Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 235 records · Page 13Linked to original sources

bioRxiv2025

Mitoxantrone inhibits and downregulates ERα through binding at the DBD-LBD interface

Targeting the estrogen receptor (ER or ER) through competitive antagonists, receptor downregulators, or estrogen synthesis inhibition remains the primary therapeutic strategy for luminal breast cancer. We have identified a novel mechanism of ER inhibition by targeting the critical interface between its DNA-binding domain (DBD) and ligand-binding domain (LBD). We demonstrate that mitoxantrone (MTO), a topoisomerase II inhibitor, binds at this previously unexplored DBD-LBD interface. Using comprehensive computational, biophysical, biochemical, and cellular analyses, we show that independent of its DNA damage response activity, MTO binding induces distinct conformational changes in ER, leading to its cytoplasmic redistribution and subsequent proteasomal degradation. Notably, MTO effectively inhibits clinically relevant ER mutations (Y537S and D538G) that confer resistance to current endocrine therapies, outperforming fulvestrant in both in vitro and in vivo assays. Our findings establish domain-domain interaction targeting as a viable therapeutic strategy for ER, with translational implications for other nuclear receptors.

cancer biology↗

bioRxiv2025

TRIM21-NUP98 interface accommodates structurally diverse molecular glue degraders

Molecular glue degraders enable targeted protein degradation by bridging interactions between target proteins and E3 ubiquitin ligases. Whereas some protein-protein interfaces exhibit the capacity to accommodate structurally diverse degraders, the extent of this adaptability across molecular glue targets remains unclear. We recently identified (S)-ACE-OH as a molecular glue degrader that recruits the E3 ubiquitin ligase TRIM21 to the nuclear pore complex by recognizing NUP98, thereby inducing the degradation of nuclear pore proteins. Here, we analyzed public compound toxicity data across a large collection of cell lines and identified two additional molecular glue degraders, PRLX 93936 and BMS-214662, that engage the TRIM21-NUP98 interface to induce the degradation of nucleopore proteins. Additionally, we confirmed that HGC652, another TRIM21-dependent molecular glue degrader, also binds at this interface. Together with our previously characterized degrader (S)-ACE-OH, these findings demonstrate that the TRIM21-NUP98 interface can accommodate structurally diverse molecular glue degraders, expanding the potential for its therapeutic exploitation.

biochemistry↗

bioRxiv2025

AAVone: A Cost-Effective, Single-Plasmid Solution for Efficient AAV Production with Reduced DNA Impurities

Currently, the most common approach for manufacturing GMP-grade adeno-associated virus (AAV) vectors involves transiently transfecting mammalian cells with three plasmids that carry the essential components for production. The requirement for all three plasmids to be transfected into a single cell and the necessity for high quantities of input plasmid DNA, limits AAV production efficiency, introduces variability between production batches, and increases time and labor costs. Here, we developed an all-in-one, single-plasmid AAV production system, called AAVone. In this system, the adenovirus helper genes (E2A, E4orf6, and VA RNA), packaging genes (rep and cap), and the vector transgene cassette are consolidated into a single compact plasmid with a 13-kb backbone. The AAVone system achieves a two- to four-fold increase in yields compared to the traditional triple-plasmid system. Furthermore, the AAVone system exhibits low batch-to-batch variation and eliminates the need for fine-tuning the ratios of the three plasmids, simplifying the production process. In terms of vector quality, AAVs generated by the AAVone system show similar in vitro and in vivo transduction efficiency, but a substantial reduction in sequences attributed to plasmid backbones and a marked reduction in non-functional snap-back genomes. In Summary, the AAVone platform is a straightforward, cost-effective, and highly consistent AAV production system - making it particularly suitable for GMP-grade AAV vectors.

bioengineering↗

bioRxiv2024

Chicken shank color determined by Inhibition of dermal melanin (ID) is mediated by a structural variation regulating CDKN2A expression

It is well established that the color of a chickens shank is primarily determined by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses black pigmentation in the dermal layer of the shank, is the sole sex-linked mutation and its molecular mechanisms remained elusive. In this study, a resource family with segregating shank colors was constructed. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP located on the Z chromosome. Subsequent linkage mapping further refined the candidate region, enabling the screening of the candidate structural variation. The candidate structural variation is associated with the yellow shank and characterized by a 143 bp deletion accompanied by a 2 bp insertion. Within the same Topologically Associating Domain, only the CDKN2A gene showed differential expression. Functional studies, including CRISPR/Cas9-edited cells, provided evidence that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. The absence of melanocytes is likely due to their apoptosis. This study completes the puzzle of chicken shank color genetics and paves the way for the application of the ID mutation in the auto-sexing of chicks which is intensively needed in layer and broiler industries.

genetics↗

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha crystalline beta

Epstein-Barr Virus (EBV) infects over 95% of the worlds population and is the most common cause of infectious mononucleosis (IM). Epidemiologic studies have linked EBV with certain cancers or autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that molecular mimicry between EBV proteins, particularly EBV nuclear antigen 1 (EBNA-1), and self-proteins is a plausible mechanism through which EBV infection may contribute to the development of autoimmune disorders. We used a systems immunology approach to investigate the magnitude, specificity, and functional properties of EBNA-1 specific antibodies in a cohort of 97 young adults with IM from presentation through 1-year post-primary infection compared to a control cohort of EBV-seropositive individuals. Levels of EBNA-1 specific IgG1 and IgG3 binding antibodies increased over the course of infection. EBNA-1 antibodies capable of mediating antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were detected at or after 6 months. Binding and ADCP- and ADCD-leveraged antibodies primarily targeted a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides in individuals with MS. Significantly higher binding and ADCD-active antibodies targeting EBNA-1 were observed in individuals with at least one HLA-DRB1*15:01 allele, a known genetic risk factor for MS; Importantly, high levels of antibodies capable of binding alpha crystalline beta (CRYAB) and mediating complement deposition were detected at 6 months and 1-year following IM; CRYAB antibodies were resistant to denaturing forces, indicating an affinity matured response. Blocking experiments confirmed that CRYAB antibodies were cross-reactive with EBNA-1. Altogether, these results demonstrate that high levels of functional antibodies targeting EBNA-1 are generated in early EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine how these antibody responses may contribute to the subsequent development of MS.

immunology↗

bioRxiv2024

Targeting and anchoring the mechanosensitive ion channel Piezo to facilitate its inhibition of axon regeneration

Mechanical force orchestrates a myriad of cellular events including inhibition of axon regeneration, by locally activating the mechanosensitive ion channel Piezo enriched at the injured axon tip. However, the cellular mechanics underlying Piezo localization and function remains poorly characterized. We show that the RNA repair/splicing enzyme Rtca acts upstream of Piezo to modulate its expression and transport/targeting to the plasma membrane via Rab10 GTPase, whose expression also relies on Rtca. Loss or gain of function of Rab10 promotes or impedes Drosophila sensory neuron axon regeneration, respectively. Rab10 mediates the cell surface expression of integrin {beta}1 (Itgb1)/mys, which colocalizes and genetically interacts with Piezo, facilitating its anchorage and engagement with the microenvironment, and subsequent activation of mechanotransduction to inhibit regeneration. Importantly, loss of Rtca, Rab10 or Itgb1 promotes CNS axon regeneration after spinal cord injury or optic nerve crush in adult mice, indicating the evolutionary conservation of the machinery.

neuroscience↗

bioRxiv2024

CellMemory: Hierarchical Interpretation of Out-of-Distribution Cells Using Bottlenecked Transformer

Identifying the genetic and molecular drivers of phenotypic heterogeneity among individuals is vital for understanding human health and for diagnosing, monitoring, and treating diseases. To this end, international consortia such as the Human Cell Atlas and the Tabula Sapiens are creating comprehensive cellular references. Due to the massive volume of data generated, machine learning methods, especially transformer architectures, have been widely employed in related studies. However, applying machine learning to cellular data presents several challenges. One such challenge is making the methods interpretable with respect to both the input cellular information and its context. Another less explored challenge is the accurate representation of cells outside existing references, referred to as out-of-distribution (OOD) cells. The out-of-distribution could be attributed to various physiological conditions, such as comparing diseased cells, particularly tumor cells, with healthy reference data, or significant technical variations, such as using transfer learning from single-cell reference to spatial query data. Inspired by the global workspace theory in cognitive neuroscience, we introduce CellMemory, a bottlenecked Transformer with improved generalization capabilities designed for the hierarchical interpretation of OOD cells unseen during reference building. Even without pre-training, it exceeds the performance of large language models pre-trained with tens of millions of cells. In particular, when deciphering spatially resolved single-cell transcriptomics data, CellMemory demonstrates the ability to interpret data at the granule level accurately. Finally, we harness CellMemorys robust representational capabilities to elucidate malignant cells and their founder cells in different patients, providing reliable characterizations of the cellular changes caused by the disease.

bioinformatics↗

bioRxiv2024

Loss of olfaction reduces caterpillar performance and increases susceptibility to a natural enemy

Insect herbivores such as caterpillars, are under strong selection pressure from natural enemies, especially parasitoid wasps. Although the role of olfaction in host-plant seeking has been investigated in great detail in parasitoids and adult lepidopterans, the caterpillar olfactory system and its significance in tri-trophic interactions remain poorly understood. In this study, we investigated the olfactory system of Pieris brassicae caterpillars and the importance of olfactory information in the interactions among this herbivore, its host plant Brassica oleracea and its primary natural enemy Cotesia glomerata. To examine the role of olfaction, we utilized CRISPR/Cas9 to knockout the odorant receptor co-receptor (Orco). This knockout (KO) impaired olfactory detection and primary processing in the brain. Orco KO caterpillars exhibited reduced weight and lost preference for their optimal food plants. Interestingly, the KO caterpillars also experienced reduced weight when challenged by the parasitoid C. glomerata whose ovipositor had been removed, and the mortality of the KO caterpillars under the attack of unmanipulated parasitoids increased. We then investigated the behavior of P. brassicae caterpillars in response to volatiles from plants attacked by conspecific caterpillars and volatiles from plants on which the caterpillars were themselves attacked by C. glomerata. After analyzing the volatile compounds involved in these interactions, we concluded that olfactory information enables caterpillars to locate suitable food sources more efficiently as well as to select enemy-free spaces. Our results reveal the crucial role of olfaction in caterpillar feeding and natural-enemy avoidance, highlighting the significance of chemoreceptor genes in shaping ecological interactions.

ecology↗

bioRxiv2024

OPUS-GO: An interpretable protein/RNA sequence annotation framework based on biological language model

Accurate annotation of protein and RNA sequences is essential for understanding their structural and functional attributes. However, due to the relative ease of obtaining whole sequence-level annotations compared to residue-level annotations, existing biological language model (BLM)-based methods often prioritize enhancing sequence-level classification accuracy while neglecting residue-level interpretability. To address this, we introduce OPUS-GO, which exclusively utilizes sequence-level annotations to provide both sequence-level and residue-level classification results. In other words, OPUS-GO not only provides the sequence-level annotations but also offers the rationale behind these predictions by pinpointing their corresponding most critical residues within the sequence. Our results show that, by leveraging features derived from BLMs and our modified Multiple Instance Learning (MIL) strategy, OPUS-GO exhibits superior sequence-level classification accuracy compared to baseline methods in most downstream tasks. Furthermore, OPUS-GO demonstrates robust interpretability by accurately identifying the residues associated with the corresponding labels. Additionally, the OPUS-GO framework can be seamlessly integrated into any language model, enhancing both accuracy and interpretability for their downstream tasks.

bioinformatics↗

bioRxiv2024

Exploring Genetic Interactions with Rare Variants Reveals Gene Networks Susceptible to Complex Diseases

Genetic interactions play a crucial role in understanding the susceptibility and etiology of complex human diseases. However, existing methods for analyzing gene-gene interactions are often limited to common variants and may not capture the effects of rare variants. In this study, we propose a novel method called GGI-RUNNER that is specifically designed for analyzing gene-gene interactions of rare variants. GGI-RUNNER evaluates the enrichment of rare variant interaction burden in patients relative to baselines in the general population. The baselines are estimated for pairwise genes by a recursive truncated negative-binomial regression model on multiple genomic features available from public data. Intensive simulations demonstrate that GGI-RUNNER exhibits substantially higher statistical power than alternative epistasis tests and maintains reasonable type I error rates even in stratified populations. Applied to real data, GGI-RUNNER identified significant rare variant interactions associated with Alzheimers disease, Hirschsprungs disease, Ulcerative colitis and Crohns disease. Furthermore, we found that these identified genes for each trait can form interconnected networks, which may provide valuable insights into the underlying molecular mechanisms.

bioinformatics↗

bioRxiv2024

Cervical transcutaneous vagus nerve stimulation enhances speech recognition in noise: A crossover, placebo-controlled study

Speech comprehension in noisy environments remains a significant challenge, even among individuals with clinically normal hearing and users of hearing aids and cochlear implants. While conventional assistive hearing devices address limitations in the auditory periphery, they do not directly enhance the brains capacity to segregate speech from background noise. Because tonic vagus nerve stimulation (VNS) has demonstrated potential for rapidly improving central sensory processing, this study investigated whether tonic transcutaneous cervical VNS (tcVNS) can augment speech-in-noise intelligibility. Two cohorts of older human adults (60-84 years) participated in a placebo-controlled, crossover study. Participants completed speech-in-noise assessments using either QuickSIN or AzBio sentences, while receiving tonic tcVNS to the neck, or placebo stimulation to the neck-shoulder junction. Speech-in-noise performance was assessed by measuring participants accuracy in repeating sentences presented at varying signal-to-noise ratios (SNR) within background babble. Tonic tcVNS improved speech-in-noise intelligibility compared to placebo. At the group-level, the SNR threshold for 50% speech intelligibility (SNR-50) improved by 0.76 dB in QuickSIN (p=0.016) and by 0.38 dB in AzBio (p=0.045). For individual participants, 50% demonstrated improvements that met a minimum clinically important difference (MCID) of 1 dB. Tonic tcVNS evoked progressively greater improvements as SNR increased in QuickSIN (p=0.021) and AzBio (p=0.00023), with the largest gains above 0 dB SNR. In 55% of participants, tcVNS improved intelligibility beyond an MCID benchmark of 4.9% at 5 dB SNR. While the magnitude of tcVNS-evoked improvements was inversely related to baseline speech-in-noise impairment (p=0.028), with the most impaired individuals demonstrating the largest gains, it did not correlate with hearing loss severity (p=0.97) or age (p=0.88). Our findings indicate that tonic tcVNS can evoke immediate and clinically meaningful enhancements in speech-in-noise comprehension. This suggests tcVNS may complement conventional assistive hearing technologies and inform novel therapies for sensory processing disorders.

neuroscience↗

bioRxiv2024

Zero valent sulfur is the product of assimilatory sulfite reductase and a substrate of cysteine synthase

The long process of the assimilatory sulfate-reduction consists of sulfate reduction to H2S and then H2S assimilation for cysteine synthesis. However, recent studies indicate that both H2S and zero valent sulfur (S0) are produced during dissimilatory sulfate reduction process, which leads to the question whether S0 also is involved in assimilatory sulfate-reduction. Herein, phylogenetic analysis grouped assimilatory sulfite reductases into five clusters and we re-examined four representatives from two major clusters. These enzymes produced both S0 and H2S from sulfite. However, S0 was more like a direct product, while H2S was just a derivative of S0 via chemical reduction. Phylogenetic analysis of cysteine synthases grouped them into six clusters, and we re-examined six representatives from two major clusters. These enzymes used both glutathione persulfide (GSSH, a common intracellular compound containing a S0 atom) and H2S as substrates to synthesize cysteine, but preferred to use GSSH. These findings indicated that S0, other than H2S, is the key intermediate during the process of inorganic sulfur converting to organic sulfur. ImportanceSulfate reduction is an important link in the global sulfur cycle. Assimilatory sulfate-reduction consists of sulfate-reduction to H2S and then H2S assimilation for cysteine synthesis. This concept was founded in 1950s and has not been challenged until today. In this study, we re-examined four representative assimilatory sulfite reductases (aSiRs) and found that these enzymes directly reduced sulfite to zero valent sulfur (S0). A small portion of produced S0 was reduced to H2S via aSiR-independent chemical reactions. Further, we re-examined six representative cysteine synthases and found that these enzymes used S0 derivative compounds (thiosulfate and glutathione persulfide) as substrates to synthesize cysteine. Thus, S0 is the key intermediate of assimilatory sulfate reduction process, other than H2S.

microbiology↗

bioRxiv2024

HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors

Aggression behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding are unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extend amygdala region critical for aggressive behaviors in both sexes of mice, with males exhibiting higher neuronal activity during the attack. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male GABAergic pSI neurons exhibited remarkable hyperexcitability due to increased Ih currents. Strikingly, modulating HCN1 expression not only adjusted this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the GABAergic pSI neurons reduced male aggression, while its overexpression markedly heightened aggression in females. Furthermore, testosterone was shown to intensify aggression by upregulating HCN1 and remodeling pSI circuits. These findings provide detailed sex-specific molecular mechanisms underlying social behaviors.

neuroscience↗

bioRxiv2024

Fusions of catalytically inactive RusA to FokI nuclease coupled with PNA enable programable site-specific double-stranded DNA breaks

Programmable site-specific nucleases have revolutionized the genome editing. However, these systems still face challenges such as guide dependency, delivery issues, and off-target effects. Harnessing the natural functions of structure-guided nucleases offer promising alternatives for generating site-specific double-strand DNA breaks. Yet, structure-guided nucleases require precise reaction conditions and validation for in-vivo applicability. To address these limitations, we developed the PNA-Coupled FokI-(d)RusA (PC-FIRA) system. PC-FIRA combines the sequence-specific binding ability of peptide nucleic acids (PNAs) with the catalytic efficiency of FokI nuclease fused to a structurally-guided inactive RusA resolvase (FokI-(d)RusA). This system allows for precise double-strand DNA breaks without the constraints of existing site-specific nuclease and structure-guided nucleases. Through in vitro optimizations, we achieved high target specificity and cleavage efficiency. This included adjusting incubation temperature, buffer composition, ion concentration, and cleavage timing. Diverse DNA structures, such as Holliday Junctions, linear, and circular DNA, were tested demonstrating the potential activity on different target forms. Further investigation has revealed the PC-FIRA system capacity for facilitating the precise deletion of large DNA fragments. This can be useful in cloning, large-fragment DNA assembly, and genome engineering, with promising applications in biotechnology, medicine, agriculture, and synthetic biology.

bioengineering↗

bioRxiv2024

RpiBeh: a multi-purpose open-source solution for real-time tracking and behavior-driven closed-loop interventions in rodent neuroethology

High-precision behavior tracking and closed-loop intervention are essential for studying the neural basis of cognition and behavior. Existing commercial systems are costly and inflexible for customization, while current open-source tools are often lack of real-time functionality and suffer from steep learning curve. To address these issues, we developed RpiBeh, an open-source, cost-effective, and versatile software tailored for rodent neuroethological research. The software features an intuitive interface with extensive customization options. RpiBeh leverages a Raspberry Pi and camera for video streaming, enabling behavior-driven closed-loop control. Additionally, it provides frame-by-frame video timestamp output for precise synchronization with external devices. For real-time tracking and locomotion pattern analysis, RpiBeh utilizes several novel algorithms and integrated newly developed deep-learning method. Specifically, we introduced two algorithms: a Background Subtraction Method (BSM) for real-time position tracking and a Frame Difference (FD) algorithm for freezing behavior detection. RpiBeh was validated in single animal real-time tracking and locomotion pattern detection, demonstrating flexibility and effectiveness in configurating behavior-triggered closed-loop reinforcement experiments including passive place avoidance task and social fear conditioning tasks. It achieved the same level of performance in tracking and locomotion pattern detection comparing to benchmark software including ANY-maze and DeepLabCut, with superior customization and expandability. Consequently, RpiBeh offers an efficient, affordable, and open-source solution for video tracking and behavior-driven closed-loop experiments.

animal behavior and cognition↗

bioRxiv2024

Optimizing a Human Monoclonal Antibody for Better Neutralization of SARS-CoV-2

SARS-CoV-2 has largely evolved to resist antibody pressure, with each successive viral variant becoming more and more resistant to serum antibodies in the population. This evolution renders all previously authorized anti-spike therapeutic monoclonal antibodies inactive, and it threatens the remaining pipelines against COVID-19. We report herein the isolation of a human monoclonal antibody with a broad but incomplete SARS-CoV-2 neutralization profile, but structural analyses and mutational scanning lead to the engineering of variants that result in greater antibody flexibility while binding to the viral spike. Three such optimized monoclonal antibodies neutralize all SARS-CoV-2 strains tested with much improved potency and breadth, including against subvariants XEC and LP.8.1. The findings of this study not only present antibody candidates for clinical development against COVID-19, but also introduce a unique engineering approach to improve antibody activity via increasing conformational flexibility.

microbiology↗

bioRxiv2024

KP.2-based monovalent mRNA vaccines robustly boost antibody responses to SARS-CoV-2

In response to the ongoing evolution of SARS-CoV-2, COVID-19 mRNA vaccines were recently updated to encode the spike protein of the KP.2 subvariant of the JN.1 sublineage. However, the immunogenicity of KP.2-based monovalent mRNA vaccines (KP.2 MV) has yet to be fully evaluated and reported, particularly against dominant and growing viral variants KP.3.1.1 and XEC, which bear some distinct mutations from KP.2. Here we report that KP.2 MV boosters elicit robust neutralizing antibody titers in a cohort of 16 healthy adult participants against all tested variants in pseudovirus neutralization assays. The highest post-boost geometric mean titers were against older variants D614G (17,293) and BA.5 (14,358), suggestive of immune imprinting, but the post-boost titers against currently dominant or growing viruses KP.3.1.1 (1,698) and XEC (1,721) were still robust. Fold-changes in titers were highest against recent JN.1 subvariants, including JN.1, KP.2, KP.3, KP.3.1.1, and XEC, (5.8-to-7.8-fold), compared to older variants D614G and BA.5 (1.6- and 2.5-fold), which suggests that KP.2 MV boosters have at least partially mitigated immune imprinting. Overall, these results show that KP.2 MV boosters elicit robust neutralizing antibodies against dominant SARS-CoV-2 viruses.

microbiology↗