Biology subjects

Han, P.

Publications and source records attributed to Han, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Catalytic and inhibitory architecture of comammox ammonia monooxygenase

Complete ammonia oxidizers (comammox) are widespread nitrifiers that can dominate ammonia oxidation in diverse environments by efficiently converting ammonia to nitrate within a single cell, yet the molecular basis distinguishing their ammonia monooxygenase (AMO) from those of canonical bacterial AMO remains unresolved. Here we report cryo-electron microscopy (cryo-EM) structures of AMO from the comammox Nitrospira inopinata (NiAMO) in inhibitor-free and allylthiourea (ATU)-bound states at 2.47 and 2.68 angstrom, respectively. NiAMO displays distinctive auxiliary-subunit organization, copper-site configuration and hydrophobic-channel architecture. Integrative molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations support a methyl-plastoquinol (methyl-PQH2)-coupled, CuD-centric catalytic model, with CuC potentially facilitating quinone redox cycling. N. inopinata exhibited broad susceptibility to several known nitrification inhibitors, and ATU-bound NiAMO structure localized the inhibitor to the CuC-CuD region, accompanied by constriction of the hydrophobic channel, which is consistent with the competitive role of ATU demonstrated in recovery assays. Multi-omics analyses further revealed an energy-limited stress response to ATU, including induction of urea transport and utilization systems. Collectively, these findings define a methyl-PQ-linked catalytic and inhibitor-responsive architecture of comammox AMO and establish a mechanistic framework for lineage-aware management of nitrification in natural and engineered ecosystems.

biophysics↗

bioRxiv2025

A Mechanosensitive GPCR at vestibular kinocilium is required for normal balance

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq-PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq, or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68, causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER+/- Grm2fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

cell biology↗

bioRxiv2025

RNA viruses in water shape the viromes of shrimp and fish in aquaculture systems

Aquatic environments host immense RNA viral diversity, yet the extent to which waterborne viruses influence the virome of aquatic animals remains unclear. Here, we conducted a comprehensive longitudinal metatranscriptomic analysis of water, shrimp, and fish across multiple culture stages in aquaculture systems. We identified 3,211 RNA viruses spanning 21 viral supergroups, with 97.4% representing novel species. Water exhibited the greatest viral diversity (3,093 species), followed by shrimp (1,280) and fish (398), with most viruses detected in shrimp and fish also detected in water. Diversity analyses revealed increasing richness and significant compositional shifts in 92 high-abundance viruses (>1,000 RPM) across culture stages. Viral abundance in aquatic animals was strongly correlated with that in water, and the temporal trajectories of the 16 most abundant viruses were closely synchronized between water and shrimp. Furthermore, 337 virus species were shared among shrimp and two fish species, of which 309 were present in water. These findings demonstrated that RNA viruses in water shape the composition and dynamics of aquatic animal viromes, underscoring the importance of water virome surveillance and management for disease prevention in shrimp aquaculture.

microbiology↗

bioRxiv2024

Exploring the Hypothetical Role of Bacteroides Species in Depression Progression: Insights from Metagenomic Analysis

Depression, a psychiatric disorder with significant morbidity and mortality, has a complex etiology. Recent advances in microbiome research have highlighted the potential role of gut microbiota in depression pathogenesis. This study utilized shotgun metagenomic sequencing to compare the fecal microbiota of 28 depression patients and 26 healthy individuals. Significant differences in gut microbiota composition were observed between the two groups. We generated 350 non-redundant high-quality metagenome-assembled Genomes (MAGs) by binning and conducted comparisons between the depression and control groups. Notably, we found that the MAGs enriched in people with depression mostly belonged to Bactendicating a close link between Bacteroides abundance and the development of depression, suggesting that Bacteroides might be a potential culprit for deroides, ipression. In the depression group, we found that the module of nitric oxide synthesis was remarkably enriched, and all Bacteroides MAGs were annotated to nitric oxide synthase, suggesting that increased levels of Bacteroides may contribute to elevated nitric oxide synthesis. Specifically, the mean relative abundance about the genomes of Bacteroides xylanisolvens, Bacteroides caccae, Bacteroides fragilis, Bacteroides stercoris and Bacteroides ovatus showed strong discriminatory power in distinguishing depressed patients from healthy individuals (AUC=0.834). This research shed light on the potential role of gut microbiota in depression and highlights specific metabolic pathways and microbial markers for further investigation. ImprotanceThis research highlighted significant differences in the composition and function of gut microbiota between individuals with depression and healthy individuals, particularly the enrichment of Bacteroides MAGs in depression patients. The upregulation of the nitric oxide synthesis pathway associated with these MAGs belong to Bacteroides in the gut of depression patients had also been observed. The mean relative abundance of a specific set of Bacteroides MAGs had been identified, which could accurately classify individuals with depression from healthy individuals (AUC=0.834). Our results suggest the importance of exploring microbial markers as potential diagnostic and therapeutic targets in managing depression.

genomics↗

bioRxiv2024

Human skin rejuvenation via mRNA

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related changes in cellular composition and function across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. Using our atlas, we have uncovered basal stem cells as a highly variable population across aging, more so than other skin cell populations, such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we developed an innovative mRNA-based treatment to mitigate the effects of skin aging. After treatment with ATF3 mRNA, cell senescence decreased 25%, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found communication between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 mRNA rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%. Furthermore, we validated the efficacy of ATF3 mRNA treatment in ex vivo human skin and in vivo mouse models. In ex vivo human skin, microneedle-mediated delivery of ATF3 mRNA induced robust rejuvenation, expanding the basal stem-cell population and enhancing dermal ECM reconstruction. In a wound healing mouse model, ATF3 mRNA reduced scarring, demonstrating strong regenerative potential for reversing age-related skin decline. We conclude that ATF3 mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

synthetic biology↗

bioRxiv2024

Sense codon-misassociated eRF1 elicits widespread ribosome stalling and induction of quality control

The rescue pathway of stalled ribosomes and ribosome-associated quality control (RQC) serves as a surveillance system for aberrant translation that senses ribosome collisions. Although the molecular mechanism has been extensively studied, the endogenous contexts of ribosome collision rescued by the system are poorly understood. Here, beginning with a study of the codon specificity of the eukaryotic translation termination factor eRF1, we show that transient binding of eRF1 to the UUA sense codon leads to ribosome collision and provides a constitutive source of rescue substrates in humans. eRF1-selective Monosome-Seq and Disome-Seq revealed that eRF1 was recruited not only to stop codons but also to near-cognate sense codons, including the UUA codon. The eRF1 on UUA codons delays translation elongation but does not trigger the termination reaction. Remarkably, Disome-Seq with the depletion of ASCC3 and 4EHP, key factors for the ribosome rescue and translation initiation repression, showed that ribosomes stalled at UUA codons consist of a subpopulation suppressed by those factors. Failure of ribosome collision repression by ASCC3-4EHP triggers stress response, such as expression of the stress-induced transcription factor ATF3. This study highlights the impact of sense codon misrecognition by the termination factor on translation homeostasis in human cells.

molecular biology↗

bioRxiv2024

Generative Modelling of Oncogene-carrying Extrachromosomal Circular DNA Biogenesis and Dynamics in Cells

Extrachromosomal circular DNAs (ecDNA) are focal gene amplifications frequently associated with cancer development and often indicating a poor prognosis. To understand the early dynamics of oncogene-carrying ecDNAs, we previously developed CRISPR-C, a tool for precise ecDNA generation by deleting specific chromosomal regions. Here, we adapted CRISPR-C to recreate tumor ecDNAs. This method also allowed us to enhance ecDNA generation efficiency by directly delivering Cas9 protein and sgRNAs as a ribonucleoprotein complex. By using the modified CRISPR-C, we successfully generated ecDNAs carrying oncogenes (EGFR, CDK4, MDM2, MYC, MYCN, FGFR2, ABCB1, and DHFR) in various human cell types. Furthermore, we demonstrated that our method could generate chimeric ecDNAs composed of target sequences from distant intra or inter-chromosomal regions. Using these generative ecDNA cell models, we studied the oncogene ecDNA expression and stability. The MDM2 expression was increased after CRISPR-C, while CDK4 was decreased indicating genomic-context dependent effect. The copy number of CRISPR-C generated CDK4 was ecDNA increased in cells after a long period of treatment with the CDK4 inhibitor palbociclib. Unlike CDK4, the CRISPR-C generated ABCB1 ecDNA was unstable in cells under normal growth conditions, but is stably retained when the cells were treated with colcemid, a recognized substrate for ABCB1. We thus provide valuable tools and an attractive platform for studying ecDNA biogenesisy and in vitro drug screening on ecDNA stability.

cancer biology↗

bioRxiv2024

MicroRNA-27a-5p downregulates the expression of proinflammatory cytokines in lipopolysaccharide-stimulated human dental pulp cells via NF-κB signaling pathway

AimTo investigate the effect of microRNA-27a-5p (miR-27a-5p) on the expression of proinflammatory cytokines in human dental pulp cells (hDPCs) stimulated by lipopolysaccharide (LPS). MethodologyExpression of miR-27a-5p was evaluated in LPS-stimulated hDPCs isolated from third molars of healthy patients by a TaqMan microRNA assay. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and a cytometric bead array were used to measure mRNA and protein expression levels, respectively, of proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemotactic protein 1 (MCP1). Luciferase assays and western blotting were conducted to assess nuclear factor {kappa}B (NF-{kappa}B) activity. Gene/protein expression of NF-{kappa}B signaling activators, i.e., transforming growth factor beta-activated kinase 1 binding protein 1 (TAB1), IL-1 receptor-associated kinase 4 (IRAK4), NF-{kappa}B p65 (RELA), and follistatin-like 1 (FSTL1), was evaluated by RT-qPCR and western blotting. Transfection of an miR-27a-5p mimic was performed using Lipofectamine RNAiMax reagent. Wildtype and mutated 3{square}-untranslated region (UTR) of TAB1-contained luciferase reporter vectors were co-transfected with the miR-27a-5p mimic. Small interfering RNA against TAB1 (siTAB1) was designed to block its expression. One-way analysis of variance and Students t-test were used to determine statistical significance ( = .05). ResultsLPS-stimulated hDPCs showed concurrent increases in the expression of miR-27a-5p and proinflammatory cytokines (IL-6, IL-8, and MCP1), and the increased expression was suppressed by NF-{kappa}B inhibitor BAY 11-0785. Transfection of the miR-27a-5p mimic downregulated expression of proinflammatory cytokines, NF-{kappa}B activity, and expression of NF-{kappa}B signaling activators (TAB1, IRAK4, RELA, and FSTL1) in LPS-stimulated hDPCs. Luciferase reporter assays revealed that miR-27a-5p bound directly to the 3{square}-UTR of TAB1. siTAB1 downregulated NF-{kappa}B activity and proinflammatory cytokine expression. Downregulation of proinflammatory cytokine expression, NF-{kappa}B activity, and NF-{kappa}B signaling activator expression (TAB1, IRAK4, and RELA) was also found in LPS-stimulated rat incisor pulp tissue explants following transfection with the miR-27a-5p mimic ex vivo. ConclusionsMiR-27a-5p, whose expression was induced by NF-{kappa}B signaling, negatively regulated the synthesis of proinflammatory cytokines via targeting NF-{kappa}B signaling. In particular, TAB1, a potent NF-{kappa}B activator, was targeted by miR-27a-5p. These results provide insights into the negative regulatory effects of miR-27a-5p, particularly those targeting the TAB1-NF-{kappa}B signaling pathway, on pulp inflammation.

pathology↗

bioRxiv2023

Chemical genetic interaction linking eIF5A hypusination and mitochondrial integrity

The eukaryotic translation factor eIF5A plays an important role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. eIF5A undergoes hypusination, a post-translational modification unique to this protein, although the role of hypusination in the function of eIF5A remains elusive. Here, we investigated the cellular defects induced by the hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Proteome, translatome, and transcriptome analyses indicated that GC7 downregulated a subset of mitochondrial proteins and DNA, causing mitochondrial stress and eliciting the integrated stress response. Chemical genomic screening using barcoded shRNA libraries identified genes encoding proteins involved in polyamine metabolism/transport and MPV17L2, a mitochondrial disease gene homologue whose product regulates mitochondrial translation. Depletion of MPV17L2 caused hypersensitivity to GC7 and phenocopied the effects of GC7 treatment. These results suggest that eIF5A hypusination and MPV17L2 synthetically regulate mitochondrial molecular synthesis and integrity.

cell biology↗

bioRxiv2023

Proliferation history and transcription factor levels drive direct conversion

The sparse and stochastic nature of reprogramming has obscured our understanding of how transcription factors drive cells to new identities. To overcome this limit, we developed a compact, portable reprogramming system that increases direct conversion of fibroblasts to motor neurons by two orders of magnitude. We show that subpopulations with different reprogramming potentials are distinguishable by proliferation history. By controlling for proliferation history and titrating each transcription factor, we find that conversion correlates with levels of the pioneer transcription factor Ngn2, whereas conversion shows a biphasic response to Lhx3. Increasing the proliferation rate of adult human fibroblasts generates morphologically mature, induced motor neurons at high rates. Using compact, optimized, polycistronic cassettes, we generate motor neurons that graft with the murine central nervous system, demonstrating the potential for in vivo therapies. One Sentence SummaryUsing a systems and synthetic biology approach to study the molecular determinants of reprogramming, we find that proliferation history and transcription factor levels drive cell fate in direct conversion to motor neurons. HighlightsO_LIminimal high-efficiency cocktail allows systematic interrogation of the reprogramming process C_LIO_LIhistory provides a principal axis to distinguish transcription factors influence C_LIO_LIof the transcription factor cocktail impacts reprogramming efficiency and dynamics C_LIO_LIof individual transcription factors differentially influence the rate of reprogramming C_LIO_LIearly hyperproliferation increases direct conversion of adult human fibroblasts C_LIO_LIptimal cocktail allows neurotrophic factor-free reprogramming and in vivo grafting C_LI

cell biology↗

bioRxiv2023

Unveiling unique microbial nitrogen cycling and novel nitrification drivers in coastal Antarctica

Although microbial nitrogen (N) cycling plays a pivotal role in Antarctic ecosystems, its underlying mechanisms are largely uncharted. In this study, we unravel the biological origin of nitrate via triple oxygen isotopic composition analysis and systematically profile functional N-cycling genes within soil and lake sediment samples from the ice-free areas of East Antarctica. We successfully reconstruct 1,968 metagenome-assembled genomes (MAGs) spanning 29 microbial phyla, enabling the analysis of the presence or absence of 52 diverse metabolic marker genes. Consistent with quantitative data, our metagenomic analyses confirm the active processes of microbial nitrogen fixation, nitrification, and denitrification. We find no detectable anaerobic ammonium oxidation (anammox) processes, underscoring a unique microbial N-cycling dynamic in the region. Notably, we identify the predominance of complete ammonia-oxidizing (comammox) Nitrospira, a recently discovered bacterial guild capable of performing the entire nitrification process within a single organism. Further genomic investigations reveal their adaptive strategies in the Antarctic environment. These strategies likely involve the synthesis of trehalose to counteract cold stress, high substrate affinity to efficiently utilize available resources, and alternative metabolic pathways to adapt to nutrient-scarce conditions. Their significant role in the nitrification process is validated through 13C-DNA-based stable isotope probing (DNA-SIP). This research provides a comprehensive illustration of nitrifications crucial contribution to the nitrogen budget in coastal Antarctica, highlighting comammox Nitrospira clade B as a novel nitrifying agent and shedding new light on the complex biogeochemical processes of nitrogen cycling in coastal Antarctica.

microbiology↗

bioRxiv2023

No-go decay dampens zinc finger protein mRNAs in vertebrates

Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms in eukaryotes. The E3 ubiquitin ligase Znf598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs. However, the impact of RQC and NGD on maintaining the translational homeostasis of endogenous mRNAs has remained unclear. In this study, we investigated the endogenous substrate mRNAs of NGD during the maternal-to-zygotic transition (MZT) of zebrafish development. RNA-Seq analysis of zebrafish znf598 mutant embryos revealed that Znf598 downregulates mRNAs encoding the C2H2-type zinc finger domain (C2H2-ZF) during the MZT. Reporter assays and disome profiling indicated that ribosomes stall and collide while translating tandem C2H2-ZFs, leading to mRNA degradation by Znf598. We further showed that mRNAs encoding C2H2-ZF were degraded in a ZNF598-dependent manner in HEK293T cells. Our results suggest that NGD maintains the quality of the translatome by mitigating the risk of ribosome collision at the abundantly present C2H2-ZF sequences in the vertebrate genome.

molecular biology↗

bioRxiv2023

Discovery of new deaminase functions by structure-based protein clustering

The elucidation of protein function and its exploitation in bioengineering have greatly contributed to the development of the life sciences. Existing protein mining efforts generally rely on amino acid sequences rather than protein structures due to technical difficulties in structural elucidation. We describe here for the use of AlphaFold2 to predict and subsequently cluster an entire protein family based on predicted structure similarities. We selected the deaminase family of proteins to analyze and through this approach identified many previously unknown deaminase properties. We applied these new deaminases to the development of new cytosine base editors with distinct features. Although we found many new double-stranded DNA deaminases from the DddA-like protein clade, we were surprised to find that most of the proteins in this family were not actually double-stranded DNA cytidine deaminases. From this protein clade, we engineered the smallest single-strand specific cytidine deaminase, which facilitates the first efficient cytosine base editor to be packaged into a single AAV vector. Importantly, we also profiled a deaminase from this clade that edits robustly in soybean plants, which previously suffered from poor editing by cytosine base editors. These newly discovered deaminases based on AI-assisted structural predictions greatly expand the utility of base editors for therapeutic and agricultural applications.

molecular biology↗

bioRxiv2023

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis

TERT reactivation occurs frequently in human malignancies. While BRAF activating mutation widely existed in cancers at various stages, TERT reactivation mainly occurs in advanced tumors. However, in vivo evidence for TERT role in cancer progression and the underlying mechanism is currently lacking. In this study, we induced TERT and/or BRAF V600E expression in mouse thyroid epithelium. TERT overexpression alone had no evident effect on tumor initiation. BRAFVE expression itself induced mediocre papillary thyroid cancer (PTC). Notably, the co-expression of BRAFVE and TERT resulted in aggressive poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome revealed that tumors from co-mutant mice were highly heterogeneous and dedifferentiation process significantly correlated with ribosomal pathways. Mechanistically, TERT boosted ribosomal RNA expression and protein synthesis. CX-5461, a rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation. Thus, TERT promotes thyroid cancer progression by inducing dedifferentiation, and ribosome biogenesis inhibition represents a potential treatment strategy for TERT-reactivated cancers. Highlights[tpltrtarr] TERT accelerated thyroid cancer dedifferentiation and metastasis in vivo [tpltrtarr]TERT regulated rRNA metabolism and MTORC1/ S6K/RPS6 activities [tpltrtarr]CX-5461 inhibited the progression of TERT-reactivated melanoma and thyroid cancer [tpltrtarr]Inhibition of rRNA induced redifferentiation of advanced thyroid cancer with TERT activation

cancer biology↗

bioRxiv2022

YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory

N6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specific Ythdf1 and Ythdf2 conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specific Ythdf2 cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of granule cells in DG. DG-specific Ythdf2 ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.

neuroscience↗

bioRxiv2022

De novo design of site-specific protein interactions with learned surface fingerprints

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic, and structural data grows. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction (PPI) networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. We exploit a geometric deep learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features critical to drive PPIs. We hypothesized these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof-of-principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1, and CTLA-4. Several designs were experimentally optimized while others were purely generated in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling a novel approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.

bioengineering↗

bioRxiv2021

Reduced sera neutralization to Omicron SARS-CoV-2 by bothinactivated and protein subunit vaccines and the convalescents

Omicron variant continues to spread all over the world. There are lots of scientific questions remaining to be answered for such a devastating variant. There are a dozen of vaccines already in clinical use. The very urgent scientific question would be whether or not these vaccines can protect Omicron variant. Here, we tested the sera from both convalescents and vaccine recipients receiving either inactivated or protein subunits vaccines (CoronaVac from Sinovac, or BBIBP-CoV from Sinopharm, or ZF2001 from Zhifei longcom) for the binding antibody titers (ELISA) and neutralization antibodies titers (pseudovirus neutralization assay). We showed that Omicron do have severe immune escape in convalescents, with 15 of 16 were negative in neutralization. By contrast, in vaccinees who received three jabs of inactivated or protein subunit vaccine, the neutralizing activity was much better preserved. Especially in the ZF2001 group with an extended period of the second and third jab (4-6 months) remains 100% positive in Omicron neutralization, with only 3.1-folds reduction in neutralizing antibody (NAb) titer. In this case, we proposed that, the multi-boost strategy with an extended interval between the second and third jab for immune maturation would be beneficial for NAb against devastating variants such as Omicron.

immunology↗

bioRxiv2021

The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells

The precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here we find that the m6A reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes. Impact statementThe m6A reader YTHDF2 negatively regulates RGC dendrite branching through destabilizing its m6A-modified target mRNAs encoding proteins controlling dendrite development and maintenance. Ythdf2 cKO improves visual acuity and alleviates acute ocular hypertension-induced glaucoma in mice.

neuroscience↗