Identification of Common Dysregulated Genes in COVID-19 and Hypersensitivity Pneumonitis: A Systems Biology and Machine Learning Approach.

A comprehensive knowledge on systems biology of severe acute respiratory syndrome coronavirus 2 is crucial for differential diagnosis of COVID-19. Interestingly, the radiological and pathological features of COVID-19 mimic that of hypersensitivity pneumonitis (HP), another pulmonary fibrotic phenotype. This motivated us to explore the overlapping pathophysiology of COVID-19 and HP, if any, and using a systems biology approach. Two datasets were obtained from the Gene Expression Omnibus database (GSE147507 and GSE150910) and common differentially expressed genes (DEGs) for both diseases identified. Fourteen common DEGs, significantly altered in both diseases, were found to be implicated in complement activation and growth factor activity. A total of five microRNAs (hsa-miR-1-3p, hsa-miR-20a-5p, hsa-miR-107, hsa-miR-16-5p, and hsa-miR-34b-5p) and five transcription factors (KLF6, ZBTB7A, ELF1, NFIL3, and ZBT33) exhibited highest interaction with these common genes. Next, C3, CFB, MMP-9, and IL1A were identified as common hub genes for both COVID-19 and HP. Finally, these top-ranked genes (hub genes) were evaluated using random forest classifier to discriminate between the disease and control group (coronavirus disease 2019 [COVID-19] vs. controls, and HP vs. controls). This supervised machine learning approach demonstrated 100% and 87.6% accuracy in differentiating COVID-19 from controls, and HP from controls, respectively. These findings provide new molecular leads that inform COVID-19 and HP diagnostics and therapeutics research and innovation.

Identification of a key glioblastoma candidate gene, FUBP3, based on weighted gene co-expression network analysis.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene. METHODS: Two GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was performed to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was applied for survival analysis to determine the significant gene, FUBP3. OS, DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis. RESULTS: GSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4 + T cells, CD8 + T cells, and macrophages) and FUBP3. CONCLUSION: FUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies.

Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.

The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a severe global health crisis; its structural protein envelope (E) is critical for viral entry, budding, production, and induction of pathology which makes it a potential target for therapeutics against COVID-19. Here, we find that the E3 ligase RNF5 interacts with and catalyzes ubiquitination of E on the 63rd lysine, leading to its degradation by the ubiquitin-proteasome system (UPS). Importantly, RNF5-induced degradation of E inhibits SARS-CoV-2 replication and the RNF5 pharmacological activator Analog-1 alleviates disease development in a mouse infection model. We also found that RNF5 is distinctively expressed in different age groups and in patients displaying different disease severity, which may be exploited as a prognostic marker for COVID-19. Furthermore, RNF5 recognized the E protein from various SARS-CoV-2 strains and SARS-CoV, suggesting that targeting RNF5 is a broad-spectrum antiviral strategy. Our findings provide novel insights into the role of UPS in antagonizing SARS-CoV-2 replication, which opens new avenues for therapeutic intervention to combat the COVID-19 pandemic.

The effect of DNA repair gene variants on COVID-19 disease: susceptibility, severity, and clinical course.

Oxidative stress (OS), which leads to DNA damage, plays a role in the pathogenesis of Coronavirus disease 2019 (COVID-19). We aimed to evaluate the role of DNA repair gene variants [X-ray repair cross complementing 4 (XRCC4) rs28360071, rs6869366, and X-ray cross-complementary gene 1 (XRCC1) rs25487] in susceptibility to COVID-19 in a Turkish population. We also evaluated its effect on the clinical course of the disease. A total of 300 subjects, including 200 COVID-19 patients and 100 healthy controls, were included in this study. These variants were genotyped using polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism (RFLP) methods. The patients were divided into three groups: those with a mild or severe infection; those who died or lived at the 28-day follow-up; those who required inpatient treatment or intensive care. There were 87 women (43.5%) and 113 men (56.5%) in the patient group. Hypertension was the most common comorbidity (26%). In the patient group, XRCC4 rs6869366 G/G genotype and G allele frequency were increased compared to controls, while XRCC4 rs6869366 G/T and T/T genotype frequencies were found to be higher in controls compared to patients. For XRCC1 rs25487, the A/A and A/G genotypes were significantly associated with COVID-19 disease. All of the patients hospitalized in the intensive care unit had the XRCC4 rs6869366 G/G genotype. In this study, we evaluated for the first time the impact of DNA repair gene variants on COVID-19 susceptibility. Results suggested that XRCC4 rs6869366 and XRCC1 rs25487 were associated with COVID-19 suspectibility and clinical course.

Activation of the AIM2 Receptor in Circulating Cells of Post-COVID-19 Patients With Signs of Lung Fibrosis Is Associated With the Release of IL-1α, IFN-α and TGF-ß.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-ß. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-ß were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.

Identification of GINS1 as a therapeutic target in the cancer patients infected with COVID-19: a bioinformatics and system biology approach.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused a series of biological changes in cancer patients which have rendered the original treatment ineffective and increased the difficulty of clinical treatment. However, the clinical treatment for cancer patients infected with COVID-19 is currently unavailable. Since bioinformatics is an effective method to understand undiscovered biological functions, pharmacological targets, and therapeutic mechanisms. The aim of this study was to investigate the influence of COVID-19 infection in cancer patients and to search the potential treatments. METHODS: Firstly, we obtained the COVID-19-associated genes from seven databases and analyzed the cancer pathogenic genes from Gene Expression Omnibus (GEO) databases, respectively. The Cancer/COVID-19-associated genes were shown by Venn analyses. Moreover, we demonstrated the signaling pathways and biological functions of pathogenic genes in Cancer/COVID-19. RESULTS: We identified that Go-Ichi-Ni-San complex subunit 1 (GINS1) is the potential therapeutic target in Cancer/COVID-19 by GEPIA. The high expression of GINS1 was not only promoting the development of cancers but also affecting their prognosis. Furthermore, eight potential compounds of Cancer/COVID-19 were identified from CMap and molecular docking analysis. CONCLUSION: We revealed the GINS1 is a potential therapeutic target in cancer patients infected with COVID-19 for the first time, as COVID-19 will be a severe and prolonged pandemic. However, the findings have not been verified actually cancer patients infected with COVID-19, and further studies are needed to demonstrate the functions of GINS1 and the clinical treatment of the compounds.

ZBTB7A promotes virus-host homeostasis during human coronavirus 229E infection.

The cellular fate after infection with human coronaviruses (HCoVs) is typically death. Previous data suggest, however, that the transcriptional state of an individual cell may sometimes allow additional outcomes of infection. Here, to probe the range of interactions a permissive cell type can have with a HCoV, we perform a CRISPR activation screen with HCoV-229E. The screen identified the transcription factor ZBTB7A, which strongly promotes cell survival after infection. Rather than suppressing viral infection, ZBTB7A upregulation allows the virus to induce a persistent infection and homeostatic state with the cell. We also find that control of oxidative stress is a primary driver of cellular survival during HCoV-229E infection. These data illustrate that, in addition to the nature of the infecting virus and the type of cell that it encounters, the cellular gene expression profile prior to infection can affect the eventual fate.

Oxytocin: An Old Hormone, a Novel Psychotropic Drug and its Possible Use in Treating Psychiatric Disorders.

BACKGROUND: Oxytocin is a nonapeptide synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Historically, this molecule has been involved as a key factor in the formation of infant attachment, maternal behavior and pair bonding and, more generally, in linking social signals with cognition, behaviors and reward. In the last decades, the whole oxytocin system has gained a growing interest as it was proposed to be implicated in etiopathogenesis of several neurodevelopmental and neuropsychiatric disorders. METHODS: With the main goal of an in-depth understanding of the oxytocin role in the regulation of different functions and complex behaviors as well as its intriguing implications in different neuropsychiatric disorders, we performed a critical review of the current state of the art. We carried out this work through the PubMed database up to June 2021 with the search terms: 1) "oxytocin and neuropsychiatric disorders"; 2) "oxytocin and neurodevelopmental disorders"; 3) "oxytocin and anorexia"; 4) "oxytocin and eating disorders"; 5) "oxytocin and obsessive- compulsive disorder"; 6) "oxytocin and schizophrenia"; 7) "oxytocin and depression"; 8) "oxytocin and bipolar disorder"; 9) "oxytocin and psychosis"; 10) "oxytocin and anxiety"; 11) "oxytocin and personality disorder"; 12) "oxytocin and PTSD". RESULTS: Biological, genetic, and epigenetic studies highlighted quality and quantity modifications in the expression of oxytocin peptide or in oxytocin receptor isoforms. These alterations would seem to be correlated with a higher risk of presenting several neuropsychiatric disorders belonging to different psychopathological spectra. Collaterally, the exogenous oxytocin administration has shown to ameliorate many neuropsychiatric clinical conditions. CONCLUSION: Finally, we briefly analyzed the potential pharmacological use of oxytocin in a patient with severe symptomatic SARS-CoV-2 infection due to its anti-inflammatory, antioxidative and immunoregulatory properties.

TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy.

OBJECTIVE: Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated. METHODS: We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n = 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline. RESULTS: Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI = 2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1-1.6), and language composite (1.1 SD, 95% CI = 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1-20.3) and executive composite (1.3 SD, 95% CI = 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (ß = 1.9, 95% CI = 0.9-3.0), DRS (ß = 7.8, 95% CI = 3.4-12.7), CDR-sob (ß = 1.9, 95% CI = 0.4-3.7), language composite (ß = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (ß = 5.2, 95% CI = 0.6-10.2). INTERPRETATION: LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438.

Long noncoding RNA CHROMR regulates antiviral immunity in humans.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA CHROMR is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. CHROMR depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that CHROMR sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, CHROMR expression is essential to restrict viral infection of macrophages. Our findings identify CHROMR as a key arbitrator of antiviral innate immune signaling in humans.

ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19.

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.

FACT subunit SUPT16H associates with BRD4 and contributes to silencing of interferon signaling.

FACT (FAcilitates Chromatin Transcription) is a heterodimeric protein complex composed of SUPT16H and SSRP1, and a histone chaperone participating in chromatin remodeling during gene transcription. FACT complex is profoundly regulated, and contributes to both gene activation and suppression. Here we reported that SUPT16H, a subunit of FACT, is acetylated in both epithelial and natural killer (NK) cells. The histone acetyltransferase TIP60 contributes to the acetylation of SUPT16H middle domain (MD) at lysine 674 (K674). Such acetylation of SUPT16H is recognized by bromodomain protein BRD4, which promotes protein stability of SUPT16H in both epithelial and NK cells. We further demonstrated that SUPT16H-BRD4 associates with histone modification enzymes (HDAC1, EZH2), and further regulates their activation status and/or promoter association as well as affects the relevant histone marks (H3ac, H3K9me3 and H3K27me3). BRD4 is known to profoundly regulate interferon (IFN) signaling, while such function of SUPT16H has never been explored. Surprisingly, our results revealed that SUPT16H genetic knockdown via RNAi or pharmacological inhibition by using its inhibitor, curaxin 137 (CBL0137), results in the induction of IFNs and interferon-stimulated genes (ISGs). Through this mechanism, depletion or inhibition of SUPT16H is shown to efficiently inhibit infection of multiple viruses, including Zika, influenza, and SARS-CoV-2. Furthermore, we demonstrated that depletion or inhibition of SUPT16H also causes the remarkable activation of IFN signaling in NK cells, which promotes the NK-mediated killing of virus-infected cells in a co-culture system using human primary NK cells. Overall, our studies unraveled the previously un-appreciated role of FACT complex in coordinating with BRD4 and regulating IFN signaling in both epithelial and NK cells, and also proposed the novel application of the FACT inhibitor CBL0137 to treat viral infections.

An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Hydroxychloroquine (HCQ)-associated cardiovascular adverse events (CVAEs) have been increasingly reported. AIM: This study aimed to present an observational, retrospective, and comprehensive pharmacovigilance analysis of CVAE associated with HCQ in patients with and without COVID-19 using the US Food and Drug Administration Adverse Events Reporting System (FAERS) data from January 2020 to December 2020. METHOD: We identified 3302 adverse event reports from the FAERS database in the year 2020 and divided them into COVID-19 and non-COVID-19 groups, respectively. Then we analyzed whether there were differences in CVAEs between the two groups. RESULTS: We found that CVAE was higher in cases with COVID-19 compared to those without COVID-19, odds ratio (OR) of 1.26 and a 95% confidence interval (95% CI) of 1.02-1.54. Cases with COVID-19 treated with HCQ exhibited relatively higher proportions of torsade de points (TdP) and QT prolongation (OR 3.10, 95% CI 2.24-4.30), shock-associated TdP (OR 2.93, 95% CI 2.13-4.04), cardiac arrhythmias (OR 2.07, 95% CI 1.60-2.69), cardiac arrhythmia terms (including bradyarrhythmias and tachyarrhythmias) (OR 2.15, 95% CI 1.65-2.80), bradyarrhythmias (including conduction defects and disorders of sinus node function) (OR 2.56, 95% CI 1.86-3.54), and conduction defects (OR 2.56, 95% CI 1.86-3.54). CONCLUSION: Our retrospective observational analysis suggested that the proportion of CVAE associated with HCQ, especially TdP and QT prolongation, was higher in patients with COVID-19. Understanding the effects of COVID-19 on the cardiovascular system is essential to providing comprehensive medical care to patients receiving HCQ treatment.

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.

Exploring the potential mechanism of emetine against coronavirus disease 2019 combined with lung adenocarcinoma: bioinformatics and molecular simulation analyses.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) may be more predisposed to coronavirus disease 2019 (COVID-19) and have a poorer prognosis. Currently, there is still a lack of effective anti-LUAD/COVID-19 drugs. Thus, this study aimed to screen for an effective anti-LUAD/COVID-19 drug and explore the potential mechanisms. METHODS: Firstly, we performed differentially expressed gene (DEG) analysis on LUAD transcriptome profiling data in The Cancer Genome Atlas (TCGA), where intersections with COVID-19-related genes were screened out. Then, we conducted Cox proportional hazards analyses on these LUAD/COVID-19 DEGs to construct a risk score. Next, LUAD/COVID-19 DEGs were uploaded on Connectivity Map to obtain drugs for anti-LUAD/COVID-19. Finally, we used network pharmacology, molecular docking, and molecular dynamics (MD) simulation to explore the drug's therapeutic targets and potential mechanisms for anti-LUAD/COVID-19. RESULTS: We identified 230 LUAD/COVID-19 DEGs and constructed a risk score containing 7 genes (BTK, CCL20, FURIN, LDHA, TRPA1, ZIC5, and SDK1) that could classify LUAD patients into two risk groups. Then, we screened emetine as an effective drug for anti-LUAD/COVID-19. Network pharmacology analyses identified 6 potential targets (IL6, DPP4, MIF, PRF1, SERPING1, and SLC6A4) for emetine in anti-LUAD/COVID-19. Molecular docking and MD simulation analyses showed that emetine exhibited excellent binding capacities to DDP4 and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CONCLUSIONS: This study found that emetine may inhibit the entry and replication of SARS-CoV-2 and enhance tumor immunity by bounding to DDP4 and Mpro.

HKAM-MKM: A hybrid kernel alignment maximization-based multiple kernel model for identifying DNA-binding proteins.

The identification of DNA-binding proteins (DBPs) has always been a hot issue in the field of sequence classification. However, considering that the experimental identification method is very resource-intensive, the construction of a computational prediction model is worthwhile. This study developed and evaluated a hybrid kernel alignment maximization-based multiple kernel model (HKAM-MKM) for predicting DBPs. First, we collected two datasets and performed feature extraction on the sequences to obtain six feature groups, and then constructed the corresponding kernels. To ensure the effective utilisation of the base kernel and avoid ignoring the difference between the sample and its neighbours, we proposed local kernel alignment to calculate the kernel between the sample and its neighbours, with each sample as the centre. We combined the global and local kernel alignments to develop a hybrid kernel alignment model, and balance the relationship between the two through parameters. By maximising the hybrid kernel alignment value, we obtained the weight of each kernel and then linearly combined the kernels in the form of weights. Finally, the fused kernel was input into a support vector machine for training and prediction. Finally, in the independent test sets PDB186 and PDB2272, we obtained the highest Matthew's correlation coefficient (MCC) (0.768 and 0.5962, respectively) and the highest accuracy (87.1% and 78.43%, respectively), which were superior to the other predictors. Therefore, HKAM-MKM is an efficient prediction tool for DBPs.