Biology subjects

Zhou, H.-Y.

Publications and source records attributed to Zhou, H.-Y..

6 recordsLinked to original sources

bioRxiv2026

Novel conserved RNA structural motifs regulate genome cyclization of yellow fever virus

The long-range RNA-RNA interaction between the termini of a flavivirus genome is controlled by multiple local RNA secondary and tertiary structures. However, a complete picture of this essential genome cyclization process is still elusive. Herein, by using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE), SHAPE and mutational profiling, in vitro RNA binding assays, and reverse genetics approaches, we demonstrated that the hairpin 2 in the capsid-coding region (cHP2) is required for efficient replication of yellow fever virus and functionally interacts with the 3'-small hairpin (sHP) during genome cyclization. Interestingly, through a combination of multidimensional chemical probing and functional characterization assays, it was discovered that the sHP forms previously unknown tertiary interactions with an immediately upstream GACG region embedded within the 3'-cyclization sequence. This crucial tertiary RNA motif accounts for a potential negative regulatory mechanism of genome cyclization and is universally conserved among the mosquito-borne-related flaviviruses, which constitute a major phylogenetic branch within the subgenus Euflavivirus, genus Orthoflavivirus. Our study highlights the intricacy of RNA-based regulation in flaviviruses.

biochemistry↗

bioRxiv2025

Viral protease-Initiated Pyroptosis Activator mRNA therapy as a Universal Antiviral Strategy

Although therapeutic drugs targeting gasdermin (GSDM)-mediated pyroptosis have made remarkable progress in treating various diseases, their potential for antiviral therapy remains largely unexplored. Inspired by the autoinhibitory mechanism of GSDM proteins and the clinical success of mRNA vaccines, herein we propose a concept of viral protease-initiated pyroptosis (VIP) mRNA therapy as a universal antiviral strategy. Using Hepatitis A virus (HAV) as a model, we rationally engineered an HAV-specific VIP activator (VIPA) by replacing the native gasdermin D (GSDMD) cleavage motif with that of HAV 3C protease. Expression of this VIPA selectively triggered pyroptosis in HAV-infected cells, thereby terminating viral replication. Remarkably, in vivo delivery of VIPA mRNA via lipid nanoparticles (LNPs) significantly suppressed viral replication and shedding, alleviated liver injury, and elicited a pyroptosis-driven antiviral immune response in uninfected cells. Similarly, VIPA against Zika virus (ZIKV) also exhibited potent antiviral efficacy in both cell culture and mouse models. Furthermore, a generative artificial intelligence (AI) platform was deployed to design de novo cleavage motifs for the SARS-CoV-2 main protease NSP5, together with experimental screening, yielding optimized VIPAs with enhanced antiviral potency. Our work establishes the concept of VIPA mRNA therapy as a versatile platform for the treatment of diverse viral infections via "kill-and-alert" mechanism.

microbiology↗

bioRxiv2025

Genomic insights into polysaccharide substrate utilization and novel genera resource mining in macroalgal epiphytic bacteria

Marine macroalgae, among the fastest photosynthesizing organisms, play a crucial role in the ocean carbon cycle by converting fixed carbon dioxide into polysaccharides. Macroalgal epiphytic bacteria possessing specific polysaccharide utilization loci (PULs) have a generalized polysaccharide degradation potential that facilitates their growth and colonization. In this study, we conducted extensive research on their polysaccharide degradation potential. Through sampled and purified epiphytic bacteria and metagenomic analysis revealed a high prevalence of novel genera and species. Two novel genera, 1117T and 3-347T, were taxonomically characterized and conducted detailed functional analyses. The results demonstrated that these genera possess abundant PULs and strong capabilities for synthesizing secondary metabolites. Furthermore, their high relative abundance on macroalgal surfaces aligns with global ecological distribution patterns. These traits facilitate their colonization, growth, and environmental adaptation on macroalgal surfaces. We further performed in-depth annotation of a large number of PULs and CAZyme genes of macroalgal epiphytic bacteria. Potential polysaccharide substrates for their degradation can be predicted and focused on. Additionally, we conducted growth curve analyses by starch, xylan, {beta}-1,3-glucan, and carboxymethyl cellulose substrates to validate the genomic predictions. In summary, our findings demonstrate that macroalgal epiphytic bacteria possess significant potential for degrading algal polysaccharides. This capability may enhance their competitiveness and survival probability on macroalgal surfaces. These bacteria, originating from different sources and genera, possess similar PULs, which may result from horizontal gene transfer or evolutionary relationships. ImportanceMacroalgae are major primary producers in coastal areas and their carbon sequestration capacity per unit area far exceeds that of terrestrial forests. In this work, we extensively studied macroalgal epiphytic bacteria with polysaccharide degradation potential. We found that epiphytic bacteria from different macroalgal sources and genera share similar PULs to degrade the same polysaccharide, which may be the result of horizontal gene transfer or evolutionary relationships. Core taxa on the macroalgal surface have gradually evolved polysaccharide-degrading abilities of different marine macroalgae in order to expand their colonization and survival chances. We also identified a large number of uncultivated algal biosphere species and unreported new genera and species for expansion of macroalgal epiphytic bacteria studies. These studies have thus highlighted the important ecological and research value of macroalgal epiphytic bacteria, especially in influencing polysaccharide carbon storage and marine carbon cycling.

microbiology↗

bioRxiv2023

A comparison of behavior paradigms assessing spatial memory in tree shrew

Spatial cognition enables animals to navigate the environment. Impairments in spatial navigation are often preclinical signs of Alzheimers disease (AD) in human. Therefore, evaluating spatial memory deficits is valuable when assessing incipient AD in animal models. The Chinese tree shrew, a close relative of primates, possesses many features that make it suitable for AD research. However, there is a scarcity of reliable behavior paradigms to monitor changes in spatial cognition in this species. To address this, we established reward-based paradigms in the radial-arm maze and the cheeseboard maze for tree shrew, and tested spatial memory of a group of twelve male animals in both tasks, along with a control water maze test, before and after bilateral lesions to the hippocampus, the brain region essential for spatial navigation. Tree shrews memorized target positions during training, and their task performance improved gradually until reaching a plateau in all three mazes. After the lesion, spatial learning was compromised in both newly-developed tasks, whereas memory retrieval was impaired in the water maze. Furthermore, individual task performance in both dry-land paradigms depended heavily on the size of remaining hippocampal tissue. Notably, all lesioned animals displayed spatial memory deficits in the cheeseboard task, but not in the other two paradigms. Our results suggest that the cheeseboard task currently represents the most sensitive paradigm for assessing spatial memory in tree shrew, with the potential to monitor progressive cognitive declines in aged or genetically modified animals developing AD-like symptoms. Significance StatementCognitive tests that monitor impairments in spatial memory play a crucial role in evaluating animal models with early-stage Alzheimers disease (AD). The Chinese tree shrew possesses many features suitable for an AD model, yet behavior tests assessing spatial cognition in this species are lacking. Here we developed novel behavior paradigms tailored to measure spatial memory in tree shrews and evaluated their sensitivity to changes in spatial learning by examining a group of hippocampus-lesioned animals. Our results indicate that the cheeseboard task effectively detects impairments in spatial memory and holds potential for monitoring the progressive cognitive decline in aged or genetically modified tree shrews that develop AD-like symptoms. This research may facilitate the use of tree shrew model in AD research.

animal behavior and cognition↗

bioRxiv2023

Protein Representation Learning via Knowledge Enhanced Primary Structure Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein representation learning has primarily benefited from the remarkable development of language models (LMs). Accordingly, pre-trained protein models also suffer from a problem in LMs: a lack of factual knowledge. The recent solution models the relationships between protein and associated knowledge terms as the knowledge encoding objective. However, it fails to explore the relationships at a more granular level, i.e., the token level. To mitigate this, we propose Knowledge-exploited Auto-encoder for Protein (KeAP), which performs tokenlevel knowledge graph exploration for protein representation learning. In practice, non-masked amino acids iteratively query the associated knowledge tokens to extract and integrate helpful information for restoring masked amino acids via attention. We show that KeAP can consistently outperform the previous counterpart on 9 representative downstream applications, sometimes surpassing it by large margins. These results suggest that KeAP provides an alternative yet effective way to perform knowledge enhanced protein representation learning. Code and models are available at https://github.com/RL4M/KeAP.

bioinformatics↗

bioRxiv2021

Genomic evidence for divergent co-infections of SARS-CoV-2 lineages

Recently, patients co-infected by two SARS-CoV-2 lineages have been sporadically reported. Concerns are raised because previous studies have demonstrated co-infection may contribute to the recombination of RNA viruses and cause severe clinic symptoms. In this study, we have estimated the compositional lineage(s), tendentiousness, and frequency of co-infection events in population from a large-scale genomic analysis for SARS-CoV-2 patients. SARS-CoV-2 lineage(s) infected in each sample have been recognized from the assignment of within-host site variations into lineage-defined feature variations by introducing a hypergeometric distribution method. Of all the 29,993 samples, 53 (~0.18%) co-infection events have been identified. Apart from 52 co-infections with two SARS-CoV-2 lineages, one sample with co-infections of three SARS-CoV-2 lineages was firstly identified. As expected, the co-infection events mainly happened in the regions where have co-existed more than two dominant SARS-CoV-2 lineages. However, co-infection of two sub-lineages in Delta lineage were detected as well. Our results provide a useful reference framework for the high throughput detecting of SARS-CoV-2 co-infection events in the Next Generation Sequencing (NGS) data. Although low in average rate, the co-infection events showed an increasing tendency with the increased diversity of SARS-CoV-2. And considering the large base of SARS-CoV-2 infections globally, co-infected patients would be a nonnegligible population. Thus, more clinical research is urgently needed on these patients.

microbiology↗