and SB 202190, which demonstrated significant therapeutic potential in anti-inflammatory, antioxidant, immune modulation, and pathway regulation.The findings presented in this study offer significant insights into the treatment of obstructive sleep apnea (OSA), suggesting ways to potentially lower drug development costs while also supporting the creation of more individualized medical plans for patients. Such advancements are vital in enhancing our understanding of the molecular mechanisms underlying OSA, which in turn can lead to the development of precision therapeutic strategies that focus on key genes involved in the condition. However, to fully substantiate the therapeutic potential of drugs that target these specific proteins, additional experimental research and clinical trials are necessary. These further investigations will be essential to confirm both the safety and efficacy of these treatments in real-world clinical environments. In summary, this study contributes new theoretical insights and practical evidence regarding the treatment of OSA, establishing a robust foundation for future research endeavors and drug development initiatives in this field. The implications of these findings could significantly influence the direction of future studies, paving the way for more effective and personalized approaches to managing OSA. Declarations Author Contributions Conceptualization, L.Z.D.; methodology, H.Q.J and Y.Q.W.; writing—original draft preparation, L.Z.D.; writing—review and editing, A.H.Z.; visualization, Y.W and S.Y.N.; supervision, Z.F.Y. All authors have read and agreed to the published version of the manuscript. The authors confirm that no paper mill and artificial intelligence was used. Author information Authors and Affiliations Third Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, Yunnan, China Lingzhi Duan,Yan Wang,Shuye Ning Kunming Hospital of Traditional Chinese Medicine, Kunming, Yunnan, China Haiqing Jing,Yanqiong Wang,Aihua Zhang Xuanwei Hospital of Traditional Chinese Medicine,Qujing, Yunnan, China Zhengfu Yang Corresponding author Correspondence to Aihua Zhang The Email Address of the Corrresponding Author： [email protected] Funding Statement This research received no external funding. Informed Consent Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers. 2015;1:15015. Published 2015 Jun 25. doi:10.1038/nrdp.2015.15 Gunta SP, Jakulla RS, Ubaid A, et al. Obstructive Sleep Apnea and Cardiovascular Diseases: Sad Realities and Untold Truths regarding Care of Patients in 2022. Cardiovasc Ther. 2022;2022:6006127. Published 2022 Aug 11. doi:10.1155/2022/6006127 Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7(8):1311-1322. doi:10.3978/j.issn.2072-1439.2015.06.11 Suhre K, McCarthy MI, Schwenk JM. Genetics meets proteomics: perspectives for large population-based studies. Nat Rev Genet. 2021;22(1):19-37. doi:10.1038/s41576-020-0268-2 He Y, Xu X, Lv M, et al. Risk factors of high inflammatory state in pediatric obstructive sleep apnea. Sleep Breath. 2025;29(1):116. Published 2025 Feb 28. doi:10.1007/s11325-025-03282-7 Rasouli S, Alizadeh Severi A, Abdolsamadi M, et al. The Association Between the C-Reactive Protein Gene Variants rs1130864 and rs2794521 and Obstructive Sleep Apnea in the Iranian Kurdish Population. Genet Test Mol Biomarkers. 2024;28(12):485-491. doi:10.1089/gtmb.2024.0395 Wang L, Wang Y, Jiao T, et al. Effects of continuous positive airway pressure treatment on arterial stiffness and inflammatory factors in patients with coronary heart disease complicated with obstructive sleep apnea. J Cardiothorac Surg. 2025;20(1):59. Published 2025 Jan 11. doi:10.1186/s13019-024-03252-2 Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017;318(19):1925-1926. doi:10.1001/jama.2017.17219 Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486-496. doi:10.1002/jrsm.1346 He D, Che X, Zhang H, et al. Integrated single-cell analysis reveals heterogeneity and therapeutic insights in osteosarcoma. Discov Oncol. 2024;15(1):669. Published 2024 Nov 18. doi:10.1007/s12672-024-01523-x Cortese R, Adams TS, Cataldo KH, et al. Single-cell RNA-seq uncovers cellular heterogeneity and provides a signature for paediatric sleep apnoea. Eur Respir J. 2023;61(2):2201465. Published 2023 Feb 9. doi:10.1183/13993003.01465-2022 Ferkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet. 2021;53(12):1712-1721. doi:10.1038/s41588-021-00978-w Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2023;4:186. Published 2023 Aug 4. doi:10.12688/wellcomeopenres.15555.3 Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29(14):1830-1831. doi:10.1093/bioinformatics/btt285 Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D646. doi:10.1093/nar/gkac1000 Yoo M, Shin J, Kim J, et al. DSigDB: drug signatures database for gene set analysis. Bioinformatics. 2015;31(18):3069-3071. doi:10.1093/bioinformatics/btv313 Liu Y, Yang X, Gan J, Chen S, Xiao ZX, Cao Y. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res. 2022;50(W1):W159-W164. doi:10.1093/nar/gkac394 Franzén O, Gan LM, Björkegren JLM. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database (Oxford). 2019;2019:baz046. doi:10.1093/database/baz046 Meliante PG, Zoccali F, Cascone F, et al. Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea. Int J Mol Sci. 2023;24(6):5478. Published 2023 Mar 13. doi:10.3390/ijms24065478 Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol. 2011;41(5):1203-1217. doi:10.1002/eji.201141550 Díaz-García E, García-Tovar S, Alfaro E, et al. Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2022;205(11):1337-1348. doi:10.1164/rccm.202106-1445OC Li C, Zhao Z, Jin J, Zhao C, Zhao B, Liu Y. NLRP3-GSDMD-dependent IL-1β Secretion from Microglia Mediates Learning and Memory Impairment in a Chronic Intermittent Hypoxia-induced Mouse Model. Neuroscience. 2024;539:51-65. doi:10.1016/j.neuroscience.2023.12.006 Cubillos-Zapata C, Troncoso-Acevedo F, Díaz-García E, et al. Sleep apnoea increases biomarkers of immune evasion, lymphangiogenesis and tumour cell aggressiveness in high-risk patients and those with established lung cancer. ERJ Open Res. 2024;10(1):00777-2023. Published 2024 Feb 19. doi:10.1183/23120541.00777-2023 Han S, Huang J, Yang C, Feng J, Wang Y. The histone demethylase KDM6B links obstructive sleep apnea to idiopathic pulmonary fibrosis. FASEB J. 2025;39(1):e70306. doi:10.1096/fj.202402813R Shen C, Zong D, Peng Y, Zhou L, Liu T, Ouyang R. Effect of continuous positive airway pressure treatment on Th17/Treg imbalance in patients with obstructive sleep apnea and a preliminary study on its mechanism. Sleep Breath. 2024;28(3):1231-1243. doi:10.1007/s11325-024-02997-3 Yang Y, Somani S. Impact of obstructive sleep apnea on the expression of inflammatory mediators in diabetic macular edema. Eur J Ophthalmol. 2023;33(1):415-420. doi:10.1177/11206721221099247 Sundaram SS, Swiderska-Syn M, Sokol RJ, et al. Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity. Hepatol Commun. 2019;3(7):883-893. Published 2019 Apr 17. doi:10.1002/hep4.1354 Zhang GH, Yu FC, Li Y, et al. Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition. J Am Heart Assoc. 2017;6(10):e006680. Published 2017 Oct 19. doi:10.1161/JAHA.117.006680 Yang L, He Y, Liu S, et al. Adipocyte-derived exosomes from obstructive sleep apnoea rats aggravate MASLD by TCONS_00039830/miR-455-3p/Smad2 axis. Commun Biol. 2024;7(1):492. Published 2024 Apr 23. doi:10.1038/s42003-024-06171-z Zhang GH, Yu FC, Li Y, et al. Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition. J Am Heart Assoc. 2017;6(10):e006680. Published 2017 Oct 19. doi:10.1161/JAHA.117.006680 Ding X, Zuo Y, Liu Z, et al. Recombinant neurotrophin-3 with the ability to penetrate the blood-brain barrier: A new strategy against Alzheimer's disease. Int J Biol Macromol. 2025;293:139359. doi:10.1016/j.ijbiomac.2024.139359 Merzon E, Magen E, Ashkenazi S, et al. The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder. Nutrients. 2023;15(23):4948. Published 2023 Nov 29. doi:10.3390/nu15234948 Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood. 2020;136(11):1225-1240. doi:10.1182/blood.2019000944 Xu F, He Y, Sun Y, et al. The TNFRSF1B Connection: Implications for Androgenetic Alopecia Pathogenesis and Treatment. FASEB J. 2025;39(9):e70553. doi:10.1096/fj.202402832R Massoni VV, Silva CMPC, Araujo LDC, et al. Expression of NET markers in experimental apical periodontitis induced in mice. Arch Oral Biol. Published online April 5, 2025. doi:10.1016/j.archoralbio.2025.106255 Yan Y, Guan S, Wang S, Xu J, Sun C. Synthesis and characterization of protocatechuic acid grafted carboxymethyl chitosan with oxidized sodium alginate hydrogel through the Schiff's base reaction. Int J Biol Macromol. 2022;222(Pt B):2581-2593. doi:10.1016/j.ijbiomac.2022.10.041 Yin X, Zhang X, Lv C, et al. Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia. Sci Rep. 2015;5:14507. Published 2015 Sep 30. doi:10.1038/srep14507 Adegunsoye A, Balachandran J. Inflammatory response mechanisms exacerbating hypoxemia in coexistent pulmonary fibrosis and sleep apnea. Mediators Inflamm. 2015;2015:510105. doi:10.1155/2015/510105 Chuang LP, Wu HP, Lee LA, et al. Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients. Int J Mol Sci. 2021;22(21):11396. Published 2021 Oct 22. doi:10.3390/ijms222111396 Asiedu SO, Kwofie SK, Broni E, Wilson MD. Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm. Biomolecules. 2021;11(5):653. Published 2021 Apr 29. doi:10.3390/biom11050653 Lu HD, Liu ZC, Zhou LY, Zhou J, Feng XR, Wang B. Influence of the TLR4-mediated p38MAPK signaling pathway on chronic intermittent hypoxic-induced rat's oxidative stress and inflammatory cytokines in rats. Eur Rev Med Pharmacol Sci. 2019;23(1):352-360. doi:10.26355/eurrev_201901_16783 Zhao W, Zhou L, Wang Y, Wang J, Sun YE, Wang Q. Single-cell transcriptome analyses of PBMCs reveal the immunological characteristics of individuals with phlegm-dampness constitution. Front Med. 2025;19(2):376-385. doi:10.1007/s11684-024-1113-3 Wu X, Li B, Wang Y, et al. Microfluidic Chip-Based Automatic System for Sequencing Patient-Derived Organoids at the Single-Cell Level. Anal Chem. 2024;96(42):17027-17036. doi:10.1021/acs.analchem.4c05111 Si S, Liu H, Xu L, Zhan S. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome. Genome Med. 2024;16(1):84. Published 2024 Jun 19. doi:10.1186/s13073-024-01356-x Christensson A, Ash JA, DeLisle RK, et al. The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome. Proteomics Clin Appl. 2018;12(3):e1700067. doi:10.1002/prca.201700067 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology → Version 1 posted Editorial decision: Revision requested 27 Jul, 2025 Reviews received at journal 22 Jul, 2025 Reviews received at journal 16 Jul, 2025 Reviewers agreed at journal 16 Jul, 2025 Reviewers agreed at journal 11 Jul, 2025 Reviewers invited by journal 29 Jun, 2025 Editor assigned by journal 26 Jun, 2025 Submission checks completed at journal 26 Jun, 2025 First submitted to journal 20 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6936975\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":478899553,\"identity\":\"a95cfd93-45cc-44f8-9bc1-8234c4f2288d\",\"order_by\":0,\"name\":\"Lingzhi Duan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Yunnan University of Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Lingzhi\",\"middleName\":\"\",\"lastName\":\"Duan\",\"suffix\":\"\"},{\"id\":478899554,\"identity\":\"a09303d4-163b-4c8f-97e6-0e830158d32f\",\"order_by\":1,\"name\":\"Yan Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Yunnan University of Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yan\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":478899555,\"identity\":\"f67f1a2e-9e0f-4b5e-a4da-ce0bd88b515c\",\"order_by\":2,\"name\":\"Haiqing Jing\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Kunming Hospital of Traditional Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Haiqing\",\"middleName\":\"\",\"lastName\":\"Jing\",\"suffix\":\"\"},{\"id\":478899556,\"identity\":\"25dcd5e7-35ab-4d1b-8543-db18e4e0991f\",\"order_by\":3,\"name\":\"Yanqiong Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Kunming Hospital of Traditional Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yanqiong\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":478899557,\"identity\":\"30954e12-fc58-41e9-bb17-26a5459b33c5\",\"order_by\":4,\"name\":\"Shuye Ning\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Yunnan University of Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shuye\",\"middleName\":\"\",\"lastName\":\"Ning\",\"suffix\":\"\"},{\"id\":478899558,\"identity\":\"d30c30a6-326a-4aa2-88cf-2b6f95aa231f\",\"order_by\":5,\"name\":\"Zhengfu Yang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Xuanwei Hospital of Traditional Chinese Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhengfu\",\"middleName\":\"\",\"lastName\":\"Yang\",\"suffix\":\"\"},{\"id\":478899559,\"identity\":\"7eafe3da-0e18-4519-953c-e087b6090239\",\"order_by\":6,\"name\":\"Aihua Zhang\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYBACCSBmBmI5NvbmA6RpMebjOZZAmpbEeRI5CsRpkZx2/OHnwra69DaGHAaGHxXbCGuRlk5Ilp7Zdji3jeHsAcaeM7cJa5GTTjggzdt2ILeNsS+BmbGNKC2Jzb95gQ5jY+YxIE6LtHQyG9AW5gQ2NmK1SM5OY7PmOXfYsI2HLeEgUX6RuJ3++DZPWZ28/PzHBx/8qCBCCxgwskHoA0SqB4E/JKgdBaNgFIyCkQcAS3k1/6ZtMCEAAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Kunming Hospital of Traditional Chinese Medicine\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Aihua\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-06-20 08:38:13\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6936975/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6936975/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s00210-026-05087-1\",\"type\":\"published\",\"date\":\"2026-02-19T15:59:45+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":85842504,\"identity\":\"bcf12740-873c-4af6-a23b-a72a9c9ca68b\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:22:45\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":134922,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eStudy Design and Flowchart of Mendelian Randomization Investigating Plasma Proteins and Sleep Apnea\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/e298d41a69690bce9818cf14.png\"},{\"id\":85845709,\"identity\":\"05b885ba-a95d-43b4-9f2a-458eb77fd7a6\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:38:45\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":348457,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eReverse Mendelian randomization analysis revealed a positive association between OSA and CELF2 (p = 0.009, OR = 1.093, CI [1.021, 1.169]), as well as negative associations with NTRK3 (p = 0.003, OR = 0.889, CI [0.823, 0.962]), MYOM2 (p = 0.026, OR = 0.915, CI [0.847, 0.989]), and ANTXR2 (p = 0.022, OR = 0.907, CI [0.835, 0.986]). This suggests that OSA may induce increased expression of CELF2, NTRK3, ANTXR2, and MYOM2, potentially augmenting oxidative stress and inflammatory responses, thereby accelerating the progression of OSA.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/dfa16153915ee4203a2ac91e.png\"},{\"id\":85842507,\"identity\":\"cbe63ced-7af5-4ba9-8f09-620b70962798\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:22:45\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":129173,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eGO enrichment results.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/fd223540bc578f229c2e6ce6.png\"},{\"id\":85842512,\"identity\":\"97ec3149-0370-4fcc-ab44-3ca0dfb2c2d4\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:22:45\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":163460,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKEGG enrichment results.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/31118cd6fd49d7383d9eaf02.png\"},{\"id\":85845710,\"identity\":\"2d7ea70a-58d9-4c4d-86cb-7cf3639495f3\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:38:45\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":187112,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDiagrams for constructing the PPI network: (a) PPI network created utilizing STRING. (b) Comprehensive PPI network of the chosen genes, featuring essential clusters of hub genes marked in green. (c) Essential subnetwork illustrating interactions between the primary hub genes.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/d8ddbd2c11f802756f7c9cee.png\"},{\"id\":85845717,\"identity\":\"4b02c809-cde3-44e4-9c4c-f133ae668122\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:38:46\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":119925,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBar Chart Of Drug Prediction Results\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/720284bcb98143dd64c8a274.png\"},{\"id\":85846836,\"identity\":\"8683d118-f802-47f1-bd60-982c9cd87d21\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:46:45\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":401543,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDocking results of available proteins small molecules.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/a1d4729c7e7b7ff3920eca90.png\"},{\"id\":85844692,\"identity\":\"d23a918a-dd38-445c-b9e1-c1f7fcb9aac0\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:30:45\",\"extension\":\"png\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":139656,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eLegend not included with this version.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"8.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/ed9b461750b0aed20009eb88.png\"},{\"id\":85844687,\"identity\":\"967d6293-3531-453c-a0c8-09cbe9827c87\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:30:45\",\"extension\":\"png\",\"order_by\":9,\"title\":\"Figure 9\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":44457,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eLegend not included with this version.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"9.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/c65f7b251f46b5324db09ee1.png\"},{\"id\":85844690,\"identity\":\"41dc72b3-6019-4ed3-b4c1-36f9eeb1d598\",\"added_by\":\"auto\",\"created_at\":\"2025-07-02 09:30:45\",\"extension\":\"png\",\"order_by\":10,\"title\":\"Figure 10\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":70466,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eLegend not included with this version.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"10.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/5dde357c6315dde49de4198e.png\"},{\"id\":103251232,\"identity\":\"de3e55c8-6433-49f6-a367-7d5482d40512\",\"added_by\":\"auto\",\"created_at\":\"2026-02-23 16:06:40\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2262029,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6936975/v1/38aeb8bd-3439-42a9-919f-19f147a4438c.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Exploring the Causal Relationship Between Plasma Proteins and Obstructive Sleep Apnea: A Study Using Genome-Wide Mendelian Randomization, Single-Cell RNA Sequencing Analysis, and Network Pharmacology\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eObstructive Sleep Apnea (OSA) is a disorder characterized by recurrent upper airway obstruction during sleep, leading to intermittent hypoxia, sleep fragmentation, and carbon dioxide retention. This condition results in increased nocturnal oxidative stress and systemic inflammatory responses, inducing abnormal activation of the sympathetic nervous system. Epidemiological studies estimate that approximately 936 million adults worldwide suffer from OSA[\\u003csup\\u003e1]\\u003c/sup\\u003e. OSA not only impairs sleep quality but also contributes to a range of serious complications, including cardiovascular diseases, cognitive dysfunction, metabolic disorders, and other systemic conditions[\\u003csup\\u003e2]\\u003c/sup\\u003e. The prevalence of OSA varies by age, sex, and body composition, with men demonstrating a higher prevalence rate compared to women[\\u003csup\\u003e3]\\u003c/sup\\u003e . Despite advances in the diagnosis of OSA, its complex pathogenesis poses significant challenges to treatment. Therefore, exploring the underlying mechanisms and therapeutic targets of OSA has substantial social significance.\\u003c/p\\u003e\\n\\u003cp\\u003ePlasma proteins, whether derived from cellular leakage or active secretion, serve as major sources of biomarkers and therapeutic targets, reflecting the metabolic activities and genetic characteristics of biological cells[\\u003csup\\u003e4]\\u003c/sup\\u003e. Previous studies have established associations between protein levels and OSA, suggesting their potential significance in the treatment of OSA. In a cross-sectional study involving 1,171 OSA patients, it was demonstrated that HsCRP levels were significantly elevated in OSA patients[\\u003csup\\u003e5]\\u003c/sup\\u003e. In a case-control study involving 100 OSA patients and 100 healthy controls, the CRP gene was confirmed to be associated with an increased risk of OSA[\\u003csup\\u003e6]\\u003c/sup\\u003e. Moreover, a randomized controlled trial involving 59 OSA patients indicated that interleukin-6 (IL-6) levels were positively correlated with the severity of OSA[\\u003csup\\u003e7]\\u003c/sup\\u003e. However, these observational studies are limited by various factors, including small sample sizes, restricted protein diversity, observational study design, and methodological constraints, rendering the causal relationships between these plasma proteins and OSA uncertain.\\u003c/p\\u003e\\n\\u003cp\\u003eMendelian Randomization (MR) is a well-established method in genetic epidemiology that uses instrumental variables (IV) in non-experimental designs to infer causal relationships between modifiable exposures and disease outcomes, minimizing confounding and reverse causation\\u003csup\\u003e[8]\\u003c/sup\\u003e. Because traditional observational studies are prone to confounding factors, the causal relationship between OSA and plasma proteins remains unclear. MR utilizes genetic variants as naturally randomized instrumental variables to assess the causality between plasma proteins and OSA\\u003csup\\u003e[9]\\u003c/sup\\u003e. This study intends to employ a research strategy combining single-cell transcriptomics with bulk RNA sequencing to systematically elucidate the molecular mechanisms of plasma proteins in the pathogenesis of OSA. Among these, single-cell transcriptomics, with its high-resolution capability to analyze cellular heterogeneity, can provide essential insights into the molecular interaction networks between plasma proteins and OSA\\u003csup\\u003e[10][11]\\u003c/sup\\u003e. Single-cell transcriptomic analysis possesses high-resolution capabilities for exploring cellular and functional properties, offering critical value for investigating the interaction mechanisms between plasma proteins and OSA. Meanwhile, large-scale RNA sequencing effectively captures comprehensive gene expression profiles, providing empirical support and enriched data for single-cell transcriptomic studies. This study aims to utilize these technological platforms to analyze drugs with potential therapeutic value and explore novel treatment pathways for OSA. By integrating plasma protein regulatory mechanisms with existing drug databases, the study seeks to identify therapeutic candidates and validate their efficacy and safety. The core objective of this study is to accurately quantify the correlation between plasma proteins and OSA, clarify their mechanisms of action, and provide innovative perspectives and strategies for precise OSA treatment.\\u003c/p\\u003e\"},{\"header\":\"2. Methods\",\"content\":\"\\u003cp\\u003eThis study employed Mendelian randomization to evaluate the causal relationship between plasma proteins and OSA. Moreover, single-cell RNA sequencing and network pharmacology methods were utilized to explore the biological significance of plasma proteins and their potential in drug development. Figure 1 illustrates the overall framework of this study.\\u003c/p\\u003e\\n\\u003ch3\\u003e2.1.Data Sources\\u003c/h3\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.1.1.Data on Plasma Proteins and OSA\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eBuilding upon the research findings of Ferkingstad et al\\u003csup\\u003e[12]\\u003c/sup\\u003e, this study references the pQTL data for 4,907 proteins documented in the deCODE database (https://www.decode.com). This study utilized GWAS methods to systematically analyze plasma protein levels among 35,559 Icelandic participants, involving a total of 4,907 aptamers. Since the exposure variables and outcome data in the MR analysis were derived from samples of different countries, it effectively minimizes population overlap issues. GWAS data for OSA were obtained from the Finnish FinnGen project (https://r12.finngen.fi/), which integrates genetic information and clinical data from more than 500,000 samples in Finland\\u0026apos;s biobank. The study utilized the latest OSA dataset from the FinnGen R12 release, which includes 56,885 diagnosed cases and 441,137 healthy controls.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.1.2 Mendelian Randomization Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study utilized a bidirectional MR framework to evaluate the causal relationship between plasma proteins and OSA\\u003csup\\u003e[13]\\u003c/sup\\u003e. Exposure data for plasma proteins were obtained from preprocessed summary statistics related to\\u0026nbsp;pQTL. In the process of selecting instruments, we calculated both the explained variance and the F-statistic for each single nucleotide polymorphism (SNP), ensuring that only those SNPs with an F-statistic greater than 10 were included. Moreover, SNPs that exhibited an effect allele frequency greater than 0.01 were retained in our analysis. To minimize redundant signals, linkage disequilibrium clustering was deliberately disabled. To evaluate the outcomes for OSA, we sourced data from a Finnish database, ensuring to eliminate any duplicate entries. A structured harmonization process was then used to align the exposure and outcome variables, which involved matching chromosome positions, adjusting for allele orientation, and excluding palindromic SNPs. Additionally, SNPs that were directly associated with OSA and had a p-value exceeding 0.05 were excluded to mitigate potential confounding bias in the study.\\u0026nbsp;This study employed multiple statistical methods, including the inverse-variance weighted (IVW) method, MR-Egger regression, weighted median method, simple mode method, and weighted mode method, to comprehensively evaluate the causal effects. To quantify the association strength, odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated. To ensure the reliability of the results, a series of sensitivity analyses were conducted, including Cochran\\u0026apos;s Q test for heterogeneity assessment, MR-Egger intercept tests to identify potential horizontal pleiotropy, leave-one-out analyses to test result stability, and funnel plot analysis for evaluating the balance in data distribution.\\u0026nbsp;In cases where the results from IVW demonstrated statistical significance with a p-value lower than 0.05, we generated four diagnostic plots: a scatter plot, a forest plot, a funnel plot, and a leave-one-out plot. The criteria used for final selection necessitated consistent directions of odds ratios across all five statistical methods employed, ensuring either that all odds ratios were greater than one or that all were less than one. Furthermore, we excluded any results from significant MR-Egger intercept tests with p-values below 0.05, while retaining the most significant measurements derived from repeated protein assessments. This rigorous approach was essential for ensuring reliable and interpretable results in our analysis.\\u003c/p\\u003e\\n\\u003cp\\u003eThis study employed a genome-wide significance threshold (p \\u0026lt; 5 \\u0026times; 10⁻⁸) as the selection criterion to perform reverse analysis on OSA-associated SNPs. To ensure the independence of instrumental variables, linkage disequilibrium clustering (r\\u0026sup2; \\u0026lt; 0.001) was applied to reduce correlations between variables, and the strength of instrumental variables (F \\u0026gt; 10) was further validated to enhance the reliability of causal inference. All data processing and statistical analyses were performed on the R 4.5.0 platform, with Mendelian randomization analysis primarily conducted using the TwoSampleMR package.\\u003c/p\\u003e\\n\\u003ch3\\u003e2.2 Enrichment Analysis\\u003c/h3\\u003e\\n\\u003cp\\u003eThis study utilized enrichment analysis techniques, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), to focus on the biological effects of various potential therapeutic targets. GO enrichment analysis was conducted to explore biological processes (BPs), molecular functions (MFs), and cellular components (CCs) at three core levels. Additionally, KEGG pathway enrichment analysis was performed on the significant genes identified through Mendelian randomization techniques. To facilitate these analyses, the R package ClusterProfiler was utilized, providing a robust framework for examining the functional roles of the selected genes within the context of their biological significance.\\u003csup\\u003e[14]\\u003c/sup\\u003e. Terms with raw p-values less than 0.05 were kept and modified with the Benjamini-Hochberg correction technique. Bubble plots were utilized to enhance the interpretability of the results.\\u003c/p\\u003e\\n\\u003ch3\\u003e2.3 Construction of Protein\\u0026ndash;Protein Interaction Network and Screening of Core Genes\\u003c/h3\\u003e\\n\\u003cp\\u003eTo further investigate the interaction mechanisms among intracellular proteins, this study constructed a protein-protein interaction (PPI) network utilizing the STRING database (https://cn.string-db.org/). For this analysis, a confidence score threshold of 0.15 was established as the minimum acceptable interaction score necessary for inclusion. Additionally, any disconnected nodes, which do not contribute to the interaction framework, were systematically removed from consideration. All other parameters were maintained at their default settings to ensure consistency in the analysis. Following the construction of this network, the generated data file was subsequently imported into Cytoscape version 3.10.0 for the purposes of visualization. To identify the most significant interactions, the cytoHubba plugin available within Cytoscape was employed to filter and highlight the top 10 genes based on their degree values, thereby designating them as core genes within the network[\\u003csup\\u003e15]\\u003c/sup\\u003e.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ch3\\u003e2.4 Drug Prediction\\u003c/h3\\u003e\\n\\u003cp\\u003eAssessing the interactions between proteins and drugs plays a fundamental role in the process of identifying whether a specific target protein can be considered a promising candidate for therapeutic intervention. This evaluation is essential, as it can provide insights into the binding affinity, specificity, and overall efficacy of potential drug candidates in modulating the activity of the target protein. Understanding these interactions not only informs the likelihood of success in drug development but also aids in the design of more effective and tailored therapeutic strategies.In this study, we utilized the Drug Signatures Database (DSigDB, http://dsigdb.tanlab.org/DSigDBv1.0/) to investigate the relationship between core genes and potential drugs[\\u003csup\\u003e16]\\u003c/sup\\u003e. The DSigDB database integrates over 22,500 gene sets, more than 17,000 chemical substances, and nearly 20,000 gene profiles, facilitating the mapping of relationships between drugs and their target genes. This research acts as an important resource for investigating drug targets and facilitating drug discovery. This study submitted the filtered core protein gene data to the DSigDB database for drug target prediction analysis, aiming to identify candidate drug molecules that may interact with these target genes, thus providing a scientific foundation for future research on targeted gene therapies. Subsequently, drug enrichment analysis was conducted using the ClusterProfiler package in R. In this analysis, the significance threshold was set at a p-value and its adjusted value (p.adjust) of 0.05 to identify drugs significantly associated with key genes. During the enrichment analysis, a hypergeometric test was employed to evaluate the enrichment of core genes within the gene clusters affected by target drugs, with a significance level defined as a p-value below 0.05. To depict the ranking of enriched drugs, the distribution of genes, and the connections between core genes and drugs, bar plots and gene-drug interaction network diagrams were created.\\u003c/p\\u003e\\n\\u003ch3\\u003e2.5\\u0026nbsp;Molecular Docking\\u003c/h3\\u003e\\n\\u003cp\\u003eTo thoroughly investigate the efficacy of candidate compounds on their target proteins and evaluate the feasibility of new drug development, this study utilized molecular docking techniques. This technique enabled a scientific evaluation of the binding affinity and diverse interaction mechanisms between candidate drugs and their specific targets. To ensure a focused analysis, we selected the top five candidate drugs based on outcomes from prior drug enrichment analyses. The molecular docking experiments were carried out utilizing the CB-Dock2 platform(https://cadd.labshare.cn/cb-dock2/index.php). Through this method, we aimed to elucidate the mechanisms underlying the interaction between these candidate compounds and their protein targets, thereby contributing to our understanding of their druggability[\\u003csup\\u003e17]\\u003c/sup\\u003e. We retrieved the structural data of the corresponding drugs from the PubChem compound database (https://pubchem.ncbi.nlm.nih.gov/) and obtained the structural data for each protein from the PDB protein database (https://www.rcsb.org/).\\u003c/p\\u003e\\n\\u003ch3\\u003e2.6 Single-Cell Sequencing\\u003c/h3\\u003e\\n\\u003cp\\u003eIn order to delve deeper into the expression characteristics and potential functionalities of specific core genes in OSA, we undertook a comprehensive single-cell sequencing analysis. This approach allowed us to closely examine the unique expression profiles of these genes within the context of the disease. For our study, we acquired the single-cell RNA sequencing dataset (SRA550660:SRS2089637), which comprises data from peripheral blood cells. This dataset was sourced from the PanglaoDB platform (https://panglaodb.se/) , an extensive database that provides valuable resources for single-cell RNA sequencing analysis[\\u003csup\\u003e18]\\u003c/sup\\u003e. The single-cell sequencing dataset constructed in this study encompasses gene expression data from peripheral blood cell populations. Through integrative analysis of these single-cell data, this study aims to accurately evaluate the expression patterns of core genes in peripheral blood cells, thereby identifying specific cell subsets that may play critical roles in the pathogenesis of OSA. To further elucidate the expression distribution characteristics of core genes in different cell types, the study utilized t-SNE dimensionality reduction technique for visualization of single-cell data.\\u003c/p\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003ch3\\u003e3.1 MR Analysis Results\\u003c/h3\\u003e\\n\\u003cp\\u003eThe findings from the MR analysis illustrated in Figure 2 revealed that 62 genetic loci are significantly linked to OSA. For example, the NTN4 gene (p = 0.003, OR = 1.076, CI [1.024, 1.129]) and the TFF2 locus (p = 0.004, OR = 1.098, CI [1.029, 1.174]) showed a positive association with OSA. In contrast, the FBP1 locus (p = 0.004, OR = 0.893, CI [0.828, 0.964]) and the RGS18 locus (p = 0.006, OR = 0.815, CI [0.703, 0.944]) exhibited a negative association with the disorder.\\u0026nbsp;Experimental data indicate that the aforementioned proteins may exert protective regulatory effects on OSA through their biological activities. Based on this finding, changes in the expression levels of specific proteins may serve as important molecular indicators for assessing the progression of OSA.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.2 Enrichment Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAs shown in Figure 3, significantly enriched BP terms include regulation of carbohydrate biosynthetic processes, response to lipopolysaccharide, and hyaluronan biosynthetic processes. In the CC category, the enrichment of phagocytic cup, platelet alpha granule lumen, and cytoplasmic vesicle lumen suggests the importance of dynamic membrane structures, secretory vesicle compartments, and extracellular matrix microenvironments. Furthermore, in the MF category, significant enrichment of endopeptidase activity, growth factor receptor binding, and D-glucose binding highlights molecular functions such as growth factor signal transduction, regulation of glucose metabolism, and inhibition of protease activity. As shown in Figure 4, the five pathways identified through KEGG enrichment analysis are the MAPK signaling pathway, TNF signaling pathway, AMPK signaling pathway, Neurotrophin signaling pathway, and NOD-like receptor signaling pathway.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.3 PPI Network and Core Gene Screening\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe 62 gene proteins were uploaded to the STRING database for network construction. The generated files were imported into Cytoscape 3.1.0 for visualization, and core genes were identified using the cytoNAC plugin. As shown in Figure 5, the PPI network comprises 61 nodes and 243 edges. The identified core genes include IL1\\u0026beta;, TGF\\u0026beta;1, EGF, SHH, SMAD2, NTRK3, G6PD, TNFRSF1\\u0026beta;, AKT2, and CTSG. Network analysis revealed that these processes are associated with upper airway anatomical abnormalities, inflammation-hypoxia vicious cycles, neuromuscular dysfunction, and systemic metabolic disorders, consistent with the fundamental pathogenesis of OSA[\\u003csup\\u003e19]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003ch3\\u003e3.4 Prediction of Candidate Drugs\\u003c/h3\\u003e\\n\\u003cp\\u003eIn the present study, we employed the Drug Signatures Database (DSigDB) to forecast potential therapeutic agents that may be effective for our research objectives. This database provided a valuable resource for identifying compounds that could be repurposed or developed further as treatments. Furthermore, we conducted a comprehensive drug enrichment analysis using the R package clusterProfiler. This analytical approach allowed us to assess the significance of the identified therapeutic targets and to understand their biological relevance, thereby enhancing the overall rigor of our findings. The results indicated that 3,4-Dihydroxybenzaldehyde (3,4-DHB), bisindolylmaleimide IX (BIM IX), chitosamine (amino sugar), ciprofloxacin, and SB 202190 are key drugs associated with the core genes (Figure 6).\\u003c/p\\u003e\\n\\u003ch3\\u003e3.5 Molecular Docking\\u003c/h3\\u003e\\n\\u003cp\\u003eIn this study, we conducted molecular docking to evaluate the binding affinity of selected candidate drugs to their specific biological targets. This approach also allowed us to assess the druggability of these targets, which is an essential consideration in drug development. To facilitate our analysis, we utilized the CB-Dock2 platform, which is designed specifically for studying molecular interactions. Our focus was on five candidate drugs, and we examined their binding interactions with the respective target proteins, as illustrated in Figure 7.Through our molecular docking analysis, we identified that the binding energy between the candidate drug SB 202190 and the target protein AKT2 was notably the lowest at -8.0 kcal/mol. This result suggests that the interaction between SB 202190 and AKT2 is highly stable, which is a desirable characteristic for effective drug-target interactions. Furthermore, our data revealed that the overall binding energies for the five candidate drugs varied between -4.7 kcal/mol and -8.0 kcal/mol, as highlighted in Table 1. This range indicates that each candidate drug demonstrates a good binding affinity toward its respective target protein, showcasing the potential for successful therapeutic applications.\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003cimg 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AZqKxtBk8XkbGxeGWV0uJqBidZwRSKoIf4mGg8MkQYjdyw8Fp81mT27djC+ZOHIhujQHaTkZYC4Sns276LjpYmausbKc/fz9ghg4iJS8SkepgweSqhUfFExwSzc38+c6cNoaHdhU52cdGc6Qgxw+luKOeKKy4kKGkMuzdvYebIRKbPvhCXomIVFMKi4kkbmozXK4BBZkTmIIZmDMUSGk5NbTM6XzdR8XEgy0TEhBEaFoUkuUkeNJiFty2koqmb7o5mFpw/mZghk6gsKCE2xsK40SPJaRVxFOziyusXojMFDfzIznrac5an0c7canYvWcQ9P74NNTiW3YdyWDApgaCEkQOrar5jJODRv73KpeMjGD59HjVtbiRbITPPvQiE7+6trLORAjzx9CvMzoxk1MwLaehw0l5VyvxL54HOOLD6f2zF9nzq9i/n5ltvQzRFkleUw7D4cNq9VnraarjwojkIxhAAVm/Mwuiq5NJrbzkj2rKdosrKpcuYOjya4ZPOH1j8naBdWZ5GkaHB5NTa+fTj9yjLP8h1l0wnctDYgdU030E6wBwWy0crN7Fx3UpSQnzMu/RK0FkHVtWcZgJgCorkw1Wb2LxuJfFBfi675hrQfbMnNTHRkRwsaWXJJ+9RW3aUaxacz75KP4c3fcR11yzAHHa889/woSl0eiDMCOagQAA9nWpbbKSGS2SOP3dg0XfGt35lKUkSHo/nvx72S1XVfsNHfdXrf9eJ83/dZR2rd2wXnmqeUy1PEMBqtSIIOlTA5/X1e36Lk8w78PWX+U/qnmyek0075svKvo5TzX+q6acysP7A16eadqKvKh/oq+oPLFdPOE5UVcVsNmA0BgaNlhQFn8dL30PkJ5n3xM9nYPnJ6nxdx7aLAcfwidt77PXA8lOtZ+C8A8tONv1EA+t8ndecYn0nGjjf12UyGTAazdA7aIDX4znl/v6q1wMdKxcG/B54vD4sBgHBYMLj8aIqcr9lmUwGRDEwbeCyTvb6y8pO5mTlJ5sGoNcLCIIRSfKfst7Jpp1IURTMZjOmM7ST0LceLFtaWtixYweGrxij8asM3NFf9frf9WUH1akcq3dsF55qni9b3peVcZLyga+/zH9S92TznGzaMV9W9nWcav5TTT+VgfUHvj7VtBN9VflAX1V/YLk6IFgOLPs6rwf+f6IvK/syx7YLLVh+LQP388BlftXrgU4sH/g+Bq5j4LL+nddfVnYyJys/2bRjvmxdp5p2IlmWGTVqFGPHnpl31771YKnRaDQazdnuv7s3qtFoNBrN98AZFyzVAQP3fl2qenzegctQe9tOUVUkWUH+N55XU1S1b95vwje9vBP1LfuEMUS/bH2yoiIPqP9lVDWwH/+Tz+e7SO09Xk/ct1+2b76sjBOO/ZMdwyeWa74b1GOpxE7ymaonDKD+db+fmm/XGRUs/ZJCeWUNtRVlyKJvYDEAPkmmrbUV1OMBTwVsXT1UVVXS0tRIW1s7DXUN+H1uQMULbNu2A9HVxub9+Rzdu6PfMr9MeX0nn69cgd8dGID5v1XcYOPzVWtR3R0Di/5rRXUdbFq/HHzHt7WutYfVy1fi6fri+rKK6tm5YS1I7oFFJ9XZ7WPp0vW4nQ0Di753ZEWhpcNGe3sL7W2teJ09OL0ildW1dHW29PuB88sKNfVNdLQ2ocoi9JZ22p0oJ7y29x3DTYFjuL4ev88FqMiKSn1TK2Ulxbi6Ok968qM5u7R3dlNcXExTXWW/wUg8/sDvYHFxMaWlJfR0tvabT3N6nFHBcndBNS+98gb/d8/P2LP6nYHFKCosWr+fB+/9IYjtfdNlFQ4UVTLv/CtY/sZT7Nqzl2deeo9n/v4Ivq5W9EBMTAxev55ln29lz/pP+i33yxwsreG9119HdNoGFv1HCovrePW5F1CdLQOL/mtHcqt559lXwN/ZNy2/rpk3X30Dd2dTv7oAO3bn8Nk7r4EUSNPzVZq7unj12X/RYy8bWPS9s/1IJa+++jR79uzk3Y+Ws3fZIqrburjx14/yq9suw+86/hlsza5l+uwL2Lr8bWRvYF93+RR+/NPfUb5/BfQe21n5Fcw//wo+e/2f7Ny9l2dffp/n/vEoYk8r+bWdvPHG29z/0J/506/uwdulnbCczbp9Cu8vWc1zTz/FhqWLUPzHT1gPldTz9yef57lnn+WHv3iYPSte6zev5vQ4o4LlsMQIXnjmcX7yt9cpLSkdWExlazcNlUcxSv0fBDYIMHfWBIYMncL1l53LDdddw5//9kfW5Xaz+JUnUXx+RozIJDQyiknTJoPBRHunHVeXHUmRaWvvxN3TDYCjx4nP60ZWFLp6nAxJSiAyKR2334/d7qCj00GXvRNJlunucWK32RH9PnyiTGtrGz6PE6fXj8Nhp8fppqO9DcnvRZJVHF0OpkweQkh8OjZHNx1trUiiP9BN3Cfi6OrC63KiKAoOexdOl4e29g58LieKquLo7sHp7MHh6MLZZccvSti7u+my21EkkUkzRhAUnAy9t1i7epykxcYQM2gooCDJCt09Trq6upAlkemzJmCISMDm6Mbe2Y4sy3TaHHTZbYCC0+3D1dOFoqp0u9zERQaTNCgd1EDyWafThcPhQPIHuot/n6xYs4NUsYMrr7iWm394N9bIQYxNjeGee39CcbOL4oOBuxc+WSUv/wgZYX4uvvpKDMGBfImH82vpFnysXrEOVVXQC3DuuZMYNmwyV18ymxuvv4ZH//JH1mT3sPjVZ9F7u3n0tz9hycpPOdIWRO2RTQO2SHM2OZRXib+zjBef+jM//M3f0VvC+srGDQ7nvdee4s233uLuO+9hzJwr+s2rOT3OqEEJwkOCKKluYMeqFdx41fmExR/PNO72iRQcOkD84AzKD2ZzxfXzQX/8YVwXsPidJVx+XiYRg8diNkCzHMHuFe+QMH4qP/3hPdxx6VgO1EtUHd3JttwGlr/2DKMmj+OWnz6Gp3w7E+dcyuMvvEWc0kRhp8COjasoLq6mrfQwsaMmc99vHuHongN4Oktodclk7d3Bpp3Z1B3aijk2mVvu+g1S3W6O2gyU7VlFfY+Bu2+5k/kT4ukwJfPi048zfHgG69fuxGZv4m//eplEUxehKcNYs2IjWUdzWP3xh2RmZnDf75+ksugAH366kZJtyxg3fSbvrt5GS30F9z/0OELLIXLbBXZvXc0HH60mI8iFkDiMfatXc82NF7GrxMHmNUspL6+h8uheLl1wMbuLGsg5uI83P1xGsrEdf0gy+7dupKbJxgv/+Afjxqfzp5fWsPXNv3D5wht4afFWOst2IYWksmz5Z9RWNZG1eRM33DqfQ8U9HN2fxbtL1iI2ZDNy0oz+Iyp/xynmMJ546T3ay/cxcWQGY2bNRVIFOrvaMOiCObBlHZdccy0VTXYqco/S5fJy4ZzJhEWn4vTLFO7fwvlzzmPp8s+55NxRWCOScErw2XufMv+cIUSnj8digBZ9NLuWvcHPf3kXeksMKApHjpZwxYVTsUZrwyKerXqcLvZnl/HCM88xKNRH2ogJfd8fi8UCgo4au5/qo+uYOWsOBnPwwEVo/sfOqCtLAEe3i3V79vLOW6+D6uqbfii/ktgQGWtEFF6fF5/Xi9vro6enB7fLedJGcGuwCb9fYtKEFPRCDCgykqwSEyLw3N8exBY8nCBHAw/+8fd0e/R4u9uZM3kUqZPP57P3P+Te6+Zw6Y23oprDGZ8+iOTBydx/z3yu+fkfef+td7jl6vk88PAveXtTARHdBTz71musOthGpr+CH9/3e268bC4X3HgXjS1NoPi45eJ5RCYPQ5V9PPjTm/n5X1/k3cXr+HjJchrydzBixBDcegt+r5PU8aMZFiPw56eeIb9FQXC1c/9dN2CIGcXQGIGF9z6ELOu56ZJ5qCmDOXDkEAa9Hp0g4HVLfPTuR/zfgvFcdeudGMMTqGzu5LP3P2ZQkpW09CHUVFagij6Q/Dx8/4/ImH4VHQ1HePh3P8MQl06no4sxMQbOu/xWPvrgQy6ZlM5tt19HfOpgGrp9LP9gEcEGD8NHj6SouqlfG/L3wRWzMnn73bc52KRj4c23cGTzZ+gEkHw+blm4gPwWHRWHNnHoUD7zzh2HqBj62hnLqpqQRQ/nTB0LiWPZv3NLYKEnOdcICTGiyCr4Pagq7Miu4tpZyURlzhpYVXMGU1RwOl309PTg93kYPzyVZ/76ID/7yyssX7MZb1fzwFkoKSjBagnGHBa4G6E5vc6oYCkrCjPGD+fVt96koEEPrg7k3h5h6/fk8rcnX+Avv7mPXUcPsPL9d3jpw1XcddddPPWnhzCqDlRB33dx4xclsrMOMWH0EAR9DHqdCQQBnaASHR2HQa8nLCoCURSZO2U4VT0G1n++lpQgHZ1CKDW5Bfj1+sCwZEFBSIqC1WRAbwqjodNPt6MV0a8QLEBY6kiaG9qZnh5B4viZ7Nq9HdEXaJtacMUClqzPomDfdsZPG43P6yckJAid2UJmxmCC4zOoa20jKsLMjInj+Mff/kjysHEYZD8xCakYTAaCI8IxGY0UNHfx0TOP8uhDPyQ0OpmYICvbduwhGC8mgxlBJyAA3ZJIVU4hik4PqoQ1OBinz4+npYWRGan86v9u5vJbf4lPhrjIcHTWEIKCzPglmVHxwejTZ7LklaeJjgnFaDVT3VSL5HUjSBImox6PT8Tm6mJoWhI/uv5ifvLgIyDo+3+Y32Eq0FhVy6TMFNYsfoPzfvBn3l70LjpEZFVgZHwQ0665jT/96y3i3IXEDZuCIksIOgFFVTmSV0qPvZ1Nm7aQmBjFus+3IYuuL1yY+0WJQ7sOM3rEEBRLElUtTgy2WuZdc8O/1aNbc/o1eyXue+gv3HXXXexc+RaSLKMqCjOmDmXEhKmIXn9v71cFAEmB2roKxqTFAf/dgC6ab8YZEywV4HBBBba2Ztx2O9dfNQ9CksjOr6K9qZon7lvIZ8tX88+33uOSWXNY+LP7ePBHN7Js2TL+9PTL9PjCEL1deDwiPr+fd5bthsod/Oz+32B3gcfXhsfjoqPTRo+9G58kY7N34PR4iTDChAuuYdOqzxg9fQxJFiNqyjCeevwZ9m/dQGNDPY1VlTgcXbi9TjKiTcSMOJe96z+isaOL4ZEKmTMv4LOVG3jiFwupsUzh45f+iSr7mTM+A0fQYBzFWQjByegFFZfbT1trB+X5OSyYM45LL17Amh35bNvyOdt3bMXW2Uyr3YHH6cDjceOwd9Lu9PHUUy9z8/wJJI+5kJzCUl548TUWzBmH3ppMeUUlTXXNOH0dhBt1hI0Yx5+feIE9m9bRUFdLkN+NnDSYD994l227dlJVfhivpwdHcxN+l5serxuPI9CL9o47bmL55sPEmFTCLEGkpE3khdffYP2mjVTX1KE2NxM1aCQfvPc+u/bt5XDWNlQl8CX/PhCAFRsP8vmn76P4RSYNG8y40WOQFQFHux2fq5vbrr2UijoHI8cMQ1R0eDx+fE4XJU027Ll7+OHPH+Caa67hNw88wOFWyN2yCtkv4vf14PPJeP1+3l2+B0PlVu795X2UN3l549WXcHU38fnGXeQdPaz1iD2LJFsNvPXyP1m2bBkXLfwFe7LyqS/Jp6WmkSnTZxIam0R5TR3tjbUA2Hq8NFXVMmrKlIGL0pwmZ1Sb5b6cMgqzs0hPCmLu3AsQ9BY+25aNq3w3w8eMBZ0JSZIINRsZMWpE30DGfgUOHsgm2OjDqZopr6whwizxf/fcSczg0eTllqOTu9AHR+B39RAaFESPakEQe0iKCSc5YySWqATSg3oYOv4CTHqBadOnUl7bTHpSKGMnTsQaHorP4yHEYmDEiLFMmzWD/MpO7K3l3HbDxbSrCRQc3sPUCSNQjUE019WROTSd0LBwnG6Fc86dTEx8CiEWI0npmRzNKyUjLogLL76MoempGCMzqCjJZfbYTMwxaTRVlRMeZKFHMmJS3egEA7K3i4j4VIpKStG72pkwew5trY2MGTqM+LQ4PD0KJpNKZsYgLr3sSiobbSRFGhg7cRKzpo5k5vmXUFDaSLjOw5Rz51FQ3IDFpBIUFESPs4sQUwgjx48jNtSKzSVw2WVzQG9l6sQx1HWKhBgVJkwex/gRw5h36ZUU1/YguFuYN+ccrGExAz/O7ywViI4MwacKHDmcR4TOwTULb6egvouynMMoXhdjRo1i/kVzSRg8jL1HignR+5AUHfX1DVgFH4MHJWANjaShvh7F78bn8dLRYSc00opbMVJeXUuE0c+P/+9OYgePZt+hbOyNpXR5JBztTUwakUZEvNZmeTZSVChvaCTnYBbDB8Uwcux4dAYzeSVlmOUeouMH4feLRJpEUodPGDi75jQ5o4e7UxSVwoo6woVuUjNHAV/3Vp968gagE/VWkVQ4eiSP0sISLp03jpiUEQNr/sdaO9wUFuXiaq5m3qWXEvSNtT18jff3Hyoua6C4tIT0IA8T52m98L6KGsg7P3Dy13Cyz/CEaar6veowpdGc6c6Y27AnJcDg+GhSM8f+G4GSk/wInURvFbcIWUeOMizRRFRcxsBa/5U6u5Pi3ENMmTrxGwyUfL339x+QVDhcUoHaVceEc7+bOem+af9ZoOQUn+EJ07RAqdGcUc7oK8v/nZOd5f/3vp2lfrvOxm3WaDSab9uZfWX5P/PthIdvZ6nfrrNxmzUajebbpgVLjUaj0Wi+ghYsNZozjNYyotGcec6oYKkCfr+I6PefdEQeejsJyvIX00rJsoIo+pEkCUmSEEWx7zk0Beju7kZVJTw+Ea/H02/eLyPJCi6nC76h5wglWcHlcsMJWQa+KaIk43Y7+22r3Lv9ivLFh9h9oozH7e7dQ19NUVScLg+KEsiUoQkMpHHiMSdJEpIo9gW8vnJZ7ktvJitKX11ZlhFFEVVVUFXo9vjoaG1BEo9nI5EkCUX+5o8XzeklyQo+nw9J/OLv3bHjJvBbpzkTnFHPWXb0ePlo8TJKDu0kMyMFU9DxwYWPaehwcnD3FoZkpPQ9ZykDucVVrF62hO72VpraOzl6OIeoUAgJj8YlCKxftZaMxFCe/2gr9uLdjJw4beCiT2rzoVI+e+NZpk+dgMFyfCza/9TGA2V8+voLnDctE8HyTfaQhc/3FrP2g+c5Z/o4MIUCsL+4jneee5Jp44ZhDu2/vvdX7+Pw6neZOmMy6C39yk6mosnOk395nOnT4rEGJQws/l7KLa4h/+ghSqvrOLRnFy6vm7zcXFISYsBg5khuMTUlR2lo66S8tISgIAuVjV2sXbGcLlsLHTYHhw7mkR5voMlpYtmSD2iqb6S66AjDR43ELQms27IDf3MZCWlDtFbl7whVhV2HClm1dDE9zWUMGTYCQR9IECHJCgdzCqkoL6ajuZrExHh0+sBvneb0OaOuLA8XVRIXbmBrdj1L33luYDGSovDasrW88+yTIB/P2SgAupAgnn36XaS2fKKiomhx6vj5fb+jrfwwwarK/IsvxBAcT5fbS01FDpIko8jy8TP33isvWVb6RqORZQXVYKKwuALF50KWZSRJ7jvbk48lklbVviTLqqKgKCqyLKP0nh0GkvaCLMuEBFs4dCQfVXQFkjL3nlEqamCe4+s+Yf4TtkeR5UCZLKMSmCcw9JmKwWziyJ4CUALpfmRFQTBaKCipxu+y923DsaHSVHTk5uYhIyJLUmBfyMffn6KoKL11ZUXBGmahJD8Xr6ut//s/xV2A7zoF6GprJMIM+fU9fPDSC0SGGunw6ehyeXl7yQYObFlGVEwsUZGR5FQ2cnTvHiwhVt5cvISOujIiIyORDFZEex1vLd/NIF8lV9xyK+9/sh1XSz4GQWB/fj2bPnkH+P5ld/muarB5KC84wtDBycQlDUY4YbjIPTm17F63hLi4eJZvOkxZ9p5+82pOjzMqWF48ZSTXXncjd917H/FJqf3KVOBocS2xFg8RIYn9nrvUAZmDE0lNG86E0cMZO2Y0P7/7KvSDz+XZJ/5ObUs72UePYNJ5SU0fjFcxsn77Ho7s2oqjx8my1RspPJKFLCvsPVJAS20pDo+fI7n5dLc0EhoaSk27g81bd7Jx8x6O7tuGy+MkOy+fPbv30dlQTYvNyfJlq6ksPEJ+TSOHs3ZTWFrFyuUrcDTXYnf72bt3DzFRBqwRCezan8OaFcvo7mxGURTKqxvZf+AwpXnZeD1edm3fR35hMWvWbKA89yA+v5/9OYUUFhWwZcce8g/upLm9k/1Hj7Jr2w489jZSBsdjDYoCQaDbK3M4rxBbQy2hwSEIegPtDidHswvYs3cfPqeNtIwUDKEx7N51mK3rV9HTbWfTjoPs27weVRbJK6+jNP8QoixztKCEuvIqzGYLep0Bu0civ6CE3bv20t32/cytqAPmzj2HGRdcwpDM4QxKTmL0qFHcvfAqanoMrHzjWW67bgFjJkxl1MiR/OiO2xgzcw5pg2JJH57JqOEjyMgYwg1XzSE88wKay0qJioigsKiMsRlRmCJTMRv1DB82AnNQ1MDVa85ieYVl7Nu3F6tRZPzUGQgGc1+ZXxGoLCvFqLqJi4zDbNEyjpwJzqhgqdPr2LDrIM/+8RckD0rqd8XSYe/B317D+GnnouoMKDrdCff1ZUQCbZk+8fg9/plz5lBS3UxnTxsPPvAodJYhqXqamhuprW/mD4/8i7bKHD76fDfrP30TCYUDhw7i7Gxg2efbaKvMpqvHictuo8sv8NenXyF711q8Hg+vvfkhHY2FVLQ6+esjj+K3V/H+2iwWvfQE+/dl0dPRgMMn8tjfXqSjbD9tXR727MlCUFUc9h7a2tt5Y8km3v7XI+QWl7B73TqaOx384a9PU1l4lJcXr2b5u89zpLCWxx/5Mz1tddgcPTQ53Dz40N8oz9nLax+vpz5/L68v38L2lR+g0+sRUFDRs3LzXurz99HtdNFta6fLLbNq01a6bA28t3wb6z58BgN+mts7aW5p5emn36HwyEa2ZVfy9rOPo+JnZ1YubW1trNt+hKLsffQ4vbidTvyCgTUr1tJaV8XKXfm89K+/w/e8HVMSRWRFQe7N7bkvt4iMaA/RaYGBLopr29m6YR0lR/Zjs3XglwW27tzL6+9+zKH9mwHQ6/VIkoLX60MRDEiuwB2CE+9AaM5Oau/domN3iqaOSee6hXfw6id7ePvpR1EVX1/duVPTiJxyFTfddBvplnYyxmoZZs4EZ1SwBJg2cTSDZszjmedeB7Gjb/qKrYdorMzl6KEj1DbVU1mQQ25pFVu2bCE7ay861fuFUU+cTicmg4ERwwYRF5cJgg5FkRmamsjP776J8FGzMLttPPbY72nqMtJUUcyk4UMJGTGLjUuWcvnl5zL9vHlYoxNIj4tm7Ogh3L5wAUPnXkXWtjVcMGceP1x4KUfsIXSVHeKDd//FxioL8Z0HuPCq2zh3wkju+s1v2X2kEKejnR9cPhtzeAKhIUYWLryMP/3zOXYW2vh4+Voayg5g1StcfvmFRCYkMWxMJjMmjuan9/8MX2gKRtHDFfNmkZVbz50LhnP9vX9k5oQxZAwZixBioL65GZ0gIAgC3S4vqz5eyvWXTGX2BecTkZRGVUsb6z5aiig6uGDaSFIyJ+H1iyREBHPzbTcxce4VOG01/Ok3tyGkTqIoP5fJSSbGzZjLunXLOWfsUC6aM4WElBTqbC42b16Hrb2BGaOTGTV19pl4KJ1WFpORLocb2R0IeOkJkWw8UEb+vjVEhEegQ2HyhLGcN3cOUXFJ0NsLNjTIxNwpY6kPG8XaxYt6l6a1U57t3LLCzr0H2bJlCw2VBcRFhXHF/HP42/MvUdHYheuEuzPNHd1MiIUf/vovvPHxFqqyA4nENafXGfULJ0oSkSFWHvr53Zhix4IkIYoSiiwTHGShpKmH/MMHae3soLG6irLqBrKysijKz0aHhKKoCL0/Oja3nwObP+eKi2YhquHIkhg4N1dV9HojiqoiCCqiJDNmUBiu0EF8/NEHjE214lFMNDW20FLdgNftQpJE/FKgXc/rV/H5RHp84GipQFYUouLjMVtCkLt7uOWmy1m1vwJbXR6gcuF557Alu5ojG1aSOG4yoi8Q1GWfBJKfjIw0goKCiIqwcvFF87j6xoWYw2OQvV50BhNen4JOL6A3mVixp5Da7e/z8/t/i1uSObjvEPbGEpLiEhHQoahqoM1UgLaWdmoq6/A4vUiiH52gR69TmTF2JDcvvJZRE6YhizJGnQ5VlZFlEVlRCRMg85wreOOpJ7CEhmMNCaazx0tDVSFOnw+/34deDQyNN3XMEG64+nImzr1Ye9wBUE7ohTx3yhgqvdHkHdyDLEtYTHpi4mMIiYxGrzOAohAcHMTYzDQyh4ztm0+UFGRFITwsFLfveI9YVFW7uDyLuSWVo9n5ZGVl0dZYgV8UkSWRcKuOiTNmYzAFIckyiiKzZfsRPB0V/OKHC5l60y8oPLxt4OI0p8EZEyxlYPmWLAqyD1FSXMxP77gErIksXX+A4iM7uXXBLB595BHuf+xvXHzuXOZecxs3LZjLY489xh0/+RWNLSoGwUlDm5P6xiaeeu5Dzk2WuOWXf6CuqQdZaaexrZ2mxhq67U5a7V10d7fR0dWNCZX519xCe205ccPGkxpqZPzF1/Dgnx5n45JF9PR0UZyXS5fdgc3RzuBQI+de9wNWLV3GkaIyLh4VQtTEi1j0zrvce+PFBI+5gqee+Cc+t4MJaZFEDplOvNUDWAky6bGGRJFTUEZFbha3XnUBN910C6sPdvCXP/2OdZ+9h7u7nYa2NrrtnbS3tdLlsFNY08xHb73GzQuvweazsmfbDrKyDjA4JQlEM2XVtZTmFuBWOzHKPs67fiG//cdLrHz/Zbq7Ownxd5E2+wJ+fd+jPP/8M1TXl2HvduBoaaGjqY1uXze25k5UVea2q+dR67QyNFqPRafnwouu5u9vLOOd116lw9aJr6qaaRdcwW8fe5YXnn+aqiObEXRnzKH0P+eXFLptbbh8Mp2dNgDGpkbxwD+e5q3PtpKTtYP6libc9iYSUtJosffgdbvpbGlCFb0IukC+QkWB3LIa8qvqMLaWcvUttyNKKr5uB7YeD+5ux4A1a84WsWY9D/zqHh577DEmz72WT1ZuY9+G1bRVlzFz5nQsUQnsPZxNXWk2EyaPot2pUl5WSFKIwshZFw9cnOY0OKPGhj1SVEVLdQnTJw8lJmEYAJ9sOUxo62EuW3g7GIJxuH20V1eSOXJo36MjogI5uQV0dTYjyaDIIqOHpzF4yCgA8ouraa6rJDImHJ/XC6IfY3g8PbZ2kqOsDBkzmdzqboI79jJq1pUASEDWgWwSo83o9EFIgkJNeRXhQXqmzToPBB37corBWcesc86nrs1HReERJo8dRnmDDVtzLRPHjyU8JoF1G3czbcIQkgalAdDR7eNQ1j7GDk0mJSPwPuvbnJTkHmDWxOG4jLHkHd5HsEmFkATctiZCg6x0u9wo6PB7vQxNjsaaOJTWinxS0kbgVbrp7PDjaG9h3KhU4gcNZ/+RAmJCQDCGMCQlEsUUzp59OcRYfYyeOI1dWfn4nW0kxUXS3O4gyKhj6qwZuPx61q5cza23XNPXkepQXilWnQ9rkIXkmAgsYXHsO1KK2d/C5GkzQH+8g8L3TZfLx6GsvaAqxEeFMXbS1L5bp11+hUN7DyB6bUwYk0HioJHsyynH1VaN0aBj9uSxGMPjAbjnNy9ydUYzhpEXMWfiKCyR8XR7RA7t34si+xk1OJHkYcevQjVnr6qmFspyc5g2fiRRSYMBKK6oJsqsED9oCI12F/mHdjNxVDrxKcMHzq45Dc6oYDmQLKtUVjWQkhBEUGjUt9J24wcWf7wSX2slC2+9kfC4by5HYGldF1vWLWVotIV5V16NwXzm92pbt+0IJTn7uXHeBFLGnzOwWPMtuvc3/+LeeaGMW3DvwCKNRnOandHBEnrbar7FdEVuCXbu2MGU4UnEDgpc5X1Tylq6aCzMYs45s9Gb//sBDb5tMrDrcAFJRhfDx08fWKz5FqlAdnY+Q9OiCItMHlis0WhOszM/WGo0Go1Gc5p9f3tlaDQajUbzNWnBUqPRaDSar3DG3YYNPCupIOiOD2c3kKqqCAPaMWVFAVU94VlKHYIQOBdQe0dYMRj0SLKCThDQ60+9/BMFxoqVMRgN30gHI0lWQJUx6A3feFts37INx7dVVhRUuXfagPVJkoyAit6g/1rvLTDmrYTxJMvSBKiAIisnHXFHr9P122+Bb17/Y1lWAuP/6gQBvSHwSInmu+3Lfs8AdDqh77dMc/qcUVlHRFkhr7gCe20ZUXEJ6E4S0Nw+kdqaWqIjgqF38GFJheKySkqLCmhsbKSpoQHZ5yUoOBiDwYgH2Lh2PSkxVlZtzcbXVkVy2pCBiz6pA4XVHNn6OUOHpqM3fnVmjq+yN7uSI7s3MzIjEcH0zfaO3X2knIIDmxg+ZDAYAtuaU97E3vUryUhLwThgjMnPt+fQULSHjCEZoAtkPPgytc02Vi9dzvBh0RjN4QOLNYBXVMnJL6GyrJhuWzuNzS1UVFbR1thAXHw4+t7PBaDN3k1rbTVRESHQO1DGgewSCo9m0VJVScrgBHQn1Nd897R2OuixdRAadvz75PQr5OYWUFleSn19HRZ8hETE9JtP8793Rp2u7M6rYu3SxfzxiRfZ9tmrA4tRVJUPNx/ipb/+9gtZR1RLGH/8wz/x1uUQHpfAqx9t5olH7sff044RyMhIx2gJIau4jh1rPw6MONN7JaooxzONKIqKqvb+rarY3Arvvr8Yf3d7YBAVlX7lx7KVqKoaWE5vBhJFUfr+qSesx6s38OYr74Gzud+oN2rvVWzf696iE+soSiDLR//tPf63TVZ59+W3wdfeN69L1vP2B8twtdcfr9+7/XV2F5+8vQhV6ulbz7FtPjb/8b9BsFr54N2PcHQW99YNjBikOU6vA5vXyF//9BesShteUzh/eOivuFur+qVZEhWVVTt28+xf/giuFgCq21y899pzpA5OYFlWJTuXvnfCkjXfNV5Z4Q/PvMWWZceGNQzILqhh+bJVHMzax+vvr6D00IZ+5ZrT44wKlsNTovnTo49w+68fpam2ZmAxNa02aoqP0NOp9D7oEKAXID0tDoQQRqbHMWZ4Jr97+OfsrNHx8XOPgSwTEx+NOTiEocPSMQWHUN3QQkdjHV1ukey8PGorihH9fgrLa7C31CHLCtX1DQguO3EpafgUqGtopq6+labaKiRZprSuidKCfESfj5aObo4cyaG1sYaa5jYqykuoqaol52g29o5mejwiRQW5JMdYiUhMob69i4qyUiTRh6qqtNvd5OUV0GPvQFFkmprbsHfaqSirpKezHVlVKCirJicnh+ycHOoqSvH4/eSXVVFTVowsiWSkxRMSkghCYJD52qYWJHsr8clp6HQCkixTVFZDbWUlsiQybGgKQdEJNLc6aKiqwO/3k5dfRnFBLqLkp6a+iZqKEhRFpb7DRldbE4nxMQhC4HZ2WVUzFcVFiP7jg0B/35n0AplDUjCbdGSOy2RweiYGUxAjhqZgMAb11TPqBCaMn4LLrQc1MPh6cWsHRtnF6HHTickYriX+/Q5TVTiSW463px6Ps38SgokjYvn7Xx/gwd/9nmmTppI+Wnve+UxwRgXL5NhImjq7yN++jouuvLZfWY9Poa64gHPnTsdkDUFFF7hi6/0nH8va0Ht1FmURuOCqG1i7+yiHCwv45U9+DfZyVEFPUUU9HyxeyR9+/QA9LSX869Ul7F63FATYd+Awnc01bD1QQN6BPdQ0tuJprSG3po1fPfgnXn36CYpysli7ZTe12bvZlVPLoqcfR1FdPPHih2z49C0OFNdQmbuX2m4vf/z9n/E1l2JziezYdwhB9tDW7mTNmg3c97s/s+mT12lo6+TzlWsora7jsT/9lZqSQv70+Au89PxTvPjGxzz/6MM42poorqoDQcfTry3m0PaVfLR6G6XZO3n+3bUc2bIUQWdAQAWDgd055WTt2ExdaxtdDWX4BCNrd+yntjSHZ99Zyv6NH2PQqTTYXSxf/jkP/uZhKgr288mWg3z28pPoBJW9BTW0NFRwpKKFXZtWU9doo7mpGYPJzMZdR6kqOMJby3ew7K1nTtpG930ly3JvBhEZWRLR6/V9OURPpNfpMBiMx9uXVQUJHUdycmg8upfxUycPnEVzFjvx96qurQvczYycek5ve+Tx709IUCgGvZVau0iE3kb8oP7pCjWnxxkVLBWguKyOzfv288oLL4Pk6Svbd6QAV3s9XS6FDrsNe0szLe12ysrKaKqvQeCLZ+HBVguyKJOeFoWtUwS/B0VWGJIcwf0/v4t6QyJKWy033HorZVWNdHfZSIoJJyJ9NIs//JgrzxvN1HPnYAiNIS0+ltBQMzdePZeRFy5kydsvMnvGZBbeehXvby1GrNjPb3//AB9tLCCsYhOXXHcncyeNJGP2RRTm5eBydTNtSDJBkUmEhZn44Z3Xccev/sCbH6xh8bJV1BzdjIBMp8uD29NDaFw0IwcF88P7fkV2gxu928bCBedT6RAI665i/vU343LLZCQk0G3Wk334EAa9DkEQ8LhEFr33KVdMT2PmuRcQFJtMTWMHH7+3BFl1YjIaqSnJR/Z6ibHo+OEPbiIyfTLNdQe57ZaraHDrcLQ3Ee63M2TMDD77+F3GDornggumEZeURL3dy+fLFuPoqCU4xEJRRS1oV0Ff25d1qdMLKmNGjmTm/Pm8/uaHIB//DmjOXn5FpbqmnvKyMlpaGtm1czvBJgFbh4OW9nb87u6Bs1CUX4jZZMYcquUyPROcUcESRWXerPG88u4iKh0G8Lb1tiGqFFY0cjAvl8+XLKakuoKCA/vYfjiXt996i81rVqBXfSAEgoWqBrKJHN2/n7FDUwkOS8FsDUHt7XEWHBxKSJCV8MgoJEnm4pmjqfMEs3ndKoZFm3How2gtLkXWCxh0OgxmC2aTiZCQYMLCwnH7dfQ4nciCSrhOITxjJM3N7UwdGk/ixDnsyy9CFD0Iqso1V1zGyu3Z5GXtZNo5k/H7JQx6AXNwEMOGDiUyZSgtrc2MG5XBwmuu4N133iBz0izMZhPh4dGEh4cTEhaBwWSkqMHBB88/we8e/inBkYNJi4ugtqUNyWXDYAy0hwkqOGWR5qJSdAY9Oh2YLEE4PD7C/T1ctmAeT/75AW67/x/4VR1BFgvWiCjCw8MQZYUxieGEjJjDR2+8SEJSBEER4dQ1NyEIInpZxmQw4PKL+Lw9XHrxRfzp1z/ikWdeRT0h0/v3XeAYBEEXSJmGqqLrPS5lWaG1rbOvF6yqqn3HJb3XmBazmdSUdOpr68Db2W/ZmrOTQ1T4bMXnvPP2O+Rk7aAwv4SV67dyePtGDhzNxt5c3nfVCSApUFtXxZiMOEDrFX0mOKOCZVFVA+WlJfg7G7nm0nmowckUlNXR1ljDT2+6iN88+AgLf/QTJmSOYMb8i7n6gln84Y9/5Po776Gp3Uu3o426xhZqa+v55PN96GuyuO/3v6e+zYmto56WtjYaGutoa2mjuaOTttYm2ts7CDXCxHlXsWHFMoZPHkOCxYQ/IZ1nn32JvAN7aG+qo7GpkeaWZpqbGxgSoSd2xGx2rvqUstoaRkULDJ0+l3c+WsXjP7mMo13JvP3PP+B1dTNjfAYdliQ8JQfBmoBRB+gtVJTVUpZ7iEvmTOSSBVfy+uItbFy7mM1bNlBVWUlDYxNtLc00N7fS3tZMdUM7j/7tcS6ZGIMpfjT7jh7lhSdfYkKShZS08dQ3NVNZUUO7oxGL5CMocwx/f/ZVsvfuoKW+msRQI50RSTz/2BNs2b6HkoJ9tLe10NJQT2drMy3trbQ3tYIqs/DmG1i99RBxBgg1mRmUNo4XXnqJnbv3U9fQSITfhTV+JP/482McOLCHLetXg6pdWdL7I9fY3I7d4aC5rpGW5kYcDht1jc00Njay72g+BTuWAQLtbR3YbDZsra3QG2S7u500NtRRVJjNjFkzwJo4cBWas1CMSc9P77mdh//wey645Dr+9Ptfcf+vH2DmpVdzweyZxAweR01DE7a2RgA6u700VVUyatLUgYvSnCZnzKMjKrB0435sdSVERwYxf8HFKIKJ15fsRK7azpgp0zFbgrEGBRMbFszIiRMxGq1YLBZMJhNFRdWEWryYwxLp6HbhsTXz4G/uISxpBBUVjZh0TsLiEpF9IjGhYRgi4pB8DjJSk0nJGIElPI6h4W6GjJuLWS8wa9YMDuZUEh8sMmrabPSyCOhJTowmY9hops+ZQX5pI+5uG7dcdx42YRDV+buZPmUSwVFxtDU3M3pUJmGhkfS4dJx73mSi45IJthoJiYilsq6B1KhgLr1iAUNSUzAljWDX1q1MzkwkZfh4GqqrSYoJB3M4gugiLDISvSwyevwUGtttWJztDJs+E2ePi4TwGKLiQzFixhqqY+TwTC6/4iqOFjUSjJ1xs85lVFIk8xZcw+6jFci2CubMvYTali4sOpn4+ARcio84aygjJkwkNjyYjm4jl11+DuitTJ06mco2Eb+9jmkzJhEfGsVVt9xCbrWduvwDXHv5fCzhcQM/0u8ln6RSVFROeLCJcGsYTo+PyFAzlvBoelweiouKmTN9FCExqVSUVWAyQ3xcDPGpQyht6yZn6zpS0wZjECVuvetWBIN14Co0ZyFBALPJhMViwWA0YjQaMZvNmC1WhqcmkZQ2hJ0HDmPwtBOfkoHoF4kyy6QOHz9wUZrT5IwblOBEigqFZTXEBPlJTE7/Ws8C/icqqmo5ejifc6YOISl95MDi/1iXR6aiopr2smzmzjsPS8SZH1DqmjspLa8lXqxl3LxrBhZrvkUf7y8l643HeGHR4oFFGo3mNDujbsMOpBNgzLBUEgcN+9YCZYcbXnnjA+LNHd9ooAQ4VNTEsg9eZezYzLMiUIoqLF6zk7ojaxk3d8HAYs23LCUslEsuukTrWazRnIHO6CtLjUaj0WjOBGf0laVGo9FoNGcCLVhqNBqNRvMVtGCp0Wg0Gs1XOKvaLFUVfD4fep2A0XR8UGpJVlBlsXda/1Q3flHEIIDOcOoOQoqq4vN4MVuM6HRffADY5xdBkTFbvpgBQlFVfD4fRr0eg/HU6zgZr09EL8gYTV9criTLqLKE0WQeWNSPpCgooojJfLyeX5RQZAmLxfyF/XGM2pu2TO1LDySgKDI6nYDBEMiAIUsSOkH4t9/X94msKMhS/2dMBcBgNCIIQl9aM1DR6/QIOh2yrPQNwH+M0WgAdPj9/t66Qt9AE5Iso0NFp//isak5O8mKgiRJfd9Oo9HwhTRcqgqSJKHXCSfNwKT53zpjnrP8OmwukUf/9RrOiixGT5nZNz2rvIbsdUsYOXFcv9EuZGDx+g0E2+qJHnTqlFx1nU4e/MXvGDXMQHTc0H5logqvLN7I3mUvcc68y/qVAbT1+PjDn/9FkKuGjFETBxafkgz89aUlNGZ9yoRZ53xhlI6deWWU71zJ0LHjgFN/UY40tnNw2buMmjQNBAEV+Gztbpa89SwXXjILOPlzei4RVq36nM3rP8fpaCO3xsbaFUtorS4lPT2N7NoOln/8AVJ3C2mZI08ZdL/vsgur2LF5EzkFhWTt3kV9Qz35udlkDE5BNVgoqqgia88OqsvL6XY60JssHCqsZc3yT6muKqOioorsozkMSwmi1W3ljbdfoSg7h7ribEaOHY8i6Nmy+wjO6jwS04doN4O+I3KKa1mxdAk52Uc4nLWfYWmJWEMj+8plWaGqsZWsvXsJEboJi0nqN7/mf++s+uZFBxuJSEmltbECSZJRegennjU8navvuhewoChq7xWTgh6447LLGDrrwkC6KVlGlvtfCSiKSnyEFREDXR2BNFayoiD2LsMoQHRqOo2NjYHpfhFFllEBURSJDzWhRsTS3tKAqgYG0T7xakOS5BPSeAXmUWQJPZCUPpjqwpq+DCqSJPUNuD13wgguvvn/UDH1peWSJBF6h0w7tvwpKXFc/6NfQu9ZqSzJpI0YT11FEeAPbKck9e2rY4KNEJs+lo/eW8H08SOYNnUqGw9Uc2jHOqyhYegEI932TiaOG6sFylNQAdFpY/7cSZgSx7Fv9Qquu/IiotLG0OUReX3JJta99zoXz5nEOQuuYeWWbA5vXc/UKaNZuyOLzPhQbrjhBgYNn4rscfDix9sYa2rnlp/8jE/XZuFqy8UjKny+Yx9bV7wHJxn/WHP2kRSVquYmYkKDiE5Jo7SwEJ/reMpBRYXN+/P58NWnyIw1kTx8Qr/5NafHWRUsESDUasUtqazfspsjuzcjyxJHyurIO7QTVZHIr6hn29atNNVW4ZN9bNt7gNaaMmob7ezfvYvso/lsXbsa2d2NrKjkVNWxddtudD4nRqMJUZI5VFzB2lWrqC3NR1VkrBYD1tAQSqoaePvt9ynJ3ofTr7B69WramuoICwvFZDJT2+lmz46d5OYVsvHzVXTaW1i1bjf5h3aiyAplTa2sXLeewzu3oEgiwVYzRlMQqirQ0eNjw+bd7N+1Hb/fzaHSakpyduNwudm8bQ/FpVUsW76SloZq9mQXsmPdcmTJS3FtK/t2bgKgxyeyee9+qnIPYjWbUTHQYnOzbuMesnZtR/IfH5RbAIKCLMQmxmLQ60iLtfLyq09xuBa2rltCyaGD/OrnPyAsedgJH4BmoGlTJxKfOhIBMJrNCKrCpXOmUOWAzW/9k3t/ejPBsUOINOl4+Lc/ZeLcBQg6iIiNxGgwI8kyM8enEJoyAVtdNQkxUXR1exmaGIklIpUQk54JE2ZgNEVoz19+R+iAa86fzi133smUWfOYcd4cYlPS+sqLGrt5/+VnufOmyxg8fjYo2snqmeDsCpaAKghUllRQVVnB/Q/9nby96/h01T5WvfUi7a3tfPrJxwxPi+dgTjGOni4ef+ZNynJ28/n+Yv78yB8oz8/iqRc/JGvncvbmV3FwwwpGjhhGQ0cPBpOJJev30XhgI0PHT+ehh56mtWgHOr0BQVGJSYhj6eYD+JqKEXQCjZ1uoqMjURQVQa9n78ESHn3kUaqyd/LS+yt5+vFHKW2s4e//eJyS4mJeffkN0hPCeXzRWooPbMBgMqHX6eju8fLiS6+glzv4++tLWfXO43z40WY2vf8adfWtPPHk42zfuJaV24/y19/9nPKSIzz21Fs05W1m5dYc3nvlObySynNvfMwgsxufJQqv14PN7eP5fz1HuNnNw899zKYPnu2/L09I7gwwNimMW371EL+4/8/MHiISEZfRr76mPwFOaEcMBLJjPQAO5hWTFO4nIiGQXqnF4WL/rj00lOfg8biQFYGq2jpWbtpDfn4W6EzoddDe5SZrz16sQUa83YGTG1EMtGNqzl5q750jURQBBb0u0LRSlH2UCL2K3hLRV3fTlh1EGnzsKe/mJz/5KZVHNp+wJM3pcvYFS0Vm+rTx/OpnP2LKFXdTeHQrs88bg6qGExRqobyxi5eefpIxaVHEh8eSOWEsqCpTp44kfVAGN999B1PnXUmrrYmt2zcyMimMjNRkho8YSqdLYvumVQwenMzYzEEEjzuXDcuWYtAFkinHh1i442c/Y+3WfVTX1nN+Zih6SziqKiMoCjNmjSExKY3rb7uBGXOuYmxqEL+89y6sScPQSU4unX8J1c1deL3N9LjcCIKA3mCgtKqBpuISElOSuff2axk1YTbjp4xGUYIZOSyFIZmZLLx8Dtfe8X8ocgg/uu0uBo26EKW9mfHTxhIWFUVZi4PGQ2sYM+N8Jk0YTVhYKIcqmlDbCwmNiue+Hy8kYfTsfvsy0LHn+P+KqpKWHEzc8FmsWL0ZWQokJdZ8DX2ZQwL/G41GuntcyN5AwPOLMi8sWsqnbz6NAQkBHU6ni2C9TFhICPQ2CcSGW1l41UXUWEaxYfFbfcvUri3Obj2Swqate1i5YgV1pdkAiDIUVdUyflRKv7qdtlbmnjeN26+7ipSpV7Fk0RvaydIZ4KwLloE2ST+iKBIbZiY6LhlRCaQ6CrbqefLRXxM2+kIe+eNjuJtL0en1CIIu0PNMEAJtgoqM3mDA4ZaoqijG6/XidHox6FRkXRCdbXWIokhoSAgxCckoSu9Vg6Jw+czRlPiiWL/oeUbMvgBVDVyhCYKAKAZ6LcqiiCL6UfUGvJIMqozDLbF/6yaGxVuJSsxAFGUUVQ2cZZrNuJ0Ohg+KYcHF5zNk9EQkUUSnE5BlFUVR8Usyfq8Xk0GHLMuosgjoUFQl0OtShYa2buz1xbhcPvx+EbNRT1uPm9Ejh3DlJfNIHDpi4O6E3p9ivyiRXVSHuyqXRW8/y8qD7Wxf8iqSqAXMr6KqgRApcDxozps6mkp3PId270QURZKjg5g8czqjxo0jxBqOTpCZPHEcCy6ex4jRxzuriX4JUZQICQvGIwd+IgVBAEFA0W7HnbVkRaWto4Pm5hbcTgcAjXYXYn0pKWOmQW/fAlmWSE5IweHoDPSJSEomITlF6zdwBjjrguXgQUkUN3nYvG498SFuZl90Mwf35FBcU0h9RRlrNu9k6sQhjJs9n4ZuPzmHj1JcXkJW1kHKS/MpzsulsCSPiux8Fsw7n0Xrsnn6mSew2ZtoKyzn+ltvYNOefDauX0uqpZnzb7iDo0dyKS6vwNFWS1SQgXHTz8Oi+jEaw+hw+sg5nE1ZVRl79x+gtiqf0sJiSssLKS6oILegiOKCUrIKCikqLsPt7EFyqeQW5pC7/xC5JblkxhoJGXsOP7z7AV545mkaW+ooyi8mr6KQo7lHKC4uoajwKMVFRZTV1ZGfl0N9TTHbjhSSm11AQUkZiToHGdOv5p6f/pLtn39MW7uNoUYZXcp0fnTb7bz5yrN0t9T27UefDEcOHKC5vo6sQ4f56PMdPPXnB5k7YwxD4qMYO/ti7nv4r+xcsxjw9fsMNP25fBL5Rw9SXttAYV4OAKNTo/nDk/9ixfbDrFmxnK07tmNvLGLw0OFkFdZQU15J1t49KK4T81UK5JTV8vmWbYTay7nyplvx+BVK83PIK66grab4hLqas0mkSc9dt17PL3/1S0ZNvRCAA8X1zBoTDfowADbt2kdp9m4uu/A87Eo4n69bgVq3l8tu+tGApWlOh7PqOUsAn6RQV1uPXvGTmBCLNTSC8sp6RK+NtLQ0Orq8SD4nMRERGEMiKCstJSrEiB8rnu5O4uMTaLU7CBZk0oePory2FZetgZjYWPSSRGJaBlWNzajuHhITowgKiaGyrglvTweZ6YPBYGXPwQJiglTGTZqM2y9RWVlJqBkwhuJytBGfEE+H3YURkaCIGFqbW0hKjMPpVzDJXvySHrNJxO03InrtjMgcil8IIjs7lyirwpBR46iuaUby2YmMiaOttYPYqGDckhmP00ZsTCwdnXasFiOCMQhXVzvD0gejWMPJOZJDYkwIsqyQFB+HYo0g58hRYoIEho2d0HeGKqlQV1uHq8tBZFQ4XR4VnddOxtAhmILCqK9vpr2jjZhQK4OHZnzh0RbNcaKkUFNbi9fVQ0J8LLHxx3NQNnd209PehNFiwaBTSEoeRIvNja2lgVCrgcGDUxGMgcd7fnT/81w/rJOM+T8gPjyY8Og4RFmltqYW0eMkNSWB4IiYE9asOZu1211EWFWMlsBt+MraesLNKjEJqXR0ubG1NRAXEUREbP/btJrT46wLlqdTdZub9auWkhKi49IFF2AM15590nwzVOCHP/sLv1oQxfjLfj6wWKPRnGZasPw3NHV6yD6wk1mTRhCZcLyrt0bz31KB4uJyUpNCCQlPGFis0WhOMy1YajQajUbzFc66Dj4ajUaj0fyvacFSo9FoNJqvcNYFS0mW+8ZPPUZRAhkyTkaSj4/Neipq7zNOqnp8NJsTHcsQcConjlP775BlpTcjxRedLJvFyRzLDtJvmqL2bu+X32FXVfWk/waWa/47A/ftyf4e+I/ez/ZUx6Tm7KcoCoqinPQ7pn33zjxnVdYRv6Ty+Y5DuBtLSEo7nkWkormDmpz9JKWl9svQoQB7c3MxOzsJjY7vmz6Q0yuxfOl64qIkQsLi+pWpwL6CSooPbCZzxNh+ZQBeSWH1ph0IzmZikwJDm31dWw8X0V66l0HpQ0Hon1mkpK6ZlpLDJAwa/KXnNFX2HioP7iA5fUjfYyGF5c3s3b6JUaPTgOOpzE4kq9DU1EpjfT2oMp3dXuprq/C5nYSGhdLl9lNdWYFO9hIUGj5wds0pKCrYbZ2YjQYEvR4VaGq10VBfi072YbJaqa5vprOlgeDQYDq6uum2d9Jh76Kny0aP24vP1Y3ZaqW8qpaOxjrCgq0YTKdOt6Y5+3Q6eigrLaWttZXOjnYiQoPQG4+n2bN1d9PR3EyI1YTOcPLvsOZ/69S/wmcgn19m1YbtZG1d3m96aJCZqLiEL/yYCEBcZCTW0OPjLp6Mw+vn3Tffoqnq0MAiVBV2HChl9afvDSwCwOOV+HD5RgoObB9Y9KUUYP3mI2z6+CMQvngFGRZiJSIm/gvvaaBQs5Go+MR+9bLLa1ny1tOAu1/dE/kVWLx6O/MvuIzDO9az81A+8664nb/86m5kn5vdhXXc/9vfUnhAG5fy31HV4eaHP/oZdSVZACgKrNpXxIIFV3Jo2yq63C5++vA/WfzqE7R1trBs226y9u3ivkee4Mk//4bd+w+yZeUHbNm+j3cXLeJXDzzKS399AMVrH7gqzVlKUlSWbd3PK88/z2tvvsF9995Dc2VuvzqHS2v4yd0/pb1kT7/pmtPnrAqWoUEGJk6biizoaWxsodvWiaoqWAQ9SWlDUFU9bo8Xh8MRGClHlkiMiCQkJoHuHjddXXY6O+y0tzShyBKqqtLtcmMVRNKGjkTtvYXZ3eOio6MTT083OkFl7MTRhEVG4/L4aGpqwuPqQVaho9NGmFlh1OQJ6PRGuno8OOw2Om0O2lqa8fn9NDS14OyyoaoqLq+PDpsNR2cngiIzeeZYDKYo6B071Gbvwm6zI0sioUYjiYPT8XplOto76epx0djYgN/noaXdRmdrcyAjigpJqYGrSkmW6bTbyRg8hJCwQG48ryRjtztw2DpRTrjla9XDBfPnM3r8BOZdMJc7rrqA1z74iHa3gcbqEiRbB688/hDnXX133zyar1ZXVUNtfTMHt6wlkMQZLrl4NuOnjmPmvCs4kFPBgwun8ugL7zIoeQg/vOpyrrvxNkaNn8K0SaO55fqrufbOXxIZGs4T/3iMFz5YwsajjTjqCgauSnOWEoDrLpzBm4ve4amXX+HHP/0Zcan98+jOmDSemEFDv+pcWfM/dFYFSwjkiyypaOTRfzzP3TdfT2ttCX9+fSXP/u5u3D12XnjnYzatWcmGtatp7+lg4Y9/Q9a6D/hw7VH+745bWfTmm9x+3c1U5myjtsPOG+9/xMb1W6gtKcZstZBdVs+HHy7i46Ur+NvDf8TdWYMkK+j0enLLGpk7/yYOLH8dhx8e/ceTtDWUoSgqeoOBz7YXctctt/LRoje59fY7+eCDl3nwby/y8K/upKOjmafffJ9F77/DL39xP22V2SiqDkFQ8XpkVm3exZrP1/HA7/9C9u7VPPzMx7z153spqq5n4W0/4J1FH3Lr3b/k1Sf/xAvvfsCt116DrTab55ds5zc/vglFhRVbD7F06ads37gO0evBIwksW76ZtZ9v4Rf3P0ZZ1oZ++9Ln8yFLEj5fYDi7a88dTcaFt3HfQw+RIjSQMe7cfvU1X67bK1FfXshjzz3Lp5tzkJ1NAPj9fjx+hTcXLUWs2suFV18P6BEAq9kIgCT58fsDJzOWoGCmz5gA6LHqRMaOnUhozKB+69KcvfQ6gejwwBB3WXvzEUQJa3hsvzqiKPdlsNGcGc66YClKCsNSonjr5ccxpZ/Hng0fce55E/C7LDg9XvYfyCbc6GbaueeSFBFL6sjRKIrClJmjkEU9D/z6LkaffzNFpUdZuXYT46MFbr3pOlJGjKDHp/LhBx8weWgcv/zJj6hQ4tn26VsYDHokUWTW+Ax+cP9D1Le04vZ6uWnuFBLTxyFLIjpVYe6ccciqlV/88Bomz78TT20eL770dzqEWOqrakiNjOTKyy6nVYCqynIMBj0GvZ7yukbWfbaEwcmhDErLwNHWwKRJI/E59YzOHERiegqXTknjx797nMP7c/nHb/+P0JGX4qo4ytjJ47GGhNFgc7P10zf5vx/eysXX3YA1yEp2XTN7V75HUlI4yZlDKKtpGLg7+1GBKy+/gMPlEm1tVajqv99p6fvsYEkDg8w25kwaQ6cSx+HNK3tLBHyyytJNWynJy8br9A6Y8+QURWXf4XzuvGIGxqj0gcWas4isgqOrG7vdjs/jCkwDKmurGT04vF9fC82Z6awLljpBJTg80OFkzJgxgawbKCiqkfjYSH527//x/Gf7ePHPv8PrdGCxGBB6e6zGxsSAOQiL1YSsQnl9PZLPgSSKmA0GvKJEc0cbss+LqkJ8xnDsdjfCCb1Kr7/ifNbltLLj03eZNGti33QVkESZiPBQBLMViyAQmxQLqoLZYsZiMSKJcHDXdqJCrAg6fSBDhSDQ4/Wj2DsZP2YYD97/Y+ZcdjuyrCLozCiqgkWvJzw2BgSIjo4BLBgEA6qqx6AHo1FPg60Hh70Zn8eDXtCh1+mxd7tB52fK+HE89pt7OOfKW/q2F/o3hyqqSn27k5b8Pbz88hM89eY66gu2ab0xvyavrFC4dxeNToFt69cwZEQGK9ftQJG9IOgIM8FLjz/Koc4oHvv1j+nuaEQ9IZfoQJKsklPewtAQL6PPuxz5S+pqznwtXonf/uEf/PjHP2b3mncAsDl91JeWMGLydOjtHTvwmDiWPk9z+p11wVJvMNHW2k5HeyeCq5HZF1xNe4cXl78Ne0cb/u4O3nzjFZqVWJxtNbS0OfD4PXQ7e+juaMTvctPl7EF19zB21CRe/XAta9eupLKyAkdFDdPOnceOHZvptHVidjVw0bXX0N7Rjd3Zg6r4GBobRNLEuZQd2kZQ1GAUVaW11YbH76bb5cTV2Yjf48Hp8+LsceF2ebB1OMitrGXz6qVcfNH5uLwWigsKsbV30OVsZlhqIh1BsXzw8hus27CJ+po83C4n3e52elwu2jpt+LzdeD1u7D09eCUfXm837Z0d2Gw9dNgdjEgMo0s/mOeeeJQ9mz+npraJVKNKjTuMj995mQ1btlBbFsijR29w97l9uLqciKJCeWMnH739JvOnjeKqC89h5Pw7uO/nv6WttvwrH0H5vlOBnYeKSLa0c/sPfsS1113HT3/5SzYcbqTq4Bb8op+ebjfp0XreePMZsnpS+M2PbqW5Mg9UFVlRcLp9uHpcqL2POe3IqWPJuy/S4bCxfMUKastLBq5WcxZJthp486UnWLp0KRfe+AsAcqvaGBfjRR+aDEBJVQ2tTVUAyJKM1+3B43Zr378zxFn16AhA5uBEutVwasuLueKyuSRkjCX/YA7BYRZGZmZgk0yUFR3llsvPwx+ejqOhisjIMBwOL2HhVqzWIFxuByGWEBZefxU+czyyx8Hsc2cwckgGF118EQ6iqSw5ytUXTiR+xCzKCgsIMxvJSI7HGhoJio4Ro4eRlpFJo81FR1050ZFh2O1ewsOsBIWG43F1EWwNRzKY0ft9ZGYOI33UeHz2ZsaMHEvikAScHR7MIRamTxzB1PMuoaisjpRwPSOmn09FURXWsCB0ZhN6ScViNuHyK0RHWBEUBb0qI4bGYtTpCDHqGZ2eyPmXXUNhWQ3jRqYxesxIZk2ZzPjZ88ktqmBorJlpM85DZwh0T3f54WjWTpISI/HJIiW1HdDdwLhx4zGGR+PutCGYzOgVkcyRQ0DQuq+fikeU2bdjP4rsZ/jwDAymIMqqG7GadHi8fjpsPcSGBYMqMXRwMiZLEKKs4vd6GDkslbw6Jz0tlViCQkmLC8EcGc/+vXtRPF10dHnQ+bqYOHYU1rBAZzDNd0On3cWkcUMJCg9kkiksq8Aqu4mKTyE7vwgUF3qdjrQhmdrjI2cAbWzYf4O9209eXjbtddXMmzuDyCRtMHWNRqP5PjjrbsOeTh0uHwX5eUwcO5TIpMEDizUajUbzHaVdWWo0Go1G8xW0K0uNRqPRaL6CFiw1Go1Go/kKWrDUaM4wWsuIRnPmOauCpaqCy+PD6w6MgHGMxy/i7HKc9HmkbqcTv+fUA4rT+0B+j9ODJAWGfRvIK0q4eroGTobebXJ6vPi8X76Ok/H4JTzunpNut9vn713nF8tO5JXk3vd+nCTJ9DidvcO1n5okSfj9fmRJQpRkfD4fkiiCqqIoal+Z5utTe/f/sX137G9JEr/wWUqy/IXpoijR1NKCz9WlDQjxHSYrCj6fD5/Xi8/n+8JnraiB4Sh9Pu8XyjSnx1n1nKXLJ/PUax/jrDrAiAnT+qaXNrZRdXgXg4cN/UKKru2HDhHs7CQ8PvDg78m0dvv42yP/IDNNIDouo1+ZosIHa/aQtfotZpw3v18ZQJdH5B/Pvoalp5a0EeMGFp+SCrz4wXrqsz5j3LRZIBj6lefVNNCcv5+UIZlfek5T3tlF6d5NpA8fBb1jDa3fkc2Kd1/kvAtnAJaBswDgU2DL1j2sWbYcg04kr7aT5Z98hL2xksxhwyhqcvDpBx9gFm0kpWUOnF1zCj5JZUdWHmuWfoJJdlLVbGf5Z8vw2NsZnJaEzhD4PCQVdhw4QknWLoYNHQQGKx6/yoefLqe1voR9uw6TlhhEcMSpU8tpzl6HCyv56N1F7N+/j8MH9zF6yCAsoYHkBwBVHS7efv0NcrJ2MXrYYMzBX545SfPtO/Wv8BnIpBdwyyqN1YWIotSXcHl4UhxTzpsPGAOJoGUZRVEQVJU5kyeRMHwssqygyDKSdOxsPkBWFKxBRhoamulqr+2bJkkSqqIgAD6dmYryUhRFRRTFwLBUvVcGFqOBFqeP1oaaQMLm3uTUkiSiqmq/7VRUtV/yar8KFdmlIAQyoBybF2BMWjLjZ89DUfVIkoSsKIhiYJmSJPdd8Q2JjmDG+Qv6xq6TZRljWDSlOQcBP6oamDYwYbYecIgG3nrrfUL1flITY1mxI591n76LADS1d9PUWEFsbHS/+TRfTi+AYgji/UXvEBkhogZF8sbrH2PytSHojz9YLgBdop4P33oH3G0AFDV2sn/Dcm5cuJBqXSw7Vy45Ycma7wqfrFLT1MKoIYMYNX4iNWXluHtsfeWiAju2bGFYajQTJk/BZA3tN7/m9Di7gqVRR0pqCp1Okc9WrGP/9g0ossSew8VUlWSjqjJF5dUcPXyY6rJiurwudu3ch729ieyCOvbv2cmuXftZt/wzvN02ZEUhu7icotxcDIIOvdGIX5LJLShi9559lGQfBlUmISmO4LBwqpraWfzxZzSU5eKRYNvO3fi7mkhKTUFvMpJT1MDuHdvYu/cga5d/Rl1LPUtWrOfovs0oikxJTT279u9n75atqL4eUlKTMJiCUFU9Da0Osg4cZfeuXbh7HOw9WER9RR6NbTY2rNtIdn4pixd/QmNtCet3ZrFp5RL8Pjc5BRXkHckCBDqcXvYdOIS9uRmzxYqKjtpWBwcOZLNn+w4kb3ffvjToYOiwTNIyMsgYksH44Wks+fRtqjxRrFv1Ad1V+fzlwV+QOiowbqXm6zHqBYYPTSU9bTBDRg5nyNBM0tLTGTEiE73B2ldPL8DQ9HRCwxIDYwQD9V1dmCx6qhvaEZw2Rk4Yf8KSNd8VJr3AjfPP4eqFtzBu+oWcO28eCYOP372p6/Rx5HAW9VVljB2R3u+KU3P6nFXBEsAvKtha2+nudvLQHx6nIGsj2/Nq+OSlf9LR1so7H32G2NNOaWUt4OXpd5ZSsH8jpa3dPPLg7+huq+KV15eSm7WGA4WVZO3YDCp09zgxmMys3LifgkNbkXQ6/v6vV2ku3oGKAKqKIAg888Zyqg6sx6eq7Nq1H7V3HEeDTk+9088ff/coXS0lvP7pBj559Z/UO5w8+eyzlJeV8ta7H2NvreOpdz6kPHcvgs6AXqfDZneyZv06vD4Hby5ez85Vr7Nuby6r3ngan1/kny+/Su6e7WzYX8I/H/kd3c5WHn9+EZ3F29lV0sJrzz2OpKi8894SZHc7XU4niizS4fKz6sOP8HjdPPvB52xZuqjfvpREEVmWEcVjV6lWbvzl7/jjP15lQroRa+yQfvU1X48oSr37VfzCPj6RJEn92iuPDZotqCqi6MUjKV9o59ScnY61ZQfuWB2/y1OUc4gQVUZnDiSHAIgPEbj7rrtokGK4/+c/w9le11emOX3OumCpKjIjh6fykx/dwvTL7yb/0GamTErHaEzAbLXSYnOyZuVnpCdHEmGJZuS4URgMJjKHpZCensnVN13PlHlX0dDayLrNmxmXaGHm1EmkDsmg0+Vn48YVjM4YzEVzzsE0bDYbP1uGQScgyzJDkmP54+N/YXdOFfW1ddw5fwLhMckoigyqwrgRqaQMSueKqy9hxrlXEh+h4xf33IwxNg3F6+Si2ecQFZuMV/XR2elApxPQ6fVUNDSxbfkaJJ+dBRdMYfDwSYwaOQSjIZbUpGiGZWZw6QWTuOb2e/B7ddx61bWkjJ6Hv6WR0WOGEpeQTFGDnfKs1Zx/4SXMmHMe1qAgDlc1kpO1Ga+3m+svmUb8kC+/UpEVlUGxFkJSJrP000+RxZ6BVTTfAFk+dYcNHZCWmsrciy7l3UUfgnj89pzm7OWUFLZs38PatWupK88FwK+oFJbXMGVcar+6IVYTU8YO58lHfknQ0POoKcnvV645Pc66YAkqshJoh4sKMxEVm4xfDLT3hQYZefTBn2PJOIdHHnoER3MFihrosiqKEnqdgKrISJIfvV6gyyNRXVWKz+fF5/UhKAqiEERnUzmyLBMUHExiUiKKoqAogbP886YMp8gVxIa3XiBt8kzozTuoqip+v4ROAFWSkf0+jGYTblFBp6rY3F72796NztVOQsIgZFlGVVUUVcZoMqPXy8yePJEbbriWwenD8Hl9KMiBNk5JQhV0+LxuTCZToH1T8qMKApIkoSgSkqrS1NGDo7YAV48LUZSw6HWgV7nw3GncdOP1RKWPHLAvhUDbriAgyQqHiurQN+ezeNG/WJPrYcfyt5DlL14Rab5K737tvVpUFIXAzQkVnyhRkFsY6H4mCKiKgnpiqjRFRVFkTHpdII3bgLZmzdnJr6iUVVZTXFyMo60RgGabC39DKQkjp0LvlaeiBL7zot+HoihMGjGEiLiUAUvTnA5nXbBMiIulrctPQV4hMSYX519xC3VVrfRInbQ0NrBr925uuvpCJsy7HFGWaW5sxuHqpqGxHndXK+1NLTh67Lg7bFw1fz6LNhTwwnNP0dHZTHtBOTfcfB07DpVRUJjPEHM7c264k/qaBhwuD163jdggPRNnz8ds9GE0heHxSzTXNdHjcVJTX4/kbKWjtYMebzcOu4fWlhbsHd1UN7ZQW11FQlIKokdPXn4+TVXVdLhaGDEoiqjx5/Drn/2Wl59/miZbM112B53eDuqbGrDZHdjszXQ7Oun2+2lpb0Hxd1Nc10pjXTOd3S6GR+kYPPkqfv7gH9m68kM67W4GC350KbP4+U9/zuuvPo/YUda3H0UF2pubUPwiTW2dbD5YzGev/YtzZ59DanwsV9x0O4/85SUK9m8DtID5dYmKSkNjG4qqo76skZaWJgTVT11zJw0NDazYsIOeql2oCHS1d+KTRdqb2wMz63S0tnVQU5zLkcOHufGm68ESN3AVmrNQtEnPL39yFw8//DATzr0CgNzKVuZOTARDoAPP7kNHqC3N5lBuGUsWvUV5SSnTp6aTnDlqwNI0p8NZOTZsXnkT9rpSzrtgNrJgYv+eI0hiD1PGZdIpB1FVVsA544bRpoZTmXuQEKsRl2hEltwkREfQ2mHDotcx/ZxzKKtpxe1oIToulgizQGh0MmUNHTSVH2X2zIlgiSU7Ox9fdycjM9MJi0lk36ECYoIFxkyYSGuXm9K8owSZdHhlM5LkIiE6knabA4MKQbGxOFpbSEhKBlMwsq2e8NhBCGaRmooO/L4eZk4eji4skaz9OaRE6kgdMZa9u48gqG4ioiOwd9gJCTLjxorg7SIsJJjOLi/6IAsWswWvvZ3Rw9KISkpj9/5DpKcmIvtcDE5Lwy+Y2bfvMEPjLKRkjunbh24RjmTtQUXBgIpbsGL0dzN+VCbBCYM5nJWD19tFsEnHtJlTQDjeOUVzai6/QnZOPrLbjsWkR1ICjx95fX4UWcKgg9nTx2MMS+DwoWxcri6Swq2MmDiNVXk1rHnq9/zol78mzmohY/TXfxRJc/ZpbO8mJgTM1jAASqtribGoGMMTOXrkMEmRIQwb8+VNJ5r/nbMyWJ4uDe1e1q76jCi9n6uvvwpTaCAPnUbzTfhkXzkFn/yLv73w5sAijUZzmmnB8t/Q3OWl+Oh+zpkyDlOo9vyh5ptV3dKNaqshY5R2RanRnGm0YKnRaDQazVc46zr4aDQajUbzv6YFS41Go9FovoIWLL+EqoKq9L9LrULvM5ffruPr0e6SazQazemmBctTUIG6NgeVZSX9pjt9fsqLi0D29Jv+TXNLCuXlJUjeb3c9mv+MqoLP78fv9+H3+ZAlEVlRcLk9+H3efnUVVT0+/YQuAj6/2C/9kihJuFwufF4vfr8fr8eL3Dvov6qCx+vD5XQi+U+eSk5zdvGLxz5vd7/jgt7RtFwuN26Xq9/weJrT56xK0fW/5BNVnlu0itx1b3HBZdf1Tbd7/ZTlHmVI+iAk1YAoyhgMx9OCfVN6RInSvKOkJCZhMJ88zZbm9Klp6+Kdxe/RUFnC/r2H0NsbaDPG8JMHHsaRv4lpc+Yh6AJp1/Lqu/jRj3+KsauCUaNGoTMF4VdU/vn0IsamqARFJCGrsHHnIX7zs3vpaa6kvLGD5cvWYPA2kTpkBG1OiaeffZlXn38GOqsYM2Uags44cLM0ZwlJUXnrkw0896/H6CjPYsqM2X3p21RgX3ETf3jwAbau+YxZ08YQHK4NTnHaqZo+iqqqPr9f9Xi9qiT61U92FqoP/fh61eP1qR63W1VVRRVFSZVEUVUURf107RZ18/o1qqLIqiQrqs/nU71er6rIkqqoquoXRdXv86uSJKqKqqg+v1/1er2q6PeroiSrXq9X9fl8qtvtUiVJVN0er+r1eFRVVVRJklW/368qiqJ6vT7V7/epbrdH9Xk9qqqqqqwoqr93eYosDXwrmm/Z/X9/T/3wX/epqqKo+wpr1E3vvqIqiqr+/p2V6oSMOLUmb6eqqqoqKar63IefqxkJMWpTxd7AQaaq6oGKTnXCBZer7/7tF6qqBCa2+RX13BlXqkWb3lZlWVGPlLWo0867Qt27/HV164EStbYkRz1S1qLOnH2RWpP16YmboznLHCptVt967UXV42hRFVnuV+bwKepTz76o1pYcVmVZ7jtmNKeXdmV5ggZ7D+vWrGT99j0YnNX4QwdTcmALeU1+Nn7wOnPnTOGz7eVsW/oymZmZ/OnJl3DX5zFz6iRyKzrZtWMLO7btIM4qoYYnsWHdeopz85B97ZgjYnjvs5Xs37sbW2Uuzf5g3n7tNWxtDbz26puEhsObn24ne8tiZs6YzM7Cdt594R+MGTWWp95YRVfVbt5dsoOaQ+uYPOd8imo72Lt9J2vWbiApSCQqKW3g29F8i4rr7Hz47rukxlmYPmUSSUPGY7CYcItu7J3d2CvzmDnvclrsLvbvz0L1OVhw8VxCowchqiqHd2xn6KjR7Nm6mQWXzMFgjcCrCqxavJLLzx9JTMZ4EqNDKO0JYe+KN/nVL+4kIj6DxOgQdhyuYd6EeMJTtGHQzlbF5bV8+Nka9m5ZxfhhKYTHpvTlpG3scLN5524+ff9DYi0e0keMRxC0FrPTTfsEeknAsy8vYXq8woUXX01pdSMITlw9Dm6/7Byy24PI37aGxGHp7N9+iKhwPSPHTWLm1Em06+P5+J1XuOyc0QyZeRl/+ceT7Nm1hwP7djJyaDIhsSnkFNWgayll2OwLeeeNT8mMldi6K58paRbixl/Ektde4O7br+JAg5vynMPEJiaSW1pBkFWmwwslh3dx5w/vYN3WHKqbC/j09ddIjDDiCYpj0XvvBQbm1vzP/OrWuVz7k99x36Mvcv89N+LpqQfAIPu4/Qd3sO5ALY76XA7llXPOyBgUc3Rf21NVow2Ubu685iLaDOkc2bt1wNKPyxiRQlePE0F2AZBb08EFw6ykTrl8YFXNGUxRweP14na7kUQ/F0wfzeJ3XiJl6nW89PzzSG57X92MuCCefOwhfvLIP3n29SW0VhzttyzN6aEFy15uIGfHbgYlxTF9VAp3/+S3+LxmUhJiGJwxhNTRo/H5JGKigrBa49AZdBiNBoKDgqhp7aatrJiouFhmTMnE5hQYkSJB6CB+/9ifaSk8wvjMDAxhmVTlHQSdEbMBklOSyByaSUbqEAYNimfE4EHEJqYiihLhoRaiYqMw6HSER4QxYdRIho1IJTo2jqb2TqoaKhElLzfOHc2P7ntY+yj/h1TA3dXFfXddzZI166nUDeeFv/8RvSAjyjB7ZALxky7k5VfewVtxgKHTL0AWfYHMI0B+USX15WUcyDpIeEwYW9etR1VEdAJ9Vxf0dvIoK6olNjYazNHYXRIVeXksvPUGFJ3pxE3SnOHafBJ//sfzPPDAAxzYtBhQsZiN/ODu6wlPTMdt7zwxsylGvcD8aSOZeNFCOtp6B9rXnFbaL2yvUCB62DDe/HgF1VXlFOQcxdNei8cTSN7rcjmRZBmvT8Yv9qDKCrIE1bUNxJlFHMZw6oqLsdk9jMqMx2RJ5Ce3X8dNP/sz73+0nA+XLsXZdJhps8/H5RbotHXgdznwi368og+fz48sS/Q43SiyhCjKOF1uFBT8XjculxOvLOPy+YgLNSPpw/A5moiJi6fFYdd6zP0PCcDadXvI3bOd4UkR/PJnP0M1haAoKj6PD6Ps4+4f3M47n21l/IhIDJZg/H4JZJkOt5+Kwwe488f3MGnSJP7vpz9jS5GN5pIjCKqEJHpBUZEkiQNFDVRu+ZS777gFu8fCkpXrGRzupcUFDQ0NX+hBqTlzRZn0/OiuhfzqV79i1LT51De24bJ34LR1M2nmOQRHxWPv6sbr6sbu6KGtsRGf18e41BCSh44euDjNaaC1WfYSgOFjRrLs8+20l+WQPjiDcnsPzsYa4tKGkVuQT0K4js5uA021ucycMh7FGkfe0b1cPHM00SMnU5BziO5uO1cuOAfFkkLW0aOEmRVmTJ9IVPIQWurqSIyLo7nNjlcn0tXSREbGYMob2/A72olKy+DowWwGJUbjJISSnEOkJMVRWlGPXurGGp5EfkE+U4cmMHL2NSx6/zNaG0qYNiqNqAStzfJ/RQVqW2zU1ZTQ0dFDW00RN169gFaflT3bthOs9jBm/BTS0wcxefI0DpS0UluaS3RYMPmVLcgNeUw75xzComLx+nwczclFbK/HqwZRV1NKUFg4zV0esvZkcfvl05hx6U2s3ZXLrtXv09jZxZH9exkcGURSxrCBm6Y5Q+kFgajICGJiYrAEh7Jq815KsnYQFxnCmDGjsYZGsnXfAQyeVpp6YN3yTzEZdIyfMoaY+MEDF6c5DbSxYQfwSSpij52QyChsNjugIMpg1AsIAkh+CZ3BQJDVgDUoDJ/XjdkSBECbvQur4CM0ItDN2+mTcNlbiU9IAgQ67D2EmQGzFVe3B0WVEABV8SNgQNHr0KsyimBA0OkRZD+SJCPoDSAI6BURRdCj1+mIiIzE6ZEQRCfBYRED3oXm26T2nlxJCjTW1xMfFYwlNApbtwefqwujDmJiY0BnQAXa2m0Y9So+v4ReUBB0BsJDLJisoXT1OJFFP7KsIPq9WIKCcXt8KKKPlORYdIYgVKDL4UCWZWRZxqAXiIoMB+1W7FnLL0m0t3UQHxWKwRIMQI/LjVkPBksQHR02zHoIj4waOKvmNNGCpUaj0Wg0X0Frs9RoNBqN5itowVKj0Wg0mq+gBUuNRqPRaL6CFiw1Go1Go/kKWgefU1ABn09EUGXMluMDmSuqiuj3YTaZQTj+APk3TVFB9PswmYzaUFeniaIGnncc+DyjIAioiorBoEOnDwyWLooSqqoEygbU1+t0qIAsywi9x4zBoEenOz4AvyhJoCjo9XoEnQ5ZUVDk/s/OGg0GBJ0u0ENaAL0+ML8kyciyCCoYTcZ+y9Wc2Y59zgaDvt/3XFFVFElGb9Bp3/8zhBYsT8EjqTz1+lLMDXt48PHn+6ZX2rrY9uHb/PieO1DN0aiqik73zR/MjS4fGz5+k5uvuY6gmMSBxZr/gQaHm92bP0cWRVqamkhJjMMtG4gMVqmu7+HcUbH/3959BtZRnI3bv/Z06aj3XixZstxkW+69UkzvLYQQIAUSSPIkeR6SEEgICTG9t1CCMWCwMe69d1uyZdmWZDWrWL2fXra8H44xtkLivPkTJJv5fQHO7M6ew6723pmdmZuxc69B1vR8tmkvvdWFpCSlUXGqhSDNSWR8Kh63l8GpSTgNVg7u3EpqSiyaPpgRmcmMnDAJncFEh93F9j27MDq6SU5MIj09naOtHg5sXkVcVAjW0AjsNhfXX1aAKT6Pdet2kREpUTB1BhqwbO1uTpXvwGuHqy8dQ+6ES/v+FGEAcnv9lBwvp/nkCebNmoo1KuFMWXVjG0VbtzJ/3jhC4geds5/QP77+u/wFTlYU/H4fQXqNzKFDaG+rR1YUFFkGICsqnPse/AWqOZrSqjqOlBSjnU4G7Zdl5NP5BwEURUX2f5mzUFFV/D4fmqqiaYGWhqoGtgHtdAshcJxkq5l77vsJwTGJgadPVUGW5XNaG7Ic+Ez47+hxuBibn82UK25k/YYtzJ2ax4TZ8xmfkUCXlMStP/wd5fvXYtRpZA0bRpTFw/xrLufYSTdKzW5uvvlmps2+CptLZujoUaxeuoY5w2NJHzeNe3/+O6oOrQfgzy98iLW9kLnX3cSGPcepP7SDCWNy2HKolPQIEzfffDNDCmbid3TT43Tz6e697N28AoAWt8qSD9/kntuvJ3bmDXz49kKxTvAFwO5VePOdxRRvWsLMqWPOCZQAzV1dvP3e+ziaT5zzudB/RLA8i0eW2V10mE8/W0rnqXKsFjOSwcLO/SVs/HwpquylvLGT7VvW0Nbayv8++kcWvfkSjtZquh0u1m7eyqa1q3F2t+CXVfYXl7Jt82Y6W2vxyzK7Dh1h6dKl1JYW0tTjYt36rRw/WsLSpZ/R1lLDmi0H2bFhJars4VS3k7VrVuJ29LJrfxnHC3ezdv1OirdvRNNU7G4vG7cXsX7VKuydbX1/ivA1yEuMYnDOaNAkzGYziqYxLCWC5NEzGZ6XyIw7f8Tvf7eA3oZjhIRaiYmNB0lPcEgkJnMwiqIQpPcx6/J5oNdjDYlBJ+kYnJ6APiKVrq7AeWusbeTI4XIUWzsP3v89kkdMQwIiYiMx6A34ZZn8nChisseTHBHKmLGj0RnMcDq/qippgBlbaxtjp+SLP+sLwLKN+2g+voVb7r2PoND4f+jqHzFkCAnJg0F0wQ4Y4kycpgFvLdmEVr2foIQRfLTwfQwmmYa2duprT/L4Cx9QvfszdhbW8tpfniQuXCVr6CimjR+BEpbG008+z8jEUKqcISx45GG2F5VycNsKklJSKKuqYXdJORs/eY+YvHwe+83jVB7Zy+8f/StVhev5bPNBfvfrn9PcUc9fX36T+pK9lFS18fyzz9Ld1cFzf/uMj996hpraen77yKN09dbz7EvvoXVVsGjrcZ773U9O/wLh66TX/5M/D50exe/jV3ddQ+LM7/Dknx7Db289865SkjTqW3rYX3KUrR+9gUmngCTh9StsLSxlwWPPcte0dMZMvQ6AXz78U1Yd83LTNddQuG0JsSlxqICqQnVtHSs27aKwcOeZAOn3fdl7ESBRUd9IR3UxPlkPqq9PudDfNECWZfx+Py5FYfmKdQxKTeatpZt5+OcPYO8MZK35gl9WUMV6zwPKP7kbfPu4gbWLVzJ94jCumzGc2+//FV63SlZiFHfdfj05M66kvamTidOHY7YkoNOBxWLBGhTMsWY79ceLyBicxtVXzeVgZSsWfx1bDzew+G/Pk5UUR2ZCPGMnz+NIyWF6um2MyIkjOTOX666YxxXX3UVaVBA/vP1mUkZOpre3l2FDM4lLTSMq3MKwUSOYMCKXHz9wFzEJWZQ3VNNefYiouHjuu3EO06//Xt+fI3yNvhjH9cXgHAAFCaPi5bFf3ktxdxzvPPsndJLvTNYQWVHQ+XyEJ2V++RgjQY9TprBwB7NnF2AKiQRgbEY4K5d/zOSbH+DHv17AruUfYAYkJHx+hUiLgZjIiC9bH33GlWmayoisdH740E94b8kW3C3Hzt1A6Hd2WWXN+m0sXbKEksL9WLydXHfFDH55311UuiI4sndj312gzzUn9C8RLE/TAYpOx+4DhXjcbpDB77CBZAyMYtRUdAY9yul3hqokBbKQyH6MipdumxtXTy96yU98ZBjZaQm88PSf6AoZwnN/eIxjR4upOrybsaNGYTCG43a70ZRARhO/142k1wXW/pT9SBKoSuC9k3q6JaGhx6cogIY1yEyH3UN8eBBTJ45h0MhRaKpoWf7XfBktAQ1N05CQ8CsQFaTjuRf+wpJ1R6nYswFVDYx8zUmNZeKE8Vx+23eQJAMSEma9jtsum8iPf/dXHnniZbrqSlAUmc3LNxCit/P7B+7k7l/8kYPFR0BR0aEycmgus2dOZfjIKSDpULVAEJWkQJAEUFUVv6Kgyj7MZhPa6ffewsChqBo2u52e7m6Mmp/Y1EzqG1qQ/T5yM+IJDY/DL8tnxiwEgqTU97lI6Eci68hpBkAfk8jTz79KW0UJFqOZfRXVlO3aTO6YCXywdCWJZhuN9hC2rVnIFZdMoaZLx441n3D9vIk0GaIpK9xOU7ud6eMz0Ky5bN+zh8GZyYSGh9KtBVF//CDpg4eybs02CPKze/N2xo7MZNuRehqO7SItfzzvvbuY7KRwuqRoli56m+G5GazZUoiv9TihKUNY9MEiLhubgZYwkRcX/JlTDVVEW/WkZub8Y5ND+H+mqLBu1xHWLP2QIckRDB4ynA63xqL3F6NzNzNyeA6xERFEZeVjsDcSlzWShR9+jK2+nIKp0wmNiELRJHbsOcTni94lJc7KzbfczOYKF8vfeZHsoYPYfaCalroyGho66G2uYP7cmVTaDHy86H0iFCdjx41Gbw4BoLXXy0cfL8def4QZs2fg0FlZtXQpcSEmtuwrZ/LQWEbPvBoQ00cGkiC9jpHD8xg7bhxJKRkER8Wzc/dBWjqbSAjWmDpnPut3H0TpPklc8iCKjlay9MMPGRRrJDt/ApKYDtTvxNSRPiprTuHpaWFwTg5tNg9+Rzfh0TF09fQQYjGiSRacji5SkuJRDVaaaqvIGZyJTxdEw8lqgsxGkpKT8SsSrW3taLKX+NhoJFMwjXV1hFiDsLu8SDoJv9dJVHg4Dp+C6nUTFhVNe1sXkRFWdCYrnW0tREeEYnf5kDQ/oWHhdHT1kBAWTERCMscratFcnQwfOQx0X84FFb4+mgZNbV04ezsJCzaRkJiMR4XGulNYLBLJiYmgN6ECXpcTFR0tLc0gKyQmxRMcEhbIPNLWia27g+CgIJLTUnB6NWoqK0hKiMRkstLbbQNJw2yE2MQU2roddHc0E2zUk5yciM4YBIDLp9DS2IxO85CSkkSFU8fv7r+HBQ//FH1oIpkZySAF5n4KA1tzayc+dy+J8XGYgkKob2wmxKQSFZtMZ7eNro42woJNxCUlI0kiWPY3ESwF4QJ2sMHOC7/6Ee++8RTG8KS+xYIgfE1EsBSEC5jNrdBeX0Nmdjo6vchvKQj/LSJYCoIgCMJ5iNGwgiAIgnAeIlgKgiAIwnmIYPkvaFpgTl1fX6wF+9/2xTw64cLyxTVz9vXzVdfRPxNYO/jf3164OAWuAXEdDBTineU/oWpQ19CCSXOTnJ555nOnz09bfS2Zg9JAF1h+7L/BI6u0NNSSkpyEwSSmhVwoZFWjs6sbZC86SYeKhoYEikpcXNSZJesAvH4Zv9tNSEgw6PRoGrR39eLsacdi0BOfknomBZhwcfL5ZRTZR1BQ8JnPFFWjs7sb2etBJ0FEqBVLSPg5+wnfPNGy/Cd8qsYbn21nwW8ePOfzLo+Pwv17QHbh88u4PN5zyr8uvX6ZoqJ9+F32vkXCAOaVNbbsP8GDDzxE6cGN7C0+zv0/+hnb1yzF7/vyXMoaLN+6l5efeAwcLQB0Onz8dcEz7Nu7jaeef5uyPavOqlm42KiaxksfrGDTZx+c83lxZRtPPfsar73yEr/9w18p2vTROeVC/xDB8iyaBi6vj96eboyazPiJBYREhODx+vG63aBpJFmDuOHW7+DXhbNy4zbWr/4cxe9BVVV67Q5cDjuqqqBp4Pb6sNttKIqMpml4/H56uruR/X4UVcXr9QYWVnY6URQZl9uHzxs4TqzZyLXX3owlPAafz4/f58Pl9uD3BoKzqmnYHG7cp48nDAxWk46xY0fT3d7GtFljKJgyh+bGHqaOHYI5OObMdhIQFhnN8ZIToDgAKG5ox91ayW3fuZfwUdMpLTx8Vs3CxUQDyuq72bJtLY011eeURYfIfO+Oa/nxT35C8qCRRMSlnVMu9A+x3N1Z6jq62L5pLVv3FGGw1eAKSqBk5zraPBbWLHyXCePz2Hy0jfUfv8ygrCx+9fgz6DqqmThuDEdr2ik8sIe9+w5iVexIIXFs3radkydOoCk9SJZwlixfQfGRYtpPFOEKiuX1l97Aa2/h3Q8+Ra/1smJ7KfvWL2bMqBEcOeXkvVcWMGLYUF77YBNNJZvYuLuM8p2rGT11Cscqmyg6UMyGLduIlJzEpnzZVSz0ry67hy1rlnLjLZfR6wtn7ecruGZeAeGJWWe20UngVAwc2rKNq6+eAUHRHGnqoObgDvJGF7B53TbuvH4CIbEi8e/FqMvupbx4N0poBOEeJwXTZp0piwgLIy42Di04jOZje5g8cyamoLBz9he+eaJleZoKvPjWUkZH+rjkyluoauwCfMh+D2NH5rCzzk3FrnV4NQM71u0kPtbMlJlzmTdzMj2WdN565WWunjKCxPw5PPPMc+wuOsz+bWsZOSwbgyWU4oo62soOkT/7Mv72tyXo7fVs2rafFKsXKTKLpe//jZmT89h1oonaY0V4NT17DxSiKR6OVDXSULaPcZPHsmztduqay3jr9bfwdVVw+GQHb738lEj4O4Bop3spvsgS8s+GBciKfM55C/wxaugkHSkpMWzeehA00WtwMdAAj8eL2+3G6/VRfOQogzOS0AdF4PN50b6id+hwSS16o4GQiKi+RUI/EMHyNCdQsm0PSYmxjEgP546778fr1EiMiWRM/nAyRxbgcssMzksh2BoPqorP60VWNapaOnA0nMQSbmXK2Cxa7RJD4114QzJ58Cc/pb3yCPmZyeQUzGDz2pWgyqQkRJKYnM6o0SMZkT+OtMQoxo/MJz59MD6/n7TkWGKSErEGG0nPTGNIdhZTJo0hNj6V+rY2NGcTs+ZewltP/pLfv7oINLGI+oXC6fb901GOegkyUlMZN3UOWzZvBndr302EC1CnV+H1v33AgiefZNv6z1j++So+Wfo521cuZfPO3XTUHT1nexWoqy4lIy4UdIF1gYX+JYLlaUFAZHY27yxehq2nk/Ljpbhtrbg9PmRZxut0oioyDrsLn98ReC+pQltXN1G4sRlDaDh5ko4uJyNzEjAExfN/P/kuN/z0cRYvXslHy1dQuXMlN914C4oUQVtbCx5bDx6XB6fDjtfnxyv7cDodyLKMy+PD6XDj9ck47DbcLjcOWcbtcREfHkyzw8S+jSuRNZXjZaUgppkMCBrgk+XAe2a/D9kf+Kff58fn99Habado2zr4Ihmwz48sf5nM2ev14fN5aG9rITU1FYyi++1iYDXomDltIpdedjnD8sdy3923MmfufLKG5ZObnUVIdBJenx/ZH0jcbXP7OXmyjoKxI/tWJfQT8c7yNB0wbNRI3vpoHQdXf8LwoUM5WNVAc1kJ0akZbNuzi6hgmaY2jROlu5gybgRSaCqbVnzCrVdPJ3zoBDav+pyejiZuuvkyFGMay9ZtIEixMWnyeGLS8zhRdhyr2URFzSl6/S6aak+QlprI4coGuptOEp6cwZZ120hOjKBLDmb/tg0kxUVw+Ggl7p5GTMHR7Ni7j3EpkYy/+m5eeP19Dm1fxeUzJxARlypSdA0ALp/GqvW7OVFykLjgIKoa2yk/WoTebKKxrZPPlq9mfKaZuEGj2Lh5F6VHDpCZGEVKzkgqO+zsXrkUs8VEddkJfvTD72CNTO57COECZNRJJCTEkZKaQlhEFPFxMSQnJ9ElS+RGBjFs/DTeX7oSX1sZqYOG0t3rpLu2lLEzLxVtmgFCzLMUhAFiSWElW195lFfe/UDcIAVhgBF/kYIwQKheyE4WabYEYSASLUtBEARBOA/RshQEQRCE8xDBUhAEQRDOQwTL/yLRwy0IgnBxEO8sv4Ld40Xnc2ENi+xb9G/RALvLg62rg5DQEIJMRsxB1r6b/cecbi/4//PvJ/z3KKqGqshIkoQGGHQSkk4Pp68L2e9Hp5NA0qHIge0A9HodOp0ev19G0xR0Oj2apiEBBqOxz1GEC52iqPhPz6mUJAmTyYgkfdl28ftlVEXGaDSi0weuH6F/iWD5FfZW1GBpOM7oOVf1Lfq3NHc52LltPeV1PRzbtYaH7ruFKZfd3Hez/9iB8hp0jccYO+cKQPwhDRR+WaWopIqOuqMER0TS7fYwMSuK5NyJqJpGY1sP+3dsJzcrFl1IMmtWfEpOWgx2QhmeHkNewVRWrtlC/bH9jCwooNetoffZuOSSGQRHJIp5tBeRvUcqWLd0MUgyRp3GA/feSWTyYAAcPoVlyzdw8ug+rpw7jtFTLz/zwCX0H9ENe7q7VJZlFFkGoGBQOsOmzEFVA5/LioLf50PTNBRVDay84vejKjKaBrKinNlX0zTeW70PU9NR7r/nO2gxg2hrrIPTmULOPo4sK8h+P5qm4ZdlNFUJtD4UBVmWzyR/Dnw/JbCWqKYxOjudkVPmomm6QH2Kevr7iVV8+ouqwcJ1+9jyyasMzs0iIz2Ddp+Fkp0bASg72cZbzz9FerSB+KRUIqIj+OiT7ahNR4hOz+HBXzxG7aFN2LCyYuFCUmJCGJI7mL3Vdn7zi5/j7Wnqe0jhAuVVNJraO5hUMIyJ02bQ0dyM+6xUfCVHy7BKNsLShvDLh5+kparonP2F/vGtX8FHA2pa2jhWfIjKE2UkxMWw4+AxZFsjXd5g9u7YRmvrKbZt2kJSbAjlTQ4O7tlJ+bHj6P1dOLRQjh89QnV5KYmxYXS74KU3FhGrNlMwcQLHWu2kmb3kjJpIWVUdZaXHOFVZRWJyHFv2l3Jw8yoS05NZt+0gsUYPLl0oBw8fpLzkGCEmPyERsdS2tHG05AiVFWXERYez/cAJ9I5avISybeNGerwqm1evJjHSRGhUfN+fKHwDytqc/OHXP+NPP7+DQSOnEhkZSX5OOtagCAiN4Xe/f4rJeeHkjBxHYnIGoSFW1qzdx/XTMpgy91oef3stU7OtxA+dRvWeTdzz43uIT8lk7IQCfv/spwwK6SQnf0rfwwoXIINOYuigVLKH5CGFJKFTHEyYPAlJb0EDosKDyR81moljRrDx4AlGZ0QSnzGkbzXCN+xb37Jstvn5+xuvY7WaWbx+P9WHN/P57jLWfPw2GPX87vEX6anay+7SNp5//Le0tTfy+KML0LtbaHGb+PDdvxGs87DrRDsv/PlxDHoNS3AQJpMJFT2yz4dBr6O8tpMlH76L1WplyYYDrFr4ArJOz9Ov/p19W1fTWFOB3mRhyfIN1JbtZVvJSZa+9ixt3b0sXbwYo+pizeb9lJbtYN3+Y6xf+BpeVeWp196k+tBmthWf4v3nnwL+MXuB8N9XfLQapa2ZmPThADR32lj88accOFbKslWbcTUdYfj4Wbz40XqWv/0MoKEoCnaHg5X7SxkS2kn+2HG4PV4URcHvD6wXG26C3AnjqK08+k8XXxcGPu2LtYD9/nPyz5YdKSRMUtCZwuF0R3uINQSQqO10Myorksy8/LNqEvrLtz5Ybi2uRGktY9zYSfzt+T8yYuq15OQNwhIUQmZKFGnp6Vx3xSU8+qdHONJmIkLvZciwYVz33evp0CfQWrafsZMncfMd32XLniNEWdqJTx1EbmYKEdHxqCpIkp4N+w8R7m9n/NgCJl91PZ8s38EVU4fwo8df4dmnX+NH108gOiWbgmE5pKeMxCtJdHf2UlReSevhIqbMmMILf32M8ROvJSc7E4Mhmri4SAYPzuCy2dO57t4f0elSQflyUW7hm2MNMuNQwO3uASAuMpTyNtjy0dv4JBNDEoMZPmoUV930HT5euRm/5kCV9BwsrcTXWMp7b71IQs6kMwtpf0HWNOzdNoLDIsQ7ywuYXVZZs34rn332GbVlhXC6O/Z4ZS0FIzP6bo6sqBw+UMgVs6YSGveP5cI371sfLEODgzl5qgNXVz0Oh4vG1k5UWUbVVGQCOQl9fhmfx0d6WiImiwVF9qO53JgNGk2dLnzd7UiKTHJiDJrBis/rxeP98h2nhoolKISW1mYU2YsEZGRm4HN6GJ2gJ2f2dbz3zkJkv5cDx0ppPFlKekICqmIi1GKiormTzvoaerxeHC31+DweVBQURUHx+1GR8LpdZ0ZWCt+8SaOySModxdYVnyL7fegkDWtEFBGhIQzOHYRHsiK7bMSFmklKTESHGUmVmVGQz0033Eh82tBARRqoioIkSYEbZkULrsoDTJp+Wd9DChcQWdVobm2nsbERp60bgKYuB3LjCeKHjA1sIyuoioKsqGzdV0pymERW/gR6bL19ahP6w7c+WM4ZnY4hfRo//+UvWfLeWxhdLTTVN9PrduF3u2jvdrHrQDHFhfu5ZtoYPMEJyO4OOhtbmV2QSfqUuWxat5riwl18/56bsHnCcTQ3UF7fSXtXJ62NLfTae7h2dgG20MHs37waZ0sZd9x5K+v3V9BRe4yHf/FzPtrbyI61n9HY2ExMhBmLOZSqdhtZMRqpky7l/377Oz5++UV6PR5s3d10uDqpO1VPl81Oa3MjXW0tdDuceJy2vj9R+AbEWQ08/cxf2HjUzpa1n1JbW4e7u4bMYTlMH55O8pi57N62naK927n3e7fT3u1Cr9mpbezF63EB4FM0uloawainpr6JvYVlvP3Sazzx0C0MmXB530MKF5Aok54ffv92fvGLXzBiUuDB52h1G7PGpoA+BIDt+ws5WV7IpsJaPlz4Gjt2b+PPf11AdWEgpZvQv8TUEcCrQuGBQoYnRaJPGMSxI4cxqB7iMrP5wY9+xyN3TyI2ZSQ5ows4fLwGR3czqbEhZOSOREFi14FC0iIlMgcXUNvcSUNVOXpJITQmBmevnSCdRv6YMdgUA4f272VYdjSxiUPYd6SSOIOd0PhMKirKCDXrSMsdTcXxEgalpWD3OMnMzMSPnqIDRWRFhxGROZgD+w8haR4iIkPp7bJhsZiQ9VYUVzdDBqUSkZDW9ycK3xAFOFhYhqPnFHnZCSRnjDhTtmP/YTKidaRl51NaUUNXexM6YMTQXEIjY3F6FYqLCpEkFZfTjdmkZ/yYYZhDYs45hnBxaO6wEx0iYbIEgmVVXQNhJmh3QndTDQoSelQKRo8iKDSi7+7CN0wEy3/heEsvD918M+8/8xBJ4+b3LRYEQRC+Jb713bD/iqe1lYd+/RBdUhio5w68EARBEL49RMtSEARBEM5DtCwFQRAE4TxEsBQEQRCE8xDB8iuomoam/r+ts/rFOrCqqn7tqbq+ju8nDExfrPQizq8gDCzineVXqGvvxNjbSlL26Yni/z+pqkZVUzN1J8qJigglLTGO2KT0vpv9x+rbOtHZWknJHiKedwYYDfD5ZGS/F5PRgIYOv8+HwajHbDLDWQtH+Px+NFnGbDGDpEPToKW7l2NHihiSGEPy4Dx0epGe62IVuFZ8SJqK0WQ6J0UXgF+WUWUZo9GATm84p0z45ok77VfodLjoaW/u+/G/rbCikX1rl3Gi1cMP7rufou2r+27y/6Tb7qK7vUmsFToAuXwa7yzZxpWXXcH6xW/x8fLVXHrJ1bz3wlP43B1ntvOpGu8sW8Pj//NTsJ0CoN3h55m/LCAuGF74YAPHty87q2bhYqJp0NjWw9/e/ZBF776O29Z2TrnD42fpmi288cqLNFcePKdM6B8iWAKyquLz+fB4PGiqyoiURHLHz0RWVDweD16vF5fTiarI+GUFj8eDx+1G9vtQlMC+Xq8XTVNRVY0PVu0i2tfKT26fz7Tb7sPjDqzQIssKXp8Pn9cLmobX58ftcqKqKm6PF1WRUVUNr8+H1+NFUQKpvBRVxevz4fF6UFWVvLREho2fiaJKeDwefH4/LpcL9XTqL6H/WE0Ss2dNxKiHS66bydQ589EI4vI54zAFx57ZzqSTGD1mIvX1naB6ACipb8HZXsOI8bMIGTSUsiNHz6pZuJjUtvby9F8WMHVwMHf/6GcEhyecKXMrKi++8SFq3W4efPABkodMOmdfoX9861N0KarGloOH2bl5I2tWryI3I5GXFq2np2I7rWoCLz/zDA0nj/PyS2+SFqlnX62Tt156noO7dqB3t1BvM7Jzxya2bthISpSZbjmIN996H8lWR86woRysqCcjWCFrxARWbdrJ3t072btxK4MHxfPO5/t488+/YdjYPJ558xMGh3iodVpYvmoxW9ZtxupvJTEzj12HjrJ180bWrV9DZmoUL32wFV/VeuSgNJ564s+0Oby88JenSAvzkzw4kPVC6D9dDh+bVy3lllsuw65Es3rpMq67dBzhiVnnbNfa66Z4y2auvnomBEVzpLmTqgPbiUvNYP/mrdx1x+VYo1PP2Ue4OLz8/gp07aWEpuehOjqJiU860w278WAVOxa/yojpc2lvaiQ5JQmd3tS3CuEb9q1vWR6p72Hj39/gjttvJjprLPaOOnzWGKrLjzM6P43dheXMGxHL3Nsf5NlnXyItWqOkqIyf3ns15iGXsXrRa9x65UwSxs7nkd/+nvQ4I9kjxjBpVB5J6UNQFAmDXs+WwmqObF/KnbffSndIGm888xg3XzsDW1gmaz/6kBunDyd91HQO7NrN8NQofHE5bPhkMWW1DWxZ8hG3XDmTtKwx2OytmMLCqDx8lLjkWMqaGxkcaiN//vf4dNEnoInFEy5UOsAgwZj8kSSNGMOaFatAE1lkLgaqBm63B5fLRa/Xy/49u7ly1hhiBxfwq98voLF0z5ltCw/sIzstkanT5vHiR9tZ//dnz6lL6B/f+mBZUt2AQe3GZArip3deRc64y4iMCMJsCkJv0JOYEEt2Th6Xzp6AJ3ww7p4e0galEZeeQlVjG87mOiwR4UwqGEF7rx+93ITBaMZsNqLX6wNplSQdReXlhEs+LBYLI8cWUFLZQ2IY3POTn/P+8i2khyvoDQbGT5xATa2DnsZq0JmpaWyht7YWa2QE37v1SkaMnEeI1YrRFI7JqCcpJoK84QUMGjIYgzUcxCjKAUHTvsioJZ3zZlkD5NO5Kr+KJEkYDUYmjM5n554i8LT33US4ALV6ZR7507M89NBDbF72PpEmjdS0FCbmJBOdNYqa6srANYOGrPjJzk4nJjKMyZdeT/GhQ32rE/rBtz5Y5mUkcaiim+Ldqyg5Vkpl+XHcbj9evwdJ03C5fHR399DS3sWw9BgiExJx2XtQ3V7yBiVR7zbSXlVBR0c3BSMzUS3puBxO7HY3iqLgcLiQFS/Dc/M4frIBd28z9u4epk0bQ1unl2jnSX782yd57Ol36G5vYuEnn5ASpZIzbBytbTZSoiwc7fKxe91qDpedoOVEET6PG4/fgV+WsTlc+L1u3G43bpdLDPnpZxqgqIERsapPQZPA7/UEUr7JMo0dNrauWhlYcl2T8Pt8KGcNSHe73MheJ6eaWsjMTAZT6Dn1CxemGJOeh378PX77298y69LryB0zkaPHa3A63SSFGEjJGkpXby8uey9j8kdzqqUZr8eJ7OikYMrUvtUJ/eBb/84yJSoYmz6WlZ8vIQovQ0cMY8eB45jkLvJGFrDwk/XEh8n0dDm5bNYEah1G6ssKGTYomeHDR6KLiqespBC3s4vrr7ucbncQB3bsANlFWFIKhw4fJS5Y4corL6PZE0TDiaOEWHzMn38la/aewOBoYPKMeazYsp8QpZvI5Bx8vW2EhcbQ1dvJ1fOnYEkeyerPPybIYSNr/FQOFh7H724iOCaB0mNlJMeGcarLT09zNRMKhmMJje77M4VviNunsnt/Me0NVcSFh9HQ2k1Lw0mCQqy0dvaya9c+CjKMRKQP58D+wzTVV5KeFENc+mAq2m3sX/c5iYkJNNY3cMdt1xMSldL3EMIFSC9JhIeFEhERQVBQMJkZ6RyraqS+oZLJ+YMYNm4aW/cWonM0M3HyJJp7/FSWHyPB7GLulbdiMFn6Vil8w8Q8y9PsDhehZgOywYTTFsh275CM3H3bD3n7D7cRnT2Z4IhIunrs6CQNg6QQEhYJQFtXL2EWFUtwJA6XB9nrQgWQJIw6CVXVCA8LA52elvYOYsKDMJisdPY6CNLJ6IxB+HweUFXCIiLp6uolMjQIVadDf3p+lcPpxmrSIRnNdHf1gE6HDhVJkvDLgS5cSdIIMugxBQdS/gjfPL+i0dvTg8mow+f1g6ZgDgrG6fIg+71YTAZi4uLQ0NHd1YVOr0dSFcIjo/isqJpNLz/CH595nnBLMEZxHi9qbr+Kq7ed6Jh4AJxuD0adhskcBEBLWxvxsZFIkphrOxCIYPkv7Dx6kpce+V9+98BNjJx3U99iQfharTxYS8u2hdz3q0f6FgmC0M9EsPwXWlu7kBUPJj3ExsWDpO+7iSB8bVweP3rFi9kqWpSCMNCIYCkIgiAI5/GtHw0rCIIgCOcjgqUgCIIgnIfohv0KiqqCqqI3/Ocr/cuKgqIo6AC9QY9O9/W97/w6vp/w9fhiInmfT88sXRYoVr9YoQBJkv4xZZumIekC2/tlBU1VMBr0SKevGU3TTq9v8GXGEuHiELgU1H/IOPIFVVXRSZI49wOACJZf4dDJeiwtVQydNLtv0b/FI8vsLSrm2JGjSD4b86aMI3f05L6b/ceOVNeja6tkxKSZwNcXhIX//9o6bdh7O0DS43M5CA0Lw+N2k56Wgs5kob2jB5+rC8kYhOr3ERsbh82j0NZYT1hoEEZTEA67k6z0WDxSCOu2bUVuayJ/eDZ5oyfg13TU1jUQadKISU4/E3SFC5+sqLS0d6G4e0hJSUVvNJ8p0zTodrjpam0kJT4KS2jUOfsK37xv/aIEX9A0Den005usqlgNekIjY76y/Mv/JrCcmQaSpJ25kS3eUoyjeA3ZE6/gqaefJy/BxJDTwfLsegL7na7vPLfBs7eVVRWr8Yvv90UFZ20gfCM0YP2mnVQf3c+a/ZW89tivyRmWxZptBxiamURRZQurl3yI6rHR2uNg2eoN6Ny9dKnB3P397xOi9IDRyvrNBxiZYOf93b1IJZ8y/fYf89v/eZQr5wzFa4jk0WffoWnz35k0/xpA9CZcDBRVY/PuYratXIzH1cugzHQM5mA4fV1V1LexeOHb9LSeIjkujJDIL7OSCP1DBEvA7ffT3dmFy2nHbLGg+WRCI8Jw+6Cnuwu32017WytWqxmb009vdxe9PT3oVB+q3kxPTzcuuw2zxYxf1nj23eUMs7Qz/7obqHHrSTW5yB01CafbQ29PDx6XE4vFTHtnL72dbViCg2hp68Ksk9F0Rrp6enD09mI0SBgMJjw+Pz093TgddsxmE4pPJTwiFL+so6ujHZ+i0dbSRLDFiN4oshN8kwanxTNmwhRsWhhdpfv45WO/YfLUmTTaJR799cM89J3ZTLnsZnKys0nLGYZRr2fsmGHsKj7C96+ey8SZlzB9+niCwhJ5a+Fa5g8PIjxnPId27WbeJZMJCYun3aHH33iciZfOF8HyIrHj8EmW/e1ZfnjXtYyfcQVGi/VMWZtT5sk/PcncUXFcees9hEYnnbOv0D++9cHS6VN558OPqK85wUtvLWREchCPvbuZpr0fosSM5r67f4DSW8FfX/wYXcdxKpwWfv3AT+luqEBR3ew+VE1d9TE+Wb4JOisJisti0YfLMLsayRk+nD3Hqsi0KkRl5PPu39+n4VQDi9//jKQwLyv2n+LX997B6LGDefmdZeQnBrG1tJ0Naxexau1uPDV7yMyfwsfLV3Pi2CHeWbiYjGQjT7y9nZ7dbxOUNo777rkXr9fJXxe8jrmrjJFTZp+njSp8XSQ483ByuKKRqj0buPraqzGarCzddojeog+59xf/B3orjR02elsaMOmBYCvLV28gyiBzqtuP7GgkPjmb1Rv2kRXqoKxLj6mrhilz5qMzBnHg2EmUUyUiWF4kZBUWvPIegyNVWojg2O5NDB2ai94YWNJu8erdNB1cRdrYuaxdsYzBqVEEh3+ZC1XoH1/9VvlbZEfpKU7t28Bdd36P//3NI8QmZZI3ahRoBqaMSSc4LIYf33IZT721kCWbShiWZCIuNok//uV/MOfN5/iO5Xznzpu4/r7/4ZW3FpERLzOkYCKzJ40iOXMoiiKh1+lYv/coSksJd995B0PmXcdbr77JL+6+jEvvf4wPXnmLJx+8nsyCmRh8TuZPn01E7ihOFB/jUHkVVds38v27b+N/f/UwSak5jB49DL/XQmZWEnGDUrh6yhDue+w5Dh2tAfWfZ7QQvjm9Lhc6SYcWWPgQCYlX3v+clQtfwGwIDNgw6PV4fD48vkDyZ02D6LBgbrtqDgfdiexa8cHp2sTDz4VOVqGzs5v29naaO3torqngqlkFXDr/Khau3kd54ZYz29bWnWDE8DyuuvQSjneY+ezNZ86pS+gf3/pg2Wlz4HD24PN6GDEoAUtMBgadgiRJeIEgiwlzcAjx0VYiU7JxOzwEhVhB02hpbaG7tR3V6yY5OgRLUAj4nch+Ga/vrKAlSTR2dCG7HGiqQnxCHF5dKKrXybXzplLu0nPswE5UVSEoPJJdOw+gd3SgN4bgcLtpamjG67KTnZlATFgCiiyDpEdVVYL1ekKjEtEbJSzBwV8MrxO+cecGtEnDcilt9NJYVoqmqiTFhBKdlEJ4RBhBQSHoNJWhQ3K44cp5DB858cx+qqaiAQlZ2RwvrzqnTuHC1eqVefgPC3jggQc4sO594mMjQW8i0WogO284NqcHVVXRVBVrUAih4VYkNEZPnonDHXiYEvrXtz5YThsxiNKOYN588TFWfL6c9upi2tpt2Fx2JFWlq9tBRU0d5RVVTMxJwJqUjqOrCW+vk2mjs7FFpFC2bxel5ZVcfsk4FFM6vW3tNLX2IMsyLS2duDx2Lpk2gaNNdhqriuk4Vcu1V8/maE0H7trD/PnJF3j87fVUlBxgyYoV5OdGEZ2Sx/HKBjKjJZqD4nl5wZN8tmwZjSdLcToc9LrasTvstHR24XZ0Y+/tpaOrG01R+v5E4b9M0zS8Hhc2uxOfL5B8e9LwNObd+zAvvP4eTSdLcfl8dHW0YAkOxeMPpG6zd3WApmI2B95XqapGZW0zLb0OeiqPccn8S9E0kL0+HHYX6r/IgykMbMlBBt588S988skn3HDng0ycdSl7D1VQ29BIeriOvFETKKs+SVtTNfNmzaS2uZPW5gZcdcXMvVqsSz0QfOvfWUYEGRg1YSoVlfWMzYgjfsgYmuuqiYkIIy4xhZUb95AeayRYg+tuuYnj1e2EWDSiw4LJzs6lYNIUDh4tI85i5+obv0PVqR7c7fWYrVa8Oj1G2U1UWCjTJ40mbcQkDhUeIn9wKNPmXsuOwgqiTE5SM7JxeryYVBcz5l1F46lW8rNTSBo8iMkTxjJh2jxqTtYzNC6K1DFTqDtRhTUyHJ3RgEVvRG8wIqsQEWYmIzkGa4R4v/FN6nJ4qTiyn6TUFIxGPSnpmegliVnjhxOZOYwjxeVUnDjG9IJM5sy/mT3FJ4nQedAZjAxOi0cfFAbA6o2FZIR0Ud+rcdPsfAYXzKLX7aO67BCm8HBiQyxExCf3PbxwARqem06Hz0xtZTHXXTWH6KTBlFefJEh1Mywvl8jkXA4c2MO00emMmHhJ392FfiDmWf4LdXYfd199I8te/hnhw/6zOZeC8O/6/kML+OkMI6Ov/3nfIkEQ+tm3vhv2X6k6VsHkifmUNXSBEuheE4T/Bg24fMZwEkdN71skCMIAIFqW/8rpif7nWzBAEARBuLiJluW/cnpFHBEoBUEQvt1EsBQEQRCE8xDdsP9EIFvE2eu4nvu/6ex1Yv8dfdeW/Xd91X5f9ZnQf768NqQvrpx/WEf47M/6Xkt9yzRNQ6eTRJ/GRe7L64KvPNfi73xgEcHyKyiqSlu3DcltIyouHr3eQFuXDdXnQlFUJE0lLjYSk8V6Jo1SYD+N7h47+OxExsShNxjRNLC5PHjs3cTGxqLTG5BlhY7OLqxGsEZEodPp0TQNh8ONTlKxhoQAIMsKLe1tRASZsIZHIkk6ZEWlta2DmLAgzNaQr/wjE745DpeXzvY29JKGpDcgy35MBj3x8fFIBiN+n5+2tnb0mkxUXCx6g4mObjuK14GqaqiqikEnkZgQh6ozU1PfgORzEx0ZSlRsIpok4XC60at+gkNDxfm+SLg9fjo62wKp9vQ64mKiMZgCy91xOlVbW1sr8VGRGCxB5+wr9I9v/TzLvjRg/b7jFO9dhdujsHXLNlJDJUo7FP78h0exYKPLLbFs6XJSIiSiEtLP7Ft44hSL33uTDz/4lFC1k6xho6lvs7F25TIqamtROppIyhjEmu2HWbLoXZZ9vITBaaHEJg+izWZnwSuLcNcVMXT0BPyqxoqNO6mtKWXnvkLSwk1Yo+NZvekgVZX7KN5XQnZWEqag0HO+v/DN2rariKrjhewra+Dzd18jNjGWbTsPMjgjkVa3nuVLPsXb00CLzcu6DZswST5a3Xr+9Mc/YvD24FN1bNtdzNAkmW0VCms/eAaPamLZoveZPm0Mfr2V5976kO7Daxg6YapIyXYR0IAVWw/yyXt/48ixo6z57DPG52cTGp0IgFdR+Xz5JipOllJ9/DiDs1LRm0TA7G/inWUfXuCVp99gSmYIl1xyKRFJWXh6e5hQkEOv10fBsFyumX8JvRE5PL/gCSAwpUQDWmtOcucdN3LFvQ/y9Evv4Wkt5++fb8LqrGfm5dfx2oeraKwsBpedH//oXmLGzOGd558Dv41QiwWv1UpT/QkA9pU3cXjjUm6+ei6hgyfz3huvUNrQybIPXuHGKy6l3BvFug/f6PPthW+SBgzJjOeWW64jJXccjpZmLrlsNtfccjsOXSh//vNTxBhsXHrNDVw2dw7JWSPobrczIT8bmwr5QwYxb948brz5Jixh8Xy+aitX5Sdx++230NCh4bM3YpAkMIVRV1kFiNWZLgayopKVEcfPf/Egt933AEPysgkKCSxMAbDxYBVHNi/i5huuZXvJKYp3rTpnf6F/iGDZhwFIGJzLw4+9zv6ta7lp/jQShk/G4wVzkAmvT8Xr82GRVEKs4V++owKumj+d9EFDmDNpFLE5BciSjq3rt5M3KI2EqGDsSLQ01nPVlbNIyxjEjGmTCE4eApqOYLOJxPg4DIZAFou6U204OtpAb2DamBHUNLWycecurD47xuBYRowewpa9ReIG2o8kIC0jAwyh+H1udAYDitNFZkIE+8sasRWv5urrrwFMKKrGtXMnMv3SuThkDYvFjKKotPW4MKidmCMHoblsuHwKG/YcZWSqEWv8cIx6ifi4RAymL1M4CRc2o17HqMGDSE3LwOWQSUrNICI+9Ux54f4DxMUFE2S0Epmcx4HNG87ZX+gfIlj2YQD++vv7SZt+C/f89Fc8/diDGHAiAR5Zz5btO3l/yefsWPoGc+ZMQ1PPTZmkarDn8Am+P3cYUvwQfN3tWIMt6AEDejzeXgD8qkZzTQW3XjUXTIGuVOWsdV3HDM3ilM9ExaGdHD1+HPDjdvoJMQYGkYRYzLic3jMtW2FgqW5sIirKjGQOdJ+V1Xfw0P8+znO//zkeWxsyBrZu38Pf319I1YliACRJh6ZBcqSFOk8E1fs3AaAo8pmHMuHCpAIulwen04ns88LpM1pZWUpqqAS6L/PQOr0uzObAuAWL1Uprq02c/wFABMs+/ECwt4fnHnuINz5Zw8c7Gli7+B3MZjDpVSZPGMft117Jz/7yKo8/9Tc6Tuw5s6+mQV1LL1LzCebccjdGTSMkMR6b3YVHBZ/iIyI0DlXVOFLWQHa4jqHTr/jK0ZFDU8J44qnnqGjxs3bFZ1wydQJJaYNwqhKg0tpjIzYqDPhyUIAwcAxKTqDmlB1HaysAuanR6MKjMeh8hEfGoNMUJo4fwz3fvYOhw8fD6dGPIUEmhucNRpc5ig3rN56uTQzqudB1ehVe+9tC/vLEnzm6dy0Ado9CeWkVoyaMOmfbqLAIvD53YJvOVjIy48U1MACIYNmHB1j0zmJsnaeYkJPEbXd+D7+i4PPL+L1e9JIOo8GIRW8GNZCr8AvVjd3s2rKBsRMLqGnqoLOtnauumMuJ+g4amzpICgkhY9hQDhytoaHsIPlTJnK0rAKn04mqafi8PnxeH5qmomkwKD6cyIwRxBp8XHnb95kxaSSSNQ5bbycnj5zgskumiz+iAUDTwOf14fX58J/ODHLJhDyC8i7hkw8X4XY7UWU/VmsQ4RGR+GXwez3ogKgIK1HRSafr0ejuseHxevG3tzB0WE6gbp8Xr8+LKst9jixcKEINOi6dM51rr7+O1JzRAFQ0d5GkNGGNzwPA4/Xh93uZMHkSDqdGt60bb1c9E+bO71Ob0B/EaNg+JKC8op7SI0c4VlpNhNzO9d+9m3W7Kjh+cCc6g56T9W0cWLuSB++/mZyJlwMSPg2eef1jNq/6gC1bt3N0zyZmTcxn1IQpHDh2ktLCPXz/htnoE/L5/R8XULRvEytXrsFVV8yMWXNoccCm1Ztxd9Uzdnw+HsnKe5+swF1XzA/uuQtrdAqRFj3GuBxWL/uE7CiJa269E/Tmvj9B+Ib1uP2sW7OS1oY60jOSSRuUQ5BRz7xLZ1NY2UTx3r2cPFWH19bI/CuupKi6l+I92wjT+xk9Ig+dJdANv2pjIZK9miMtLoZEaVx1+/dx+CQ2rl1He2Mtwwaf+25LuHAYdBJxcTEkJSURHBoBwMHSRsblhhKTnAPA+8tWILeVM2XSJDrlSLZuXMnEvFSmXHadGAU9AIh5loIwQNz90NP8dLLGmFt+1bdIEIR+JrphBWEAUIHEKCPBaRl9iwRBGABEy1IQBEEQzkO0LAVBEAThPESwFARBEITzEMFSEARBEM5DvLP8JxRVDWQEMOgBCUVRgUD6JACDXgfSPz5rqKoKmoZO/+VQb1XT0FQV/VmfKYqCTuKcrCWaqoF0bnonWVHQSxKS7stjyYqCXichfcXxhf6lAepZKzGhaSBJaJqGQa8/k1D8iyJNU9GddW4VRUVVZSQkDEbjmc+Fi4umaWfuKZIkodfpzrk2vuqeIfQvESy/gtcvU1h6An1PK7l5uViCIzhS00xPYxV6owEDkDsomfjULPTGL5ep8ssKxSUn8HefomDSBMzB4SiqRlVdE91NtRSMG43RFIzd5eNQURHRJoUhY8ZjMJqQNY2qE3VYTQqpg7IA6PH5OHSwkNQIC4NyR6I3GHB6/RQWFTM4MYLE9KxzgqjQ/1w+lUPFx7B3nCImIhS/pqPX7iDYqGfS5DGYgqLObNvY3o2tqZ68oYPBGIyqaWzbU0x3YzkhOh1z5s/FEBx9Tv3CxeFUSxfHSoqQtMBD8+TxBVgjYuF0qr+Kuhbaq44yZvQwQmKSxOIjA4C40/ahAs+8vYLO4xsIS8lgwYvv0l66i/DoWBa8+Bo6dyMxmTn834K/s/HT189Zs3Hl9iNsWvURC974hGd/+wtUv4fdR2vZvPwDGp0uFr3+Gn6Pi0VL17Fj81p+9tunWbPwOdAUmju7+eNbH7L+07cA6PHKvPXqOwTp/CxcX0jhxiX4ZJWXXvkAST7FWwtXc6qy8KxvLgwERr2EVxfKgieeJCbIgT4yhcd++1f0jhb0xuAz2/lUjVXb9/L8H38HjhYAKlvsfPzOS+SPHsbq4x1s+vjds2oWLhaqBlsPlrBv5w5KSk+w6O136WmtPVN+oqmbtWtW8u6ytTz3+P+ieuzn7C/0DxEs+/ACm5evJsaiJycthbu+fxcGaxzJSeEER4URH5XAiKw0xlx6LYsWfXp6gbxAyBwcY+Hh3z/OU6++xMbiJjyNJSz8dBU5sRZmzZrH6qIqakr2MGvcMB557I/c9evfs2btNvB2kxoTxfCC0Xi9gfq2HqzCUXuYSZPGMeOyG/jo40/ZUlzJif0rmD59PsbBBSx5580+317ob0a9REZaAsHBZtLyMklMSSUoJJxBGQnoDV+u42vSSYwtGIdfsZ5ekRhOtHdixsegrBFEp6RjDhKrM12MVE3lypkFPPb449x6zwPMunQ20QlpZ8pTI4384kd38ctHnsIYk4nf6zxnf6F/iGDZhwW44s7v8IOH3+D5P/2GxDCVxLx8vF4NCYlem422zm4KN61h2qSxQOCGJgEj8ocG/l3xM3rkMLS4DMoOHiY9KZ4gI+iNBrp7u8gdEuhmteo18sdPBWP4mTq+eH+lqgq19S3Ijl6SokKwe/0cLi4kyqADdORmxlN6sgkQ64UONIqioNPpUGQFRZbR6b545/2PAu+kAl1smqbh1yQOFh+iqXgvuSOH991cuICpqoqqquglicjQwBKHJ46VYTWZsYQHumABQq2hOGUDmz5dyIhBaZjCviwT+o8Ill/hF7fP4tn3l7CqqJ7bb76e1upDGA0SPkXPvsJiVm7YiOI4hdEaguwKpNz6gqxqHNh/iIe+ezlScBya4j0zYEdRNTQ1kFLL5lOwNdZwxy3Xgv4fB3LMGDuUuJGT2bxpNes2rifcakCvj0BCBQIDRlRVFcHyAvSvhgkYJI0xI/OZfuVVvPLqeyCLVsXFwKtqnKio4WhJCd1tpwBQNCivrmJYWuQ/3IrrWnspb2nhqedeoruh7JwyoX+IYNmHG6gpLuGSCbmsWvEJwYMvZdOqTzHpNcx6hSsuncU9t93Mz554jQXPfUBT6ZcpuvyyQvHxOnKiJJJHz8KgqqQNHUJHtw23rKApMnGxKXh9fg7uKWHmuFyCk4agaVrgzeeZd/gaMcESTzz6v0QMmkjJvt3cfM1V5A4bglsyoigKDc1dZKQkiBRdA1Dg4UhD0klIkoSmgU6SUFUVWVFoamoPdNyffojSdGcP3tDQ63QkxCbR3tYKvp6zyoQLlc2vsnLdZj7+6GNOlh4AoMvhpaXyBDkF4+B0y1PTVFRNIy8lglf//DCp4+bT3RZ4py30LxEs+9CAj5as58jBnbRWVTF5RBZZQ0ZS09hBR2sbZRVVnDhRxd6165gyLpe49Gw4PTBoxbZiPv3odTocTpYuXUJjTSXfveUqiqo62bNjH1Ny00gcPppX3l9J0YFVVJ5qZcknH2Hv7cblUWiub6G5qQWv245XVqmqqqGipp7pw1OZeOXtzByTRWTGaIqK9tF6pJDb77y179cX+pmsapysb6K9o4u6ypPU19XS3dVGRU0dJ2tr2bzrAGXbPwUkmhubaW1ro+1UoKUhSRI9vXZqaiopOXKAGTNnQFBi30MIF6AYk56Hfvw9Hv3DY4yadjUAhVXNjE5Q0FsDKdpO1NTR3lxHfXMH+w8WcazqJNfPyCMxa2Sf2oT+IFJ09aEHQsPCaW/roqfXQW5yGBPmXkNFVROxIWaiYuNxuv3o7K3c/9MfEpoQSK8ja3Do8DG8tg4aGk5h9DuYOn40OUNycWHG09nMrTdegc8QS3HRQTwOO7V1taSHGxhZMA6bV8Pd0UF8fDTZ2RmoumAKS0rJDFW54sbbQDJg0cGgEWMpLTnMzIIs8sbP6fv1hX7mk6G2tp6UhBgiQ6LxqwqpidGExCTglWUa6uqZNimf4Kgkmk81EhUTSnxcPDHJGZxos3F06zpyhw4h1GDghttuBp0Y5HMxkCQwGAwYDAZ0p+dW221uRo/KISg0MJ2o8GgpwZqDNreBsiNFRFqNTJo0CWtEXJ/ahP4g5lkKwgCxaPcJDrz9GC+881HfIkEQ+pnohhWEASI7JoJrrr7hnLm7giAMDKJlKQiCIAjnIVqWgiAIgnAeIlgKgiAIwnmIYCkIgiAI5yHeWX4FRVXx+/3oTqdWMhkNyCr4vB4MBj2gQ9NUzGbTOWmyFFXD6/GgqQoWixm9wYimgd/vQ9M0jAY9Or0Bv6zg83qQAEuQBZ1Oj6ppeD1eDHoJoykwXcAvK6iKDGiYjCYknQ5ZUVFkP5IEJpNJZCMYYDTA5/ViMhnPXBten4zf58FsMmIwmnB7vEiagtliwa+oSKqKompIaEh6PZKmYjCa8Hi9aIqCxWw6J7uNcOFTVQ2/7AdNQ6+TMPQ5v35ZRlUUdDoJozj3A4KYZ/kVNu4rZfnn73Kqrp5dm7eREm5gc1knD/3oXpzdJympaGbNZ5+SnWwlPDblTMA6XNHCE4//gXdffYl4s4us4aOp73Sx+KNF7N6/H5Org8T0TFbvKOGJP/6e1R++x7BBccSkZFHb3sHDf3oFV9UBRk6Yik/RWLp+Fzt2bGD7tu0Mig0lJDqeVVuL2LJhCUeLihk6OBVjUGCNSWFgaHPKPP/kkwzNjMEaEYeiwhufbuFXD9xHgsVFQmYu9/x6AYdWvcOQ0fks3rSL8sKdvPr3JRzYvJS6dhfVRRvBEsUTT73IOy8+R4Sul8EjRiPpDH0PJ1ygDlecYumnizl6rJhT1UXk5Oah0weColtW+XTZRrZv30BteSlDhmShN4qVuvqb6Ibtwws8+9eXuWVcBnfc/l3Sx0zG22tjzsxRBMXGMHPCRH58751IWdN54pFHTu8RWMGnua6al/76G37wh1dZ8MoiPF0neHfxGmKVDm65615een8NTTVHCVI9fPT+66TPvps3Xn4e/HYy42JJHj6Sro5GAPaUNlK+dTEP3nc7qWOv5v03nqe0qYdlbz7H/T/8HrX+ZFZ++Hqfby/0t4rKet55/zOO7l4NgF4Hcy+fRmh0KNNmX05Vi53ZQ6P504IFJCTncsW06XzvnvuJSB5Edmo0P7r7O8y67EZOnmzm2Ucf4oE/v8kL7yzBfqq476GEC9ia9ZvItnq59b4fUnyklp6mujNlGwurKN+8iJ/c/0P2lLZRtGXpOfsK/UMEyz70QHLOcH7+6Csc3rWWy6aMJGXMDGSvhsFgpKfXRkdHJ5LsJCY+EQg87UvAlXMmYQ6NY2J+BvFZY1BkHdu37CRvUApR4UF4TXqaGxq4ZO5kJH0Q0yaNJDQh90xPqsWkx2AM1NfY0kFPeyeyqmPi6DxOtvWyces2QvVu9IZQho/NY9f+ktNhWhgIfIpGY101P/vtr/lkxS5UOZCHUFM1jCYzO/aXUb5jFXd/5zosUemY9ZCeGAOAXqc7s7JLYnoWV18xm6DIREYNSSYldzx6neiKu5jkDh/JG0s28MlrLzJ1TD6RyYFMRACH9+8nLiEUo95MVFoeh3dtPWdfoX+IYNmHAXjpyQfInnErt97zS57/w4Mong4kScKn6Dh85BirNm1j12dvM3PqJDQ1EOkkAL0eTYO9RaV8/4p8iM/D19WBNdiMHtBk8Hp7AAm/qnGqupzbbrgSDGF9vwZjh2bQokWwY+0yCg/uRY+K2+UnWC8BEkEmA3a780zLVuh/x+o7CLNXc/ddt1HRbabmwFoAdDqJHq/Kn194CZOnAb31/Ou9SnodmgaHj1Vy04yhWFNH991EuICoGrjdHlwuF7Lfx5zxIxg8aR7vvv0BFp3zTBcsgMPrxmQOJAo3W6w0NfWIhSoGABEs+/ABdHXw1CM/5b1lq/hkbztblv0dsxksBpXL583ie7fewH2PPMOfFrxE64l9Z/ZVNahptmOwNTL7pjsxaBqhCYk4HB58moaCQnhoLLKqcai8maFJIQyZNPfLlE1njdXJTY7g0ccewRSZyNbNO5k5bihJqdl4VD1oGp09TqKjws/k0xT6l6pp7Nyyjza3m13rV2ONjufz5RtAU9DQERmk44c/+AGvLzvOkjeewOf1nHMDlDi9gOiZ+qCu3YXSWc/lt9z6L9N6CQNfi1fm/x5dwP3338/OdYv4fNUGbh6TxCMvLeTJV5fRUVt8+hxrRIdF4vW7AQ1nbycZGfFiIN8AIIJlH37gnb99TOvJcibkpnHt9TehSjo0WcHj9uFwu/H7/Vh0JsCAdNY9rLSum5XLPiYzKZyS41XYOju44up5HK1pora2g7TwEIbkDWdzYR3Hdn1OfHIChw4fwu1yoWoasldFlmU0TUXTICc9AbcphWSLh2vuuJ9ZE4fjC42jp72RqpIyrr5stjiFA4AGHDnZRrJUzQ033smMGTP42S8fYu3OcrpPHgLA7XRzy+x8nn7nPZ75tIjXn/glzu5WQENRNTx+Bb/Hi6YGutUrTvWyfMmHpCdaOVLeQEtrc5+jCheSOJOe3/zyfv7yl78weuZ11Da24HZ2cvnEwYyaNhOX10dndw8OWxeTJk+ku1uhs7sDX+dJplx+Td/qhH4gRsN+hfqGFjraG6moaiTW5OLyK69j97EmGiuPYzabaevoomzPHu69+zqGTLwEkPCq8PFnazlZsoOK+nZqSw8zKjeTUQXjOXGqk8bqY1w/dzKmlOH8/Z236Wquobi0CtepCkaPH0eHQ6No30HwdDN8xFB8koVVG3fiaynjO7dcS0hcGhFBekJistl3YBeDgmHejbeg04uWZX/zyirLlqzB6+hgwuSJBAWH0dBm4/DxE+i8DtrdGl2NDUSHGBk/ahidWih7t24m2KCQlzeYE80uSg7tR+f3MiwnHVNYDIs/30Dl4W1UNXRQXVLIyJxMwmPP330rDEw6SSLEGkxoaCgWs4W45ETK6k5RV3uKscOTGZI/kR0HjqBzNDN2dD5uQyyHDu2lICuJ8TMvEyOhBwAxz7IP7XSHh8sr4+jpIC4+BjDQ1WvHYpBwef0oPi/REaEYLNYz+ykauB02NPSoqozZaMASHAxI+BQNn7OXkLAI/LKGx9ULkgFVVbAGmTCYgvD4ZXxuJ5oGwRYT6M3Ye3uJio485/sBdHXbiIq0nh6OJPQ3RdNw2BygKYSEWNEbjNicHkw6BbdXRlVULBYTfr+PEGtIYI6twYTH7SYyzIrdq4HsQkGP1ShhCArBabehSXpURcFk1BEUbBVdcRcZt1/BbesiKjo28N9eLwaJM/Ose7p7iIiM6LOX0F9EsBQEQRCE8/ivB0tN01BPv4cRBEEQhH9GkiR0uoE5DuO/Hix7enqoqKgYsP8DBEEQhP6nqipJSUmkpKT0LRoQ/uvB0mazUV1dLYKlIAiC8E9pmkZ8fDyJiQNzINt/PVgKgiAIwoVONPcEQRAE4TxEsBQEQRCE8xDBUhAEQRDOQwRLQRAEQTgPESwFQRAE4TxEsBQEQRCE8xDBUhAEQRDOQwRLQRAEQTiP/w9xbfMluVVrjgAAAABJRU5ErkJggg==\\\"\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDocking results of available proteins with small molecules.\\u003c/p\\u003e\\n\\u003ch3\\u003e3.6 Single-Cell Sequencing\\u003c/h3\\u003e\\n\\u003cp\\u003eIn this research, we made use of the PanglaoDB platform to conduct a comprehensive analysis of the expression levels of core genes within peripheral blood mononuclear cells (PBMCs). Furthermore, we specifically selected datasets associated with PBMCs to perform a detailed single-cell RNA sequencing analysis. This approach allowed us to delve deeper into the gene expression profiles at the single-cell level, enhancing our understanding of the functional roles of these core genes in PBMCs.The results showed that the IL1\\u0026beta; gene was significantly expressed in T cells, dendritic cells, Langerhans cells, and gamma delta T cells, with the highest expression in T cells, suggesting that IL1\\u0026beta; is involved in immune regulation and inflammatory responses. The TGF\\u0026beta;1 and SHH genes were highly expressed in dendritic cells and T cells, indicating their critical roles in oxidative stress and inflammatory responses. The SMAD2 gene was significantly expressed across various cell types, with the highest expression observed in gamma delta T cells. The AKT2 gene was significantly expressed in platelets and gamma delta T cells, suggesting its potential roles in cellular survival, apoptosis, and metabolic regulation. The TNFRSF1\\u0026beta; gene was significantly expressed in all cell types, with the highest level observed in T cells. The G6PD gene was significantly expressed in T cells and platelets, suggesting its involvement in immune regulation and oxidative stress processes (Figures 8, 9, and 10).\\u003c/p\\u003e\\n\\u003cp\\u003eThese results further elucidate the roles of these genes in the pathogenesis of OSA and provide valuable insights and theoretical support. Firstly, most potential targets are highly expressed in T cells and dendritic cells, indicating their critical roles in immune regulation, oxidative stress, inflammatory responses, and metabolic processes, thereby promoting the onset and progression of OSA and its related complications. Meanwhile, some genes are significantly expressed in platelets, suggesting their potential involvement in the development of cardiovascular diseases, which is consistent with previous clinical studies.\\u003c/p\\u003e\"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cp\\u003eUnder specific conditions, the plasma proteome demonstrates notable stability, significant variability, and predictability, thus establishing itself as a crucial resource for research concerning obstructive sleep apnea (OSA). Various studies have documented these characteristics, highlighting the plasma proteome\\u0026rsquo;s relevance in understanding the complexities associated with OSA. Despite the inherent individual differences in plasma protein profiles, the application of robust statistical methodologies in extensive studies has effectively reduced variability, which in turn aids in the identification of key proteins that are associated with OSA. This understanding is particularly vital for improving both the diagnosis and the overall comprehension of OSA.In the course of this study, molecular research analysis methods were employed to pinpoint 62 potential therapeutic targets within the plasma proteome related to OSA. To ascertain the biological significance of these identified targets, enrichment analysis and protein-protein interaction (PPI) network analysis were performed, facilitating the identification of core genes associated with OSA. Additionally, drug prediction and molecular docking studies were conducted to explore potential therapeutic options. The validation of the therapeutic potential of these identified genes was further enhanced through single-cell sequencing techniques. The results of these analyses indicated that most of the predicted drugs operate through mechanisms that are anti-inflammatory, antioxidant, and related to immune regulation\\u0026mdash;key processes that play a fundamental role in the management and treatment of OSA. Consequently, these findings not only broaden the clinical applications of existing pharmaceuticals but also lay a theoretical foundation for their prospective utilization in the treatment of OSA.\\u003c/p\\u003e \\u003cp\\u003eAmong the identified core genes, IL1β, a key pro-inflammatory cytokine, is a core member of the interleukin-1 family and plays a pivotal role in immune regulation and inflammatory responses\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn20\\\" id=\\\"#FNLinkFn20\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. Intermittent hypoxia (IH), a clinical characteristic of OSA, activates the inflammasome (NLRP) via the ROS/TXNIP/NLRP3 pathway, promoting the maturation and release of IL-1β and IL-18. This further stimulates the secretion of other pro-inflammatory cytokines (IL-6, TNF-α, IL-18), exacerbating systemic inflammation. Concurrently, IL-1β acts on neuronal IL-1 receptors, impairing hippocampal synaptic plasticity and leading to cognitive dysfunction\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn21\\\" id=\\\"#FNLinkFn21\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn22\\\" id=\\\"#FNLinkFn22\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.TGFβ1 is a multifunctional factor that plays a significant role in metabolic disorders, inflammation regulation, and fibrosis associated with OSA. TGFβ1 is closely associated with the occurrence, progression, and prognosis of OSA\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn23\\\" id=\\\"#FNLinkFn23\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. It promotes the generation of reactive oxygen species (ROS) by upregulating NOX4 expression, leading to oxidative stress damage. Meanwhile, elevated levels of TGF-β1 in peripheral blood reduce Treg cells and suppress Foxp3 expression, while increasing Th17 cell counts and associated inflammatory factors (IL-17, IL-6), thereby exacerbating the inflammatory response\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn24\\\" id=\\\"#FNLinkFn24\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn25\\\" id=\\\"#FNLinkFn25\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.EGF is a small-molecule polypeptide, and intermittent hypoxia (IH) can elevate EGF levels, promoting the release of inflammatory factors (ICAM, IL6)\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn26\\\" id=\\\"#FNLinkFn26\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. SHH primarily participates in the pathophysiological process of OSA-related complications through the activation of the Hedgehog signaling pathway. IH can induce hypoxia-inducible factor-1α (HIF-1α) to further activate SHH, promoting epithelial-mesenchymal transition (EMT) and accelerating disease progression. Moreover, it is positively correlated with liver injury markers (AST, ALT) and fibrosis markers (α-SMA, K7)\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn27\\\" id=\\\"#FNLinkFn27\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.SMAD2 is a transcriptional regulator that promotes the development and progression of OSA complications by participating in metabolic regulation and tissue fibrosis\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn28\\\" id=\\\"#FNLinkFn28\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. Adipocyte-derived exosomes under OSA upregulate long non-coding RNA, suppress miR-455-3p expression, and subsequently activate the SMAD2 signaling pathway. This leads to the accumulation of fat, triglycerides, and cholesterol in hepatocytes, exacerbating liver damage in metabolic-associated steatotic liver disease (MASLD)\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn29\\\" id=\\\"#FNLinkFn29\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.In cardiac perivascular fibrosis, the IH conditions of OSA promote endothelial-to-mesenchymal transition (EndMT) by activating the SMAD2/3 pathway, manifested by enhanced endothelial cell migration and increased collagen secretion, resulting in vascular endothelial remodeling\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn30\\\" id=\\\"#FNLinkFn30\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. NTRK3, a gene encoding tropomyosin receptor kinase, currently has no direct research linking it to OSA. However, NTRK3 regulates pathways related to oxidative stress and inflammatory responses and enhances the activity of antioxidant enzymes, thereby mitigating oxidative stress and inflammation-induced damage\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn31\\\" id=\\\"#FNLinkFn31\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.G6PD is a key enzyme in the pentose phosphate pathway, primarily responsible for producing nicotinamide adenine dinucleotide phosphate (NADPH). NADPH plays a vital role in cellular antioxidant processes, particularly in red blood cells\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn32\\\" id=\\\"#FNLinkFn32\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. Oxidative stress damage is a hallmark of OSA, and G6PD deficiency reduces NADPH production, rendering cells more vulnerable to oxidative damage\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn33\\\" id=\\\"#FNLinkFn33\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. Currently, no studies have directly linked TNFRSF1β, AKT2, or CTSG to OSA. However, these genes are critical regulators involved in oxidative stress, inflammatory responses, and immune modulation. Thus, we hypothesize their relevance to OSA and regard them as potential therapeutic targets for OSA\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn34\\\" id=\\\"#FNLinkFn34\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn35\\\" id=\\\"#FNLinkFn35\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003e3,4-DHB, BIM IX, and SB 202190 are potential therapeutic agents for OSA that can improve OSA and its complications by modulating inflammatory responses, oxidative stress, and apoptotic processes. 3,4-DHB, a natural phenolic acid compound also known as protocatechuic acid (PCA), can inhibit oxidative stress and inflammatory damage by targeting and regulating the MAPK signaling pathway. Animal studies indicate that PCA scavenges free radicals (DPPH and ABTS) in SD rats, reduces IL-1β levels in the brain, and suppresses excessive microglial activation, thereby alleviating neuroinflammation induced by CIH\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn36\\\" id=\\\"#FNLinkFn36\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. PCA upregulates the expression of brain-derived neurotrophic factor (BDNF) and synapsin (SYN), enhances synaptic function by modulating the MAPK pathway, and repairs synaptic ultrastructural damage caused by CIH\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn37\\\" id=\\\"#FNLinkFn37\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.BIM IX is a protein kinase C (PKC) inhibitor that regulates downstream signaling pathways (MAPK and PI3K/AKT pathways) by inhibiting PKC. Intermittent hypoxia (IH) activates the ERK/PI3K pathways via PKC, promoting IL-8 expression in monocytes and exacerbating inflammatory responses. BIM IX can alleviate OSA-associated systemic inflammation by blocking this pathway\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn38\\\" id=\\\"#FNLinkFn38\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn39\\\" id=\\\"#FNLinkFn39\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.SB 202190 is a p38 MAPK inhibitor that blocks the activity of p38 MAPK, thereby suppressing the production of inflammatory cytokines\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn40\\\" id=\\\"#FNLinkFn40\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. Although no direct studies have explored the application of SB 202190 in sleep apnea, its ability to suppress inflammation and regulate cellular immunity suggests it might be a potential therapeutic agent for OSA. All three drugs have demonstrated their potential in inhibiting the MAPK signaling pathway, which is consistent with previous KEGG analysis results. The results obtained from molecular docking studies demonstrate that the compounds 3,4-DHB, BIM IX, and SB 202190 exhibit stable interactions with their respective target molecules. The calculated binding energies for these compounds fall within the range of -4.7 to -8.0 kcal/mol. This range of binding energies not only highlights the affinity of these compounds for their targets but also reinforces their potential role in the intervention of obstructive sleep apnea (OSA). This intervention is believed to occur through the modulation of antioxidant and anti-inflammatory pathways, which are crucial in mitigating the effects associated with this condition.\\u003c/p\\u003e \\u003cp\\u003eTo sum up, the drug targets revealed in this research are strongly linked to OSA and show considerable potential for therapeutic applications. These results endorse the creation of OSA therapies that focus on particular molecules and offer essential theoretical and practical groundwork for the advancement of upcoming treatments.\\u003c/p\\u003e \\u003cp\\u003eWhile this study has achieved substantial advancements in its findings, it is important to acknowledge specific limitations that still exist. One major limitation is that the study population primarily comprises individuals of European ancestry. This concentration may restrict the extent to which the findings can be generalized to a wider population. To ensure that these results are truly applicable across different demographics, additional research that includes a more diverse array of ethnic groups is essential. Such investigations would help verify the applicability of the findings beyond the current study's demographic scope.This study does not include severity stratification analysis of OSA, which may introduce a certain degree of confounding bias. However, the elevated expression of key genes (IL1β and TGFβ1) in peripheral blood mononuclear cells and their strong association with the MAPK signaling pathway are closely linked to the pathological characteristics of OSA\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn41\\\" id=\\\"#FNLinkFn41\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. These findings indicate that these genes play pivotal roles in the pathological mechanisms of OSA. Future research should validate the specificity of these targets in well-defined patient groups with varying severity and further investigate their regulatory differences across different degrees of OSA.\\u003c/p\\u003e \\u003cp\\u003eMoreover, although this study did not include severity stratification analysis, single-cell RNA sequencing reveals that the elevated expression of core genes (IL1β, TGFβ1, SHH) in T cells and dendritic cells is closely associated with mechanisms involving inflammatory responses, immune regulation, and oxidative stress\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn42\\\" id=\\\"#FNLinkFn42\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn43\\\" id=\\\"#FNLinkFn43\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eThe findings of this study indicate that the identified genes may collectively contribute to the pathogenic processes underlying OSA, with their influence manifesting in varying degrees of severity across different cases. It is clearly important for future research to incorporate subtype classification data, as doing so will provide a deeper understanding of the specific roles these genes play and the mechanisms through which they operate in distinct pathological scenarios.While significant efforts were undertaken to reduce bias in our analysis, it is important to note that MR analyses are still susceptible to the effects of unmeasured confounding factors or the phenomenon of pleiotropy, where a single gene impacts multiple traits. To address the robustness of our findings, we employed a range of sensitivity analyses. The research strategy employed included MR-Egger regression analysis, weighted median and mode methods, Cochran's Q test, and MR-PRESSO pleiotropy detection techniques. Although these methods have been extensively validated, the study should recognize a limitation, namely the absence of external validation using datasets independent of the current study (UK Biobank data). To enhance the credibility of the study's conclusions, conducting repeated analyses using independent pQTL datasets is crucial. Future research should focus on integrating resource-rich and high-quality datasets to comprehensively validate the preliminary findings of this study. Additionally, the precision of protein-ligand molecular docking relies on the quality of their structural models. While single-cell sequencing offers valuable insights, its inherent limitations\\u0026mdash;including dataset selection biases and variability in analytical platforms\\u0026mdash;can lead to an incomplete picture of certain cell types' phenotypic and functional profiles. Although promising drug targets have emerged from this research, their real-world effectiveness remains unproven and must be rigorously tested through both preclinical studies and clinical trials. Additionally, chronic kidney disease (CKD) has been shown to dramatically reshape the plasma proteome's composition, introducing further complexity to biomarker discovery and therapeutic development\\u003csup\\u003e[\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn44\\\" id=\\\"#FNLinkFn44\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e][\\u003c/sup\\u003e\\u003ca class=\\\"FNLink\\\" href=\\\"#Fn45\\\" id=\\\"#FNLinkFn45\\\"\\u003e\\u003c/a\\u003e\\u003csup\\u003e]\\u003c/sup\\u003e. The lack of consideration for CKD during the data filtering process in this study may potentially impact the results. This oversight highlights a significant limitation in the current research framework, as CKD could influence the outcomes related to OSA. To enhance the reliability and validity of future studies, it is essential to address these limitations comprehensively. By doing so, researchers can improve their understanding of OSA, its underlying mechanisms, and the effectiveness of various therapeutic strategies aimed at managing this condition. This approach will ultimately contribute to more accurate conclusions and better clinical practices.\\u003c/p\\u003e \\u003cp\\u003eBased on the findings and limitations identified in this study, we put forth a series of recommendations aimed at shaping future research endeavors in a more fruitful direction. To begin with, it is crucial to enhance the generalizability of our results by incorporating study populations that represent a variety of ethnic backgrounds and geographic regions. By doing so, we can better validate the applicability of our findings to a wider range of patient groups, allowing for a more comprehensive understanding of the issues at hand.In addition, future research should consider the integration of multi-omics data along with environmental factors. This multidisciplinary approach will enable investigators to delve into the molecular mechanisms of obstructive sleep apnea (OSA) from a more holistic viewpoint. By incorporating various biological data types, researchers can uncover intricate relationships and processes that may not be evident when examining singular aspects of the disease. Furthermore, employing higher-resolution structural biology techniques and molecular dynamics simulations can enhance the precision of molecular docking analyses, thereby producing more reliable and meaningful results.Another promising avenue for future investigations lies in the combination of spatial transcriptomics with single-cell multi-omics technologies. This integration will significantly bolster the comprehensiveness and accuracy of data interpretation, allowing for a finer resolution in depicting the functional characteristics of distinct cellular subpopulations involved in OSA. Such detailed insights are vital for advancing our understanding of how various cells contribute to the overall pathology of the condition.Moreover, it is essential for future studies to validate the targets identified in this research through a variety of approaches, including laboratory settings, animal models, and early-phase clinical trials. This multi-tiered validation process will help determine the clinical applicability and safety of the identified targets, ultimately paving the way for potential therapeutic advancements.Finally, we recommend that future study designs take into account kidney function-related parameters and actively exclude patients with CKD. This step is critical for minimizing potential confounding effects that could skew the results and lead to misleading conclusions. In conclusion, by adopting these proposed strategies, future research efforts are anticipated to deepen our understanding of the pathogenesis of pulmonary fibrosis (PF), broaden the array of possible therapeutic interventions, and, most importantly, enhance patient outcomes.\\u003c/p\\u003e\"},{\"header\":\"5. Conclusions\",\"content\":\"\\u003cp\\u003eThis study integrated Mendelian randomization (MR) analyses to identify 62 potential therapeutic targets associated with OSA and to screen core genes, systematically evaluating the causal relationships between plasma proteins and OSA. Furthermore, reverse Mendelian randomization analysis identified four key genes associated with OSA, offering new insights into the bidirectional causal relationship between plasma proteins and OSA. The results indicate that these key genes play vital roles in oxidative stress, inflammatory responses, and immune regulation and are predominantly expressed in T cells and dendritic cells. Through drug enrichment and molecular docking analyses, the study identified candidate drugs, including 3,4-DHB, BIM IX, and SB 202190, which demonstrated significant therapeutic potential in anti-inflammatory, antioxidant, immune modulation, and pathway regulation.The findings presented in this study offer significant insights into the treatment of obstructive sleep apnea (OSA), suggesting ways to potentially lower drug development costs while also supporting the creation of more individualized medical plans for patients. Such advancements are vital in enhancing our understanding of the molecular mechanisms underlying OSA, which in turn can lead to the development of precision therapeutic strategies that focus on key genes involved in the condition. However, to fully substantiate the therapeutic potential of drugs that target these specific proteins, additional experimental research and clinical trials are necessary. These further investigations will be essential to confirm both the safety and efficacy of these treatments in real-world clinical environments. In summary, this study contributes new theoretical insights and practical evidence regarding the treatment of OSA, establishing a robust foundation for future research endeavors and drug development initiatives in this field. The implications of these findings could significantly influence the direction of future studies, paving the way for more effective and personalized approaches to managing OSA.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eAuthor Contributions\\u003c/p\\u003e\\n\\u003cp\\u003eConceptualization, L.Z.D.; methodology, H.Q.J and Y.Q.W.; writing\\u0026mdash;original draft preparation, L.Z.D.; writing\\u0026mdash;review and editing, A.H.Z.; visualization, Y.W and S.Y.N.; supervision, Z.F.Y. All authors have read and agreed to the published version of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors confirm that no paper mill and artificial intelligence was used.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAuthor information\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors and Affiliations\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eThird Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, Yunnan, China\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eLingzhi Duan,Yan Wang,Shuye Ning\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eKunming Hospital of Traditional Chinese Medicine, Kunming, Yunnan, China\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eHaiqing Jing,Yanqiong Wang,Aihua Zhang\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eXuanwei Hospital of Traditional Chinese Medicine,Qujing, Yunnan, China\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eZhengfu Yang\\u003c/p\\u003e\\n\\u003cp\\u003eCorresponding author\\u003c/p\\u003e\\n\\u003cp\\u003eCorrespondence to\\u0026nbsp;Aihua Zhang\\u003c/p\\u003e\\n\\u003cp\\u003eThe Email Address of the Corrresponding Author：kmzahys@126.com\\u003c/p\\u003e\\n\\u003cp\\u003eFunding Statement\\u003c/p\\u003e\\n\\u003cp\\u003eThis research received no external funding.\\u003c/p\\u003e\\n\\u003cp\\u003eInformed Consent Statement\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003eConflicts of Interest\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare no conflict of interest.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eL\\u0026eacute;vy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers. 2015;1:15015. Published 2015 Jun 25. doi:10.1038/nrdp.2015.15\\u003c/li\\u003e\\n\\u003cli\\u003eGunta SP, Jakulla RS, Ubaid A, et al. Obstructive Sleep Apnea and Cardiovascular Diseases: Sad Realities and Untold Truths regarding Care of Patients in 2022. Cardiovasc Ther. 2022;2022:6006127. Published 2022 Aug 11. doi:10.1155/2022/6006127\\u003c/li\\u003e\\n\\u003cli\\u003eFranklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis. 2015;7(8):1311-1322. doi:10.3978/j.issn.2072-1439.2015.06.11\\u003c/li\\u003e\\n\\u003cli\\u003eSuhre K, McCarthy MI, Schwenk JM. Genetics meets proteomics: perspectives for large population-based studies. Nat Rev Genet. 2021;22(1):19-37. doi:10.1038/s41576-020-0268-2\\u003c/li\\u003e\\n\\u003cli\\u003eHe Y, Xu X, Lv M, et al. Risk factors of high inflammatory state in pediatric obstructive sleep apnea. Sleep Breath. 2025;29(1):116. Published 2025 Feb 28. doi:10.1007/s11325-025-03282-7\\u003c/li\\u003e\\n\\u003cli\\u003eRasouli S, Alizadeh Severi A, Abdolsamadi M, et al. The Association Between the C-Reactive Protein Gene Variants rs1130864 and rs2794521 and Obstructive Sleep Apnea in the Iranian Kurdish Population. Genet Test Mol Biomarkers. 2024;28(12):485-491. doi:10.1089/gtmb.2024.0395\\u003c/li\\u003e\\n\\u003cli\\u003eWang L, Wang Y, Jiao T, et al. Effects of continuous positive airway pressure treatment on arterial stiffness and inflammatory factors in patients with coronary heart disease complicated with obstructive sleep apnea. J Cardiothorac Surg. 2025;20(1):59. Published 2025 Jan 11. doi:10.1186/s13019-024-03252-2\\u003c/li\\u003e\\n\\u003cli\\u003eEmdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017;318(19):1925-1926. doi:10.1001/jama.2017.17219\\u003c/li\\u003e\\n\\u003cli\\u003eBowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486-496. doi:10.1002/jrsm.1346\\u003c/li\\u003e\\n\\u003cli\\u003eHe D, Che X, Zhang H, et al. Integrated single-cell analysis reveals heterogeneity and therapeutic insights in osteosarcoma. Discov Oncol. 2024;15(1):669. Published 2024 Nov 18. doi:10.1007/s12672-024-01523-x\\u003c/li\\u003e\\n\\u003cli\\u003eCortese R, Adams TS, Cataldo KH, et al. Single-cell RNA-seq uncovers cellular heterogeneity and provides a signature for paediatric sleep apnoea. Eur Respir J. 2023;61(2):2201465. Published 2023 Feb 9. doi:10.1183/13993003.01465-2022\\u003c/li\\u003e\\n\\u003cli\\u003eFerkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet. 2021;53(12):1712-1721. doi:10.1038/s41588-021-00978-w\\u003c/li\\u003e\\n\\u003cli\\u003eBurgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2023;4:186. Published 2023 Aug 4. doi:10.12688/wellcomeopenres.15555.3\\u003c/li\\u003e\\n\\u003cli\\u003eLuo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29(14):1830-1831. doi:10.1093/bioinformatics/btt285\\u003c/li\\u003e\\n\\u003cli\\u003eSzklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D646. doi:10.1093/nar/gkac1000\\u003c/li\\u003e\\n\\u003cli\\u003eYoo M, Shin J, Kim J, et al. DSigDB: drug signatures database for gene set analysis. Bioinformatics. 2015;31(18):3069-3071. doi:10.1093/bioinformatics/btv313\\u003c/li\\u003e\\n\\u003cli\\u003eLiu Y, Yang X, Gan J, Chen S, Xiao ZX, Cao Y. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res. 2022;50(W1):W159-W164. doi:10.1093/nar/gkac394\\u003c/li\\u003e\\n\\u003cli\\u003eFranz\\u0026eacute;n O, Gan LM, Bj\\u0026ouml;rkegren JLM. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database (Oxford). 2019;2019:baz046. doi:10.1093/database/baz046\\u003c/li\\u003e\\n\\u003cli\\u003eMeliante PG, Zoccali F, Cascone F, et al. Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea. Int J Mol Sci. 2023;24(6):5478. Published 2023 Mar 13. doi:10.3390/ijms24065478\\u003c/li\\u003e\\n\\u003cli\\u003eDinarello CA. A clinical perspective of IL-1\\u0026beta; as the gatekeeper of inflammation. Eur J Immunol. 2011;41(5):1203-1217. doi:10.1002/eji.201141550\\u003c/li\\u003e\\n\\u003cli\\u003eD\\u0026iacute;az-Garc\\u0026iacute;a E, Garc\\u0026iacute;a-Tovar S, Alfaro E, et al. Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2022;205(11):1337-1348. doi:10.1164/rccm.202106-1445OC\\u003c/li\\u003e\\n\\u003cli\\u003eLi C, Zhao Z, Jin J, Zhao C, Zhao B, Liu Y. NLRP3-GSDMD-dependent IL-1\\u0026beta; Secretion from Microglia Mediates Learning and Memory Impairment in a Chronic Intermittent Hypoxia-induced Mouse Model. Neuroscience. 2024;539:51-65. doi:10.1016/j.neuroscience.2023.12.006\\u003c/li\\u003e\\n\\u003cli\\u003eCubillos-Zapata C, Troncoso-Acevedo F, D\\u0026iacute;az-Garc\\u0026iacute;a E, et al. Sleep apnoea increases biomarkers of immune evasion, lymphangiogenesis and tumour cell aggressiveness in high-risk patients and those with established lung cancer. ERJ Open Res. 2024;10(1):00777-2023. Published 2024 Feb 19. doi:10.1183/23120541.00777-2023\\u003c/li\\u003e\\n\\u003cli\\u003eHan S, Huang J, Yang C, Feng J, Wang Y. The histone demethylase KDM6B links obstructive sleep apnea to idiopathic pulmonary fibrosis. FASEB J. 2025;39(1):e70306. doi:10.1096/fj.202402813R\\u003c/li\\u003e\\n\\u003cli\\u003eShen C, Zong D, Peng Y, Zhou L, Liu T, Ouyang R. Effect of continuous positive airway pressure treatment on Th17/Treg imbalance in patients with obstructive sleep apnea and a preliminary study on its mechanism. Sleep Breath. 2024;28(3):1231-1243. doi:10.1007/s11325-024-02997-3\\u003c/li\\u003e\\n\\u003cli\\u003eYang Y, Somani S. Impact of obstructive sleep apnea on the expression of inflammatory mediators in diabetic macular edema. Eur J Ophthalmol. 2023;33(1):415-420. doi:10.1177/11206721221099247\\u003c/li\\u003e\\n\\u003cli\\u003eSundaram SS, Swiderska-Syn M, Sokol RJ, et al. Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity. Hepatol Commun. 2019;3(7):883-893. Published 2019 Apr 17. doi:10.1002/hep4.1354\\u003c/li\\u003e\\n\\u003cli\\u003eZhang GH, Yu FC, Li Y, et al. Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition. J Am Heart Assoc. 2017;6(10):e006680. Published 2017 Oct 19. doi:10.1161/JAHA.117.006680\\u003c/li\\u003e\\n\\u003cli\\u003eYang L, He Y, Liu S, et al. Adipocyte-derived exosomes from obstructive sleep apnoea rats aggravate MASLD by TCONS_00039830/miR-455-3p/Smad2 axis. Commun Biol. 2024;7(1):492. Published 2024 Apr 23. doi:10.1038/s42003-024-06171-z\\u003c/li\\u003e\\n\\u003cli\\u003eZhang GH, Yu FC, Li Y, et al. Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition. J Am Heart Assoc. 2017;6(10):e006680. Published 2017 Oct 19. doi:10.1161/JAHA.117.006680\\u003c/li\\u003e\\n\\u003cli\\u003eDing X, Zuo Y, Liu Z, et al. Recombinant neurotrophin-3 with the ability to penetrate the blood-brain barrier: A new strategy against Alzheimer\\u0026apos;s disease. Int J Biol Macromol. 2025;293:139359. doi:10.1016/j.ijbiomac.2024.139359\\u003c/li\\u003e\\n\\u003cli\\u003eMerzon E, Magen E, Ashkenazi S, et al. The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder. Nutrients. 2023;15(23):4948. Published 2023 Nov 29. doi:10.3390/nu15234948\\u003c/li\\u003e\\n\\u003cli\\u003eLuzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood. 2020;136(11):1225-1240. doi:10.1182/blood.2019000944\\u003c/li\\u003e\\n\\u003cli\\u003eXu F, He Y, Sun Y, et al. The TNFRSF1B Connection: Implications for Androgenetic Alopecia Pathogenesis and Treatment. FASEB J. 2025;39(9):e70553. doi:10.1096/fj.202402832R\\u003c/li\\u003e\\n\\u003cli\\u003eMassoni VV, Silva CMPC, Araujo LDC, et al. Expression of NET markers in experimental apical periodontitis induced in mice. Arch Oral Biol. Published online April 5, 2025. doi:10.1016/j.archoralbio.2025.106255\\u003c/li\\u003e\\n\\u003cli\\u003eYan Y, Guan S, Wang S, Xu J, Sun C. Synthesis and characterization of protocatechuic acid grafted carboxymethyl chitosan with oxidized sodium alginate hydrogel through the Schiff\\u0026apos;s base reaction. Int J Biol Macromol. 2022;222(Pt B):2581-2593. doi:10.1016/j.ijbiomac.2022.10.041\\u003c/li\\u003e\\n\\u003cli\\u003eYin X, Zhang X, Lv C, et al. Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia. Sci Rep. 2015;5:14507. Published 2015 Sep 30. doi:10.1038/srep14507\\u003c/li\\u003e\\n\\u003cli\\u003eAdegunsoye A, Balachandran J. Inflammatory response mechanisms exacerbating hypoxemia in coexistent pulmonary fibrosis and sleep apnea. Mediators Inflamm. 2015;2015:510105. doi:10.1155/2015/510105\\u003c/li\\u003e\\n\\u003cli\\u003eChuang LP, Wu HP, Lee LA, et al. Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients. Int J Mol Sci. 2021;22(21):11396. Published 2021 Oct 22. doi:10.3390/ijms222111396\\u003c/li\\u003e\\n\\u003cli\\u003eAsiedu SO, Kwofie SK, Broni E, Wilson MD. Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm. Biomolecules. 2021;11(5):653. Published 2021 Apr 29. doi:10.3390/biom11050653\\u003c/li\\u003e\\n\\u003cli\\u003eLu HD, Liu ZC, Zhou LY, Zhou J, Feng XR, Wang B. Influence of the TLR4-mediated p38MAPK signaling pathway on chronic intermittent hypoxic-induced rat\\u0026apos;s oxidative stress and inflammatory cytokines in rats. Eur Rev Med Pharmacol Sci. 2019;23(1):352-360. doi:10.26355/eurrev_201901_16783\\u003c/li\\u003e\\n\\u003cli\\u003eZhao W, Zhou L, Wang Y, Wang J, Sun YE, Wang Q. Single-cell transcriptome analyses of PBMCs reveal the immunological characteristics of individuals with phlegm-dampness constitution. Front Med. 2025;19(2):376-385. doi:10.1007/s11684-024-1113-3\\u003c/li\\u003e\\n\\u003cli\\u003eWu X, Li B, Wang Y, et al. Microfluidic Chip-Based Automatic System for Sequencing Patient-Derived Organoids at the Single-Cell Level. Anal Chem. 2024;96(42):17027-17036. doi:10.1021/acs.analchem.4c05111\\u003c/li\\u003e\\n\\u003cli\\u003eSi S, Liu H, Xu L, Zhan S. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome. Genome Med. 2024;16(1):84. Published 2024 Jun 19. doi:10.1186/s13073-024-01356-x\\u003c/li\\u003e\\n\\u003cli\\u003eChristensson A, Ash JA, DeLisle RK, et al. The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome. Proteomics Clin Appl. 2018;12(3):e1700067. doi:10.1002/prca.201700067\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"naunyn-schmiedebergs-archives-of-pharmacology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"nsap\",\"sideBox\":\"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)\",\"snPcode\":\"210\",\"submissionUrl\":\"https://submission.nature.com/new-submission/210/3\",\"title\":\"Naunyn-Schmiedeberg's Archives of Pharmacology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Plasma proteins, Obstructive sleep apnea, Mendelian randomization, Single-cell RNA-seq, Network pharmacology\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6936975/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6936975/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eObservational studies suggest that plasma proteins play a crucial role in the development and progression of obstructive sleep apnea (OSA); however, the causal relationship between plasma proteins and OSA remains controversial. This study conducted a comprehensive evaluation of the causal relationships between 4,907 plasma proteins and OSA by employing bidirectional Mendelian randomization (MR) analysis, network pharmacology strategies, and single-cell sequencing techniques. The plasma protein data used in this study were derived from Ferkingstad et al.'s research (n=35,559), and OSA-related data were obtained from genome-wide association studies (GWAS) conducted on European populations through Finland's biobank (FinnGen). This study utilized multi-omics integration strategies, including enrichment analysis, protein-protein interaction (PPI) network construction, drug target prediction, molecular docking simulation, and single-cell transcriptome sequencing, to investigate the biological mechanisms of identified targets and evaluate their potential applications in drug development. MR analysis identified 62 plasma proteins significantly associated with OSA risk, including NTN4 (p=0.003, OR=1.076, CI [1.024, 1.129]) and TFF2 (p=0.004, OR=1.098, CI [1.029, 1.174]). Further reverse Mendelian analysis revealed causal relationships between OSA and the CELF2, NTRK3, ANTXR2, and MYOM2 genes. PPI network analysis identified 10 core genes, including IL1β, TGFβ1, EGF, SHH, and SMAD2, which participate in critical pathological processes in OSA, such as oxidative stress, inflammatory responses, and immune regulation. Through drug prediction analysis, this study identified compounds with potential therapeutic effectiveness, including 3,4-DHB, BIM IX, and SB 202190, and molecular docking studies further confirmed their high binding affinity to target proteins. Single-cell sequencing revealed high expression levels of key genes in T cells and dendritic cells, thereby confirming the critical role of these cells in the pathological progression of OSA. A total of 62 candidate therapeutic targets for OSA were identified in this study, with 10 of these targets deemed important candidates for clinical trials. These findings not only enrich the understanding of the molecular pathological mechanisms underlying OSA but also offer new perspectives for developing targeted therapeutic strategies to treat the condition. By facilitating the establishment of more precise and personalized disease management approaches, these results are expected to advance the development of therapeutic drugs for OSA and substantially reduce the economic costs associated with new drug development.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Exploring the Causal Relationship Between Plasma Proteins and Obstructive Sleep Apnea: A Study Using Genome-Wide Mendelian Randomization, Single-Cell RNA Sequencing Analysis, and Network Pharmacology\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-02 09:22:40\",\"doi\":\"10.21203/rs.3.rs-6936975/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-07-27T23:21:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-07-22T23:01:13+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-07-16T06:30:03+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"40086350841771952366126917132036707426\",\"date\":\"2025-07-16T05:25:06+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"261318485565956223979697730755311591664\",\"date\":\"2025-07-11T15:21:43+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-06-29T20:34:02+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-06-27T01:40:17+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-06-27T01:38:50+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Naunyn-Schmiedeberg's Archives of Pharmacology\",\"date\":\"2025-06-20T08:26:01+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"naunyn-schmiedebergs-archives-of-pharmacology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"nsap\",\"sideBox\":\"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)\",\"snPcode\":\"210\",\"submissionUrl\":\"https://submission.nature.com/new-submission/210/3\",\"title\":\"Naunyn-Schmiedeberg's Archives of Pharmacology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"9d40455c-6330-4b5e-a0b1-1190b69e9d9b\",\"owner\":[],\"postedDate\":\"July 2nd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-02-23T16:03:32+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-6936975\",\"link\":\"https://doi.org/10.1007/s00210-026-05087-1\",\"journal\":{\"identity\":\"naunyn-schmiedebergs-archives-of-pharmacology\",\"isVorOnly\":false,\"title\":\"Naunyn-Schmiedeberg's Archives of Pharmacology\"},\"publishedOn\":\"2026-02-19 15:59:45\",\"publishedOnDateReadable\":\"February 19th, 2026\"},\"versionCreatedAt\":\"2025-07-02 09:22:40\",\"video\":\"\",\"vorDoi\":\"10.1007/s00210-026-05087-1\",\"vorDoiUrl\":\"https://doi.org/10.1007/s00210-026-05087-1\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6936975\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6936975\",\"identity\":\"rs-6936975\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}