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Zhang, Y.-Y.

Publications and source records attributed to Zhang, Y.-Y..

17 recordsLinked to original sources
bioRxiv2026

Postsynaptic TAK1-GluN2B axis supports hippocampal synaptic integrity and cognitive function during aging

Transforming growth factor {beta}-activated kinase 1 (TAK1) is a serine/threonine kinase best known for its roles in immune and stress-response signaling, yet its physiological function in mature neurons remains poorly understood. Here we identify neuronal TAK1 as a regulator of excitatory synaptic integrity, hippocampal plasticity and memory. Conditional reduction of TAK1 in forebrain excitatory neurons impaired short- and long-term memory and was accompanied by attenuated long-term potentiation in the hippocampus. At the cellular level, TAK1 deficiency reduced dendritic spine density and suppressed excitatory synaptic transmission, whereas genetic or pharmacological disruption of TAK1 kinase activity recapitulated these synaptic deficits. Mechanistically, TAK1 localized to the postsynaptic compartment of excitatory synapses and associated with PSD-95. Phosphoproteomic analysis of isolated postsynaptic density fractions revealed coordinated changes in synaptic phosphorylation following TAK1 reduction, including decreased phosphorylation of the NMDA receptor subunit GluN2B at serine 920. Analyses of phosphodeficient and phosphomimetic GluN2B mutants supported a role for S920 phosphorylation downstream of TAK1 in maintaining dendritic spine density, excitatory synaptic transmission and spontaneous synaptic calcium activity. Notably, synaptic TAK1 level was reduced in the aged hippocampus. Re-expressing neuronal TAK1 in aged mice increased dendritic spine density, enhanced hippocampal synaptic plasticity, and improved memory performance. Together, these findings define a postsynaptic TAK1-GluN2B signaling axis that supports excitatory synaptic function and suggest that reduced synaptic TAK1 signaling may contribute to hippocampal vulnerability during aging.

neuroscience↗
bioRxiv2026

Hierarchical Assembly of Native Cytoplasmic Lattices Revealed by Cryo-EM

Oocytes depend on maternal factors for maturation and early embryogenesis. Cytoplasmic lattices (CPLs) are distinctive fibrillar structures in mammalian oocyte cytoplasm implicated in maternal factor storage and developmental competence, yet their molecular composition and architecture remain elusive. Here, we use cryo-electron microscopy to resolve the high-resolution structure of native mouse oocyte CPLs. We identify 14 intrinsic components of multiple copies that assemble into filaments in which PADI6-mediated self-assembly and two subtypes of subcortical maternal complexes (SCMCs) form the core scaffold. Unexpectedly, we discover that /{beta}-tubulin dimers and two autoinhibited ubiquitination modules (UHRF1-UBE2D3, SKP1-FBXW18) are internal components of CPLs. We also uncover multivalent interactions that organize adjacent CPL filaments into higher-order helical bundles. By integrating CPL structure with biochemical and proteomic data, we propose a hierarchical assembly mechanism of CPLs, from subcomplexes to filaments to supramolecular lattices. Our study offers mechanistic insights into how maternal proteins are spatially organized to ensure successful early embryonic development and provides a structural foundation for understanding female infertility related to CPL-associated gene mutations.

developmental biology↗
bioRxiv2025

Multiple Routes to Metacognitive Judgments of Working Memory in the Macaque Prefrontal Cortex

The ability to evaluate ones own memory is known as metamemory. Whether metamemory is inherent to memory strength or requires additional computation in the brain remains largely unknown. We investigated the metacognitive mechanism of working memory (WM) using two-photon calcium imaging in the prefrontal cortex of macaque monkeys, who were trained to memorize spatial sequences of varying difficulties. In some trials, after viewing the sequence, monkeys could opt out of retrieval for a smaller reward, reflecting their confidence in WM (meta-WM). We discovered that PFC neurons encoded WM strength by jointly representing the remembered locations through population coding and their associated uncertainties. This WM strength faithfully predicted the monkeys recall performance and opt-out decisions. In addition to memory strength, other factors-- trial history and arousal--encoded in baseline activity predicted opt-out decisions, serving as cues for meta-WM. We identified a code of meta-WM itself that integrated WM strength and these cues. Importantly, WM strength, cues, and meta-WM were represented in different subspaces within the same PFC population. The dynamics and geometry of PFC activity implement metacognitive computations, integrating WM strength with cues into a meta-WM signal that guides behavior.

neuroscience↗
bioRxiv2025

Structural basis for the RC-LH1 supercomplex of Dinoroseobacter shibae for anaerobic anoxygenic photosynthesis

Aerobic anoxygenic phototrophic (AAP) bacteria are essential for oceanic carbon cycling. However, the architecture and structural adaptations of their photosynthetic systems to ensure adequate light harvesting, electron transport, and oxidative resilience in oxygen-rich environments remain poorly understood. In this study, we present the 2.4-[A] cryo-EM structure of the reaction center-light-harvesting 1 (RC-LH1) supercomplex from Dinoroseobacter shibae DFL-12, a marine AAP bacterial symbiont of benthic dinoflagellates. This RC-LH1 supercomplex features a closed LH1 ring comprising 17 {beta}-subunits, each containing two spheroidenones per {beta}-heterodimer--a previously unreported configuration in phototrophic bacteria. The cytochrome subunit of the RC is truncated to three hemes, in contrast to the four-heme configuration found in anaerobic relatives. The structure also reveals elongated bacteriochlorophyll (BChl) spacing, accounting for its blue-shifted absorption maximum that is optimized for low-light benthic environments. Furthermore, we identify a previously unknown protein-LRC (Light-Respiratory Connector), which structurally bridges the RC and LH1 components and exhibits homology to NADH oxidoreductase subunit E, suggesting a functional coupling between photochemical and respiratory electron transport. Collectively, these specific structural features allow AAP bacteria to balance anoxygenic photosynthesis and protection against oxidative damage, providing a mechanistic framework for them to thrive in oxygenated marine environments. Our study provides insights into the structural and functional variability of bacterial photosynthesis in response to oxygenated marine environments.

biochemistry↗
bioRxiv2025

Heat stress negatively affects betalain biosynthesis in Amaranthus tricolor through down-regulation of CYP76AD1 and 5GT

Orphan crops are considered essential climatic-resilient genetic resources due to their native adaptability to various ecological environments. Amaranthus tricolor is one of a few common vegetables widely cultivated in tropical and subtropical regions. Strong vigor, abiotic-stress adaptability, and nutrition richness make it an ideal vegetable to provide food and nutrient security for smallholders. However, the breeding efforts depend on the field yield trials because little genomic information or genetic resources can be accessed. To fill this gap, we first used the Illumina and Pacbio sequencing systems to assemble a novel reference genome of A. tricolor using a Japanese variety Bayam. Together with a core collection developed in our previous study, we investigated the genetic mechanism of betalain biosynthesis under optimal and heat-stress conditions. Betalain is an antioxidant phytonutrient commonly appearing in beets and amaranths. As a result, ATR1.0CH03_5131103 which associate with ATR1.0ch03g000565 was identified in the optimal condition. Meanwhile, according to the transcriptomic profiles in this study, ATR1.0ch03g000565 also show significantly differential expressions under control and heat stress conditions, suggesting this candidate gene regulates the optimal performance of CYP76AD1. Meanwhile, among the homologous genes involving in the betalain biosynthesis, CYP76AD1 and 5GT were down-regulated under heat stress conditions; cDOPA was up-regulated. This result suggested heat stress reduces betacyanin biosynthesis through the downregulation of CYP76AD1 and 5GT; despite that the upregulation of cDOPA cannot rescue the decrease of betalain. More molecular experiments are required to address the regulation of these three enzymes.

plant biology↗
bioRxiv2024

Pre-rRNA spatial distribution and functional organization of the nucleolus

The self-organized nucleolus is where the pre-ribosomal RNA (pre-rRNA) processing and pre-ribosomal ribonucleoprotein (RNP) assembly take place. Here we present the spatiotemporal distribution of pre-rRNA intermediates in the human nucleolus, revealing a segregated spatial distribution of small subunit (SSU) and large subunit (LSU) precursors. Notably, the 5 external transcribed spacer (5 ETS)-containing SSU pre-rRNAs are retained across FC-DFC-PDFC regions, while the internal transcribed spacer 2 (ITS2)-containing LSU pre-rRNAs move to PDFC-GC regions for processing. Inhibiting 5 ETS processing disrupts the SSU pre-rRNA distribution and the nested FC-DFC sub-nucleolar structure. Cells in amniotes possess a multi-layered nucleolus, whereas anamniotes have only a bipartite structure with a merged FC-DFC. Kinetic labeling of pre-rRNA outflow shows a 7-fold higher pace in tetrapartite nucleoli over that in bipartite nucleoli, indicating that the emergence of the nested FC-DFC may facilitate an efficient SSU pre-rRNA processing over the course of evolution. Collectively, depicting the spatiotemporal distribution of pre-rRNAs reveals a key role of processing steps in organizing the multi-layered nucleolus and suggests a possible evolutionary advantage of the multi-layered structure in amniotes.

molecular biology↗
bioRxiv2024

Spatially global effects of feature-based attention in functional subdivisions of human subcortical nuclei

Attention can prioritize the processing of non-spatial features throughout the visual field. While human subcortical nuclei are known to play important roles in spatial attention, the subcortical mechanisms of feature-based attention remain elusive. Using high-resolution 7T fMRI, we investigated the spatially global effects of color-based attention in functional subdivisions of human subcortical nuclei. Paying attention to a color matching the unattended stimulus across the visual field selectively modulated BOLD signals in the parvocellular (P) layers of the lateral geniculate nucleus (LGN) of the thalamus, enhancing the response to the unattended stimulus while reducing the response to the attended stimulus. The spatially global effects of color-based attention were also found in the deeper layers of the superior colliculus (SC), early visual cortices, and the intraparietal sulcus (IPS) of the parietal lobe. Effective connectivity analyses further revealed enhanced feedforward and feedback connectivity between LGN and V1, along with top-down modulation from IPS through the SC and ventral pulvinar. Finally, attended color can be decoded from multi-voxel response patterns in frontoparietal regions. These findings demonstrate that color-based attention selectively modulates color processing in P subdivisions of the LGN of the thalamus throughout the visual field, controlled by top-down signals from the parietal cortex through the SC and pulvinar. HighlightsO_LIColor-based attention selectively modulates parvocellular activity in the LGN throughout the visual field. C_LIO_LISpatially global effect of feature-based attention significantly modulates activity in the deeper layers of the SC. C_LIO_LIFeature-based attention enhances both feedforward and feedback connectivity between the LGN and V1. C_LIO_LITop-down signals from IPS through the SC and pulvinar controls feature-based attention. C_LI

neuroscience↗
bioRxiv2023

Replication-driven HBV cccDNA loss in chimeric mice with humanized livers

Hepatitis B virus (HBV) infection is largely noncytopathic and requires the establishment of covalently closed circular DNA (cccDNA), which is considered stable in the nuclei of infected cells. Although challenging, approaches to directly target cccDNA molecules or kill infected cells are recommended to eliminate cccDNA. Herein, cccDNA levels were investigated in HBV-infected chimeric mice with humanized livers. HBV-infected cells support robust replication, progressively retain viral products, and head for cytopathic destruction and cccDNA loss. It is difficult for infected cells to retain cccDNA and remain noncytopathic. Replication-driven cccDNA loss is observed at both phases of spread of and persistent infection. The cccDNA replenishment is required to compensate for cccDNA loss. Blocking cccDNA replenishment pathways reduces cccDNA levels by >100-fold. These results prove an unconventional cccDNA elimination strategy that does not directly target cccDNA but aims to transform spontaneous cccDNA loss into progressive cccDNA elimination by blocking cccDNA replenishment.

microbiology↗
bioRxiv2022

eccDB: a comprehensive repository for eccDNA-mediated chromatin contacts in multi-species

The role of extrachromosomal circular DNA (eccDNA) has been highlighted. More recently, eccDNA-chromosome interactions were identified, suggesting a potential role of eccDNA in transcriptional regulation. Several databases currently provide valuable resources for the study of eccDNAs. However, these databases are primarily focused on Human eccDNAs and do not provide analysis of eccDNA-chromosome interaction and eccDNA gene expression in different tissues. Herein, to further integrate available resources for eccDNA data across multiple species, we developed the eccDB database. The current version of eccDB has collected a total of 1,317,182 eccDNAs in 424 samples from four species (homo sapiens, mus musculus, saccharomyces cerevisiae, and arabidopsis thaliana). eccDB provides regulatory and epigenetic information on eccDNA, including typical enhancers, super-enhancers, transcription factors, DNA methylation positions, risk SNPs, expression quantitative trait locus, chromatin accessibility regions, and chromHMM states. In particular, eccDB provides eccDNAs intrachromosomal and interchromosomal interaction analysis to predict the transcriptional regulatory functions of eccDNA. Moreover, eccDB identifies eccDNAs from unknown DNA sequences and analyzes the functional and evolutionary relationships of an eccDNA among different species. Overall, eccDB offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher the molecular regulatory mechanisms of eccDNA. eccDB is freely available at http://www.xiejjlab.bio/eccDB

bioinformatics↗
bioRxiv2022

Metabolic functional redundancy of the CYP9A subfamily members leads to P450-mediated lambda-cyhalothrin resistance in Cydia pomonella

BACKGROUNDThe evolution of insect resistance to pesticides poses a continuing threat to sustainable pest management. While much is known about the molecular mechanisms that confer resistance in model insects and few agricultural pests, far less is known about fruit pests. RESULTSHere we found that functional redundancy and preference of metabolism by cytochrome P450 monooxygenases (P450s) genes in the CYP9A subfamily confer resistance to lambda-cyhalothrin in Cydia pomonella, a major invasive pest of pome fruit. A total of four CYP9A genes, including CYP9A61, CYP9A120, CYP9A121, and CYP9A122, were identified from C. pomonella. Among these, CYP9A120, CYP9A121, and CYP9A122 were predominantly expressed in the midgut of larvae. The expression levels of these P450 genes were significantly induced by LD10 of lambda-cyhalothrin and were overexpressed in a field-evolved lambda-cyhalothrin resistant population. Knockdown of CYP9A120 and CYP9A121 by RNA-mediated interference (RNAi) increased the susceptibility of larvae to lambda-cyhalothrin. In vitro assays demonstrated that recombinant P450s expressed in Sf9 cells can metabolize lambda-cyhalothrin, but with functional redundancy and divergence through regioselectivity of metabolism. CYP9A121 preferred to convert lambda-cyhalothrin to 2'-hydroxy-lambda-cyhalothrin, whereas CYP9A122 only generated 4'-hydroxy metabolite of lambda-cyhalothrin. Although possesses a relatively low metabolic capability, CYP9A120 balanced catalytic competence to generate both 2'- and 4'-metabolites. CONCLUSIONCollectively, these results reveal that metabolic functional redundancy of three members of the CYP9A subfamily leads to P450-mediated lambda-cyhalothrin resistance in C. pomonella, thus representing a potential adaptive evolutionary strategy during its worldwide expansion.

molecular biology↗
bioRxiv2021

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes

Retroviruses are widely distributed in all vertebrates, as are their endogenous form, endogenous retrovirus (ERV), which serves as "fossil" evidence to trace the ancient origins and history of virus-host interactions over millions of years. The retroviral envelope (Env) plays a significant role in host range determination, but major information on genetic diversification in anamniotes is lacking. Here, by incorporating multiple-round in silico similarity search and phylogenomic analysis, 25498 ERVs with gamma-type Env (GTE), covalently associated Env, were discovered by searching against all 974 available fish and 19 amphibian genomes, but no beta-type Env (BTE), noncovalently associated Env, were found. Furthermore, a nine-type classification system of anamniote GTE was proposed by combining phylogenetic and domain/motif analyses. The elastic genomic organization and overall phylogenetic incongruence between anamniotic Env and its neighboring polymerase (Pol) implied that early retroviral diversification in anamniotic vertebrates was facilitated by frequent recombination. At last, host opioid growth factor receptor (OGFr) gene capturing by anamniotic ERVs with GTE was reported for the first time. Overall, our findings overturn traditional Pol genotyping and reveal a complex evolutionary history of anamniotic retroviruses inferred by Env evolution. Author summaryAlthough the retroviral envelope (Env) protein in amniotes has been well studied, its evolutionary history in anamniotic vertebrates is ambiguous. By analyzing more than 25000 ERVs with gamma-type Env (GTE) in anamniotes, several important evolutionary features were identified. First, GTE were found to be widely distributed among different amphibians and fish. Second, nine types of GTE were discovered, revealing the great genetic diversity. Third, GTE-containing ERVs have rampantly proliferated in certain amphibians such as Ambystoma mexicanum, and the copy number was found to be markedly higher than 10000. Fourth, the incongruence between the Env and Pol phylogenies suggested that frequent recombination shaped the early evolution of anamniote retroviruses. Fifth, an ancient horizontal gene transfer event was discovered from anamniotes to ERVs with GTE. These findings reveal a complex evolution pattern for retroviral Env in anamniotes.

microbiology↗
bioRxiv2021

ACKR3 induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes. Its atypical "intercepting receptor" signaling properties have established ACKR3 as the main regulator in pathophysiological processes in many diseases. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in both human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with adjacent non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear {beta}-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of {beta}-arrestin-1 ({beta}-arr1), leading to the interaction of {beta}-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear {beta}-arr1-induced interaction of NOLC1 with Fibrillarin. HIGH LIGHTSO_LIACKR3 is an atypical G protein-coupled receptor (GPCR) C_LIO_LIACKR3 promotes colorectal tumorigenesis C_LIO_LIACKR3 induces nuclear translocation of {beta}-arr1 C_LIO_LINuclear {beta}-arr1 interacts with NOLC1 to activate Fibrillarin C_LIO_LIInteraction of NOLC1 to Fibrillarin leads to perturbation of rRNA biogenesis C_LI

cancer biology↗
bioRxiv2021

Viromes in Marine Ecosystems Reveal Remarkable Invertebrate RNA Virus Diversity

Ocean viromes remain poorly understood and little is known about the ecological factors driving aquatic RNA virus evolution. In this study, we used a meta-transcriptomic approach to characterize the viromes of 58 marine invertebrate species across three seas. This revealed the presence of 315 newly identified RNA viruses in nine viral families or orders (Durnavirales, Totiviridae, Bunyavirales, Hantaviridae, Picornavirales, Flaviviridae, Hepelivirales, Solemoviridae and Tombusviridae), with most of them are sufficiently divergent to the documented viruses. With special notice that we first time revealed an ocean virus rooting to mammalian hantaviruses. We also found evidence for possible host sharing and switch events during virus evolution. In sum, we demonstrated the hidden diversity of marine invertebrate RNA viruses.

microbiology↗
bioRxiv2021

Generation of human blastocyst-like structures from pluripotent stem cells

Human blastocysts are comprised of the first three cell lineages of the embryo: trophectoderm, epiblast, and primitive endoderm, all of which are essential for early development and organ formation1,2. However, due to ethical concerns and restricted access to human blastocysts, we lack a comprehensive understanding of early human embryogenesis. To bridge this knowledge gap, we need a reliable model system that recapitulates early stages of human embryogenesis. Here we report a [~]three-dimensional (3D), two-step induction protocol for generating blastocyst-like structures (EPS-blastoids) from human extended pluripotent stem (EPS) cells. Morphological and single-cell transcriptomic analyses revealed that EPS-blastoids contain key cell lineages and are transcriptionally similar to human blastocysts. Furthermore, EPS-blastoids also exhibited the developmental potential to undergo post-implantation morphogenesis in vitro to form structures with a cellular composition and transcriptome signature similar to human embryos that had been cultured in vitro for 8 or 10 days. In conclusion, human EPS-blastoids provide a new experimental platform for studying early developmental stages of the human embryo. HighlightsA method for generating human blastoids from EPS cells. Human blastoids resemble blastocysts in terms of morphology and cell lineage composition. Single-cell transcriptomic analyses reveal EPI, PE, and TE cell lineages in human blastoids. Human blastoids mimic in vitro the morphogenetic events of pre- and early post-implantation stages.

developmental biology↗
bioRxiv2020

Multiple infiltration and cross-species transmission of foamy viruses across Paleozoic to Cenozoic era

Foamy viruses (FVs) are complex retroviruses that can infect humans and other animals. In this study, by integrating transcriptomic and genomic data, we discovered 412 FVs from 6 lineages in amphibians, which significantly increased the known set of FVs in amphibians. Among these lineages, salamander FVs maintained a co-evolutionary pattern with their hosts that could be dated back to the Paleozoic era, while, on the contrary, frog FVs were much more likely acquired from cross-species (class level) transmission in the Cenozoic era. In addition, we found three distinct FV lineages had integrated into the genome of a salamander. Unexpectedly, we identified a potential exogenous form of FV circulated in caecilian, demonstrating the existence of exogenous form of FV besides mammals. Our discovery of rare phenomena in amphibian FVs has overturned our collective understanding of the macroevolution of the complex retrovirus. ImportanceFoamy viruses (FVs) represent, more so than other viruses, the best model of co-evolution between a virus and a host. This study represents so far, the largest investigation of amphibian FVs and revealed 412 FVs of 6 distinct lineages from three major orders of amphibians. Besides co-evolutionary pattern, cross-species and repeated infection were also observed during evolution of amphibian FVs. Remarkably, expressed FVs including a potential exogenous form were discovered, suggesting live FVs could be underestimated in nature. These findings revealed the multiple origin and complex evolution of amphibian FVs started from the Paleozoic era.

microbiology↗
bioRxiv2020

The genomic and transcriptomic foundations of viviparous seed development in mangroves

Vivipary in plants refers to a specific seed development and reproductive strategy where seeds minimize the dormancy stage and germinate while still attached to their maternal plants. It is one of the most unique adaptive genetic features used by many mangrove species where elongated hypocotyls aid in quick root emergence to anchor the seedling in coastal intertidal wetlands. The genetic mechanisms behind mangrove vivipary, however, remain elusive. Using comparative genomic and transcriptomic technologies to investigate viviparous mangroves and their close inland relatives, we found that a full array of gene expression profiles were altered, including key plant hormone metabolic pathways, high expression of embryonic signature genes, and reduced production of proanthocyanidins and storage proteins. Along with these changes, a major gene regulating seed dormancy, Delay of Germination-1 (DOG1), is entirely missing or defunct within the entire linage of the four genera with true viviparous characteristics. These results suggest a systemic level change is required to warrant the genetic program of mangrove vivipary. Understanding of the molecular processes of vivipary could benefit the design of pregerminated propagules for forestation in harsh environments or prevent precocious germination of grain crops pre- and post-harvest.

genomics↗