BACKGROUND:The escalating global burden of stress and depression underscores an urgent need to unravel their complex interrelationships and underlying mechanisms. This investigation delves into the intricate dynamics between stress and depression, spotlighting the Neuroimmunoinflammatory Stress Model (NIIS), which elucidates the pivotal role of cellular and molecular pathways in mediating these conditions. METHODS:Through an exhaustive review of literature spanning epidemiology, neurobiology, and psychoneuroimmunology, this study synthesizes the current understanding of stress and depression. It accentuates the definitional scopes, interplay, and intricacies of the NIIS model, which integrates neuroimmune-inflammatory responses into the conceptual framework of the stress-depression interaction. RESULTS:By identifying stress as a multifactorial reaction to perceived adversities and depression as a manifestation of prolonged stress exposure, our analysis foregrounds the NIIS model. This paradigmatic model reveals the transition from normal stress responses to pathological neuroinflammatory pathways, highlighting neurotransmitter imbalances, disruptions in neuronal and glial homeostasis, and ensuing low-grade neuroinflammation as key factors in the pathogenesis of depression under chronic stress conditions. The NIIS model identifies prolonged cellular pro-inflammatory stress of neurons and microglia as a fundamental pathological subsystem of many neuropsychiatric disorders. In turn, neuroinflammation and associated neurodegenerative processes are complications of chronic psychoemotional stress, which can clinically manifest as depression. CONCLUSION:The NIIS model views depression as the terminal stage of chronic stress, pathogenetically linked to latent neuroinflammation. This insight not only advances our understanding of their etiopathogenesis but also paves the way for developing precise therapeutic interventions.

IntroductionThe fields of allergy and immunology are increasingly recognizing the transformative potential of artificial intelligence (AI). Its adoption is reshaping research directions, clinical practices, and healthcare systems. However, a systematic overview identifying current statuses, emerging trends, and future research hotspots is lacking.MethodsThis study applied bibliometric analysis methods to systematically evaluate the global research landscape of AI applications in allergy and immunology. Data from 3,883 articles published by 21,552 authors across 1,247 journals were collected and analyzed to identify leading contributors, prevalent research themes, and collaboration patterns.ResultsAnalysis revealed that the USA and China are currently leading in research output and scientific impact in this domain. AI methodologies, especially machine learning (ML) and deep learning (DL), are predominantly applied in drug discovery and development, disease classification and prediction, immune response modeling, clinical decision support, diagnostics, healthcare system digitalization, and medical education. Emerging trends indicate significant movement toward personalized medical systems integration.DiscussionThe findings demonstrate the dynamic evolution of AI in allergy and immunology, highlighting the broadening scope from basic diagnostics to comprehensive personalized healthcare systems. Despite advancements, critical challenges persist, including technological limitations, ethical concerns, and regulatory frameworks that could potentially hinder further implementation and integration.ConclusionAI holds considerable promise for advancing allergy and immunology globally by enhancing healthcare precision, efficiency, and accessibility. Addressing existing technological, ethical, and regulatory challenges will be crucial to fully realizing its potential, ultimately improving global health outcomes and patient well-being.

Background: Autism spectrum disorder (ASD) presents significant challenges for both individuals and caregivers, often leading to stress, anxiety, and depression. Although mindfulness-based interventions (MBIs) have emerged as a promising approach to alleviate these burdens, this field lacks a comprehensive bibliometric analysis. Aim: We discuss future research hotspots and directions, with the aim of helping researchers quickly identify key areas for collaboration and development in this field, thereby advancing the clinical application of MBIs and improving the physical and mental well-being of autistic individuals and their caregivers. Methodology: We analyzed data from the Web of Science Core Collection (WoSCC), which included 335 articles authored by 1213 researchers and published in 146 journals. We employed bibliometric tools to examine publication trends, citations, key authors, and institutions. We conducted keyword and thematic evolution analyses to identify research hotspots and emerging trends. Findings: Since 2013, research on MBIs for ASD has significantly increased, with the USA leading in both output and impact. Family-centered mindfulness interventions focused on caregivers' well-being, particularly for mothers, were a key theme. Researchers widely used psychometric tools like the Beck Anxiety Inventory (BAI) and Parenting Stress Index (PSI). Emerging trends include the integration of MBI with artificial intelligence and remote interventions, which address sensory processing and social communication in ASD.

Under the influence of inflammation, pancreatic β cells can transdifferentiate into cells with a different phenotype. When inflammation decreases, the opposite process is possible. We studied the effect of intramuscular injection of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt (APH) on the structural and functional characteristics of the pancreatic islets in rats with experimental type 2 diabetes mellitus. Insulin-producing, glucagon-producing, and proliferating cells were identified by immunohistochemistry. After APH administration, an increase in the number of β cells, a decrease in the number of α cells and cells synthesizing both insulin and glucagon (insulin-glucagon-positive) were observed; mitotic activity of β cells did not change. It is likely that APH promotes transdifferentiation of α cells into β cells by changing the microenvironment of endocrine cells and reducing inflammation in pancreatic islets.

Type 2 diabetes mellitus is characterized by a mild inflammatory reaction in the pancreas, which affects the structure and function of the pancreatic islets: the number of β-cells decreases and the number of α-cells increases. The work examined the features of β-cell differentiation in the development of experimental type 2 diabetes mellitus and while reducing the inflammatory process. Biochemical, histological methods, enzyme-linked immunosorbent assay, immunohistochemical methods were used using primary antibodies to insulin, glucagon, proliferation marker Ki-67 and secondary antibodies labeled with fluorescent dyes. Streptozotocin and nicotinamide were used to model type 2 diabetes mellitus, and the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione was used to reduce the inflammatory response. Previous studies have shown that it changes the macrophage phenotype from proinflammatory M1 to anti-inflammatory M2. In type 2 diabetes mellitus, against the background of a decrease in the number of macrophages with the CD163 marker and the concentration of the cytokine TGF-β1, which have an anti-inflammatory effect, in the pancreatic islets, a decrease in the number of β-cells and their functional activity was observed, while the content of α-cells synthesizing glucagon increased. After administration of the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione, the opposite picture was observed in the pancreatic islets: against the background of an increase in the number of CD163+ macrophages and the content of TGF-β1, the number of β cells increased and the number of α cells decreased-cells. The increase in the number of insulin-synthesizing cells was not accompanied by their mitotic activity. It is likely that a decrease in the number of CD163+ macrophages and the level of the antiinflammatory cytokine TGF-β1 in the islets are factors contributing to changes in the cell microenvironment and, as a consequence, the differentiation of β-cells into α-cells. On the contrary, an increase in the number of CD163+ macrophages and TGF-β1 against the background of administration of the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione presumably promotes reverse differentiation of α-cells into β-cells and restoration of insulin synthesis pancreas. Targeted effects on the microenvironment of cells in the pancreatic islet in type 2 diabetes mellitus may be a new approach to treating the disease.

BackgroundInborn Errors of Immunity (IEI) are characterized by a heightened susceptibility to infections, allergies, and various other health complications. Health-Related Quality of Life (HRQOL) in patients with IEI is a critical area of research that demands attention due to the impact of IEI on patients’ lives. This study utilized bibliometric methods, aiming to comprehensively explore the research content and hotspots in the field of HRQOL in patients with IEI.MethodsThis bibliometric analysis utilized data from the Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI) within the Web of Science core datasets up to January 1, 2024. The study focused on literature that addressed HRQOL in IEI patients, involving a total of 1,807 authors and 309 articles published across 112 journals. The analysis included publication volume and growth trends, country and institutional contributions, authorship, and journal analysis.ResultsThe research found that despite the importance of HRQOL in IEI, the volume of publications in this field remains consistently low, with no significant increase in trend. The USA leads in publication and citation volumes, reflecting a geographical imbalance in research contributions. Key journals in this field include the Journal of Clinical Immunology, Frontiers in Immunology, and the Journal of Allergy and Clinical Immunology. The study highlights that while treatments like hematopoietic stem cell transplants and gene therapy have improved patient IEI survival rates, they still often come with significant side effects impacting HRQOL. The analysis underlines the need for comprehensive HRQOL assessments in IEI, considering the physical and psychological impacts of treatments.ConclusionsThis study represents a bibliometric analysis focusing on HRQOL in patients with. It underscores the need for more extensive and systematic research in this area, emphasizing the importance of a multidisciplinary approach. Despite advancements in medical treatments for IEI, there is a crucial need to focus on HRQOL to enhance patient satisfaction and overall well-being. The findings advocate for more personalized treatment plans and a better understanding of the psychosocial needs of patients with IEI to improve their quality of life.

Background: Spontaneous intracerebral hemorrhage (ICH) is one of the leading causes of mortality in intensive care units. The role of systemic hyperintense inflammation (SHI) in the pathogenesis of critical complications of ICH remains a poorly understood problem. There is a specific variant of severe ICH associated with increased intracranial pressure and occlusion of intracranial vessels, defined as ineffective cerebral blood flow (IECBF). Methods: To evaluate the role of SHI in the pathogenesis of severe (comatose) ICH in a dynamic comparison of patients with IECBF (n-26) and without IECBF (n-52). The SHI integral score criterion (SI scale) was used, including certain values of plasma concentrations of IL-6, IL-8, IL-10; TNF-α, PCT, cortisol, myoglobin, troponin I, D-dimer, and, additionally, SOFA scale values. Blood levels of ACTH and neuron-specific enolase (NSE) were also assessed. Results: Twenty-eight-day mortality in severe ICH reached 84.6% (without IECBF) and 96.2% (with IECBF). Clear signs of SHI were detected in 61.5%/87.8% (without IECBF) and 0.0%/8.7% (with IECBF) within 1–3/5–8 days from the onset of ICH manifestation. The lower probability of developing SHI in the IECBF group was associated with low blood NSE concentrations. Conclusions: The development of SHI in ICH is pathogenetically related to the permeability of the blood–brain barrier for tissue breakdown products and other neuroinflammatory factors.

BackgroundGiven the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the impact of animal-assisted activities and therapies (AAAT) on various ASD symptoms.MethodsA meticulous search of databases, including Scopus and PubMed, was conducted to gather relevant research on AAAT for ASD. This process led to the selection of 45 studies encompassing 1,212 participants. The chosen studies were then subjected to a meta-analysis to evaluate the efficacy of AAAT in alleviating core ASD symptoms.ResultsThe meta-analysis revealed significant improvements in several core ASD symptoms due to AAAT. Notably, there were improvements in social communication (MD = −4.96, 95% CI [−7.49, −2.44]), irritability (MD = −2.38, 95% CI [−4.06, −0.71]), hyperactivity (MD = −4.03, 95% CI [−6.17, −1.89]), and different word usage skills (MD = 20.48, 95% CI [7.41, 33.55]). However, social awareness (MD = −1.63, 95% CI [−4.07, 0.81]), social cognition (MD = −3.60, 95% CI [−9.36, 2.17]), social mannerisms (MD = −0.73, 95% CI [−2.55, 1.09]), social motivation (MD = −1.21, 95% CI [−2.56, 0.13]), lethargy (MD = −1.12, 95% CI [−3.92, 1.68]), and stereotypical behaviors (MD = −0.23, 95% CI [−1.27, 0.80]) did not significantly improve.ConclusionThe study demonstrates the potential of AAAT in improving certain core symptoms of ASD, such as social communication, irritability, hyperactivity, and word usage skills. However, the effectiveness of AAAT in other ASD symptom domains remains uncertain. The research is limited by the absence of long-term follow-up data and a high risk of bias in existing studies. Therefore, while the findings indicate the promise of AAAT in specific areas, caution is advised in generalizing its efficacy across all ASD symptoms.

Recently,in their 2024 study,Dong et al.[1]revealed the pivotal role of neutrophils in the immune response of myocardial ische-mia-reperfusion injury(MIRI)via single-cell RNA sequencing(scRNA-seq),and identified the existence and function of a novel neutrophil subset with repair phenotype,which participates in the cardio-protection of MIRI by regulating the polarization of macrophages via Ym-1.This finding not only deepens our under-standing of cellular interactions within MIRI but also opens new therapeutic avenues.

Hennekam Lymphangiectasia–Lymphedema Syndrome 3 (HKLLS3) is a rare genetical disorder caused by mutations in a few genes including ADAMTS3. It is characterized by lymphatic dysplasia, intestinal lymphangiectasia, severe lymphedema and distinctive facial appearance. Up till now, no extensive studies have been conducted to elucidate the mechanism of the disease caused by various mutations. As a preliminary investigation of HKLLS3, we sorted out the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) that might affect the structure and function of ADAMTS3 protein by using a variety of in silico tools. A total of 919 nsSNPs in the ADAMTS3 gene were identified. 50 nsSNPs were predicted to be deleterious by multiple computational tools. 5 nsSNPs (G298R, C567Y, A370T, C567R and G374S) were found to be the most dangerous and can be associated with the disease as predicted by different bioinformatics tools. Modelling of the protein shows it can be divided into segments 1, 2 and 3, which are connected by short loops. Segment 3 mainly consists of loops without substantial secondary structures. With prediction tools and molecular dynamics simulation, some SNPs were found to significantly destabilize the protein structure and disrupt the secondary structures, especially in segment 2. The deleterious effects of mutations in segment 1 are possibly not from destabilization but from other factors such as the change in phosphorylation as suggested by post-translational modification (PTM) studies. This is the first-ever study of ADAMTS3 gene polymorphism, and the predicted nsSNPs in ADAMST3, some of which have not been reported yet in patients, will serve for diagnostic purposes and further therapeutic implications in Hennekam syndrome, contributing to better diagnosis and treatment.

We studied the role of alpha-fetoprotein (AFP) in regulation of differentiation and functional activity of human myeloid-derived suppressor cells (MDSC) in vitro . To obtain MDSC, CD11b + cells were isolated from the peripheral blood of healthy donors followed by cytokine induction (IL-1β+GM-CSF) into the MDSC phenotype. The cell functions were assessed by the expression of indoleamine 2,3-dioxygenase (IDO) and arginase-1 (Arg1) and cytokine profile of the cell cultures. Native AFP did not affect the total number of MDSC and the percentage of polymorphonuclear MDSC (PMN-MDSC), but increased the number of monocytic MDSC (M-MDSC). AFP did not change the expression of Arg1, but in low concentrations (10 and 50 U/ml) increased the number of IDO-containing cells. AFP modulated the cytokine profile of CD11b + cells: it reliably decreased the level of IL-19 (50 and100 U/ml) and showed a tendency to decrease the levels of IL-34, MMP-2, sCD163, CHI3L1, OPN and to increase the levels of IL-29, IL-32, APRIL, PTX3, and sTNF-R1. Thus, we have demonstrated a regulatory effect of native AFP at the level of MDSC generated from CD11b + cells under conditions of cytokine induction in vitro .

Mental disorders often accompany autoimmune diseases, for example, since 1949 it has been known about “myxedematous madness”, a psychosis caused by hypothyroidism. The most common cause of hypothyroidism is Hashimoto's autoimmune thyroiditis. It is also known about another neuropsychiatric disorder associated with autoimmune thyroiditis, Hashimoto's encephalopathy. It is a severe dysfunction of the central nervous system, the pathogenesis of which is not associated with hormonal disorders. Cytokines are regulators and participants of inflammation, including autoimmune. Certainly, when we are talking about high concentrations cytokines, we mean systemic inflammation. The minimal or mediocre fluctuations in cytokines within the ranges that are characteristic of healthy status or normergic acute phase response in disease cannot be interpreted from the point of view of binary endocrinological logic. In the CNS, cytokines are able to influence on the neuroendocrine control of systemically regulated functions. It is also important that glial cells (astroglia, microglia) are capable of producing a number of cytokines and can affect neurons and develop behavioral changes. In addition, the ability of a number of cytokines outside the CNS itself to act on vagal afferents and through them to convey information to the CNS, affecting its state and functions, has been proven. It is reasonable to assume that minimal fluctuations in cytokine levels may also affect the state and function of the CNS. The aim of the study was to investigate the levels of cytokines in patients with thyroiditis; in patients with thyroiditis associated with mental disorders; in a group of healthy individuals; and evaluate the effect of cytokine levels on clinical manifestations. In the group of patients with thyroiditis and mental disorders, the levels of CCL20/MIP3α, IL-13, IL-2, IL-27, IL-5 were significantly higher than in other groups. At the same time, no positive correlation was found between the clinical manifestations of mental disorders and the levels of cytokines. A positive correlation was found between the levels of some cytokines and free triiodothyronine, as well as the level of antithyroid antibodies. Mental disorders associated with autoimmune thyroiditis may be associated with changes in the cytokine profile and result from neuroinflammation.

In HIV-positive individuals taking antiretroviral therapy, coinfection with hepatitis C virus (HCV) increases systemic inflammation, which interferes with the CD4 + T-cells regeneration. This study evaluated the effect of HCV eradication on systemic inflammation and CD4 + T-cell regeneration in patients who gave poor response to antiretroviral therapy, the so-called “immunological non-responders” (INRs). HIV-infected patients who received a course of direct-acting antivirals for treating hepatitis C were examined. The control groups included HIV/HCV-coinfected INRs and relatively healthy volunteers. It was established for the first time that HCV eradication is not accompanied by a complete suppression of systemic inflammation, but improves the T-cell pool composition: in INRs, the blood CD4 + /CD8 + T-lymphocyte ratio increases and approaches those of healthy individuals. Apparently, in INRs treated for hepatitis C, the immune system recovery takes time and may be incomplete.

Hennekam syndrome (HS) is an autosomal recessive disease in the pathogenesis of which lymphangiectasia and lymphedema plays a key role. HS is associated with mutations in CCBE1, FAT4, and ADAMTS3 proteins that somehow affect the activation of the primary lymphangiogenic growth factor VEGF-C. We used several in silico methods to test this theory. According to NCBI, FAT4 gene contains 3,343 non-synonymous SNPs, of which 298 were predicted to be deleterious using SIFT and Polyphen2. These 298 SNPs were further studied using various mutation prediction tools. Our results showed that eleven nsSNPs (D2978G, V986D, Y1912C, R4799C, D1022G, G4786R, D2439E, E2426Q, R4643C, N1309I, and Y2909H) detected by these tools are deleterious. Additionally, three mutations in FAT4 gene (rs12650153, rs1567047, and rs1039808) in patient suspected with HS were discovered through candidate variant filtering of whole-exome sequencing, and in silico study of these mutations revealed that these are highly destabilizing the protein structure and function. Using molecular dynamics simulation (MDS) we focused on the mutations (11 mutations predicted by our insilco study, 3 reported in the patient and 5 already published mutations for HS and VMS), while one mutation (G4786R) was detected in the MPDZ domain. The RMSD and RMSF supports the destability of mutant protein compared to wild type. The mutations found in this cohort of studies have not previously been reported for HS. These mutations may contribute to better understanding of disease predisposition associated with FAT4 Cadherin-like domain activation and further aid to effective approaches for diagnosis and treatment of the disorder.

Currently, there is rationale for separating the systemic manifestations of classical inflammation from systemic inflammation (SI) itself as an independent form of the general pathological process underlying the pathogenesis of the most severe acute and chronic diseases. With this aim in view, we used integral scales of acute and chronic SI (ChSI), including the following blood plasma parameters: interleukins 6, 8, 10; tumor necrosis factor alpha; C-reactive protein; D-dimer; cortisol; troponin I; myoglobin. The presence of multiple organ dysfunction according to the SOFA score was also taken into account. The effectiveness of the scales was tested in groups of intensive care patients during different periods of acute trauma, sepsis, and septic shock. The ChSI scale was applicable under systemic autoimmune diseases, chronic purulent infections, chronic limb threatening ischemia, and end-stage renal disease of various genesis. The number of examined patients was 764 in total. The scales allowed us to verify specific phases of acute SI and identify pathogenetic risk factors of lethal outcomes, as well as the most severe variants of the chronic pathologies course. These scales are open adaptable systems (in terms of the nomenclature and choice of indicators). They are primarily intended for scientific research. However, the SI verification methodology presented in this paper may be useful for developing advanced criteria for assessing both the typical links in the pathogenesis of many diseases and the severity of the overall condition of patients for clinical practice.

Myeloid-derived suppressor cells (MDSCs) are a cell population involved in the regulation of immune response by means by inhibiting it in pathologies, as well as during pregnancy. This review summarizes the available data on the effect of MDSCs on different components of innate and adaptive immunity, taking into account the different ways in which their immunosuppressive functions are carried out. Analysis of current studies on the mechanisms of suppression of the MDSC immune response are presented, and an assessment is given of the role of MDSCs in maintaince of immune tolerance during pregnancy. Data on MDSCs in various pathological conditions during pregnancy and the content of MDSCs in umbilical-cord blood weree[amined, and the relationship between these cells and the immune status was reviewed.

Abstract Background: Congenital neutropenia (CN) is a primary immunodeficiency disease (PID), which is associated with recurrent bacterial infections, autoimmunity, hematological malignancies, and neuropsychiatric symptoms. Understanding the protein-protein interaction (PPI) network of CN genes and finding candidate CN genes is crucial for early CN diagnosis. The purpose of current study was to investigate the PPI network of CN genes and use computational techniques to identify candidate CN genes.Methods: PPI data for CN and PID genes provided from the STRING database were examined using network density and biological distance. Gene expression data of patients with CN were obtained from the Gene Expression Omnibus, and then Pearson’s correlation coefficient, a PPI database, and Kyoto Encyclopedia of Genes and Genomes were used to identify candidate CN genes. We then assessed our hypotheses and discovered CN genes that were differently expressed. Results: Characterization of the majority of CN genes were done by high network density and low biological distance whereas low network density and large biological distance were used to characterize most PID genes. The CN genes are functionally relative to each other compared to PID genes. It showed that they are similar and closely related. Next, we found 15 candidate CN genes with biological functions comparable to known CN genes, and other genes have subsequently been identified as CN-related genes. The SRC gene reported in our study may be a good candidate gene for Heneekem syndrome. The candidate gene “STAT3” was downregulated in peripheral blood neutrophils and B cells in CN patients compared to healthy controls (HC), whereas in blood sample the level was up regulated in CN patients relative to HC. Conclusion: Our findings will contribute in the early diagnosis of CN by providing a better understanding of the CN gene complexity.

T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases.

An innate immune defect is a defect in the innate immune response that reduces the response to infection, this can occurs in genes important for activation regulation and proliferation of the innate immune cells or pathways important for the function of innate immunity. The purpose of this study was to identify novel biomarkers of interferon Receptor 7 through bioinformatics analysis and elucidate the possible molecular mechanism. The GSE 66486 datasets containing microarray data from IRF7 and UNC93B patients and healthy controls were downloaded from the GEO database and analyzed by the GEO2R web tool to obtain different expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI), and Biological Networks Gene Oncology tool (BiNGO) were then performed to elucidate the molecular mechanism of IRF7. A total of 490 DEGs were identified, of which 14 were hub genes, and involved in ribosome biogenesis, rRNA processing, gene expression, mRNA processing, nuclear lumen, intracellular non-membrane-bounded organelle, nucleoplasm, small-subunit processome, antigen processing and presentation pathway, and ribosome biogenesis in eukaryotes. Antigen processing and presentation pathway, and ribosome biogenesis in eukaryotes possibly form the basis of IRF7 or UNC93B disorders, while our study provides a list of genes and pathways that are disrupted in IRF7/UNC93B, which has the potential to be used in the clinic for diagnosis and targeted therapy of such disorders in future.

Single-nucleotide polymorphisms in the ELANE (Elastase, Neutrophil Expressed) gene are associated with severe congenital neutropenia, while the ELANE gene provides instructions for making a protein called neutrophil elastase. We identified disease susceptibility single-nucleotide polymorphisms (SNPs) in the ELANE gene using several computational tools. We used cutting-edge computational techniques to investigate the effects of ELANE mutations on the sequence and structure of the protein. Our study suggested that eight nsSNPs (rs28931611, rs57246956, rs137854448, rs193141883, rs201723157, rs201139487, rs137854451, and rs200384291) are the most deleterious in ELANE gene and disturb protein structure and function. The mutants F218L, R34W, G203S, R193W, and T175M have not yet been identified in patients suffering from SCN and cyclic hematopoiesis, while C71Y, P139R, C151Y, G214R, and G203C reported in our study are already associated with both of the disorders. These mutations are shown to destabilize structure and disrupt ELANE protein activation, splicing, and folding and might diminish trypsin-like serine protease efficiency. Prediction of posttranslation modifications highlighted the significance of deleterious nsSNPs because some of nsSNPs affect potential phosphorylation sites. Gene-gene interactions showed the relation of ELANE with other genes depicting its importance in numerous pathways and coexpressions. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking. This research sheds light on how ELANE failure upon mutation results in disease progression, including congenital neutropenia, and validation of these novel predicted nsSNPs is required through the wet lab.