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Biology subjects

Tien, H.

Publications and source records attributed to Tien, H..

4 recordsLinked to original sources

Aiki-XP: leakage-controlled multimodal prediction of within-species relative protein expression at pan-bacterial scale

Generalizable protein-expression prediction can accelerate protein engineering, inform disease mechanisms, and help optimize heterologous recombinant protein production. Protein expression is governed by many interacting parameters that no single omics view captures. We develop Aiki-XP, a multimodal platform integrating four biological scales (genome, operon, coding sequence, protein) plus biophysical features across 492,026 genes from 385 bacterial species. Aiki-XP predicts within-species relative abundance (per-species z-score rank), not absolute copies per cell. Under a leakage-controlled gene-operon split Aiki-XP reaches Spearman{rho} nc = 0.592 versus 0.509 for ESM-C 600M alone, and each tier of a monotone protein[->]operon[->]genome deployment ladder yields a statistically significant gain; a five-recipe rank-average ensemble adds a further +0.016. All recipes were locked before external evaluation; transfer to heterologous, cross-species, and novel-phylum benchmarks demonstrates utility and limits. Ablations and scaling experiments identify operon-scale genomic context, not protein-language-model capacity, as the rate-limiting input at this scale; one foundation model per biological scale suffices, with same-scale stacking adding little.

bioinformatics↗

A broad and potent neutralization epitope in SARS-related coronaviruses

Many neutralizing antibodies (nAbs) elicited to ancestral SARS-CoV-2 through natural infection and vaccination generally have reduced effectiveness to SARS-CoV-2 variants. Here we show therapeutic antibody ADG20 is able to neutralize all SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize all VOCs, albeit with reduced potency against Omicron. Thus, this highly conserved and vulnerable site can be exploited for design of universal vaccines and therapeutic antibodies.

microbiology↗

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics. One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.

immunology↗

Structural basis of a public antibody response to SARS-CoV-2

Molecular-level understanding of human neutralizing antibody responses to SARS-CoV-2 could accelerate vaccine design and facilitate drug discovery. We analyzed 294 SARS-CoV-2 antibodies and found that IGHV3-53 is the most frequently used IGHV gene for targeting the receptor binding domain (RBD) of the spike (S) protein. We determined crystal structures of two IGHV3-53 neutralizing antibodies +/- Fab CR3022 ranging from 2.33 to 3.11 [A] resolution. The germline-encoded residues of IGHV3-53 dominate binding to the ACE2 binding site epitope with no overlap with the CR3022 epitope. Moreover, IGHV3-53 is used in combination with a very short CDR H3 and different light chains. Overall, IGHV3-53 represents a versatile public VH in neutralizing SARS-CoV-2 antibodies, where their specific germline features and minimal affinity maturation provide important insights for vaccine design and assessing outcomes.

microbiology↗