Biology subjects

Uriu, K.

Publications and source records attributed to Uriu, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Structure and antigenicity of the 2026 Bundibugyo virus glycoprotein

An outbreak of ebolavirus disease caused by a new zoonotic spillover of Bundibugyo virus (BDBV) is currently spreading at an unprecedented pace in the Democratic Republic of the Congo and Uganda. The outbreak has resulted in 7,733 cases with a case-fatality ratio of 48%, yet no BDBV-specific vaccines or therapeutics are available. The ebolavirus glycoprotein (GP) promotes viral entry and is the target of neutralizing antibodies and vaccine development. Here, we engineered a soluble, prefusion-stabilized GP trimer from a contemporary BDBV isolate and determined its cryo-electron microscopy structure bound to the broadly neutralizing antibody EBOV-515. It reveals the molecular basis for EBOV-515 cross-reactivity and suggests that the antibody inhibits viral entry by interfering with NPC1 engagement in addition to trapping GP in the prefusion conformation and hindering glycan cap cleavage. Mapping lineage-defining substitutions identified changes in GP1 and GP2, including R506S within an antigenic site targeted by multiple broadly neutralizing antibodies recognizing the fusion loop. Nevertheless, we found that several glycan cap-, GP base-, and HR2-directed antibodies cross-reacted and neutralized BDBV DRC/2026 GP pseudovirus with potency comparable or greater to that observed against earlier BDBV isolates and the Zaire ebolavirus Makona/2024 isolate. These findings define the antigenic properties of contemporary BDBV GP and delineate conserved epitopes as ideal targets for antibody therapeutics and for the development of pan-ebolavirus vaccines.

biochemistry↗

bioRxiv2026

Circadian temperature compensation is intrinsically linked with metabolism and redox signaling

Circadian rhythms are a universal property of organisms, and a defining property of these oscillators is the ability to maintain a precise period at different temperatures. Indeed, the discovery in the 1950s of this property, known as "temperature compensation," was a watershed event in our understanding of biological timekeeping. Since that time, however, almost no general principles have emerged that uncover the mechanistic basis of how circadian timekeepers defy the rules" of temperature dependence of biochemical reactions. A genetic investigation of circadian temperature compensation revealed that the sensing of metabolism and ensuing modulation of the core mechanism preserves a constant circadian period. Intracellular redox sensing of metabolic rate is intrinsic to this compensation, and this relationship is conserved in bacterial and mammalian cells. These insights explain previously inexplicable observations of the interaction between redox reactions and circadian timekeeping. These results introduce a previously unknown linkage between temperature compensation and metabolism.

cell biology↗

bioRxiv2026

Experimental SARS-CoV-2 infection using horseshoe bats

Horseshoe bats are known as the natural reservoir of sarbecoviruses. To understand how horseshoe bats coexist with sarbecoviruses in nature, experimental infection can provide direct evidence. However, in vivo infection studies using horseshoe bats have been lacking because of the difficulty of maintaining insectivorous bats in a laboratory setting. Here, we established a stable husbandry system for greater horseshoe bats (Rhinolophus ferrumequinum) and performed experimental infection with SARS-CoV-2. In contrast to Syrian hamsters which showed substantial viral replication, infected horseshoe bats exhibited low-level but persistent viral replication in the lung without overt disease. Histological analyses revealed that inflammatory lesions in the bat lungs were spatially restricted and temporally delayed compared with those in hamsters. Transcriptomic analyses further showed preferential activation of tissue repair pathways but limited inflammatory responses following infection. Notably, bats expressed several interferon-stimulated genes prior to infection. Our results suggest that a host strategy combining constitutive antiviral state, limited inflammation and enhanced tissue repair may result in controlled viral replication without overt disease, likely enabling horseshoe bats to coexist with sarbecoviruses.

microbiology↗

bioRxiv2025

Humoral immunity induced by XEC monovalent vaccines against SARS-CoV-2 variants including XEC, LP.8.1, NB.1.8.1, XFG, and BA.3.2

After the emergence of SARS-CoV-2 Omicron variant at the end of 2021, Omicron has highly diverged into various sublineages: e.g., BA.5 in 2022, XBB.1.5 in 2023, JN.1 in 2024. Currently, several JN.1 subvariants including XEC, LP.8.1, NB.1.8.1 and XFG are circulating worldwide. Additionally, recent studies show that BA.3.2, a descendant of Omicron BA.3, exhibits profound immune evasion potential. On December 5, 2025, BA.3.2, was designated a variant under monitoring by the WHO. To prevent COVID-19, several countries including Japan have continuously developed and approved variant-adapted vaccines: e.g., ancestral/BA.5 bivalent vaccine in 20223, XBB.1.5-based monovalent vaccine in 20234, JN.1-based monovalent vaccine in 2024, and LP.8.1-based monovalent vaccine in 2025. Since XEC was more prevalent than LP.8.1 at the beginning of 2025 in Japan, two Japanese pharmaceutical companies, Daiichi Sankyo and Meiji Seika Pharma, have produced XEC-based vaccines. Here, we investigated the antiviral immunity induced by XEC-based monovalent vaccines against recently circulating SARS-CoV-2 variants, as well as BA.3.2, in the Japanese population. To assess the neutralizing antibody response induced by XEC-based vaccines, we obtained sera from individuals who had been vaccinated with the XEC-based mRNA monovalent vaccine produced by Daiichi Sankyo (N=22) or the XEC-based self-amplifying replicon vaccine produced by Meiji Seika Pharma (N=20). We collected sera before and 3-4 weeks after vaccination and then performed a neutralization assay using these sera with lentivirus-based pseudoviruses harboring spike proteins of B.1.1, BA.5, XBB.1.5, JN.1, XEC, LP.8.1, NB.1.8.1, XFG and BA.3.2. The 50% neutralization titers of the sera against all variants tested were significantly increased in after vaccination in both Daiichi Sankyo cohort (2.1-fold to 11.9-fold, P<0.0001) and Meiji Seika Pharma cohort (1.4-fold to 3.9-fold, P<0.0005). Consistent with our recent study using the sera from LP.8.1-based vaccinees, the humoral immunity induced by XEC-based vaccines against JN.1 and its subvariants (XEC, LP.8.1, NB.1.8.1 and XFG) was greater than that against other variants (B.1.1, BA.5, XBB.1.5 and BA.3.2). Notably, our result showed that the XEC-based mRNA vaccine induces a stronger humoral immunity compared to the XEC-based replicon vaccine, and even the LP.8.1-adapted vaccines. However, it should be noted that our cohorts are relatively small and may include confounding factors that affect the results, such as age, sex, history of natural infection and vaccination status. Future investigations with larger cohorts are required to better understand this possibility. To compare the immune status induced by XEC- and LP.8.1-based vaccines, we analyzed the cross-neutralization induced by these vaccines using antigenic cartography. The antigenic map was depicted based on the 50% neutralization titers values obtained from this study and our recent study using LP.8.1-based vaccine sera. The cartography showed that the immune status induced by XEC-based vaccines was similar to that induced by LP.8.1-based vaccines against the nine SARS-CoV-2 variant antigens tested. In sum, our investigations, including the recent one8, suggest that all 4 of the JN.1 subvariants-based vaccines that we tested induce profound humoral immunity against a broad range of SARS-CoV-2 variants.

microbiology↗

bioRxiv2025

Humoral immunity induced by LP.8.1 monovalent vaccines against a broad range of SARS-CoV-2 variants including XEC, NB.1.8.1, XFG, and BA.3.2

In the spring of 2025, multiple SARS-CoV-2 Omicron JN.1 subvariants were circulating, with LP.8.1 among the major variants. Pharmaceutical companies such as Pfizer/BioNTech, Moderna, and Novavax/Takeda adopted monovalent LP.8.1 for their 2025-2026 season vaccines, following recommendations issued by the WHO in May 2025. As of November 2025, SARS-CoV-2 variants including LP.8.1, XEC, NB.1.8.1, and XFG--all designated as variants under monitoring--were circulating. In terms of the spike gene, these recent variants as well as LP.8.1 are derived from JN.1. Moreover, BA.3.2, a BA.3 descendant with multiple mutations in the spike gene, has recently emerged and exhibits robust immune evasion. In Japan, the rollout of the LP.8.1-based vaccination has progressed since the end of September 2025. We previously reported the humoral immunity induced by the XBB.1.5-based monovalent vaccine in 2023 and the JN.1-based monovalent vaccine in 2024 in the Japanese population. Here, we investigated the efficiency of humoral immunity induced by two LP.8.1-based vaccines, the mRNA vaccine from Pfizer/BioNTech and the recombinant protein-based vaccine from Novavax/Takeda, in Japan. We performed neutralization assays using sera obtained from individuals who received the LP.8.1 mRNA vaccine from Pfizer/BioNTech (N=29) or the LP.8.1 recombinant protein vaccine from Novavax/Takeda (N=20) with pseudoviruses harboring spike proteins of B.1.1, BA.5, XBB.1.5, JN.1, LP.8.1, XEC, NB.1.8.1, XFG and BA.3.2. In both mRNA and protein-based vaccinee groups, the change in 50% neutralizing titer (NT50) against variants that were predominant before JN.1 (i.e., B.1.1, BA.5 and XBB.1.5) were smaller than those against JN.1 and its subvariants, including LP.8.1, XEC, NB.1.8.1 and XFG. Consistent with recent studies, neutralizing antibodies against BA.3.2 were induced by both vaccines. However, the induction fold change of BA.3.2 was smaller than those of JN.1 and its subvariants. Next, we tested humoral immune response of participants who received both JN.1-based vaccine in 2024 and LP.8.1-based vaccine in 2025 (N=15). Approximately a year after the JN.1-based vaccination, neutralization titer has waned against all variants tested. However, when we compare the NT50s of pre-vaccination sera between 2025 and 2024, those in 2025 against all variants except for B.1.1 were significantly higher than those last year. This suggests that the cross-neutralizing antibodies induced by JN.1-based vaccination were still maintained for a year. Furthermore, the neutralization abilities against the JN.1 sublineages tested and BA.3.2 were significantly reboosted after the LP.8.1-based vaccination. Our study shows immune boosting by the LP.8.1-based vaccine is effective in achieving cross-neutralization against a broad range of JN.1 sublineages in a JN.1-naive population and in recalling waning humoral immunity against these subvariants.

microbiology↗

bioRxiv2025

Attractive and repulsive couplings between circadian pacemaker neurons promote entrainment to light-dark cycles with after-effect

The mammalian circadian pacemaker, suprachiasmatic nucleus (SCN), comprises a core region that receives light signals from the retina and a shell region that outputs pacemaking rhythms to peripheral tissues. The free-running period (FRP) of animals in constant darkness (DD) correlates with the period of the preceding LD cycle, a phenomenon known as after-effect. To elucidate the mechanisms underlying robust entrainment and after-effect, we analyzed phase oscillator models incorporating attractive and repulsive couplings that respectively decrease or increase phase differences between oscillators. Attractive coupling from the core to shell regions accounts for experimentally observed phase relationships between these regions under LD cycles. Remarkably, repulsive coupling from the shell to core regions promotes SCN entrainability to LD cycles. Furthermore, after transfer to DD, the FRP slowly returns to the intrinsic SCN period, reflecting the after-effect. Our analysis identifies an SCN coupling architecture that underlies stable daily activity rhythms.

physiology↗

bioRxiv2024

Robust antiviral humoral immunity induced by JN.1 monovalent mRNA vaccines against a broad range of SARS-CoV-2 Omicron subvariants including JN.1, KP.3.1.1 and XEC

As of November 2024, SARS-CoV-2 Omicron JN.1 subvariants, such as KP.2 (JN.1.11.1.2), KP.3 (JN.1.11.1.3), KP.3.1.1 (JN.1.11.1.3.1.1), and XEC -- a recombinant lineage between KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3) -- have been circulating in several countries. To control the infection with SARS-CoV-2 Omicron JN.1 subvariants, JN.1 monovalent mRNA vaccines have been developed. Some previous reports showed that the JN.1 monovalent mRNA vaccine of Pfizer/BioNTech (US/Germany) increased antiviral humoral immunity against JN.1 subvariants and XEC. However, the efficacy of other available JN.1 monovalent mRNA vaccines (e.g., Daiichi-Sankyo, Japan) remains unassessed. To validate the antiviral efficacy induced by JN.1 mRNA vaccines, sera were collected from individuals vaccinated with Pfizer/BioNTech JN.1 mRNA vaccine (N=15) or Daiichi-Sankyo JN.1 mRNA vaccine (N=19) before and 3-4 weeks after vaccination. We then performed a neutralization assay using these sera and pseudoviruses. Both Pfizer/BioNTech JN.1 vaccine (2.4-to 8.0-fold, P=0.0001) and Daiichi-Sankyo JN.1 vaccine (2.3-to 13-fold, P=0.0001) boosted antiviral humoral immunity against all variants tested with statistical significance. While the Pfizer/BioNTech mRNA vaccine encodes the full-length JN.1 spike (S), the Daiichi-Sankyo mRNA vaccine encodes the receptor-binding domain of JN.1 S. Our data suggest that the receptor-binding domain of JN.1 S can effectively induce antiviral humoral immunity against JN.1 subvariants and XEC comparable to the full-length JN.1 S. However, it should be considered that the sizes of our cohorts are relatively small (<20 donors per cohort), and donor characteristics, such as age, sex, underlying disease status, and previous SARS-CoV-2 infection, may critically affect the experimental results. Future investigations with larger cohorts will address this concern. When compared to vaccination with JN.1 mRNA vaccines, our previous investigations showed that the natural infection of JN.1 and KP.3.3 elicited poorer antiviral humoral immunity against JN.1 and its subvariants. Our results suggest that the JN.1 mRNA vaccination more robustly induces antiviral humoral immunity against recent JN.1 subvariants than the natural infection of JN.1 subvariants regardless of manufacturer. Moreover, as we reported last year, the humoral immunity induced by XBB.1.5 monovalent mRNA vaccine against XBB.1.5 was weaker than that against ancestral B.1.1. However, in the case of JN.1 monovalent mRNA vaccine, here we showed that the 50% neutralization titer against XBB.1.5 is greater than that against ancestral B.1.1. These observations imply that immune imprinting has shifted from that biased toward pre-Omicron to that biased toward Omicron, depending on the time and/or number of immune stimuli (e.g., infection and/or vaccination).

microbiology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 XEC variant

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (e.g., S:R346T, S:F456L, and S:Q493E), have emerged concurrently. As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3 and is the most predominant SARS-CoV-2 variant in the world. Thereafter, XEC, a recombinant lineage of KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3), was first identified in Germany on August 7, 2024. XEC acquired two S substitutions, S:T22N and S:F59S, compared with KP.3 through recombination, with a breakpoint at genomic position 21,738-22,599. We estimated the relative effective reproduction number (Re) of XEC using a Bayesian multinomial logistic model based on genome surveillance data from the USA, the United Kingdom, France, Canada, and Germany, where this variant has spread as of August 2024. In the USA, the Re of XEC is 1.13-fold higher than that of KP.3.1.1. Additionally, the other countries under investigation herein showed higher Re for XEC. These results suggest that XEC has the potential to outcompete the other major lineage including KP.3.1.1. We then assessed the virological properties of XEC using pseudoviruses. Pseudovirus infection assay showed that the infectivity of KP.3.1.1 and XEC was significantly higher than that of KP.3. Although S:T22N did not affect the infectivity of the pseudovirus based on KP.3, S:F59S significantly increased it. Neutralization assay was performed using three types of human sera: convalescent sera after breakthrough infection (BTI) with XBB.1.5 or KP.3.3, and convalescent sera after JN.1 infection. In all serum groups, XEC as well as KP.3.1.1 showed immune resistance when compared to KP.3 with statistically significant differences. In the cases of XBB.1.5 BTI sera and JN.1 infection sera, the 50% neutralization titers (NT50s) of XEC and KP.3.1.1 were comparable. However, we revealed that the NT50 of XEC was significantly (1.3-fold) lower than that of KP.3.1.1. Moreover, both S:T22N and S:F59S significantly (1.5-fold and 1.6-fold) increased the resistance to KP.3.3 BTI sera. Here we showed that XEC exhibited higher pseudovirus infectivity and higher immune evasion than KP.3. Particularly, XEC exhibited more robust immune resistance to KP.3.3 BTI sera than KP.3.1.1. Our data suggest that the higher Re of XEC than KP.3.1.1 is attributed to this property and XEC will be a predominant SARS-CoV-2 variant in the world in the near future.

microbiology↗

bioRxiv2024

Multiple Notch ligands in the synchronization of the segmentation clock

Notch signaling is a ubiquitous and versatile intercellular signaling system that drives collective behaviors and pattern formation in biological tissues. During embryonic development, Notch is involved in generation of collective biochemical oscillations that form the vertebrate body segments, and its failure results in embryonic defects. Notch ligands of the Delta family are key components of this collective rhythm, but it is unclear how different Delta ligands with distinct properties contribute to relaying information among cells. Motivated by the zebrafish segmentation clock, in this work we propose a theory describing interactions between biochemical oscillators, where Notch receptor is bound by both oscillatory and nonoscillatory Delta ligands. Based on previous in vitro binding studies, we first consider Notch activation by Delta dimers. This hypothesis is consistent with experimental observations in conditions of perturbed Notch signaling. Then we test an alternative hypothesis where Delta monomers directly bind and activate Notch, and show that this second model can also describe the experimental observations. We show that these two hypotheses assign different roles for a non-oscillatory ligand, as a binding partner or as a baseline signal. Finally, we discuss experiments to distinguish between the two scenarios. Broadly, this work highlights how a multiplicity of ligands may be harnessed by a signaling system to generate versatile responses.

developmental biology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 KP.3.1.1 variant

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions e.g., S:R346T, S:F456L, and S:Q493E, have emerged concurrently. Thereafter, JN.1 subvariants, such as LB.1 (JN.1.9.2.1), KP.2.3 (JN.1.11.1.2.3), and KP.3.1.1 (JN.1.11.1.3.1.1), which convergently acquired a deletion of Serine at the 31st position in S (S:S31del) in addition to the above substitutions, have emerged and spread as of June 2024. We recently reported the virological features of JN.1 subvariants including KP.2, KP.3, LB.1, and KP.2.3.2,3 Here, we investigated the virological properties of KP.3.1.1. First, we estimated the relative effective reproduction number (Re) of KP.3.1.1 using a Bayesian multinomial logistic model4 based on genome surveillance data from Spain, the USA, France, Canada, and the UK, where this variant has spread as of June 2024. In Spain, the Re of KP.3.1.1 is over 1.2-fold higher than that of JN.1 and even higher than those of KP.2, KP.3, LB.1, and KP.2.3. Additionally, the other countries under investigation herein show higher Re for KP.3.1.1. However, it must be noted there is the possibility of overestimation in these countries due to more limited KP.3.1.1 sequence numbers. These results suggest that KP.3.1.1 will spread worldwide along with other JN.1 sublineages. We then assessed the virological properties of KP.3.1.1 using pseudoviruses. The pseudovirus of KP.3.1.1 had significantly higher infectivity than that of KP.3. Neutralization of KP.3.1.1 was tested using i) convalescent sera after breakthrough infection (BTI) with XBB.1.5 or EG.5, ii) convalescent sera after the infection with HK.3 or JN.1, and iii) sera after monovalent XBB.1.5 vaccination. The 50% neutralization titer (NT50) against KP.3.1.1 was significantly lower than KP.3 (1.4-1.6-fold) in all four groups of convalescent sera tested. KP.3.1.1 also showed a 1.3-fold lower NT50 against XBB.1.5 vaccine sera than KP.3. Moreover, KP.3.1.1 showed stronger resistance with a 1.3-fold lower NT50 with statistical significances to the convalescent sera infected with EG.5 and HK.3 than KP.2.3. Altogether, KP.3.1.1 exhibited a higher Re, higher pseudovirus infectivity, and higher neutralization evasion than KP.3. These results align with our recent report that the JN.1 subvariants with S:S31del (e.g., KP.2.3 and LB.1) exhibited enhanced Re and immune evasion compared to the other JN.1 subvariants without S:S31del (e.g., JN.1, KP.2, and KP.3), highlighting the evolutionary significance of S:S31del in the JN.1 lineages.

microbiology↗

bioRxiv2024

Statistical description of mobile oscillators in embryonic pattern formation

Synchronization of mobile oscillators occurs in numerous contexts, including physical, chemical, biological and engineered systems. In vertebrate embryonic development, a segmental body structure is generated by a population of mobile oscillators. Cells in this population produce autonomous gene expression rhythms, and interact with their neighbors through local signaling. These cells form an extended tissue where frequency and cell mobility gradients coexist. Gene expression kinematic waves travel through this tissue and pattern the segment boundaries. It has been shown that oscillator mobility promotes global synchronization. However, in vertebrate segment formation, mobility may also introduce local fluctuations in kinematic waves and impair segment boundaries. Here we derive a general framework for mobile oscillators that relates local mobility fluctuations to synchronization dynamics and pattern robustness. We formulate a statistical description of mobile phase oscillators in terms of a probability density. We obtain and solve diffusion equations for the average phase and variance, revealing the relationship between local fluctuations and global synchronization in a homogeneous population of oscillators. Analysis of the probability density for large mobility identifies a mean-field transition, where locally coupled oscillators start behaving as if each oscillator was coupled with all the others. We extend the statistical description to inhomogeneous systems to address the gradients present in the vertebrate segmenting tissue. The theory relates pattern stability to mobility, coupling and pattern wavelength. The general approach of the statistical description may be applied to mobile oscillators in other contexts, as well as to other patterning systems where mobility is present.

developmental biology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 KP.3, LB.1 and KP.2.3 variants

The SARS-CoV-2 JN.1 variant, arising from BA.2.86.1 with a substitution in the spike (S) protein, S:L455S, exhibited increased fitness and outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 and KP.3, which convergently acquired S protein substitutions such as S:R346T, S:F456L, and S:Q493E, have emerged concurrently. Furthermore, JN.1 subvariants such as LB.1 and KP.2.3, which convergently acquired S:S31del in addition to the above substitutions, have emerged and spread as of June 2024. Here we investigated the virological properties of KP.3, LB.1 and KP.2.3. We estimated the relative effective reproduction number (Re) of KP.3, LB.1, and KP.2.3 using a Bayesian multinomial logistic model based on the genome surveillance data from Canada, the UK, and the USA, where these variants have spread from March to April 2024. The Re of KP.3 is more than 1.2-fold higher than that of JN.1 and higher than or comparable to that of KP.2 in these countries. Importantly, the Re values of LB.1 and KP.2.3 are even higher than those of KP.2 and KP.3. These results suggest that the three variants we investigated herein, particularly LB.1, and KP.2.3, will become major circulating variants worldwide in addition to KP.2 and KP.3. The pseudovirus infectivity of KP.2 and KP.3 was significantly lower than that of JN.1. On the other hand, the pseudovirus infectivity of LB.1 and KP.2.3 was comparable to that of JN.1. Neutralization assay was conducted by using four types of breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections as well as monovalent XBB.1.5 vaccine sera. In all four groups of BTI sera tested, the 50% neutralization titers (NT50) against LB.1 and KP.2.3 were significantly lower than those against JN.1 (2.2-3.3-fold and 2.0-2.9-fold) and even lower than those against KP.2 (1.6-1.9-fold and 1.4-1.7 fold). Although KP.3 exhibited neutralization resistance against all BTI sera tested than JN.1 (1.6-2.2-fold) with statistical significance, there were no significant differences between KP.3 and KP.2. In the case of infection-naive XBB.1.5 vaccine sera, the NT50 values of JN.1 subvariants were very low. In the case of XBB.1.5 vaccine sera after natural XBB infection, the NT50 values against KP.3, LB.1 and KP.2.3 were significantly lower than those of JN.1 (2.1-2.8-fold) and even lower than KP.2 after infection (1.4-2.0-fold). Overall, our results suggest that the S substitutions convergently acquired in the JN.1 subvariants contribute to immune evasion, and therefore, increase their Re when compared to parental JN.1. More importantly, LB.1 and KP.2.3 exhibited higher pseudovirus infectivity and more robust immune resistance than KP.2. These data suggest that S:S31del is critical to exhibit increased infectivity, increased immune evasion, and therefore, potentially contributes to increased Re.

microbiology↗

bioRxiv2024

Impacts of the feedback loop between sense-antisense RNAs in regulating circadian rhythms

Antisense transcripts are a unique group of non-coding RNAs that are transcribed from the opposite strand of a sense coding gene in an antisense orientation. Even though they do not encode a protein, these transcripts play a regulatory role in a variety of biological processes, including circadian rhythms. We and others found an antisense transcript, Per2AS, that is transcribed from the strand opposite the sense transcript Period2 (Per2) and exhibits a rhythmic and antiphasic expression pattern compared to Per2 in mouse. By assuming that Per2AS and Per2 mutually repress each other, our previous mathematical model predicted that Per2AS regulates the robustness and the amplitude of circadian rhythms. In this study, we revised our previous model and developed a new mathematical model that mechanistically described the mutually repressive relationship between Per2 and Per2AS via transcriptional interference. We found that the simulation results are largely consistent with experimental observations including the counterintuitive ones that could not be fully explained by our previous model. These results indicate that our revised model serves as a foundation to build more detailed models in the future to better understand the impact of Per2AS-Per2 interaction in the mammalian circadian clock. Our mechanistic description of Per2AS-Per2 interaction can also be extended to other mathematical models that involve sense-antisense RNA pairs that mutually repress each other.

systems biology↗

bioRxiv2024

Virological characteristics of the SARS-CoV-2 KP.2 variant

The JN.1 variant (BA.2.86.1.1), arising from BA.2.86(.1) with the S:L455S substitution, exhibited increased fitness and outcompeted the previous dominant XBB lineage by the biggening of 2024. JN.1 subsequently diversified, leading to the emergence of descendants with spike (S) protein substitutions such as S:R346T and S:F456L. Particularly, the KP.2 (JN.1.11.1.2) variant, a descendant of JN.1 bearing both S:R346T and S:F456L, is rapidly spreading in multiple regions as of April 2024. Here, we investigated the virological properties of KP.2. KP.2 has three substitutions in the S protein including the two above and additional one substitution in non-S protein compared with JN.1. We estimated the relative effective reproduction number (Re) of KP.2 based on the genome surveillance data from the USA, United Kingdom, and Canada where >30 sequences of KP.2 has been reported, using a Bayesian multinomial logistic model. The Re of KP.2 is 1.22-, 1.32-, and 1.26-times higher than that of JN.1 in USA, United Kingdom, and Canada, respectively. These results suggest that KP.2 has higher viral fitness and potentially becomes the predominant lineage worldwide. Indeed, as of the beginning of April 2024, the estimated variant frequency of KP.2 has already reached 20% in United Kingdom. The pseudovirus assay showed that the infectivity of KP.2 is significantly (10.5-fold) lower than that of JN.1. We then performed a neutralization assay using monovalent XBB.1.5 vaccine sera and breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections. In all cases, the 50% neutralization titer (NT50) against KP.2 was significantly lower than that against JN.1. Particularly, KP.2 shows the most significant resistance to the sera of monovalent XBB.1.5 vaccinee without infection (3.1-fold) as well as those who with infection (1.8-fold). Altogether, these results suggest that the increased immune resistance ability of KP.2 partially contributes to the higher Re more than previous variants including JN.1.

microbiology↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 JN.1 variant

The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion. BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins. S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other "FLip" variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant. Here, we investigated the virological properties of JN.1.

microbiology↗

bioRxiv2023

Antiviral humoral immunity against SARS-CoV-2 Omicron subvariants induced by XBB.1.5 monovalent vaccine in infection-naive and XBB-infected individuals

To control infection with SARS-CoV-2 Omicron XBB subvariants, the XBB.1.5 monovalent mRNA vaccine has been available since September 2023. However, we have found that natural infection with XBB subvariants, including XBB.1.5, does not efficiently induce humoral immunity against the infecting XBB subvariants. These observations raise the possibility that the XBB.1.5 monovalent vaccine may not be able to efficiently induce humoral immunity against emerging SARS-CoV-2 variants, including a variety of XBB subvariants (XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and HK.3) as well as BA.2.86. To address this possibility, we collected two types of sera from individuals vaccinated with the XBB.1.5 vaccine; those who had not been previously infected with SARS-CoV-2 and those who had been infected with XBB subvariants prior to XBB.1.5 vaccination. We collected sera before and 3-4 weeks after vaccination, and then performed a neutralization assay using these sera and pseudoviruses.

microbiology↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 Omicron HK.3 variant harboring the "FLip" substitution

In November 2023, SARS-CoV-2 XBB descendants, including EG.5.1 (XBB.1.9.2.5.1), the currently predominant lineage, are circulating worldwide according to Nextstrain. EG.5.1 has a characteristic amino acid substitution in the spike protein (S), S:F456L, which contributes to its escape from humoral immunity. EG.5.1 has further evolved, and its descendant lineage harboring S:L455F (i.e., EG.5.1+S:L455F) emerged and was named HK.3 (XBB.1.9.2.5.1.1.3). HK.3 was initially discovered in East Asia and is rapidly spreading worldwide. Notably, the XBB subvariants bearing both S:L455F and S:F456L substitutions, including HK.3, are called the "FLip" variants. These FLip variants, such as JG.3 (XBB.1.9.2.5.1.3.3), JF.1 (XBB.1.16.6.1) and GK.3 (XBB.1.5.70.3), have emerged convergently, suggesting that the acquisition of these two substitutions confers a growth advantage to XBB in the human population. Here, we investigated the virological properties of HK.3 as a representative of the FLip variants.

microbiology↗

bioRxiv2023

Clock driven waves of Tbx6 expression prefigure somite boundaries

The segmented body plan of vertebrates is established during embryogenesis by periodic and sequential formation of multi-cellular structures called somites. Somitogenesis is an example of patterning by a biological oscillator, the segmentation clock, which manifests as traveling waves of oscillating Hes/Her gene expression, reiterating during the formation of each1-3. How these waves are converted into the striped Mesp gene expression pattern that prefigures morphological somite boundaries4-8 remains unclear. Here, we image this conversion in real-time at single-cell resolution in zebrafish, using light-sheet microscopy of a novel reporter of Tbx6, a key activator of Mesp expression. We observe cellular oscillations and kinematic waves of Tbx6 expression that are driven by Hes/Her genes. Tbx6 waves arrest precisely in boundary cells that eventually express Mesp, thereby prefiguring the Mesp pattern, whereas Hes/Her waves do not. Although Hes/Her oscillations began before somitogenesis9-11, the first Tbx6 wave defines the boundary cells of the anterior-most somite, forming the head-trunk interface. Our findings imply that Tbx6 acts as a genetic clutch, converting Her/Hes pacemaker waves into Mesp stripes. We propose that this clock design shields the pacemaker from external perturbations, allowing flexible and robust patterning, making it of interest for organoids and tissue-engineering.

developmental biology↗