Biology subjects

Zhai, G.

Publications and source records attributed to Zhai, G..

12 recordsLinked to original sources

bioRxiv2025

Temporal boundary gating of auditory sensitivity

Perception unfolds over time, but whether continuous sounds are sampled with uniform sensitivity is unknown. We combine human psychophysics, EEG and rodent neurophysiology to show that local auditory change detection is strongly gated by stimulus boundaries. In humans, brief perturbations inserted at different temporal positions within 0.5-1-s tones revealed an inverted U-shaped sensitivity profile: detection was attenuated near sound onset and offset and maximal mid-epoch, with EEG change responses showing a closely matching dependence on change timing. Electrocorticography in awake rats exhibited homologous temporal weighting, and analogous profiles for amplitude changes and visual motion demonstrated cross-feature and cross-modal generality. To uncover circuit mechanisms, we recorded single units along the inferior colliculus-medial geniculate body-auditory cortex pathway together with laminar local field potentials in A1. Onset-locked suppression of change responses emerged in midbrain and was progressively amplified in thalamus and cortex, whereas the full start-end profile was expressed in granular-layer alpha-gamma power. A simple biophysically grounded model in which onset responses saturate and cortical populations integrate over finite temporal windows recapitulates this pattern, explaining how stimulus boundaries disrupt prospective and retrospective integration and thereby degrade change detection near the beginning and end of sounds.

neuroscience↗

bioRxiv2025

Haploinsufficiency of KPNA7 causes otosclerosis, likely due to the release of import inhibition of PTHrP and the reactivation of chondrogenesis in the globuli interossei

Otosclerosis is a genetic bone disorder restricted to the otic capsule and a common cause of conductive hearing loss with both familial and sporadic cases. To date, 14 genomic loci (OTSC) and four underlying OTSC genes (MEPE, SERPINF1, FOXL1, SMARCA4) have been identified in autosomal dominant families. A combined genetic/genomics approach on five affected siblings of Northern European ancestry from the island of Newfoundland, Canada identified a premature stop mutation in Karyopherin subunit 7 (KPNA7, c.49C>T, p.R17X). KPNA7 maps to OTSC2 (7q22.1) and encodes the newest of the seven-member importin- family of nuclear transporters and plays a critical role in early embryonic cleavage events and zygotic genome activation. Previous studies reveal that recessive KPNA7 variants cause skeletal abnormalities, including scoliosis and ocular hypertelorism in two sisters with Partial Corpus Callosum Agenesis-Cerebellar Vermis Hypoplasia With Posterior Fosa Cysts Syndrome and more recently, have been implicated in preimplantation embryo arrest (PREMBA) (OMIM 614107). Interestingly, KPNA7 is also a maternal factor with an exclusively embryonic role and likely inhibits non-classical NLS transport of PTHrP, a known activator of chondrogenesis. We propose that KPNA7 haploinsufficiency causes a failure in nuclear transport inhibition of PTHrP in the quiescent embryonic cells of the globuli interossei in the otic capsule and re-activates chondrogenesis. The KPNA7 discovery provides new insights into the pathogenesis of otosclerosis and potential for targeted therapies. Author SummaryOtosclerosis is a distinctly human genetic bone disorder of the otic capsule and a major cause of progressive hearing loss in young adults, particularly in females. Even though otosclerosis has been recognized as a distinct entity for a long time, both its pathogenesis and restriction to the otic capsule remains a mystery. Here, we use a combined genetic/genomics approach to identify a premature stop mutation in five affected siblings of Northern European ancestry from the island of Newfoundland, Canada. KPNA7 encodes the newest of the seven-member importin- family of nuclear transporters and plays a critical role in early embryonic cleavage events and zygotic genome activation. Based on the unique features of the otic capsule, we hypothesize that the premature stop mutation in KPNA7 leads to haploinsufficiency causing a failure in nuclear transport inhibition of PTHrP and reactivates chondrogenesis in the otherwise quiescent embryonic cells within the otic capsule. The KPNA7 discovery provides new insights into the pathogenesis of otosclerosis and potential for targeted therapies.

genetics↗

bioRxiv2025

Male-Biased Cyp17a2 Governs Antiviral Sexual Dimorphism in Fish via STING Stabilization and Viral Protein Degradation

Differences in immunity between males and females in living organisms are generally thought to be due to sex hormones and sex chromosomes, and it is often assumed that males have a weaker immune response. Here we report that in fish, males exhibit stronger antiviral immune responses, the male-biased gene cyp17a2 as a critical mediator of this enhanced response. First, we observed that male zebrafish exhibit enhanced antiviral resistance compared to females, and notably, zebrafish lack sex chromosomes. Through transcriptomic screening, we found that cyp17a2 was specifically highly expressed in male fish. Cyp17a2 knockout males were equivalent to wild-type males in terms of sex organs and androgen secretion, but the ability to upregulate IFN as well as antiviral resistance was greatly reduced. Then, Cyp17a2 is identified as a positive IFN regulator which located at endoplasmic reticulum, and specifically interacts with and enhances STING mediated antiviral responses. Mechanistically, Cyp17a2 stabiles STING expression by recruiting the E3 ubiquitin ligase bloodthirsty-related gene family member 32 (btr32), which facilitates K33-linked polyubiquitination. The capacity of IFN induction of Cyp17a2 was abolished when STING is knockdown. Meanwhile, Cyp17a2 also attenuates viral infection directly to strengthen the antiviral capacity as an antiviral protein, Cyp17a2 degrades the spring viremia of carp virus (SVCV) P protein by utilizing USP8 to reduce its K33-linked polyubiquitination. These findings reveal a sex-based regulatory mechanism in teleost antiviral immunity, broadening our understanding of sexual dimorphism in immune responses beyond the conventional roles of sex chromosomes and hormones.

immunology↗

bioRxiv2025

Orchestrating Self-Replication in Artificial Cells through Digital Microfluidics

A defining feature of living cells is their ability to self-replicate; but creating artificial cells with this capability remains challenging, due to the complexity of biological division machinery. Rather than seeking to reconstitute this machinery, here we take direct control of DNA replication and compartment division using digital microfluidics. This approach allows us to precisely orchestrate these two fundamental processes, providing insight into how they must be coupled for successful self-replication. Our system achieves autonomous cycles of replication and division, with daughter compartments inheriting parental DNA and maintaining genetic continuity across multiple generations - a key feature of living systems that has been di!cult to achieve in artificial cells. By implementing these processes through direct physical manipulation rather than biochemical complexity, we provide a simple testbed that will help to disentangle the essential requirements for self-replicating systems.

synthetic biology↗

bioRxiv2025

Construction of Complete Telomere-to-Telomere Genome Assembly of the Rabbit Using Haploid Embryonic Stem Cells

The rabbit owns commercial importance in meat and fur production, and also has long served as a valuable animal model in biomedical research. Yet, the complete assembly of a high-quality rabbit reference genome has not been established. Here, we present a telomere-to-telomere (T2T) genome assembly of the New Zealand White (NZW) rabbit, the most complete and accurate rabbit genome to date. Using a haploid embryonic stem cells (haESCs) to overcame the challenges of homologous sequence interference and structural variation, we generate a genome with a contig N50 of 137.71 Mb, anchoring all chromosomes with only three gaps, through integrating long-read sequencing (PacBio HiFi, Oxford Nanopore), Hi-C, and Illumina data. Quality assessments reveal near-complete coverage of the BUSCO mammalian gene set, with 99.61% completeness. Notably, this complete assembly allowed for the first comprehensive annotation of the rabbit immunoglobulin loci and major histocompatibility complex region, which were previously unresolved in earlier genome versions. The NZW-T2T assembly based on haESCs not only provides a critical resource for advancing rabbit-based research, but also set a new benchmark for de novo genome assembly for other animals with complex genome.

genomics↗

bioRxiv2024

D-lactate derived from intestinal bacteria drives lysine D-lactylation to modulate transcription in liver cells

Emerging evidence indicates that the accumulated D-lactate (D-la) from intestinal bacteria induces diverse effects in human intestinal injury diseases. However, its regulatory mechanism and functional consequence remain unclear. Here, we show that the secreted D-la induces lysine D-lactylation (K-Dla) to modulate transcription in host cells. We uncover K-Dla in HepG2 cells stimulated by D-la from E. coli secretions. Then, we confirm the occurrence of D-la-driven K-Dla by four orthogonal approaches. We further validate that the existence of K-Dla in organisms by detecting the mouse liver and human intestinal tissue. Besides, we demonstrate a SCOT1-catalyzed biosynthetic pathway of D-lactyl-CoA, serving as a key donor for K-Dla. Next, we identify the K-Dla landscape with 2895 sites and further suggest the regulation of histone K-Dla in transcription by MNase ChIP-seq and RNA-seq assays. Finally, we show the potential effect of K-Dla on inhibiting the hepatocellular carcinoma cell proliferation. In summary, we report that the secreted D-la can induce K-Dla to regulate transcription, providing a new insight into the function of D-la secreted by gut microbiota and the effect of protein chemical modifications induced by bacterial secretions.

molecular biology↗

bioRxiv2024

Segmentation and Feature Extraction of Fingernail Plate and Lunula Based on Deep Learning

This paper proposes a novel deep learning method for accurate segmentation of the fingernail plate and lunula. To achieve this, we designed a new network structure called Nailnet, which segments the fingernail from images of the whole hand. The results show that Nailnet achieved an Intersection over Union (IoU) score of 0.9529 and an accuracy of 0.9725 for fingernail plate segmentation. For lunula segmentation, Nailnet achieved an IoU score of 0.7784 and an accuracy of 0.8846. Additionally, Nailnet successfully recognized the fingernail index, enabling the extraction of various fingernail phenotypes, including plate color, plate shape, lunula color, and lunula proportion.

bioinformatics↗

bioRxiv2023

Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy

Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in Drosophila and human cellular models of Tauopathy. Our previous study showed that Drosophila spermine synthase (dSms) deficiency impairs lysosomal function and blocks autophagy flux. Interestingly, partial loss-of-function of SMS in heterozygous dSms flies extends lifespan and improves the climbing performance of flies with human Tau (hTau) overexpression. Mechanistic analysis showed that heterozygous loss-of-function mutation of dSms reduces hTau protein accumulation through enhancing autophagic flux. Measurement of polyamine levels detected a mild elevation of spermidine in flies with heterozygous loss of dSms. SMS knock-down in human neuronal or glial cells also upregulates autophagic flux and reduces Tau protein accumulation. Proteomics analysis of postmortem brain tissue from AD patients showed a significant albeit modest elevation of SMS protein level in AD-relevant brain regions compared to that of control brains consistently across several datasets. Taken together, our study uncovers a correlation between SMS protein level and AD pathogenesis and reveals that SMS reduction upregulates autophagy, promotes Tau clearance, and reduces Tau protein accumulation. These findings provide a new potential therapeutic target of Tauopathy.

neuroscience↗

bioRxiv2022

A reductase in the lipid metabolism at cross roads between cuticular wax production and jasmonic acid-mediated defenses in maize

Cuticular wax is the first physical layer to protect plants from herbivore infestations. Although wax and jasmonic acid (JA) biosynthesis are the two most studied branches of lipid metabolism, the mechanism how cuticular wax production modulates plant chemical defenses is unclear. Here, we show that the maize (Zea mays) GL8 gene, encoding 3-ketoacyl reductase during fatty acid elongation in the biosynthesis of very long chain fatty acids (VLCFA), functions as a turning point between wax production and JA-mediated defenses. The fall armyworm (Spodoptera frugiperda) larvae consumed more tissue but gained a lower performance on gl8/Ye478 mutant plants. gl8/Ye478 mutant displayed higher JA-mediated defenses constitutively, and also more inducible by herbivore stimulation. The comprehensive transcriptomic and lipidomic analyses further demonstrated that ZmGL8 mutation up-regulates the JA biosynthesis pathway by promoting the accumulation of lysophospholipids and modulation of galactolipid synthase genes ZmDGD and ZmMGD. The phenotypic and transcription comparisons of the maize and Arabidopsis wax-deficient mutants suggest a conserved wide-spread trade-off between wax production and chemical defense in both 18:3 and 16:3 plants. These results illustrate a critical role of VLCFA metabolism as a switch to control the balance between cuticular wax physical barrier and JA-mediated chemical defenses during plant-herbivore coevolution history.

plant biology↗

bioRxiv2021

Structural architecture of a dimeric paramyxovirus polymerase complex

Human parainfluenza virus type 3 (hPIV3), a member of non-segmented, negative-strand RNA viruses (nsNSVs), is the second most common cause of severe respiratory disease in pediatrics. The transcription and replication processes of nsNSVs are catalyzed by a multi-functional RNA-dependent RNA polymerase (RdRp) complex composed of the large protein (L) and the phosphoprotein (P). Previous studies have shown that the polymerase can adopt a dimeric form, however, the structure of the dimer and how it functions are not understood. Here we determined the cryo-EM structure of hPIV3 L-P complex at 2.7 [A] with substantial structural details. A putative catalytic magnesium ion could be built in our structure, and structural comparison revealed atomic features conserved with other RNA viruses. Interactions identified between the two priming and intrusion loops and the connector domain potentially trigger the spatial movement of three C-terminal L domains for different steps of transcription and replication. Structural comparison with other nsNSV RdRps suggests common features of L-P binding. Furthermore, we report for the first time the structural basis of the L-L interaction in the partially modelled dimeric L-P structure, in which the connector domain of one L is positioned at the putative RNA template entry of the other L. Based on these findings, we propose a model by which L dimerization promotes efficient conversion of nascent RNA into a template.

molecular biology↗

bioRxiv2019

A cell-free platform based on nisin biosynthesis for discovering novel lanthipeptides and guiding their overproduction in vivo

Lanthipeptides have extensive therapeutic and industrial applications; however, since many are bactericidal, traditional in vivo platforms are limited in their capacity to discover and mass produce novel lanthipeptides as bacterial organisms are often critical components in these systems. We developed a cell-free protein synthesis (CFPS) platform that enables rapid genome mining, screening and guiding overproduction of lanthipeptides in vivo. For proof-of-concept studies, the type I lanthipeptide, nisin, was selected. Four novel lanthipeptides with anti-bacterial activity were identified among all nisin analogs in the NCBI database in a single day. Further, we coupled the CFPS platform with a screening assay for gram-negative bacterial growth and identified a potent nisin mutant, M5. The titer of nisin and nisin analogs significantly improved with CFPS platform guidance. Owing to the similarities in biosynthesis, our CFPS platform is broadly applicable to other lanthipeptides, provides a universal method for lanthipeptides discovery and overproduction.

synthetic biology↗

bioRxiv2019

MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing

Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.

neuroscience↗