Biology subjects

Park, M.

Publications and source records attributed to Park, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Effect of Terpenes from Poria Cocos: Verifying Modes of Action against Alzheimer's disease Using Molecular Docking, Drug-induced Transcriptomes and Diffusion Network

Poria cocos is used to treat various diseases because of its unique terpenes. However, no study verifying its modes of action using only its compounds based on in silico experiments has been conducted. Here, molecular docking and drug-induced transcriptome analyses were performed to confirm the modes of action of Poria cocos. Additionally, a diffusion network analysis method was proposed to confirm its modes of action against Alzheimers. First, Poria cocos terpenes were collected from standard databases for molecular docking. They were then used for large-scale molecular docking using druggable proteomes, and the modes of action of lanostane and seco-lanostane, unique to Poria cocos, were confirmed. Additionally, the brain cell line was treated with Poria cocos to produce Poria cocos-induced transcriptome data, and the transcriptome-based modes of action of Poria cocos were confirmed. Finally, a diffusion network was constructed using Alzheimers, which acts on both modes of action, and submodules of Alzheimers with which terpenes interact were identified. It was confirmed that Poria cocos acts on the Wnt signaling pathway, Zn-to-anterograde axonal transport, autophagy impairment, insulin and AGE-RAGE signaling pathways, and apoptosis mechanisms. This study identified the modes of action of Poria cocos using biological data and in silico methods.

bioinformatics↗

bioRxiv2023

Albumin-binding recombinant human IL-18BP ameliorates macrophage activation syndrome and atopic dermatitis via direct IL-18 inactivation

Given the clinical success of cytokine blockade in managing diverse inflammatory human conditions, this approach could be exploited for numerous refractory or uncontrolled inflammatory conditions by identifying novel targets for functional blockade. IL-18, a pro-inflammatory cytokine, is relatively underestimated as a therapeutic target, despite accumulated evidence indicating the unique roles of IL-18 in acute and chronic inflammatory conditions, such as macrophage activation syndrome. Herein, we designed a new form of IL-18 blockade, i.e., APB-R3, a long-acting recombinant human IL-18BP linked to human albumin-binding Fab fragment, SL335, for extending half-life. We then explored the pharmacokinetics and pharmacodynamics of APB-R3. In addition to an extended serum half-life, APB-R3 alleviates liver inflammation and splenomegaly in a model of the macrophage activation syndrome induced in IL-18BP knockout mice. Moreover, APB-R3 substantially controlled skin inflammation in a model of atopic dermatitis. Thus, we report APB-R3 as a new potent IL-18 blocking agent that could be applied to treat IL-18-mediated inflammatory diseases.

immunology↗

bioRxiv2023

Comparative study of the mechanism of natural compounds with similar structures using docking and transcriptome data for improving in silico herbal medicine experimentations

Natural products have successfully treated several diseases using a multi-component, multi-target mechanism. However, a precise mechanism of action has not been identified. Systems pharmacology methods have been used to overcome these challenges. However, there is a limitation as those similar mechanisms of similar components cannot be identified. In this study, comparisons of physicochemical descriptors, large-scale molecular docking analysis, and RNA-seq analysis were performed to compare the mechanisms of action of similar compounds and to confirm the changes observed when similar compounds were mixed and used. We propose an advanced method for in silico experiments in herbal medicine research based on the results. First, physicochemical descriptors were calculated based on the chemical structures of oleanolic acid (OA), hederagenin (HG), and gallic acid (GA). Similarities were confirmed by calculating the Euclidean, cosine, and Tanimoto distances between the descriptors. Next, the mechanisms of action of OA, HG, and GA were compared and confirmed through in silico-based systems pharmacology analysis using the BATMAN-TCM platform. The proteins interacting with the three compounds were verified through large-scale molecular docking analysis using the druggable proteome. Finally, a drug response transcriptome study was performed using OA, HG, GA, and a combination of OA and HG (COH) with similar structures.A comparison of physicochemical descriptors confirmed that OA and HG were very close. In particular, the two compounds showed a concordance rate of > 99% at cosine and Tanimoto distances. The systems pharmacology analysis results confirmed that OA and HG shared more than 86% of their predicted target proteins and differed only in GA. Systems pharmacology analysis revealed that OA and HG share the mechanisms of cardiac muscle contraction, oxidative phosphorylation, and non-alcoholic fatty liver disease. In a molecular docking analysis of the 50 major druggable proteins, OA and HG shared 38 proteins, while GA shared a few with proteins derived from the other two compounds. In addition, OA and HG were confirmed to act on gonadotropin-releasing hormone (GnRH) secretion, type 2 diabetes mellitus, cholinergic synapses, and calcium signaling pathways, and docking analysis visualization confirmed that the two components interact at the same site. RNA-seq analysis also showed that the differentially expressed genes and pathways derived from OA and HG were similar, and it was confirmed that COH had similar results to OA and HG. Our study has three novel findings. First, an advanced network pharmacology research method was suggested by partially presenting a solution to the difficulty in identifying multicomponent mechanisms. Second, a new natural product analysis method was proposed using large-scale molecular docking analysis. Finally, various biological data and analysis methods were used, such as in silico system pharmacology, docking analysis, and drug response RNA-seq. The results of this study are meaningful in that they suggest an analysis strategy that can improve existing systems pharmacology research analysis methods by showing that natural product-derived compounds with the same scaffold have the same mechanism.

bioinformatics↗

bioRxiv2023

Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), the presence of CD34 and lack of CD38 expression (CD34posCD38neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-{gamma} induces CD38 upregulation in LSC-enriched CD34posCD38neg AML blasts, but not in CD34posCD38neg HSCs. To leverage the IFN-{gamma} mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38pos blasts. Activated CD4pos and CD8pos T cells not only kill AML blasts but also produce IFN{gamma}, which leads to CD38 expression on CD34posCD38neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38neg and CD38pos AML blasts, which culminates in LSC depletion. Statement of significanceThis work represents a potential advancement in the treatment of AML, as it involves the release of IFN-{gamma} by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.

cancer biology↗

bioRxiv2022

Long-read genomes reveal pangenomic variation underlying yeast phenotypic diversity

Understanding the genetic causes of trait variation is a primary goal of genetic research. One way that individuals can vary genetically is through the existence of variable pangenomic genes - genes that are only present in some individuals in a population. The presence or absence of entire genes could have large effects on trait variation. However, variable pangenomic genes can be missed in standard genotyping workflows, due to reliance on aligning short-read sequencing to reference genomes. A popular method for studying the genetic basis of trait variation is linkage mapping, which identifies quantitative trait loci (QTLs), regions of the genome that harbor causative genetic variants. Large-scale linkage mapping in the budding yeast Saccharomyces cerevisiae has found thousands of QTLs affecting myriad yeast phenotypes. To enable the resolution of QTLs caused by variable pangenomic genes, we used long-read sequencing to generate highly complete de novo assemblies of 16 diverse yeast isolates. With these assemblies we resolved growth QTLs to specific genes that are absent from the reference genome but present in the broader yeast population at appreciable frequency. Copies of genes also recombine onto chromosomes where they are absent in the reference genome, and we found that these copies generate additional QTLs whose resolution requires pangenome characterization. Our findings demonstrate the power of long-read sequencing to identify the genetic basis of trait variation.

genomics↗

bioRxiv2022

Structural elements facilitate extreme long-range gene regulation at a human disease locus

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 megabases. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. While we observed pronounced changes in locus topology between cell-types, analysis of single chromatin fiber traces revealed that these ensemble-average differences arise not from the presence of cell-type unique conformations, but through changes in frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which are positioned near its 3D geometric center and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multiloop, centrally clustered geometry, suggesting a mechanism for gene regulation over ultralong ranges. Four short bullet points that convey the key message of the paperSOX9 domain topology dynamically changes during a developmental transition Structural elements promote TAD-wide interactions, stripe formation and transcription Structural elements are CTCF-dependent and situated centrally in the 3D TAD structure Polymer simulations of multi-loop model best recapitulate topological features

molecular biology↗

bioRxiv2022

Presymptomatic neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy

There is significant evidence suggesting aggregated misfolded alpha-synuclein, a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinsons disease (PD) and other synucleinopathies. Animal models are essential for understanding and developing treatments for these diseases. However, despite modelling human pathology, most endpoints studied in mice do not translate to humans. Furthermore, the progression by which alpha-synuclein misfolding affects human-relevant measures such as brain volume and underlying subtle, high-level cognitive deficits is poorly understood. Here we used a mouse model of synucleinopathy; hemizygous M83 human A53T alpha-synuclein transgenic mice inoculated with recombinant human alpha-synuclein preformed fibrils (PFF) injected in the right striatum to initiate alpha-synuclein misfolding and aggregation. We examined alpha-synuclein-induced atrophy at 90 days post-injection using ex vivo magnetic resonance imaging as well as high-level cognition and motor function, as biomarkers of alpha-synuclein toxicity. We observed widespread atrophy in bilateral regions that project to or receive input from the injection site, highlighting a network of regions that are consistent with structural changes observed in humans with PD. Moreover, we detected early deficits in reversal learning with touchscreen testing in PFF-injected mice prior to motor dysfunction, consistent with the pathology observed in cortical-striatal and thalamic loops. We show, using translational approaches in mice, that progression of prion-like spreading of alpha-synuclein causes selective atrophy via connected brain regions leading to high-level cognitive deficits. We propose that precise imaging and cognitive biomarkers can provide a more direct and human-relevant measurement of alpha-synuclein-induced toxicity in pre-clinical testing. Significance StatementThe work described in this manuscript showcases the utility of state-of-the-art methodologies (magnetic resonance imaging and touchscreen behavioural tasks) to examine endophenotypes, both in terms of symptomatology and neuroanatomy, of alpha-synuclein propagation in a mouse model of synucleinopathy. Our work further validates the M83-Hu-PFF mouse model of synucleinopathy-associated pathogenesis of neurodegenerative diseases while highlighting precise imaging and cognitive biomarkers of protein misfolding toxicity. Specifically, we identified rapid and translational biomarkers that can serve as a proxy for the direct examination of cellular levels for pathology. We anticipate that these biomarkers can measure progression of toxicity, specifically in the early phases, and may be more reliable than end stage pathology and more useful as endpoints in the examination of novel therapeutics.

neuroscience↗

bioRxiv2022

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway.

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials. Once sentence summaryPD-L1 promotes oncolytic virus efficacy.

cancer biology↗

bioRxiv2022

PML and PML-like exonucleases restrict retrotransposons in jawed vertebrates

We have uncovered a novel role for the promyelocytic leukemia (PML) gene and novel PML-like DEDDh exonucleases in the maintenance of genome stability through the restriction of LINE-1 (L1) retrotransposition in jawed vertebrates. Although the PML tumour suppressor protein in mammals is SUMOylated and forms nuclear bodies, we found that the spotted gar PML ortholog and related proteins in fish are not SUMOylated and function as cytoplasmic DEDDh exonucleases. In contrast, more closely related avian and turtle PML proteins are predicted to be SUMOylated and localized both to the cytoplasm and to nuclear bodies. We also identified PML-like exon 9 (Plex9) genes in teleost fishes that encode exonucleases sharing homology to gar PML. In an example of convergent evolution and akin to TREX1, gar PML and zebrafish Plex9 proteins suppressed L1 retrotransposition and could complement TREX1 knockout in mammalian cells. We also characterized the first non-mammalian TREX1 homologs in axolotl. Following export to the cytoplasm, the human PML-I isoform also restricted L1 through its conserved C-terminus and suppressed CGAS activation. Thus, PML first emerged as a cytoplasmic suppressor of retroelements, and this function is retained in amniotes despite its role in the assembly of nuclear bodies and the acquisition of SUMO-modification.

molecular biology↗

bioRxiv2022

Epstein-Barr virus nuclear antigen proteins deploy diverse mechanisms to bind the human genome

Viral transcription factors (vTFs) are known to bind the human genome and impact critical biological processes. However, a vTF can infect multiple cell-types, and the extent to which they deploy the same mechanisms for DNA binding across different cell-types is poorly understood. We used the Epstein-Barr virus Nuclear Antigen Proteins 2 and 3 (EBNA2 and EBNA3) to address this gap, the two widely studied vTFs associated with cancers, as case studies. We analyze multiple ChIP-seq datasets of these vTFs from different human cell-lines using a state-of-the-art convolutional neural network model. We show that each vTF uses both cell-type specific and cell-type independent cofactors to bind the human genome. Interestingly, each vTF requires [~]10 cofactors consistently across all binding peaks. Such dependency on a large number of cofactors is in contrast to human TFs since human TFs typically co-bind with 2-3 cofactors. Our de novo motif finding approach also reveals novel sequence motifs at the ChIP peaks of these vTFs. These critical signals were missed by previous studies doing enrichment analysis using known human TFs. Finally, we find that although a vTF impacts similar biological processes across cell-types, it also impacts distinct biological processes in a cell-type specific manner. Our study provides a roadmap for integrative analysis of vTF binding and pinpointing their diverse mechanisms of targeting the human genome across different human cell-types.

genomics↗

bioRxiv2022

Beyond TADs: microscopy reveals 2 axes of chromosome organization by CTCF and cohesin

While population level analyses reveal significant roles for CTCF and cohesin in mammalian genome organization, their contribution to chromatin structure and gene regulation at the single-cell level remain incompletely understood 1-4. Here, we use a super-resolution microscopy approach, Optical Reconstruction of Chromatin Architecture (ORCA) 5 to measure the effects of removal of CTCF or cohesin on genome folding across genomic scales. In untreated embryonic stem cells, we observe intricate, frequently stacked loops of chromatin which are largely dissolved upon cohesin removal. The loops compact chromatin at the < 3 Mb scale, increasing proximity between sequences not only within but also between TADs. We find multi-way contacts among loop anchors, preferentially at TAD borders, and these hubs largely dissolve upon CTCF degradation. CTCF-hubs bridge intervening TAD boundaries while keeping border distal regions from neighboring TADs apart outside the hub. Cohesin dependent loops at the < 3 Mb scale impede mixing at larger chromosomal scales through steric effects of loop stacking, dramatically reducing genomic cross-talk. Disruption of this ordered chromosomal structure led to increased cell-cell variability in gene expression, exceeding changes to average expression. Together our data revise the TAD-centric understanding of CTCF and cohesin, and provide a multi-scale, structural picture of how they organize the genome on the single-cell level through distinct contributions to loop stacking.

biophysics↗

bioRxiv2022

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Protection from SARS-related coronaviruses with spillover potential and SARS-CoV-2 variants could prevent and/or end pandemics. We show that mice immunized with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicit cross-reactive anti-sarbecovirus antibodies against conserved class 1/4 and class 3 RBD epitopes. Monoclonal antibodies (mAbs) identified from initial screening of <10,000 single B-cells secreting IgGs binding two or more sarbecovirus RBDs showed cross-reactive binding and neutralization of SARS-CoV-2 variants and animal sarbecoviruses. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes and revealed neutralization mechanisms, potentials for intra-spike trimer crosslinking by single IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticles to identify therapeutic pan-sarbecovirus and pan-variant mAbs and to elicit them by vaccination.

immunology↗

bioRxiv2022

HMMerge: an Ensemble Method for Improving Multiple Sequence Alignment

Despite advances in method development for multiple sequence alignment over the last several decades, the alignment of datasets exhibiting substantial sequence length heterogeneity, especially when the input sequences include very short sequences (either as a result of sequencing technologies or of large deletions during evolution) remains an inadequately solved problem. We present HMMerge, a method to compute an alignment of datasets exhibiting high sequence length heterogeneity, or to add short sequences into a given "backbone" alignment. HMMerge builds on the technique from its predecessor alignment methods, UPP and WITCH, which build an ensemble of HMMs for the backbone alignment and add the remaining sequences into the backbone alignment using the ensemble. HMMerge differs from UPP and WITCH by building a new HMM for each query sequence: it uses a novel ensemble approach to combine the HMMs, each weighted by the probability of generating the query sequence, into a single HMM. Then it applies the Viterbi algorithm to add the query sequence into the backbone alignment. We show that using this "merged" HMM provides better accuracy than the current approach in UPP and matches or improves on WITCH for adding short sequences into backbone alignments. HMMerge is freely available at https://github.com/MinhyukPark/HMMerge.

bioinformatics↗

bioRxiv2022

Development of fluoroquinolone resistance through antibiotic tolerance in Campylobacter jejuni

Antibiotic tolerance not only enables bacteria to survive under acute antibiotic exposures but also provides bacteria with a window of time to develop antibiotic resistance. Campylobacter jejuni is increasingly resistant to clinically important antibiotics, particularly fluoroquinolones (FQs). Currently, little is known about antibiotic tolerance and its effects on resistance development in C. jejuni. Here, we show that exposure to ciprofloxacin and tetracycline at concentrations 10 and 100 times higher than the minimum inhibitory concentration (MIC) induce antibiotic tolerance in C. jejuni, whereas gentamicin and erythromycin treatment cause cell death. Interestingly, FQ resistance is rapidly developed in C. jejuni after tolerance induction by ciprofloxacin and tetracycline. Furthermore, alkyl hydroperoxide reductase plays a critical role in preventing FQ resistance development in C. jejuni during antibiotic tolerance by alleviating oxidative stress. Together, these results demonstrate that exposure of C. jejuni to antibiotics used to treat campylobacteriosis can induce antibiotic tolerance and that FQ-resistant (FQR) C. jejuni rapidly emerges through tolerance induction by FQs and non-FQ antibiotics. Work presented in this study shows mechanisms underlying the high prevalence of FQR C. jejuni and provides an insight into the effects of antibiotic tolerance on resistance development. ImportanceAntibiotic tolerance compromises the efficacy of antibiotic treatment by extending bacterial survival and developing mutations associated with antibiotic resistance. Despite growing public health concerns about antibiotic resistance in C. jejuni, antibiotic tolerance has not yet been investigated in this important zoonotic pathogen. Here, our results show that exposure of C. jejuni to ciprofloxacin and tetracycline, a common agricultural antibiotic, develops antibiotic tolerance, which subsequently facilitates the emergence of FQR C. jejuni. Since antibiotic-resistant C. jejuni is transmitted primarily from animals to humans, our study suggests that non-FQ drugs, such as tetracycline, used for animals can also promote FQ resistance development by inducing antibiotic tolerance in C. jejuni. Overall, the findings in this study help us understand mechanisms of resistance development through the induction of antibiotic tolerance.

microbiology↗

bioRxiv2022

NSF/αSNAP2-mediated cis-SNARE complex disassembly precedes membrane fusion generating the cell plate during Arabidopsis cytokinesis

Eukaryotic membrane fusion requires trans-SNARE complexes bridging the gap between adjacent membranes (Jahn and Scheller, 2006). Fusion between a transport vesicle and its target membrane transforms the trans-into a cis-SNARE complex. The latter interacts with the hexameric AAA+-ATPase NSF and its co-factor SNAP, forming a 20S complex (Zhou et al., 2015; Zhao and Brunner, 2016). ATPase activity disassembles the SNARE complex into Qa-SNARE, which folds back onto itself, and its partners (Huang et al., 2019; Kim et al., 2021). Fusion of identical membranes has a different sequence of events (Baker and Hughson, 2016). The fusion partners each have cis-SNARE complexes to be broken up by NSF and SNAP. The Qa-SNARE monomers are then stabilized by interaction with Sec1-type regulators (SM proteins) to form trans-SNARE complexes, as shown for the yeast vacuole (Baker et al., 2015). Membrane fusion in Arabidopsis cytokinesis is formally akin to vacuolar fusion (Muller and Jurgens, 2016). Membrane vesicles fuse with one another to form the partitioning membrane known as cell plate. Cis-SNARE complexes of cytokinesis-specific Qa-SNARE KNOLLE and its SNARE partners are assembled at the ER and delivered by traffic via Golgi/TGN to the cell division plane (Karnahl and Park et al., 2017). SM protein KEULE is required for the formation of trans-SNARE complexes between adjacent membrane vesicles (Park et al., 2012). Here, we identify the missing NSF-type AAA+-ATPase and its adaptor SNAP2 required for disassembly of KNOLLE cis-SNARE complexes. In addition, we show that NSF is also required for other trafficking pathways and interacts with the respective Q-SNAREs. In conclusion, the SNARE complex disassembly machinery is conserved in plants and plays a unique essential role in cytokinesis.

plant biology↗

bioRxiv2022

Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2

The spike protein of SARS-CoV-2 is a critical antigen present in all approved SARS-CoV-2 vaccines. This surface viral protein is also the target for all monoclonal antibody therapies, but it is unclear whether antibodies targeting other viral proteins can also improve protection against COVID-19. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naive mice. On the next day, the recipient mice were challenged intranasally with SARS-CoV-2 to evaluate whether nucleocapsid-specific humoral responses affect viral control. Interestingly, mice that received nucleocapsid-specific sera exhibited enhanced control of a SARS-CoV-2 infection. These findings provide the first demonstration that humoral responses specific to an internal coronavirus protein can help clear infection, warranting the inclusion of other viral antigens in next-generation SARS-CoV-2 vaccines and providing a rationale for the clinical evaluation of nucleocapsid-specific monoclonals to treat COVID-19. HighlightsA SARS-CoV-2 nucleocapsid vaccine elicits robust nucleocapsid-specific antibody responses. This nucleocapsid vaccine generates memory B cells (MBC). Nucleocapsid-specific humoral responses do not prevent SARS-CoV-2 infection. Nucleocapsid-specific humoral responses help control a SARS-CoV-2 infection.

immunology↗

bioRxiv2022

EpiBERTope: a sequence-based pre-trained BERT model improves linear and structural epitope prediction by learning long-distance protein interactions effectively

MotivationEpitopes are the immunogenic regions of antigen that are recognized by antibodies in a highly specific manner to trigger an immune response. Predicting such regions is extremely difficult yet contains profound implications for complex mechanisms of humoral immunogenicity. ResultsHere, we present a BERT-based epitope prediction model called EpiBERTope, a pre-trained model on the Swiss-Prot protein database, which can predict both linear and structural epitopes using protein sequences only. The model achieves an AUC of 0.922 and 0.667 for linear and structural epitope datasets respectively, outperforming all benchmark classification models including random forest, gradient boosting, naive Bayesian, and support vector machine models. In conclusion, EpiBERTope is a sequence-based model that captures content-based global interactions of antigen sequences, which will be transformative in epitope discovery with high specificity. Contactminjun.park@standigm.com

bioinformatics↗

bioRxiv2022

UPP2: Fast and Accurate Alignment Estimation of Datasets with Fragmentary Sequences

MotivationMultiple sequence alignment (MSA) is a basic step in many bioinformatics pipelines. However, achieving highly accurate alignments on large datasets, especially those with sequence length heterogeneity, is a challenging task. UPP (Ultra-large multiple sequence alignment using Phylogeny-aware Profiles) is a method for MSA estimation that builds an ensemble of Hidden Markov Models (eHMM) to represent an estimated alignment on the full length sequences in the input, and then adds the remaining sequences into the alignment using selected HMMs in the ensemble. Although UPP provides good accuracy, it is computationally intensive on large datasets. ResultsWe present UPP2, a direct improvement on UPP. The main advance is a fast technique for selecting HMMs in the ensemble that allows us to achieve the same accuracy as UPP but with greatly reduced runtime. We show UPP2 produces more accurate alignments compared to leading MSA methods on datasets exhibiting substantial sequence length heterogeneity, and is among the most accurate otherwise. Availabilityhttps://github.com/gillichu/sepp Contactwarnow@illinois.edu

bioinformatics↗