Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 541 records · Page 30Linked to original sources

bioRxiv2024

Interpreting prediction intervals and distributions for decoding biological generality in meta-analyses

Despite the importance of identifying predictable regularities for knowledge transfer across contexts, the generality of ecological and evolutionary findings is yet to be systematically quantified. We present the first large-scale evaluation of generality using new metrics. By focusing on biologically relevant study levels, we show that generalization is not uncommon. Overall, 20% of meta-analyses will produce a non-zero effect 95% of the time in future replication studies with a 70% probability of observing meaningful effects in study-level contexts. We argue that the misconception that generalization is exceedingly rare is due to conflating within-study and between-study variances in ecological and evolutionary meta-analyses, which results from focusing too much on total heterogeneity (the sum of within-study and between-study variances). We encourage using our proposed approach to elucidate general patterns underpinning ecological and evolutionary phenomena.

ecology↗

bioRxiv2024

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

bioRxiv2024

Cell-type-specific splicing of transcription regulators and Ptbp1 by Rbfox1/2/3 in the developing neocortex

How master splicing regulators crosstalk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq of the developing neocortex uncover that transcription regulators are enriched for differential splicing, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glia progenitors induces neuronal splicing events preferentially in transcription regulators such as Meis2 and Tead1. Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon in Ptbp1. Simultaneous ablation of Rbfox1/2/3 in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform of Meis2 promotes Tgfb3 transcription, while the Meis2 neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex.

developmental biology↗

bioRxiv2024

A stable 15-member bacterial SynCom promotes Brachypodium growth under drought stress

Rhizosphere microbiomes are known to drive soil nutrient cycling and influence plant fitness during adverse environmental conditions. Field-derived robust Synthetic Communities (SynComs) of microbes that mimic the diversity of rhizosphere microbiomes can greatly advance a deeper understanding of such processes. However, assembling stable, genetically tractable, reproducible, and scalable SynComs remains challenging. Here, we present a systematic approach using a combination of network analysis and cultivation-guided methods to construct a 15-member SynCom from the rhizobiome of Brachypodium distachyon. This SynCom incorporates diverse strains from five bacterial phyla and demonstrates strong stability both in vitro and in planta. Genomic analysis of the individual strains revealed that they encode multiple plant growth-promoting traits, some of which were validated by laboratory phenotypic assays. Additionally, most strains encoded genes both for the synthesis of osmoprotectants (trehalose and betaine) and Na+/K+ transporters. These traits likely enabled the resilience of Brachypodium to drought stress where plants amended with SynCom recovered better than without. We further observed preferential colonization of SynCom strains around root tips under stress, likely due to active interactions between plant root metabolites and bacteria. Our results represent significant progress towards building and testing stable model SynComs for a better understanding of plant-microbe interactions.

microbiology↗

bioRxiv2024

Photochemical processes drive thermal responses of dissolved organic matter in the dark ocean

How dissolved organic matter (DOM) responds to climate warming is critical for understanding its role in future ocean carbon cycling. Here, we use a highly resolved dataset of over 800 DOM samples covering the surface waters to the deep Atlantic, Southern, and Pacific oceans to examine the changes in DOM molecular composition in response to warming water temperatures, referred to as DOM thermal responses. Towards the deep waters, the strength (i.e., overall magnitude) and diversity (i.e., variation among molecules) of these thermal responses both decline. However, these responses show opposite trends with the concentration of more recalcitrant molecules, decreasing and increasing, respectively. These contrasting trends concur with the observation that, compared to the strength of thermal responses, their diversity is more strongly explained by photochemical processes of DOM. By projecting global ocean thermal responses from 1950 to 2020 using environmental temperature, salinity and radiation, we predict that increases in the diversity of thermal responses are unexpectedly largest at deeper depths (> 1,000 m). Such increases could elevate the recalcitrant deep-ocean carbon sink by approximately 10 Tg C yr-1, which accounts for > 5% of the carbon flux reaching and persisting in the deep ocean. Our findings highlight the role of photochemical processes in imprinting DOM thermal responses, offering new insights into the future capacity of the oceanic carbon sink under global climate change.

ecology↗

bioRxiv2024

Quantitative site-specific glycoproteomics by ZenoTOF reveals glyco-signatures for breast cancer diagnosis

Intact glycopeptide characterization by mass spectrometry has proven a versatile tool for site-specific glycoproteomics analysis and biomarker screening. Here, we present a method using the ZenoTOF instrument with optimized fragmentation for intact glycopeptide identification and demonstrate its ability to analyze large-cohort glycoproteomes. From 124 clinical serum samples of breast cancer, non-cancerous diseases, and non-disease controls, a total of 6901 unique site-specific glycans on 807 gly-cosites of proteins were detected. Much more differences of glycoproteome were observed in breast diseases than the proteome. By employing machine learning, 15 site-specific glycans were determined as potential glyco-signatures in detecting breast cancer. The results demonstrate that our method provides a powerful tool in glycoproteomic analyses for biomarker discovery studies.

cancer biology↗

bioRxiv2024

Endophilin A1 facilitates organization of the GABAergic postsynaptic machinery to maintain excitation-inhibition balance

The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits and the lack of typical postsynaptic dense structure, there are relatively few studies on the regulatory mechanisms for inhibitory synaptic structure and function, and insufficient understanding of the cellular and molecular abnormalities of inhibitory synapses in neurological and neuropsychiatric disorders. Here, we report a crucial role for endophilin A1 in inhibitory synapses. We show that endophilin A1 directly interacts with the inhibitory postsynaptic scaffold protein gephyrin in excitatory neurons, and promotes organization of the inhibitory postsynaptic density and synaptic recruitment/stabilization of the {gamma}-aminobutyric acid type A receptors via its plasma membrane association and actin polymerization promoting activities. Loss of endophilin A1 by gene knockout in mouse hippocampal CA1 pyramidal cells weakens inhibitory synaptic transmission and causes imbalance in the excitatory/inhibitory function of neural circuits, leading to increased susceptibility to epilepsy. Our findings identify endophilin A1 as an iPSD component and provide new insights into the organization and stabilization of inhibitory postsynapses to maintain E/I balance as well as the pathogenesis of epilepsy.

neuroscience↗

bioRxiv2024

Mechanosensing by Piezo1 regulates osteoclast differentiation via PP2A-Akt axis in periodontitis

Mechanical stimulus to the multicellular bone unit (MBU) plays a key role in normal bone remodeling, whereas disuse osteoporosis, for example, represents loss of bone owing to lack of mechanical stresses. The analogy can be applied to a variety of pathogenic bone lytic complications, including periodontitis, in which local mechanical stress appears to be diminished. The activation of mechanosensitive Piezo1 Ca2+ channel expressed by osteoblasts and osteocytes in the MBU elicits the osteogenic signals in those cells. However, since osteoclast (OC)-specific Piezo1-gene knockout mice showed no skeletal phenotype, it has been assumed that Piezo1 might not play any role in OC-mediated bone remodeling. Here, however, we showed that mechanical stimulation of Piezo1 expressed on preosteoclasts (pre-OCs) downmodulates OC formation and, hence, bone resorptive activity in periodontitis, accompanied by significantly reduced expression of NFATc1, a master transcription factor for RANKL-induced OC-genesis. We know that the Ca2+/calcineurin/NFAT axis upregulates NFATc1 activation in pre-OCs. Interestingly, Piezo1-elicited Ca2+ influx did not affect NFATc1 expression. Instead, PP2A-mediated dephosphorylation of Akt downregulated NFATc1 in Piezo1-activated pre-OCs. However, systemic administration with Yoda1, a Piezo1 chemical agonist, or local injection of PP2A agonist, significantly downregulated the bone resorption induced in a mouse model of periodontitis, together with reduced numbers of TRAP+/phospho-Akt+ pre-OCs in local bone. These results suggest that mechanosensing by Piezo1 expressed on pre-OCs can downmodulate the RANKL-induced OC-genesis via the PP2A/Akt-dephosphorylation pathway, but that such Piezo1-mediated downregulation of bone resorption is attenuated in periodontitis. Significance StatementThe mechanosensitive Ca2+ channel Piezo1 plays important regulatory roles in a variety of cellular activities. RANKL-mediated OC-genesis requires permissive co-stimulatory signal from ITAM receptors, such as OSCAR and TREM2, to trigger the calcineurin/calmodulin signaling axis via Ca2+ oscillation, thereby upregulating NFATc1 expression. Activation of Piezo1 remarkably suppressed RANKL-induced NFATc1 activation which, in turn, reduced OC-genesis. Such mechanical activation of Piezo1 expressed on pre-OCs induced intracellular Ca2+ influx. Nonetheless, PP2A-mediated dephosphorylation of Akt, not the calcineurin/calmodulin pathway, suppressed NFATc1 in RANKL-elicited OC-genesis and resultant bone resorption, both in vitro and in vivo. These results indicate that mechanostress applied to pre-OCs can downregulate pathogenic OC-genesis and that Piezo1, as the mediator, is a novel molecular target for the development of anti-osteolytic therapies.

cell biology↗

bioRxiv2024

Histone serves as an eat-me signal to induce RAGE-mediated phagocytosis

The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can induce phagocytosis in both professional and nonprofessional phagocytes. We found that histones are another ligand for RAGE. Binding between histones and RAGE is increased when DNA is attached to histones. While histones are chromosomal proteins in healthy cells, they are exposed to the cell surface as a complex with DNA when cells undergo apoptosis. The phagocytosis of apoptotic cells by either professional or nonprofessional phagocytes is enhanced when histones are present on the surface of apoptotic cells. Thus, histones serve as eat-me signals. In RAGE knockout cells, the phagocytosis of apoptotic cells was not influenced by the removal of histones, indicating that RAGE is required for the removal of histones from histone-presenting cells. In RAGE knockout mice, wound healing and removal of apoptotic cells from wound sites are delayed, suggesting that RAGE-mediated phagocytosis functions under physiological conditions.

cell biology↗

bioRxiv2024

Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitination

Ubiquitin (Ub) is a post-translational modification that largely controls proteostasis through mechanisms spanning transcription, translation, and notably, protein degradation. Ub conjugation occurs through a hierarchical cascade of three enzyme classes (E1, E2, and E3s) involving >1000 proteins that regulate the ubiquitination of proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized, partly due to a lack of inhibitors. For example, the cellular roles of the promiscuous E2 UBE2D/UBCH5 are not well described. Here, we develop a highly selective, multivalent, engineered protein inhibitor for the UBE2D family that simultaneously targets the RING- and backside-binding sites. In HeLa cells, these inhibitors phenocopy knockdown of UBE2D by reducing the IC50 to cisplatin and whole-cell proteomics reveal an increased abundance of [~]20% of the identified proteins, consistent with reduced Ub degradation and proteotoxic stress. These precision tools will enable new studies probing UBE2Ds central role in proteome management.

biochemistry↗

bioRxiv2024

SLC35A2 modulates paramyxovirus fusion events during infection

Paramyxoviruses are significant human and animal pathogens that include mumps virus (MuV), Newcastle disease virus (NDV) and the murine parainfluenza virus Sendai (SeV). Despite their importance, few host factors implicated in paramyxovirus infection are known. Using a recombinant SeV expressing destabilized GFP (rSeVCdseGFP) in a loss-of-function CRISPR screen, we identified the CMP-sialic acid transporter (CST) gene SLC35A1 and the UDP-galactose transporter (UGT) gene SLC35A2 as essential for paramyxovirus infection. SLC35A1 knockout (KO) cells showed significantly reduced binding and infection of SeV, NDV and MuV due to the lack of cell surface sialic acids, which act as their receptors. However, SLC35A2 KO cells revealed unknown critical roles for this factor in virus-cell and cell-to-cell fusion events during infection with different paramyxoviruses. While the UGT was essential for virus-cell fusion during SeV entry to the cell, it was not required for NDV or MuV entry. Importantly, the UGT promoted the formation of larger syncytia during MuV infection, suggesting a role in cell-to-cell virus spread. Our findings demonstrate that paramyxoviruses can bind to or enter A549 cells in the absence of canonical galactose-bound sialic-acid decorations and show that the UGT facilitates paramyxovirus fusion processes involved in entry and spread.

microbiology↗

bioRxiv2024

NRH, a potent NAD+ booster, improves glucose homeostasis and lipid metabolism in diet-induced obese mice though an active adenosine kinase pathway.

NAD+ deficiency underlies obesity-induced metabolic disturbances. Here we evaluated the treatment effect of a new and potent NAD+ enhancer, dihydronicotinamide riboside (NRH), in diet-induced obese mice with hyperglycemia and hyperlipidemia. Administering NRH for 7 weeks improved glucose homeostasis by enhancing pancreatic beta-cell functional mass, increasing muscle insulin sensitivity, and reducing hepatic gluconeogenesis. NRH treatment also mobilized fat deposition, reduced circulating lipid, and improved white adipose function. Significant elevation in multi-tissue NAD+ levels and sirtuin (SIRT) activities, especially SIRT3, mediated these metabolic improvements. Inhibiting adenosine kinase (ADK), a newly recognized enzyme in the NRH-induced NAD+ synthesis pathway, blocked NRHs effect in improving glucose and lipid metabolism. ADK inhibition also reduced tissue NAD+ elevation and the subsequent activation of SIRT3, suggesting an active ADK pathway is necessary for NRH-induced metabolic benefits. These observations, for the first time, establish NRH as a promising intervention for correcting obesity-induced metabolic syndrome.

pharmacology and toxicology↗

bioRxiv2024

Temporally discordant chromatin accessibility and DNA demethylation define short and long-term enhancer regulation during cell fate specification

Epigenetic mechanisms govern the transcriptional activity of lineage-specifying enhancers; but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly-resolved timeline of DNA demethylation, chromatin accessibility, and transcription factor occupancy during neural progenitor cell differentiation. We show thousands of enhancers undergo rapid, transient accessibility changes associated with distinct periods of transcription factor expression. However, most DNA methylation changes are unidirectional and delayed relative to chromatin dynamics, creating transiently discordant epigenetic states. Genome-wide detection of 5-hydroxymethylcytosine further revealed active demethylation begins ahead of chromatin and transcription factor activity, while enhancer hypomethylation persists long after these activities have dissipated. We demonstrate that these timepoint specific methylation states predict past, present and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to mediate short and long-term enhancer regulation during cell fate specification.

genomics↗

bioRxiv2024

Tactile Mechanisms and Afferents Underlying the Rat Pup Transport Response

Juvenile rodents and other altricial mammals react with calming, immobility and folding up of feet to parental pickup, a set of behaviors referred to as transport response. Here we investigate sensory mechanisms underlying the rat transport response. Grasping rat pups in anterior neck positions evokes strong immobility and folding up of feet, whereas more posterior grasping positions have lesser effects on immobility and foot position. Transport responses are enhanced by slow (1Hz) and even more so by fast (4Hz) gentle shaking and translation of the pup, features consistent with parental transport. In response to lateral grasping, the forepaw below the grasping position points downwards and the forepaw lateral to the grasping position points upwards and medially. Such forepaw adjustments put the pups center of gravity below the grasping point, optimizing pup transportability along with folding up of feet and tail lifting. Tactile stimuli on the back, belly, tail, whisker, dorsal forepaws and dorsal hind-paws do not significantly affect the behaviour of anterior-neck-held pups. Instead, ground contact or paw stimulation consistent with ground contact disrupts transport responses. We identify afferents mediating the transport response by examining membrane labelling with FM1-43 following anterior neck grasping. We observe a dense innervation of the anterior neck skin region ([~]30 terminals/ mm2). We also observed an age-related decrease of cytochrome oxidase reactivity in the rat somatosensory cortical neck representation, a possible correlate to the developmental decrease in the pup transport response. We conclude anterior neck grasping and loss of ground contact trigger calming and postural adjustments for parental transport in rat pups, responses putatively driven from the densely innervated anterior neck skin.

neuroscience↗

bioRxiv2024

OPUS-Design: Designing Protein Sequence from Backbone Structure with 3DCNN and Protein Language Model

Protein sequence design, also known as protein inverse folding, is a crucial task in protein engineering and design. Despite the recent advancements in this field, which have facilitated the identification of amino acid sequences based on backbone structures, achieving higher levels of accuracy in sequence recovery rates remains challenging. It this study, we introduce a two-stage protein sequence design method named OPUS-Design. Our evaluation on recently released targets from CAMEO and CASP15 shows that OPUS-Design significantly surpasses several other leading methods on both monomer and oligomer targets in terms of sequence recovery rate. Furthermore, by utilizing its finetune version OPUS-Design-ft and our previous work OPUS-Mut, we have successfully designed a thermal-tolerant double-point mutant of T4 lysozyme that demonstrates a residual enzyme activity exceeding that of the wild-type T4 by more than twofold when both are subjected to extreme heat treatment at 70{degrees}C. Importantly, this accomplishment is achieved through the experimental verification of less than 10 mutant candidates, thus significantly alleviating the burden of experimental verification process.

bioengineering↗

bioRxiv2024

Comprehensive Genomic and Evolutionary Analysis of Biofilm Matrix Clusters and Proteins in the Vibrio Genus

Vibrio cholerae pathogens cause cholera, an acute diarrheal disease resulting in significant morbidity and mortality worldwide. Biofilms in vibrios enhance their survival in natural ecosystems and facilitate transmission during cholera outbreaks. Critical components of the biofilm matrix include the Vibrio polysaccharides produced by the vps-1 and vps-2 gene clusters and the biofilm matrix proteins encoded in the rbm gene cluster, together comprising the biofilm matrix cluster. However, the biofilm matrix clusters and their evolutionary patterns in other Vibrio species remain underexplored. In this study, we systematically investigated the distribution, diversity, and evolution of biofilm matrix clusters and proteins across the Vibrio genus. Our findings reveal that these gene clusters are sporadically distributed throughout the genus, even appearing in species phylogenetically distant from V. cholerae. Evolutionary analysis of the major biofilm matrix proteins RbmC and Bap1 shows that they are structurally and sequentially related, having undergone structural domain and modular alterations. Additionally, a novel loop-less Bap1 variant was identified, predominantly represented in two phylogenetically distant Vibrio cholerae subspecies clades that share specific gene groups associated with the presence or absence of the protein. Furthermore, our analysis revealed that rbmB, a gene involved in biofilm dispersal, shares a recent common ancestor with Vibriophage tail proteins, suggesting that phages may mimic host functions to evade biofilm-associated defenses. Our study offers a foundational understanding of the diversity and evolution of biofilm matrix clusters in vibrios, laying the groundwork for future biofilm engineering through genetic modification.

evolutionary biology↗

bioRxiv2024

Low-cost and highly efficient generation of near-complete bacterial pathogen genomes by TELL-Seq

Recent evidences suggest that de novo genome assembly can provide additional insights into genomic variation landscape beyond short-read NGS analyses. Despite the advent of longread sequencing technologies, generating high-quality bacterial genome assemblies remains expensive and requires high-quality and large quantities of DNA. TELL-Seq, an emerging linked-read technology, has been reported as a low-cost alternative for producing nearcomplete genome assembly in certain bacterial species. However, a systematic assessment of its performance and characteristics in de novo bacterial genome assembly has not yet been conducted. To address this, we benchmarked TELL-Seq using a set of clinical and standard bacterial pathogens with a wide range of genome size (2.0 6.4 Mbp), GC-content (32% - 68%), genome complexity (mappability from 0.15 to 0.60) and Gram types. Our findings indicate that, with 1/6 cost and 1/15,000 of DNA compared to PacBio HiFi, TELL-Seq could generate as high quality near-complete bacterial genome assemblies. The optimal depth for assembly is around 200x, as increased depth improves contiguity and completeness, though quality plateaus at 250x. In general, genome complexity was significantly correlated with assembly quality, but GC-content was not. Nevertheless, genomes with extreme GC-content may require higher depths for accurate assembly. Our study suggests that TELL-Seq could be a scalable method for large-scale bacterial genomic surveys. The data generated from this study could serve as a benchmark dataset for further algorithm development. Impact StatementAn increasing body of literature have shown that de novo genome assembles could provide additional insights into genomic variation beyond standard short-read technologies. Its particularly useful in clinical and epidemiological studies of bacteria, due to high variable nature of their genomes. Although great advances have been made in long-read sequencing technology, its still expensive with high requirement over sample DNAs quality and quantity, limiting its adoption in large-scale studies or surveys. Linked-read technology is an inexpensive alternative which used single molecule barcoding to mark origin of reads for better scaffolding of contigs assembled from normal short reads. TELL-Seq, as one of these promising technologies, was reported to be able to inexpensively and efficiently generate near-complete bacterial de novo genomic assemblies with low DNA inputs. Theres not yet a systematic benchmarking of this technology in bacterial pathogens. In this study, a set of clinically important bacterial pathogens with a wide spectrum of GC-content, genome size, genome complexity, and Gram Type were used to investigate the performance of TELL-Seq technology in de novo genome assembly. We found that, with about 1/6 of cost and 1/15000 of DNA quantity, it could generate comparable de novo assemblies compared to standard reference genomes or PacBio HiFi assemblies, while beating conventional short-read assemblies. We found several key factors, such as genome complexity, and sequencing depth, which would impact the quality of the assembly. Our study suggests that a sequencing depth of 200x is sufficient to achieve satisfactory results. Our study has revealed characteristics of this technology in bacterial genome assembly and paved the way for its large-scale application in clinical or epidemiological surveys. Data SummaryO_LIRaw sequencing data for all isolates have been deposited to SRA, accessible through these NCBI BioProject PRJNA1133244. C_LIO_LIA full list of SRA BioSample accession numbers are available in Tab S5. C_LIO_LIAssemblies and analyses companion this paper is available at: https://github.com/x-lab/tellseq_bacteria C_LI

bioinformatics↗

bioRxiv2024

Multi-strategies embedded framework for neoantigen vaccine maturation

Effective cancer immunotherapy hinges on the precise recognition of neoantigens, presented as binary complexes with major histocompatibility complex (MHC) molecules, by T cell receptors (TCR). The development of immunogenic peptide predictors and generators plays a central role in personalizing immunotherapies while reducing experimental costs. However, the current methods often fall short in leveraging structural data efficiently and providing comprehensive guidance for neoantigen selection. To address these limitations, we introduce NEOM, a novel neoantigen maturation framework encompassing five distinct modules: "policy", "structure", "evaluation", "selection" and "filter". This framework is designed to enhance precision, interpretability, customizability and cost-effectiveness in neoantigen screening. We evaluated NEOM using a set of random synthetic peptides, followed by available clinically-derived peptides. NEOM achieved higher performance on generated peptide quality compared to other baseline models. Using established predictors for filtering revealed a substantial number of peptides with immunogenic potential. Subsequently, a more rigorous binding affinity evaluation using free energy perturbation methods identified 6 out of 38 candidates showing superior binding characteristics. MHC tetramer peptide exchange assays and flow cytometry experiments further validate five of them. These results demonstrate that NEOM not only excels in identifying diverse peptides with enhanced binding stability and affinity for MHC molecules but also augments their immunogenic potential, showcasing its utility in advancing personalized immunotherapies.

bioinformatics↗