Daron M Standley's research while affiliated with Osaka University and other places

Publications (184)

Preprint
B and T cell receptor repertoire data has the potential to fundamentally change the way we diagnose and treat a wide range of diseases. However, there are few resources for storing or analyzing repertoire data. InterClone provides tools for storing, searching, and clustering repertoire datasets. Efficiency is achieved by encoding the complementarit...
Preprint
The mechanism of T cell triggering upon engagement with a peptide-MHC (pMHC) complex remains a challenging problem. In order to observe structural and dynamics changes in the T cell receptor (TCR) upon pMHC binding, we carried out coarse grained molecular dynamics simulations of TCR-only and TCR-pMHC systems starting from a recently solved cryo-EM...
Preprint
To assess the frequency of SARS-CoV-2 infection enhancing antibodies in the general population, we searched over 64 million heavy chain antibody sequences from healthy and COVID-19 patient repertoires for sequences similar to 11 previously reported enhancing antibodies. Although the distribution of sequence identities was similar in COVID-19 and he...
Article
Antibodies recognize their cognate antigens with high affinity and specificity, but the prediction of binding sites on the antigen (epitope) corresponding to a specific antibody remains a challenging problem. To address this problem, we developed AbAdapt, a pipeline that integrates antibody and antigen structural modeling with rigid docking in orde...
Article
Decoy receptor proteins that trick viruses to bind to them should be resistant to viral escape because viruses that require entry receptors cannot help but bind decoy receptors. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for coronavirus cell entry. Recombinant soluble ACE2 was previously developed as a biologic against acute respi...
Preprint
Antibodies recognize their cognate antigens with high affinity and specificity, but the prediction of binding sites on the antigen (epitope) corresponding to a specific antibody remains a challenging problem. To address this problem, we developed AbAdapt, a pipeline that integrates antibody and antigen structural modeling with rigid docking in orde...
Article
The Omicron (B.1.1.529) SARS-CoV-2 variant contains an unusually high number of mutations in the spike protein, raising concerns of escape from vaccines, convalescent serum and therapeutic drugs. Here we analyzed the degree to which Omicron pseudovirus evades neutralization by serum or therapeutic antibodies. Serum samples obtained 3 months after t...
Article
Toll-like receptor (TLR) stimulation induces glycolysis and the production of mitochondrial reactive oxygen species (ROS), both of which are critical for inflammatory responses in macrophages. Here, we demonstrated that cyclin J, a TLR-inducible member of the cyclin family, reduced cytokine production in macrophages by coordinately controlling glyc...
Article
Motivation The scoring of antibody-antigen docked poses starting from unbound homology models has not been systematically optimized for a large and diverse set of input sequences. Results To address this need, we have developed AbAdapt, a web server that accepts antibody and antigen sequences, models their 3D structures, predicts epitope and parat...
Article
Full-text available
Single cell transcriptomic approaches are becoming mainstream, with replicate experiments commonly performed with the same single cell technology. Methods that enable integration of these datasets by removing batch effects while preserving biological information are required for unbiased data interpretation. Here, we introduce Canek for this purpos...
Article
Full-text available
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associa...
Article
Full-text available
The p47 immunity-related GTPase (IRG) Irgb6 plays a pioneering role in host defense against Toxoplasma gondii infection. Irgb6 is recruited to the parasitophorous vacuole membrane (PVM) formed by T. gondii and disrupts it. Despite the importance of this process, the molecular mechanisms accounting for PVM recognition by Irgb6 remain elusive because...
Preprint
Full-text available
The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit appr...
Preprint
Breakthrough infection is often observed for the SARS-CoV-2 Delta variant, and neutralizing antibody levels are associated with vaccine efficiency ¹ . Recent studies revealed that not only anti-receptor binding domain (RBD) antibodies ² but also antibodies against the N-terminal domain (NTD) play important roles in positively 3,4 or negatively ⁴⁻⁸...
Article
Full-text available
The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. We estimated diversity of each site on a multiple sequence alignment (MSA) of the Spike (S) proteins from close relatives of SARS-CoV-2 that infected bat and pangolin before the pandemic. T...
Preprint
mRNA-based vaccines provide effective protection against most common SARS-CoV-2 variants. However, identifying likely breakthrough variants is critical for future vaccine development. Here, we found that the Delta variant completely escaped from anti-N-terminal domain (NTD) neutralizing antibodies, while increasing responsiveness to anti-NTD infect...
Preprint
The p47 immunity-related GTPase (IRG) Irgb6 plays a pioneering role in host defense against Toxoplasma gondii infection. It is recruited to the parasitophorous vacuole membrane (PVM) formed by T. gondii and disrupts it. Despite the importance of this process, the molecular mechanisms accounting for PVM recognition by Irgb6 remain elusive due to lac...
Article
Full-text available
Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we...
Article
Antibodies against the receptor-binding-domain of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal-domai...
Article
Full-text available
While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19⁻ disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two p...
Preprint
Full-text available
The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. Based on molecular evolutionary analysis of S protein, we found a significant correspondence in the location of amino acid substitutions between SARS-CoV-2 variants recently emerging and th...
Preprint
Full-text available
The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. Based on molecular evolutionary analysis of the S protein, we found a significant correspondence in the location of amino acid substitutions between SARS-CoV-2 variants recently emerging an...
Preprint
Full-text available
The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. Based on molecular evolutionary analysis of the S protein, we found a significant correspondence in the location of amino acid substitutions between SARS-CoV-2 variants recently emerging an...
Chapter
The Database of Aligned Structural Homologs (DASH) is a tool for efficiently navigating the Protein Data Bank (PDB) by means of pre-computed pairwise structural alignments. We recently showed that, by integrating DASH structural alignments with the multiple sequence alignment (MSA) software MAFFT, we were able to significantly improve MSA accuracy...
Preprint
Full-text available
SARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we...
Article
Full-text available
The SARS-CoV-2 S protein is a major point of interaction between the virus and the human immune system. As a consequence, the S protein is not a static target but undergoes rapid molecular evolution. In order to more fully understand the selection pressure during evolution, we examined residue positions in the S protein that vary greatly across clo...
Article
Full-text available
B cell receptors (BCRs) and T cell receptors (TCRs) make up an essential network of defense molecules that, collectively, can distinguish self from non-self and facilitate destruction of antigen-bearing cells such as pathogens or tumors. The analysis of BCR and TCR repertoires plays an important role in both basic immunology as well as in biotechno...
Article
Full-text available
One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5’UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome thr...
Article
Full-text available
Alcohol dehydrogenases (ADHs) catalyze the reversible reduction of a carbonyl group to its corresponding alcohol. ADHs are widely employed for organic synthesis due to their lack of harm to the environment, broad substrate acceptance, and high enantioselectivity. This review focuses on the impact and relevance of ADH enantioselectivities on their b...
Article
Full-text available
The lipopolysaccharide (LPS)–induced endocytosis of Toll-like receptor 4 (TLR4) is an essential step in the production of interferon-β (IFN-β), which activates the transcription of antiviral response genes by STAT1 phosphorylated at Tyr ⁷⁰¹ . Here, we showed that STAT1 regulated proinflammatory cytokine production downstream of TLR4 endocytosis ind...
Article
We utilized acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD), wild type and Trp288Ala mutant, to reduce halogenated acetophenone analogs to their corresponding (S)- and (R)-alcohols beneficial as pharmaceutical intermediates. Reduction by wild type resulted in excellent (S)-enantioselectivity for all of the substrates tested. Mean...
Article
Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by ap...
Article
Both (S) and (R) forms of enantiomerically pure 2-tetralols, and their substituted analogs, are fundamental pharmaceutical intermediates. Here, we utilized the wild type and an engineered form of a highly enantioselective acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD) to produce (S)- and (R)-2-tetralols, and their substituted an...
Preprint
Full-text available
One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5’UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome thr...
Article
Full-text available
Toxoplasma gondii is an obligate intracellular protozoan parasite capable of infecting warm-blooded animals by ingestion. The organism enters host cells and resides in the cytoplasm in a membrane-bound parasitophorous vacuole (PV). Inducing an interferon response enables IFN-γ–inducible immunity-related GTPase (IRG protein) to accumulate on the PV...
Article
Full-text available
Enzyme engineering has been widely employed to tailor the substrate specificity and enantioselectivity of enzymes. In this study, we mutated Trp288, an unconserved residue in the small binding pocket of an acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD). Trp288 mutants showed substrate specificity expansion towards bulky-bulky ke...
Article
Full-text available
Aliphatic ketones, such as 2-butanone and 3-hexanone, with only one carbon difference among side chains adjacent to the carbonyl carbon are difficult to be reduced enantioselectively. In this study, we utilized an acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD) to reduce challenging aliphatic ketones such as 2-butanone (methyl et...
Article
Full-text available
The original version of this article contains error for some of the authors corrections were not included during correction stage
Article
Full-text available
RNA-modulating factors not only regulate multiple steps of cellular RNA metabolism, but also emerge as key effectors of the immune response against invading viral pathogens including human immunodeficiency virus type-1 (HIV-1). However, the cellular RNA-binding proteins involved in the establishment and maintenance of latent HIV-1 reservoirs have n...
Chapter
Full-text available
Structural modeling plays a key role in protein function prediction on a genome-wide scale. For B and T lymphocyte receptors, the critical functional question is: which antigens and epitopes are targeted? With emerging B cell receptor (BCR) and T cell receptor (TCR) sequencing methods improving in both breadth and depth, there is a growing need for...
Article
Full-text available
Regnase-1-mediated mRNA decay (RMD), in which inflammatory mRNAs harboring specific stem-loop structures are degraded, is a critical part of proper immune homeostasis. Prior to initial translation, Regnase-1 associates with target stem-loops but does not carry out endoribonucleolytic cleavage. Single molecule imaging revealed that UPF1 is required...
Article
Full-text available
Here, we describe a web server that integrates structural alignments with the MAFFT multiple sequence alignment (MSA) tool. For this purpose, we have prepared a web-based Database of Aligned Structural Homologs (DASH), which provides structural alignments at the domain and chain levels for all proteins in the Protein Data Bank (PDB), and can be que...
Article
Full-text available
APOBEC3G (A3G) is a cellular protein that inhibits HIV-1 infection through virion incorporation. The interaction of the A3G N-terminal domain (NTD) with RNA is essential for A3G incorporation in the HIV-1 virion. The interaction between A3G-NTD and RNA is not completely understood. The A3G-NTD is also recognized by HIV-1 Viral infectivity factor (V...
Article
Full-text available
Repertoire Builder (https://sysimm.org/rep_builder/) is a method for generating atomic-resolution, three-dimensional models of B cell receptors (BCRs) or T cell receptors (TCRs) from their amino acid sequences.
Article
Full-text available
We describe a method for clustering BCRs based on sequence and predicted structural features in order to identify groups with similar antigen and epitope binding specificity.
Poster
Full-text available
In this poster, the enantioselectivity phenomenon of a robust alcohol dehydrogenase from Geotrichum candidum was described through the reduction of a series of cyclic and non-cyclic ketones. The mutant variants enantioselectivity was found to be independent of Prelog's rule.
Article
Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and polyposis at the nose and paranasal sinus and a high concentration of IgE in nasal polyps (NPs). The causative antigen and pathogenesis of CRSwNP remain unknown. Objective: We aimed to identify reactive allergens of IgE antibodies p...
Article
AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remains unknown. Here, we show that the le...
Article
Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of inhibitors for γ-secretase, another intram...
Article
Full-text available
The evolutional process of disease-associated autoantibodies in systemic lupus erythematosus (SLE) remains to be established. Here we show intraclonal diversification and affinity maturation of anti-nuclear antibody (ANA)-producing B cells in SLE. We identified a panel of monoclonal ANAs recognizing nuclear antigens, such as double-stranded DNA (ds...
Article
Full-text available
The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadb...
Poster
Rational design approaches have been employed widely to control enzymatic properties (e.g enantioselectivity, substrate specificity, and stability) of various enzymes[1]. Rational design focusing on the residue within the substrate binding site has proven to be effective in controlling the enantiopreference of several enzymes [2, 3]. In this study...
Article
Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-assoc...
Article
Full-text available
The AT-rich interactive domain-containing protein 5a (Arid5a) plays a critical role in autoimmunity by regulating the half-life of Interleukin-6 (IL-6) mRNA. However, the signaling pathways underlying Arid5a-mediated regulation of IL-6 mRNA stability are largely uncharacterized. Here, we found that during the early phase of lipopolysaccharide (LPS)...
Article
Full-text available
Purpose Evidence suggests that circulating serum microRNAs (miRNAs) might preferentially target immune-related mRNAs. If this were the case, we hypothesized that immune-related mRNAs would have more predicted serum miRNA binding sites than other mRNAs and, reciprocally, that serum miRNAs would have more immune-related mRNA targets than non-serum mi...
Article
Full-text available
Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a...