Pest Manag Sci. 2024 Dec 26. doi: 10.1002/ps.8618. Online ahead of print.

ABSTRACT

BACKGROUND: Casuarina equisetifolia, a crucial species of coastal windbreaks, is highly susceptible to infestation by Anoplophora chinensis. This stem-boring pest poses a significant threat to the health and sustainability of Casuarina equisetifolia forests. Understanding the molecular mechanisms underlying the host preference of A. chinensis to Casuarina equisetifolia is essential for developing effective pest management strategies.

RESULTS: Through field surveys, we identified two cultivars of Casuarina equisetifolia that exhibited differing levels of host preference for A. chinensis. Further analysis of multi-omics data (phenomics, transcriptomics, and metabolomics) from these cultivars revealed that longifolene plays a significant role in attracting A. chinensis to Casuarina equisetifolia. Additionally, the jasmonic acid (JA) signaling pathway was found to suppress longifolene accumulation, primarily through the interaction between the jasmonate ZIM-domain (JAZ) proteins and the terpene synthase (TPS) gene. Moreover, we identified a critical JAZ component, CeJAZ3, whose overexpression led to the down-regulation of TPS expression levels and, consequently, a reduced release of longifolene.

CONCLUSION: We confirmed that the negative regulator of host preference, CeJAZ3, in the JA signaling pathway can suppress the expression of TPSs, thereby down-regulating the accumulation of longifolene in Casuarina equisetifolia and indirectly suppressing the attraction of host plants to A. chinensis, which provides a basis for the integrated management of A. chinensis. © 2024 Society of Chemical Industry.

PMID:39723485 | DOI:10.1002/ps.8618

Pharmgenomics Pers Med. 2024 Dec 21;17:573-609. doi: 10.2147/PGPM.S350238. eCollection 2024.

ABSTRACT

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease's complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression.

METHODS: This review was conducted through a state-of-The-art literature search, primarily utilizing PubMed to gather peer-reviewed articles. We focused on the most comprehensive and cited studies to ensure a thorough understanding of the genetic and molecular landscapes of MM.

RESULTS: We detail primary and secondary alterations such as translocations, hyperdiploidy, single nucleotide variants (SNVs), copy number alterations (CNAs), gene fusions, epigenetic modifications, non-coding RNAs, germline predisposing variants, and the influence of the tumor microenvironment (TME). Our analysis highlights the heterogeneity of MM and the challenges it poses in treatment and prognosis, emphasizing the distinction between driver mutations, which actively contribute to oncogenesis, and passenger mutations, which arise due to genomic instability and do not contribute to disease progression.

CONCLUSION & FUTURE PERSPECTIVES: We report key controversies and challenges in defining the genetic drivers of MM, and examine their implications for future therapeutic strategies. We discuss the importance of systems biology approaches in understanding the dependencies and interactions among these alterations, particularly highlighting the impact of double and triple-hit scenarios on disease outcomes. By advancing our understanding of the molecular drivers and their interactions, this review sets the stage for novel therapeutic targets and strategies, ultimately aiming to improve clinical outcomes in MM patients.

PMID:39723112 | PMC:PMC11669356 | DOI:10.2147/PGPM.S350238

Front Genet. 2024 Dec 10;15:1500684. doi: 10.3389/fgene.2024.1500684. eCollection 2024.

ABSTRACT

We present MMPred, a software tool that integrates epitope prediction and sequence alignment algorithms to streamline the computational analysis of molecular mimicry events in autoimmune diseases. Starting with two protein or peptide sets (e.g., from human and SARS-CoV-2), MMPred facilitates the generation, investigation, and testing of mimicry hypotheses by providing epitope predictions specifically for MHC class II alleles, which are frequently implicated in autoimmunity. However, the tool is easily extendable to MHC class I predictions by incorporating pre-trained models from CNN-PepPred and NetMHCpan. To evaluate MMPred's ability to produce biologically meaningful insights, we conducted a comprehensive assessment involving i) predicting associations between known HLA class II human autoepitopes and microbial-peptide mimicry, ii) interpreting these predictions within a systems biology framework to identify potential functional links between the predicted autoantigens and pathophysiological pathways related to autoimmune diseases, and iii) analyzing illustrative cases in the context of SARS-CoV-2 infection and autoimmunity. MMPred code and user guide are made freely available at https://github.com/ComputBiol-IBB/MMPRED.

PMID:39722794 | PMC:PMC11669352 | DOI:10.3389/fgene.2024.1500684

Biol Direct. 2024 Dec 26;19(1):143. doi: 10.1186/s13062-024-00573-z.

ABSTRACT

Oral squamous cell carcinoma (OSCC) is the most frequent type of oral malignancy with high metastasis and poor prognosis. The deubiquitinating enzyme Ubiquitin Specific Peptidase 44 (USP44) regulates the mitotic checkpoint, and its deficiency leads to aneuploidy and increases tumor incidence. However, the role of USP44 in OSCC is not well understood. Herein, we analyzed mRNA sequencing data of OSCC samples downloaded from the TCGA and GEO databases and found that USP44 was decreased in human OSCC tissues and was positively correlated to the survival of OSCC patients. To investigate the biological impact of USP44, we used recombinant lentiviruses to overexpress or knockdown USP44 expression in OSCC cell lines, which were also injected subcutaneously or into the lateral tail vein of Male BALB/c nude mice to model tumorigenesis or lung metastasis in vivo, respectively. The results showed that overexpression of USP44 inhibited malignant cell phenotypes in vitro and suppressed tumor growth and lung metastasis in vivo, while its downregulation had the opposite effects. Comprehensive proteomic analyses through Co-IP mass spectrometry and label-free quantitative LC-MS/MS methods identified 112 differentially expressed proteins positively regulated by USP44, among which 13 were involved in cancer-related pathways including apoptotic signaling and cell cycle regulation. PPI analysis identified Hexamethylene Bis-Acetamide-Inducible Protein 1 (HEXIM1) as the hub protein. Upregulation of USP44 enhanced HEXIM1 protein stability, leading to its higher expression in OSCC cells. Silencing of HEXIM1 further enhanced the malignant phenotype of OSCC cells. At the same time, HEXIM1 knockdown reversed the antitumor effects of USP44. These findings demonstrated that USP44 acted as a critical tumor suppressor in OSCC by inhibiting cell proliferation and metastasis through the stabilization of HEXIM1 protein, suggesting that USP44-HEXIM1 axis is a promising target for OSCC therapy.

PMID:39722007 | DOI:10.1186/s13062-024-00573-z

Am J Chin Med. 2024 Dec 24:1-19. doi: 10.1142/S0192415X24500964. Online ahead of print.

ABSTRACT

Ginseng-containing Shentao Ruangan granules (STR) have been a well-known Chinese medicine prescription for the treatment of hepatocellular carcinoma (HCC) in China for decades. This study aimed to establish an in silico experimental framework to decipher the underlying mechanism of STR in the treatment of HCC. Microarray analysis, network pharmacology, RNA-sequencing (RNA-seq), bioinformatics analysis, and in vivo and in vitro experiments were used as integrated approaches to uncover the effects and mechanisms of action of STR. The introduction of STR significantly suppresses the proliferation and metastasis of HepG2 and Huh7 cells. STR treatment notably suppressed the growth of transplanted Huh7 tumors. Furthermore, STR administration reduced the expression of various epithelial-to-mesenchymal transition (EMT)-related proteins including N-cadherin, vimentin, and [Formula: see text]-catenin. By employing a systems biology approach, 21 common genes were identified across RNA-seq data, TCGA-HCC dataset, and network pharmacology analysis. Finally, of these genes nine were found to be associated with both OS and PFS in patients with HCC within the TCGA cohort. Validation of candidate genes by qPCR and WB identified a significant downregulation in the expression of pGSK3[Formula: see text] and RELA protein with increasing concentrations of STR. These results elucidated the mechanism by which STR inhibits tumor growth and EMT of HCC may be related to the GSK3[Formula: see text]/RELA pathway.

PMID:39721956 | DOI:10.1142/S0192415X24500964

J Chromatogr A. 2024 Dec 21;1741:465624. doi: 10.1016/j.chroma.2024.465624. Online ahead of print.

ABSTRACT

Odor-active compounds are major quality parameters in food and other consumer products. In the analysis of odorants, gas chromatography (GC) plays a dominant role and is particularly indispensable for odorant screening by GC-olfactometry (GC-O). Whereas artifact formation during workup before GC analysis has been widely discussed, artifact formation during GC injection has not been adequately addressed so far. Using a set of 14 test compounds, we evaluated ten different GC injection approaches. Artifact-producing reactions were particularly 1,2-eliminations. Linalyl acetate additionally showed [1,3]-sigmatropic shifts. On-column injection was confirmed as the gold standard, with virtually zero artifact formation observed not only with classic cold on-column injection in the oven, but also with on-column injection in a programmable temperature vaporizing (PTV) injector. Substantial artifact formation was observed when a high fixed injector temperature was combined with splitless injection. This applied to the injection of liquid samples but even more so to headspace solid-phase microextraction (HS-SPME) approaches. In conclusion, we recommend using on-column injection whenever aiming at a representative odorant spectrum, such as in GC-O. In targeted analysis, critical approaches such as SPME should be carefully tested for artifact formation. For the evaluation of the artifact formation potential of different injection approaches, cedryl acetate emerged as an excellent test compound.

PMID:39721401 | DOI:10.1016/j.chroma.2024.465624

Front Pharmacol. 2024 Dec 10;15:1535754. doi: 10.3389/fphar.2024.1535754. eCollection 2024.

NO ABSTRACT

PMID:39720594 | PMC:PMC11666486 | DOI:10.3389/fphar.2024.1535754

Mol Ther Oncol. 2024 Nov 23;32(4):200908. doi: 10.1016/j.omton.2024.200908. eCollection 2024 Dec 19.

ABSTRACT

Patients with osteosarcoma (OS), a debilitating pediatric bone malignancy, have limited treatment options to combat aggressive disease. OS thrives on insulin growth factor (IGF)-mediated signaling that can facilitate cell proliferation. Previous efforts to target IGF-1R signaling were mostly unsuccessful, likely due to compensatory signaling through alternative splicing of the insulin receptor (IR) to the proliferative IR-A isoform. Here, we leverage splice-switching oligonucleotides (SSOs) to mitigate IR splicing toward the IR-B isoform. We show that SSOs can modulate cancer cell hallmarks and anoikis-resistant growth. Furthermore, we engineered the SSO sequence in an U7 snRNA packaged in an adeno-associated virus (AAV) to test the feasibility of viral vector-mediated gene therapy delivery. We noted modest increases in IR-B isoform levels after virus transduction, which prompted us to investigate the role of combinatorial treatments with dalotuzumab, an anti-IGF-1R monoclonal antibody. After observing additive impacts on phosphoprotein phosphorylation and anoikis-resistant growth with the dalotuzumab and SSO combination, we treated OS cells with dalotuzumab and the AAVrh74.U7 snRNA IR virus, which significantly slowed OS cell proliferation. While these viruses require further optimization, we highlight the potential for SSO therapy and viral vector delivery, as it may offer new treatment avenues for OS patients and be translated to other cancers.

PMID:39720325 | PMC:PMC11666956 | DOI:10.1016/j.omton.2024.200908

Cell Mol Biol Lett. 2024 Dec 24;29(1):157. doi: 10.1186/s11658-024-00676-5.

ABSTRACT

Gastric cancer (GC) represents a prevalent malignancy globally, often diagnosed at advanced stages owing to subtle early symptoms, resulting in a poor prognosis. Exosomes are extracellular nano-sized vesicles and are secreted by various cells. Mounting evidence indicates that exosomes contain a wide range of molecules, such as DNA, RNA, lipids, and proteins, and play crucial roles in multiple cancers including GC. Recently, with the rapid development of mass spectrometry-based detection technology, researchers have paid increasing attention to exosomal cargo proteins. In this review, we discussed the origin of exosomes and the diagnostic and prognostic roles of exosomal proteins in GC. Moreover, we summarized the biological functions of exosomal proteins in GC processes, such as proliferation, metastasis, drug resistance, stemness, immune response, angiogenesis, and traditional Chinese medicine therapy. In summary, this review synthesizes current advancements in exosomal proteins associated with GC, offering insights that could pave the way for novel diagnostic and therapeutic strategies for GC in the foreseeable future.

PMID:39719600 | DOI:10.1186/s11658-024-00676-5

Commun Biol. 2024 Dec 25;7(1):1699. doi: 10.1038/s42003-024-07404-x.

ABSTRACT

Mental health disorders emerge from complex interactions among neurobiological processes across multiple scales, which poses challenges in uncovering pathological pathways from molecular dysfunction to neuroimaging changes. Here, we proposed a multiscale fusion (mFusion) method to evaluate the relevance of each gene to the neuroimaging traits of mental health disorders. We combined gene-neuroimaging associations with gene-positron emission tomography (PET) and PET-neuroimaging associations using protein-protein interaction networks, where various genes traced by PET maps are involved in neurotransmission. Compared with previous methods, the proposed algorithm identified more disease genes on both simulated and empirical data sets. Applying mFusion to eight mental health disorders, we found that these disorders formed three clusters with distinct associated genes. In summary, mFusion is a promising tool of prioritizing genes for mental health disorders by establishing gene-PET-neuroimaging pathways.

PMID:39719509 | DOI:10.1038/s42003-024-07404-x

BMJ Open Diabetes Res Care. 2024 Dec 24;12(6):e004506. doi: 10.1136/bmjdrc-2024-004506.

ABSTRACT

INTRODUCTION: Lifestyle determinants of 2-hour glucose concentration in people with type 2 diabetes and interindividual differences need to be identified.

RESEARCH DESIGN AND METHODS: 38 participants with type 2 diabetes, treated with lifestyle advice and/or metformin, tracked their physical activity, sleep and dietary intake, while continuously monitoring interstitial glucose concentrations for 11 periods of four consecutive days each. A linear mixed-effects model was used to quantify the effect of sleep, stress, current glucose, carbohydrate intake and exercise on glucose levels 2 hours later.

RESULTS: The final model identified carbohydrate intake (grams) in the past 5 min as well as in the past 30 min, sleep duration during the previous night (hours) and physical activity (metabolic equivalents) over the past 12 hours as significant fixed effects that influenced glucose concentrations 2 hours later. In addition, carbohydrate intake in the past 5 and past 30 min, and physical activity in the past and future 30 min were included as random or individualized effects. Although carbohydrate intake led to increased glucose concentrations in 2 hours in all individuals, the magnitude of this effect varied between individuals. The physical activity on glucose concentrations in 2 hours varied among individuals as well, in terms of magnitude and in terms of direction (showing either increase or decline).

CONCLUSIONS: Carbohydrate intake, sleep and physical activity at specific points in time have both fixed as well as individualized effects on glucose concentrations 2 hours later in individuals with type 2 diabetes. Interindividual differences in glycemic response to lifestyle components call for personalized advice in the management of type 2 diabetes.

PMID:39719391 | DOI:10.1136/bmjdrc-2024-004506

Exp Neurol. 2024 Dec 22:115128. doi: 10.1016/j.expneurol.2024.115128. Online ahead of print.

ABSTRACT

tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5'tiRNAGly-GCC, which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5'tiRNAGly-GCC revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5'tiRNAGly-GCC binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5'tiRNAGly-GCC is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.

PMID:39719207 | DOI:10.1016/j.expneurol.2024.115128

Neuro Oncol. 2024 Dec 24:noae233. doi: 10.1093/neuonc/noae233. Online ahead of print.

NO ABSTRACT

PMID:39718993 | DOI:10.1093/neuonc/noae233

Nucleic Acids Res. 2024 Dec 24:gkae1265. doi: 10.1093/nar/gkae1265. Online ahead of print.

ABSTRACT

Homologous recombination is a key evolutionary force that varies considerably across bacterial species. However, how the landscape of homologous recombination varies across genes and within individual genomes has only been studied in a few species. Here, we used Approximate Bayesian Computation to estimate the recombination rate along the genomes of 145 bacterial species. Our results show that homologous recombination varies greatly along bacterial genomes and shapes many aspects of genome architecture and evolution. The genomic landscape of recombination presents several key signatures: rates are highest near the origin of replication in most species, patterns of recombination generally appear symmetrical in both replichores (i.e. replicational halves of circular chromosomes) and most species have genomic hotspots of recombination. Furthermore, many closely related species share conserved landscapes of recombination across orthologs indicating that recombination landscapes are conserved over significant evolutionary distances. We show evidence that recombination drives the evolution of GC-content through increasing the effectiveness of selection and not through biased gene conversion, thereby contributing to an ongoing debate. Finally, we demonstrate that the rate of recombination varies across gene function and that many hotspots of recombination are associated with adaptive and mobile regions often encoding genes involved in pathogenicity.

PMID:39718992 | DOI:10.1093/nar/gkae1265

J Clin Invest. 2024 Dec 24:e174249. doi: 10.1172/JCI174249. Online ahead of print.

ABSTRACT

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.

PMID:39718828 | DOI:10.1172/JCI174249

Mol Biol Cell. 2024 Dec 24:mbcE24060245. doi: 10.1091/mbc.E24-06-0245. Online ahead of print.

ABSTRACT

The question of how changes in chemoattractant concentration translate into the chemotactic response of immune cells serves as a paradigm for the quantitative understanding of how cells perceive and process temporal and spatial information. Here, using a microfluidic approach, we analyzed the migration of neutrophil-like HL-60 cells to a traveling wave of the chemoattractants fMLP and leukotriene B4 (LTB4). We found that under a pulsatile wave that travels at a speed of 95 and 170 µm/min, cells move forward in the front of the wave but slow down and randomly orient at the back due to temporal decrease in the attractant concentration. Under a slower wave, cells re-orient and migrate at the back of the wave; thus, cell displacement is canceled out or even becomes negative as cells chase the receding wave. FRET-based analysis indicated that these patterns of movement correlated well with spatiotemporal changes in Cdc42 activity. Furthermore, pharmacological perturbations showed that (re-)orientation in front and back of the wave had different susceptibility to Cdc42 and ROCK inhibition. These results suggest that pulsatile attractant waves may recruit or disperse neutrophils, depending on their speed and degree of cell polarization.

PMID:39718770 | DOI:10.1091/mbc.E24-06-0245

Plant Cell Environ. 2024 Dec 24. doi: 10.1111/pce.15347. Online ahead of print.

ABSTRACT

Lymantria xylina is the most important defoliator, damaging the effective coastal windbreak tree species Casuarina equisetifolia. However, the underlying genetic mechanisms through which C. equisetifolia responds to L. xylina attacks remain unknown. Here, we compared the transcriptional, phytohormone and metabolic differences between susceptible (S) and resistant (R) C. equisetifolia cultivars in response to L. xylina feeding. The main L. xylina-induced resistance in C. equisetifolia was a jasmonate (JA) response and JA synthesis was highly induced by L. xylina feeding at both the transcriptional and metabolic levels, thus promoting flavonoid accumulation. The JA response was highly activated by L. xylina feeding on the R but not in the S cultivar, although the JA signalling pathway was intact in both cultivars. We found a single amino acid mutation in the homologues of glutamate receptor-like protein 3.6 (CeGLR3.6T807I) in the S cultivar. Compared with the GLR3.6 homologues in the R cultivar, phosphorylation of CeGLR3.6T807I was not induced by insect feeding, leading to a decreased JA response in the S cultivar. Collectively, this study provides new insights into the function of CeGLR3.6 in regulating the JA response of C. equisetifolia to L. xylina feeding.

PMID:39718115 | DOI:10.1111/pce.15347

Biomed Khim. 2024 Dec;70(6):394-402. doi: 10.18097/PBMC20247006394.

ABSTRACT

Anuclear blood cells, platelets, are the basis for the formation of blood clots in human vessels. While antiplatelet therapy is most often used after ischemic events, there is a need for its personalization due to the limited effectiveness and risks of bleeding. Previously, we developed a series of computational models to describe intracellular platelet signaling and a set of experimental methods to characterize the platelets of a given patient. To build a personalized model of platelet signaling, we also conducted research on platelet proteomics. The aim of this study was to personalize the central module of intracellular platelet signaling responsible for the formation of calcium oscillations in response to activation. The model consists of 26 ordinary differential equations. To personalize the model, proteomics data were used and unknown model parameters were selected based on experimental data on the shape and frequency of calcium oscillations in single platelets. As a result of the study, it has been shown that the key personalized parameters of the platelet oscillatory response are the degree of asymmetry of a single calcium spike and the maximum frequency of oscillations. Based on the listed experimentally determined parameters and proteomics data, an algorithm for personalization of the model has been proposed. Here we considered three healthy pediatric donors of different ages. Based on the models, personal curves of platelet calcium response to activation were obtained. The analysis of the models has shown that while there is a large heterogeneity of individual indicators of intracellular signaling, such as the activity of calcium pumps (SERCA) and inositoltriphosphate (IP₃) receptors (IP₃R), these indicators compensate each other in each donors. This observation is confirmed by the analysis of proteomics data from 15 healthy patients: this analysis demonstrates a correlation between the total amount of SERCA and IP₃R. Thus, several new features of human platelet calcium signaling are shown and an algorithm for personalizing its model is proposed.

PMID:39718102 | DOI:10.18097/PBMC20247006394

Biomed Khim. 2024 Dec;70(6):381-393. doi: 10.18097/PBMC20247006381.

ABSTRACT

The review summarizes recent achievements and future prospects in the use of chronobiotics for regulating circadian rhythms regulation. Special attention is paid to the mechanisms' action, their classification, and the impact of chemical interventions on the biological clock. Chronobiotics defined as a diverse group of compounds capable of restoring disrupted circadian functions, addressing challenges such as irregular work schedules, artificial light exposure or ageing. The review categorizes these compounds by their pharmacological effects, molecular targets, and chemical structures, underlining their ability to enhance or inhibit key circadian components like CLOCK, BMAL1, PER, and CRY. A particular focus is placed on the therapeutic applications of chronobiotics, including their potential for treating sleep disorders, metabolic issues, and age-related rhythm disturbances, underscoring their wide-ranging applicability in health care. Chronobiotic compounds have promising roles in maintaining physiological rhythms, supporting healthy aging, and enhancing personalised health care. Given their diverse therapeutic potential, chronobiotics are positioned as a significant avenue for further clinical application, marking them as a crucial area of ongoing research and innovation.

PMID:39718101 | DOI:10.18097/PBMC20247006381

Elife. 2024 Dec 24;13:RP99833. doi: 10.7554/eLife.99833.

ABSTRACT

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the receptor binding motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in variants of concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 were detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

PMID:39717902 | DOI:10.7554/eLife.99833