Biology subjects

Lv, K.

Publications and source records attributed to Lv, K..

10 recordsLinked to original sources

bioRxiv2026

TRACER navigates rearrangement-driven sesterterpene chemical space via multimodal enzyme-product representation learning

Skeletal rearrangement drives the immense structural complexity of terpene, yet predicting it remains a formidable challenge due to sequence-function decoupling in terpene synthases. Here, we established TRACER (terpene rearrangement annotation via co-attentive enzyme-product representation), a multimodal framework mapping the latent associations between sequence-derived enzyme representations and product chemotypes. Retrospective validation proved TRACERs exceptional precision in predicting compound classes and discriminating skeletal rearrangement (SR) from non-skeletal rearrangement (NSR) pathways. TRACER-guided genome mining characterized two bifunctional synthases, FsPS and AcPS, uncovering four unprecedented carbon skeletons. Density functional theory calculations deciphered these cyclization cascades, pinpointing a critical 5/6/11 tricyclic intermediate as the key branching node for scaffold diversification. Mutagenesis and molecular dynamics simulations suggested that E305 in FsPS enables rearrangement by maintaining active-site water exclusion, whereas its alanine mutation causes premature carbocation quenching. Collectively, this work establishes a predictive paradigm for the rational discovery and mechanistic elucidation of complex terpene architectures.

synthetic biology↗

bioRxiv2026

Disease diagnosis via sperm motility variations induced by body fluids in bioassay

Precise diagnosis of high-risk conditions such as cardiovascular and cerebrovascular diseases still remains a challenge. We previously developed a microfluidic chip for sperm selection and observed that sperm motility is highly sensitive to environmental changes. Building on this finding, we hypothesized that motility traits of sperm could be differentially modulated by body fluids from healthy versus diseased individuals, thereby serving as potential biomarkers for disease diagnosis. To test this hypothesis, we designed a diagnostic system in which mouse sperm were co-incubated with serum samples from patients with myocardial infarction, cerebral infarction, and pancreatitis, along with matched healthy controls. Key kinematic parameters--including motility rate (MR), curvilinear velocity (VCL), straight-line velocity (VSL), linearity (LIN), and amplitude of lateral head displacement (ALH)--were analyzed using a multiparameter sperm quality analysis system. The results revealed that disease-specific serum induced distinct and reproducible changes in sperm motility patterns, enabling accurate discrimination between healthy and pathological conditions. Evaluation of these motility parameters demonstrated high diagnostic performance, with area under the receiver operating characteristic curve (AUC) values ranging from 0.719 to 0.888. This sperm-based bioassay offers a non-invasive, rapid, and cost-effective platform for disease detection and personalized health assessment, with the potential to complement existing diagnostic approaches.

bioengineering↗

bioRxiv2025

ERAD Activity Distinguishes the Functional Heterogeneity of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) rely on precisely controlled proteostasis to sustain lifelong self-renewal, yet whether intrinsic proteostatic characteristics can prospectively define functional diversity within the HSC pool remains unknown. In this study, we developed a dual-fluorescence reporter system to visualize endoplasmic reticulum-associated degradation (ERAD) activity in vivo and discovered that ERAD activity can prospectively predicts the long-term reconstitution potential of HSCs. Remarkably, ERAD states were maintained through self-renewal, revealing an inheritable "proteostatic memory" within the HSC pool. Transcriptomic and functional analyses identified SOCS2 as a key regulator of this process: SOCS2 inhibits JAK2 signaling to sustain ERAD activity, whereas hyperactive JAK2 interacts with the ERAD E3 ligase Hrd1 and suppresses VCP-mediated misfolded substrate. These findings define a SOCS2-JAK2-ERAD axis that connects cytokine signaling to intrinsic proteostasis remodeling, establishing ERAD activity as a predictive and heritable marker of HSC function and providing a conceptual framework for understanding hematopoietic stem cell heterogeneity.

cell biology↗

bioRxiv2025

Dynamic alterations of DNA methylation and transcriptome in adaptation to and recovery from the space environment

Space exploration presents tremendous health challenges. Here, we report time series of multi-omic and phenotypic profiles of seventeen astronauts from six China Manned Space missions with continuous spaceflight durations ranging from 13 to 180 days. We revealed a key role of DNA methylation regulation in reshaping gene expression patterns to adapt to the space environment. Long-duration spaceflight showed more alterations in epigenetic modifications correlated with alternative splicing and protein acetylation. During recovery, an "overrange rebound" phenomenon was observed, furthermore, a mathematical model was established to describe this implying important phenomenon. Moreover, we revealed the correlations between molecular alterations and phenotypic changes such as coagulation activation and bone intensity loss. Additionally, we performed ground-based simulation experiments to estimate the impacts of individual stressors in the space environment on DNA methylation. In summary, our study highlights the importance and complexity of epigenetic regulation in adaptation to and recovery from the space environment.

genomics↗

bioRxiv2025

Segmented poly(A) tails with microRNA target sites confer tissue-specific regulation for mRNA therapeutics

Targeted delivery and controlled expression of mRNA-LNPs are critical for the development of safe and effective mRNA medicines. However, efficient post-delivery regulation of mRNA-LNP expression remains challenging. In this study, we engineered segmented poly(A) tail variants that function as gene-specific regulatory elements for synthetic mRNAs. Specifically, we inserted microRNA target sites (MTS) for miR-122 or miR-142 at various positions of the poly(A) tail of synthesized luciferase reporter mRNA. These modifications significantly reduced luciferase expression in non-target tissues in vitro and in vivo, demonstrating position-dependent selective expression control. Furthermore, by incorporating triple-MTS sequences for miR-142, miR-126, and miR-148a in all possible combinations at the 5 end of the poly(A) tail, we identified triple-MTS arrangements that simultaneously decrease luciferase activities in three non-target hepatic cell types, while preserving robust expression in hepatocytes. The results highlighted the importance of MTS insertion order for optimal mRNA silencing. These triple-MTS modules significantly expanded the utility of single miRNA-responsive elements, enabling cell-type selective regulation for mRNA therapeutics. By complementing tissue-tropic delivery LNPs, our mRNA cargo regulatory elements have the potential to improve tissue and cell type selectivity as a novel platform for post-delivery regulation of mRNA-LNP.

bioengineering↗

bioRxiv2023

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus evolution. Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the viruss affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

microbiology↗

bioRxiv2022

Peritoneal M2 macrophage-derived extracellular vesicles as natural multi-target nanotherapeutics to attenuate cytokine storm after severe infections

Cytokine storm is a primary cause for multiple organ damage and death after severe infections, such as SARS-CoV-2. However, current single cytokine-targeted strategies display limited therapeutic efficacy. Here, we report that peritoneal M2 macrophages-derived extracellular vesicles (M2-EVs) are multi-target nanotherapeutics to resolve cytokine storm. In detail, primary peritoneal M2 macrophages exhibited superior anti-inflammatory potential than immobilized cell lines. Systemically administrated M2-EVs entered major organs and were taken up by phagocytes (e.g., macrophages). M2-EVs treatment effectively reduced excessive cytokine (e.g., TNF- and IL-6) release in vitro and in vivo, thereby attenuated oxidative stress and multiple organ (lung, liver, spleen and kidney) damage in endotoxin-induced cytokine storm. Moreover, M2-EVs simultaneously inhibited multiple key proinflammatory pathways (e.g., NF-{kappa}B, JAK-STAT and p38 MAPK) by regulating complex miRNA-gene and gene-gene networks, and this effect was collectively mediated by many functional cargos (miRNAs and proteins) in EVs. In addition to the direct anti-inflammatory role, human peritoneal M2-EVs expressed angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2 spike protein, and thus could serve as nanodecoys to prevent SARS-CoV-2 pseudovirus infection in vitro. As cell-derived nanomaterials, the therapeutic index of M2-EVs can be further improved by genetic/chemical modification or loading with specific drugs. This study highlights that peritoneal M2-EVs are promising multifunctional nanotherapeutics to attenuate infectious diseases-related cytokine storm.

immunology↗

bioRxiv2022

Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling

Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA Polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2200 ChIP-Seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA, and identified robust binding of multiple TF families to canonical TF motifs on rDNA. Using a 47S-FISH-Flow assay developed for nascent rRNA quantification, we demonstrated that targeted degradation of CEBPA (C/EBP alpha), a critical hematopoietic TF with conserved rDNA binding, caused rapid reduction in rRNA transcription due to reduced Pol I occupancy. Our work identifies numerous potential rRNA regulators, and provides a template for dissection of TF roles in rRNA transcription. HIGHLIGHTSO_LIMultiple cell-type-specific transcription factors (TFs) bind canonical motifs on rDNA. C_LIO_LIThe hematopoietic TF CEBPA binds to active rDNA alleles at a conserved site. C_LIO_LICEBPA promotes Polymerase I occupancy and rRNA transcription in myeloid progenitors. C_LIO_LIWe present 47S-FISH-Flow, a sensitive assay to quantify nascent rRNA. C_LI

molecular biology↗

bioRxiv2021

Bacterium-Enabled Transient Gene Activation by Artificial Transcription Factor for Resolving Gene Regulation in Maize

Cellular functions are diversified through intricate transcription regulations, and an understanding gene regulation networks is essential to elucidating many developmental processes and environmental responses. Here, we employed the Transcriptional-Activator Like effectors (TALes), which represent a family of transcription factors that are synthesized by members of the {gamma}-proteobacterium genus Xanthomonas and secreted to host cells for activation of targeted host genes. Through delivery by the maize pathogen, Xanthomonas vasicola pv. vasculorum, designer TALes (dTALes), which are synthetic TALes, were used to induce the expression of the maize gene glossy3 (gl3), a MYB transcription factor gene involved in the cuticular wax biosynthesis. RNA-Seq analysis of leaf samples identified 146 gl3 downstream genes. Eight of the nine known genes known to be involved in the cuticular wax biosynthesis were up-regulated by at least one dTALe. A top-down Gaussian graphical model predicted that 68 gl3 downstream genes were directly regulated by GL3. A chemically induced mutant of the gene Zm00001d017418 from the gl3 downstream gene, encoding aldehyde dehydrogenase, exhibited a typical glossy leaf phenotype and reduced epicuticular waxes. The bacterial protein delivery of artificial transcription factors, dTALes, proved to be a straightforward and powerful approach for the revelation of gene regulation in plants.

plant biology↗

bioRxiv2019

LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization

Long non-coding RNAs (lncRNAs) play key roles in various biological processes. However, the roles of lncRNAs in macrophage polarization remain largely unexplored. In this study, thousands of lncRNAs were identified that are differentially expressed in distinct polarized bone marrow-derived macrophages (BMDMs). Among them, Dnmt3aos (DNA methyltransferase 3A, opposite strand), as a known lncRNA, locates on the antisense strand of Dnmt3a. Functional experiments further confirmed that Dnmt3aos were highly expressed in M(IL-4) macrophages and participated in the regulation of Dnmt3a expression, and played a key role in macrophage polarization. The DNA methylation profiles between the Dnmt3aos knockdown group and the control group in M(IL-4) macrophages were determined by MeDIP-seq technique for the first time, and the Dnmt3aos-Dnmt3a axis-mediated DNA methylation modification-regulated macrophage polarization related gene IFN-{gamma} was identified. Our study will help to enrich our knowledge of the mechanism of macrophage polarization and will provide new insights for immunotherapy in macrophage-associated diseases.

cell biology↗