Biology subjects

Nie, L.

Publications and source records attributed to Nie, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Shared and distinct temporal representations of Chinese words across imaged, silent, and overt speech

How internal speech relates to overt speech remains a fundamental question in speech production: do different forms of speech preserve a common neural representation of the intended word, or does that representation change as speech becomes articulated? We used time-resolved electroencephalography to characterize representations of 10 Chinese words during imagined, silent, and overt speech. Word identity was reliably decodable in all three modes, but its temporal dynamics differed: imagined-speech representations peaked earlier and were less temporally stable, whereas silent and overt speech showed stronger and more sustained representations. Cross-mode decoding revealed word-discriminative information shared across all three mode pairs, with substantially stronger generalization between silent and overt speech. However, direct comparison of word-level representational geometry revealed robust correspondence only between silent and overt speech, indicating that transferable information across modes does not necessarily imply preservation of the broader relational structure among words. Representational similarity analyses further showed distinct visual-form, semantic, and phonetic dynamics across speech modes, with late visual-form and phonetic information contributing uniquely to the geometry shared by silent and overt speech. Controlling for time-matched surface electromyography preserved the overall silent-overt neural correspondence and within-mode phonetic representations, while eliminating the unique phonetic contribution to their shared geometry, suggesting that peripheral articulation accounts for part, but not all, of this common structure. Together, these findings show that imagined, silent, and overt speech share word representations at different levels and suggest that representational geometry and temporal stability are progressively reorganized as internal speech is translated into articulation.

neuroscience↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

Multidimensional variation and population stratification across 8000 complete human centromeres

Human centromeres are indispensable for the faithful segregation of chromosomes during cell division, yet their highly repetitive nature has historically precluded comprehensive characterization, leaving fundamental questions about their sequence diversity, evolution trajectories and function dynamics unresolved. Here, we generated 6,312 complete human centromere sequences from 320 phased genome assemblies in Asian Pan-Genome project phase 1. By integrating the assemblies from the Human Pangenome Reference Consortium (HPRC) and Human Genome Structural Variation Consortium (HGSVC), we constructed a multidimensional genetic variation map encompassing over 8,000 gapless centromeres. Centromeric satellite arrays account for 4.19% to 6.01% of the whole genome, with substantial variations in size and architecture across chromosomes. Using a refined alpha satellite clustering approach that captures global diversity, we identified 195 higher-order repeat (HOR) arrays, 56.4% of which are absent from the T2T-CHM13 reference genome. Extensive structural variations across multiple dimensions exhibit population stratification, including centromeric haplotypes (CenHaps), ultra-large pericentric inversions spanning up to 36.6 Mbp, and inter-chromosomal HOR sharing that reflects sequence exchange among chromosomes. Integrating CENP-A CUT&Tag experiments and long-read-based DNA methylation profiles, we demonstrate that 16.8% of centromeres harbor multiple potential kinetochore assembly sites, and CenHap-specific local HOR homogenization is associated with kinetochore positioning. Despite global suppression of recombination at centromeres, we observed asymmetric linkage disequilibrium flanking centromeres and an ancient recombination event within the centromere of chromosome 19. Furthermore, contrary to the prevailing assumption of high mutation rates in centromeres, our estimates based on stringent orthology reveal no significantly higher single-base substitution rates for centromeres relative to flanking pericentromeric regions with substantial variations across chromosomes, despite extraordinary structural plasticity. Collectively, these multi-scale centromeric variations provide a global view of human centromere diversity and population stratification, fundamentally redefine centromere evolution through a dual-track model balancing structural innovation with mutational constraint, and establish an essential resource for investigating centromere biology and a baseline reference for diagnosing centromere-associated disorders.

genomics↗

bioRxiv2026

Deciphering complete archaic introgression sequences in modern human genomes

Genetic introgression from archaic hominins has profoundly reshaped the genetic diversity and adaptive potential of modern humans, yet the full catalog of introgressed sequences, particularly those residing in structurally complex regions has remained elusive. Here, we present ASMaid (ASseMbly-based archaic introgression detector), a Hidden Markov Model-based framework that leverages haplotype-resolved pangenome assemblies to identify archaic-derived sequences with unprecedented completeness. By integrating both single-nucleotide genotype and structural variation (SV) signals, ASMaid captures significantly more intact archaic segments than conventional reference-based approaches. Applying ASMaid to a global panel of 610 phased human genome assemblies, we show that non-African individuals carry approximately 79.8 Mbp of Neanderthal and 8.3 Mbp of Denisovan sequences, representing substantial increases over previous estimates, respectively. Notably, we detected several centromere-spanning archaic segments, including EAS-specific calls on chromosomes 5 and 7. Our assembly-based approach uncovered 1,701 archaic-derived SVs, revealing a previously overlooked layer of archaic functional legacy. High-frequency introgressed loci are enriched in pathways associated with metabolism, immunity, and nervous system (e.g. CTNNA2 linked to early-onset schizophrenia risk), underscoring the fundamental role of introgression in modulating modern human traits. Notably, we identified dozens of loci potentially facilitating local adaptation, such as PRDM16 involved in adipocyte differentiation and cold tolerance, and CSGALNACT2 associated with chondroitin sulfate synthesis. Furthermore, our analysis delineates three distinct Denisovan introgression pulses in Eastern Eurasian genomes, in which the first two pulses are shared across East Eurasian and Oceanian populations, while the third remain primarily exclusive in East Asians. Reflecting these complex introgression events, 31 Denisovan-derived segments, including the TBX15-WARS2 locus, are inferred to have been introduced via at least two events. This comprehensive map of archaic introgression provides a fundamental resource for understanding how ancient gene flow continuously shapes human phenotypic diversity and adaptation.

evolutionary biology↗

bioRxiv2026

Directed evolution of compact synthetic promoters via AlphaGenome and genetic algorithms

Compact tissue-specific promoters are highly desirable for gene therapy because viral vectors possess limited packaging capacity. However, existing promoter engineering strategies rely primarily on rational design or de novo sequence generation and lack efficient approaches for compressing long native promoters while preserving regulatory specificity. Although genome foundation models have substantially improved sequence-to-function prediction, they have not been effectively translated into computational platforms for promoter engineering. Here, we present VirEvo, a computational promoter engineering framework that integrates a virtual dual-luciferase assay (VirDLA), genome-foundation-model-guided genetic evolution, and an orthogonal Pan-Tissue Consistency Filter (PTCF). VirDLA introduces an internal-reference normalization strategy inspired by dual-luciferase reporter assays, enabling relative comparison of promoter activity across tissues without retraining AlphaGenome. Guided by these normalized activity scores, VirEvo iteratively optimizes promoter selectivity, off-target activity, and sequence length. Using the human p16INK4a promoter as a proof of concept, VirEvo evolved a compact synthetic promoter, SRP2M, of only 398 bp, representing an 85.9% reduction in sequence length. Experimental validation using dual-luciferase reporter assays in senescent IMR90 fibroblasts demonstrated that SRP2M retained 77% of wild-type senescence selectivity while reducing basal leakage to 52% of the wild-type level. Together, these results demonstrate the feasibility of genome-foundation-model-guided promoter engineering. VirEvo provides a generalizable framework for designing compact tissue-specific regulatory elements and extends the application of genome foundation models from functional prediction to synthetic regulatory engineering.

synthetic biology↗

bioRxiv2026

Integrating Histology with Spatial Molecular Programs Using a Multimodal Foundation Model

Histopathological assessment remains central to cancer diagnosis and stratification, yet its mechanistic interpretation remains limited without molecular context. To address this, we developed SQUALL, a multimodal foundation model integrating histology with spatial molecular programs. For pretraining, we assembled histMol, a large-scale corpus of 1.76 billion paired histology-spatial transcriptomics spots/bins across 33 tissues and 12 platforms from 3,446 tissue sections. Following pretraining, SQUALL enables transcriptome-wide virtual biomarker profiling, prognostically relevant spatial niches discovery, and integrative disease progression modeling. Leveraging its multimodal embeddings, SQUALL identifies niches associated with tertiary lymphoid structure (TLS) maturation and ovarian cancer relapse, reconstructs molecular trajectories of breast cancer invasion across 325,112 spots, and uncovers underlying transcriptional programs. Applied to whole-slide images from 898 patients, SQUALL outperforms existing pathology foundation models in outcome prediction while enabling interpretable risk stratification. Together, these results establish spatially aligned multimodal pretraining as a new paradigm for extending molecular insights into pathology images.

bioinformatics↗

bioRxiv2026

NuGraph: Graph-Based Reasoning over 3D Primitives for Nucleus Segmentation Correction

Correcting segmentation errors in large-scale 3D nuclei reconstructions requires reasoning about which fragments belong to the same nucleus across densely packed regions. Existing correction methods rely on local pairwise fragment matching, which cannot resolve the global topology of nuclear clusters and fails to recover missing morphology. We propose NO_SCPLOWUC_SCPLOWGO_SCPLOWRAPHC_SCPLOW, a graph-based reasoning framework that operates over atomic 3D primitives obtained by decomposing erroneous masks. NO_SCPLOWUC_SCPLOWGO_SCPLOWRAPHC_SCPLOW encodes primitive geometry via a 3D point-cloud backbone and performs global relational reasoning through graph attention, capturing inter-primitive dependencies across entire clusters rather than isolated pairs. A primitive-proposal contrastive loss aligns local primitive features with nucleuslevel semantics, improving grouping accuracy in dense regions. The resulting proposals are then refined by a shaperefinement network that predicts signed distance fields to restore smooth morphology. To train without manual error annotations, we develop a self-supervised data engine that synthesizes realistic segmentation errors from clean nuclei labels. To benchmark correction at brain scale, we curate NucEMFix, the first brain-wide EM benchmark of nuclei error cases across FAFB and MICrONS (8,000+ annotated error nuclei). NO_SCPLOWUC_SCPLOWGO_SCPLOWRAPHC_SCPLOW attains 87.99% F1 on NucEMFix-F (FAFB) and 86.20% on NucEMFix-M (MICrONS), outperforming both re-segmentation baselines (e.g., +8.6% over nnU-Net) and pairwise correction methods, while reducing curation effort by over 100x relative to manual proofreading. Code and data are available at https://mingzhiwang618.github.io/NucEMFix.

neuroscience↗

bioRxiv2025

Structural basis of DNA N6-adenine methylation in eukaryotes

As a transcription-associated epigenetic mark abundantly present in many unicellular eukaryotes, DNA N6-adenine methylation (6mA) is maintained by the AMT1 complex. However, the structure-function relationship of the AMT1 complex remains to be fully elucidated. Here, we employ AlphaFold3 (AF3) for de novo structural modeling of the AMT1 complex, complemented by molecular dynamics simulations. Functional relevance of key structural features, especially those of the AMT1 ternary complex with the double-stranded DNA (dsDNA) substrate and the cofactor, are validated by extensive mutagenesis, both in vivo and in vitro. Our analysis reveals the structural basis for DNA substrate recognition, base flipping, and catalysis in this prototypical eukaryotic DNA 6mA-methyltransferase. It also allows us to delineate the reaction pathway for processive methylation involving translocation of the AMT1 complex along the dsDNA. As the active site is conserved across the MT-A70 family of eukaryotic N6-adenine methyltransferases, the structural insight will facilitate rational design of specific inhibitors.

molecular biology↗

bioRxiv2025

A distinct class of eukaryotic demethylases safeguards the positional fidelity of N6-methyladenine (6mA)

DNA N6-methyladenine (6mA) has recently been rediscovered as an epigenetic mark in eukaryotes. Several demethylases responsible for 6mA removal have been identified in multicellular eukaryotes. However, despite the much higher abundance of 6mA in unicellular species, no such enzymes have been reported and the biological significance of 6mA removal in these organisms remain unclear. Here, we identify and functionally characterize DMT3 as a dedicated 6mA demethylase in unicellular eukaryotes. DMT3 targets both fully and hemi-methylated ApT dinucleotides on DNA. It is predominantly localized at transcription start sites (TSS), where it antagonizes the activity of the 6mA methyltransferase AMT1. Deletion or catalytic inactivation of DMT3 leads to genome-wide ectopic 6mA deposition specifically at TSS regions, driven by AMT1, and is accompanied by increased chromatin accessibility and elevated enrichment of transcription-associated histone marks. These epigenetic alterations disrupt gene expression, reduce osmotic stress resistance, and impair the initiation of sexual reproduction. Together, our findings uncover a critical 6mA demethylase in unicellular eukaryotes, and highlight the essential role of active 6mA removal in maintaining transcriptional and developmental integrity.

genetics↗

bioRxiv2025

Optically detected and radio wave-controlled spin chemistry in cryptochrome

Optically addressable spin systems, such as nitrogen-vacancy centers in diamond, have been widely studied for quantum sensing applications. In this work, we demonstrate that certain flavoproteins -- specifically cryptochrome and iLOV -- which generate spin correlated radical pairs upon optical excitation, also exhibit optically detected magnetic resonance (ODMR). Remarkably, the iLOV protein, commonly used in cellular imaging, displays ODMR contrast approaching 50%. We present initial applications including widefield magnetic field sensing and spatial modulation of photoluminescence using radiofrequency pulses and magnetic field gradients. Our results establish radical pairs in proteins as a novel platform for optically addressable spin systems, offering the key advantages of molecular designability and genetic encodability. Moreover, due to the spin-selective nature of radical pair chemistry, the results lay the groundwork for future radiofrequency-based manipulation of biological systems.

biophysics↗

bioRxiv2025

INHBA promotes the progression of gastric cancer by activating MAPK signaling pathway via targeting ITGA6

Gastric cancer (GC) is one of the most common malignancies, ranking as the fifth most common cancer and the fourth leading cause among cancer related deaths worldwide. Upregulated INHBA expression in gastric cancer tissues compared to adjacent non-cancerous tissues was confirmed by immunohistochemistry and qRT-PCR analysis. This increased expression of INHBA was found to be significantly associated with the incidence of tumor lesion, lymph node metastasis and the progression to more advanced TNM stages in patients. Functional experiments showed that INHBA could promote the proliferation of GC cells, enhance migration and invasion in vitro, while simultaneously facilitating the inhibition of apoptosis. To test whether INHBA regulated the tumor growth in vivo, the animal studies were performed. The indicated that INHBA over-expression promoted the tumor growth, including weight and volume. Moreover, this study demonstrated through a series of experiments including RNA-seq, Co-IP, Co-IF, Western blot, and Rescue studies that INHBA promotes the progression of GC by targeting ITGA6 to regulate the MAPK signaling pathway. In summary, understanding the role of INHBA/ITGA6/MAPK in tumourigenesis could provide new insights into gastric cancer therapy and targeted inhibition of INHBA might be a potential therapeutic approach for GC treatment.

cancer biology↗

bioRxiv2025

YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma

Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activity in vivo and showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing. KEY POINTSO_LIYX0798 showed high selectivity, target binding affinity, and anti-tumor efficacy in overcoming resistance to various therapies. C_LIO_LIYX0798 had good oral pharmacokinetics and anti-tumor effects that resulted from transcription reprogramming towards tumor cell killing. C_LI

cancer biology↗

bioRxiv2024

Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in neurons

Persistent DNA double-strand breaks (DSBs) are enigmatically implicated in neurodegenerative diseases including Huntingtons disease (HD), the inherited late-onset disorder caused by CAG repeat elongations in Huntingtin (HTT). Here we combine biochemistry, computation and molecular cell biology to unveil a mechanism whereby HTT coordinates a Transcription-Coupled Non-Homologous End-Joining (TC-NHEJ) complex. HTT joins TC-NHEJ proteins PNKP, Ku70/80, and XRCC4 with chromatin remodeler Brahma-related Gene 1 (BRG1) to resolve transcription-associated DSBs in brain. HTT recruitment to DSBs in transcriptionally active gene- rich regions is BRG1-dependent while efficient TC-NHEJ protein recruitment is HTT-dependent. Notably, mHTT compromises TC-NHEJ interactions and repair activity, promoting DSB accumulation in HD tissues. Importantly, HTT or PNKP overexpression restores TC-NHEJ in a Drosophila HD model dramatically improving genome integrity, motor defects, and lifespan. Collective results uncover HTT stimulation of DSB repair by organizing a TC-NHEJ complex that is impaired by mHTT thereby implicating dysregulation of transcription-coupled DSB repair in mHTT pathophysiology. Highlights* BRG1 recruits HTT and NHEJ components to transcriptionally active DSBs. * HTT joins BRG1 and PNKP to efficiently repair transcription related DSBs in brain. * Mutant HTT impairs the functional integrity of TC-NHEJ complex for DSB repair. * HTT expression improves DSB repair, genome integrity and phenotypes in HD flies.

neuroscience↗

bioRxiv2024

Immune Cell Influence on Diffuse Large B-Cell Lymphoma: A Mendelian Randomization Analysis

ObjectiveTo elucidate the causal relationship between immune cells and diffuse large B-cell lymphoma (DLBCL), we conducted a Mendelian randomization analysis. MethodsMendelian randomization (MR) leverages genetic variants as instruments to infer causal effects from observational data. Here, we performed a two-sample MR analysis to assess the causal impact of 731 immune cell types on DLBCL. We employed various MR techniques, including the weighted median estimator (WME) and inverse variance weighting (IVW), and conducted sensitivity analyses to ensure result robustness. Additionally, reverse MR analysis was performed to explore the potential causal relationship between DLBCL and immune cells. ResultsWe identified seventeen immune features with causal links to DLBCL, categorized across various cellular groups: four in B cells, two in T cell maturation stages, six in Tregs, four in the TBNK group, and one in dendritic cells (DCs). Sensitivity analyses confirmed the absence of heterogeneity, horizontal pleiotropy, and bias in our findings. Reverse causal analysis revealed a causal association between DLBCL and one of the seventeen immune cell types identified. ConclusionsOur MR analysis of seventeen immune cell types uncovers the complex interactions between the immune system and DLBCL, providing crucial insights into the tumor microenvironment and potential avenues for targeted immunotherapy.

immunology↗

bioRxiv2024

Regulation of angiogenesis by signal sequence-derived peptides

BackgroundThe neuropilin-like, Discoidin, CUB and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long signal sequence (SS) composed of N-terminal (N) and C-terminal (C) subdomains, separated by a transition (tra) subdomain. DCBLD2 interacts with VEGFR-2 and regulates VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. The exact mechanisms by which DCBLD2 interacts with VEGFR2 to modulate VEGF signaling remain unclear. MethodsSearching for VEGFR2 interacting DCBLD2 domains, we generated various constructs containing different DCBLD2 domain combinations and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells. Several peptides were synthesized based on the identified domain, and their effect on VEGF signaling was assessed in vitro in cell culture and in vivo using matrigel plug and corneal micropocket assays. The effect of the lead peptide was further evaluated using a murine hindlimb ischemia model. ResultsDCBLD2 SS interacted with VEGFR2 and promoted VEGF signaling. SS was not cleaved in the mature DCBLD2 and its hydrophobic transmembrane traC segment, but not the N subdomain, was involved in DCBLD2-VEGFR2 interaction. The smallest unit in DCBLD2 SS that interacts with VEGFR2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS traCs effect on VEGF-signaling, while shorter or longer poly-leucine sequences were less effective. Finally, a synthetic traC peptide enhanced VEGF signaling in vitro, promoted VEGF-induced angiogenesis in vivo, and improved blood flow recovery following hindlimb ischemia. ConclusionDCBLD2 SS along with its derivative peptides can promote VEGFR2 signaling and angiogenesis. Synthetic peptides based on DCBLD2 SS hold promise as therapeutic agents for regulating angiogenesis. Importantly these findings refine the traditional view of signal sequences as mere targeting elements, revealing a role in cellular signaling. This opens new avenues for research and therapeutic strategies.

cell biology↗

bioRxiv2024

Carbon Dots and Single-walled Carbon Nanotubes Enhances Maize Shading Stress Tolerance

Low sunlight availability/shading stress is one of the major abiotic stresses, limiting plant photosynthesis and biomass production. Maize is a C4 species and requires more sunshine for efficient photosynthesis rate. Thus, maize is a highly shade-sensitive species. We used carbon dots (CDs) and single-walled carbon nanotubes (SWCNTs) as a foliar application to enhance maize photosynthesis under no-shading and shading stress. The results revealed that under shading stress, the higher concentration of CDs and SWCNTs reduced the MDA (Malondialdehyde) content and increased the expression level of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) genes. Moreover, under shading stress, CDs and SWCNTs increased the average thickness of leaf lamina, vascular bundle, mesophyll, and epidermis. CDs and SWCNTs reduced the damaging effects of shading stress on the chloroplast (Ch) formation. CDs and SWCNTs upregulated Rubisco and related genes under shading stress. The chlorophyll fluorescence parameters, including the efficiency of quantum yield of photosystem II (Fv/Fm), electron transport rate (ETR), non-photochemical quenching coefficient (NPQ), and photochemical quenching coefficient (qP) were improved with the foliar application of CDs and SWCNTs under shading stress. Higher stomatal conductance, intercellular CO2 concentration, transpiration, and net photosynthesis were observed in maize plants treated with CDs and SWCNTs under shading stress. The results of our study suggest that using higher concentrations of CDs and SWCNTs can enhance plant growth and photosynthesis under shading stress conditions. However, to avoid nanotoxicity, great care is recommended when selecting different concentrations of nanomaterials based on the growing conditions.

physiology↗

bioRxiv2023

Mass spectrometry imaging links interxylary cork formation with phytochemical distribution in Scutellaria baicalensis

Interxylary cork, an anomalous cork structure of plant, is occasionally seen in older roots of Scutellaria baicalensis Georgi (Lamiaceae). Xylem tissues encircled by interxylary corks gradually decay. Efforts have been made to elucidate the development of interxylary cork in S. baicalensis, but the variation of phytochemical accumulation in different root tissues segmented by interxylary cork has not been studied. In this investigation, mass spectrometry imaging was employed to visualize the in situ phytochemicals in the decayed root of S. baicalensis (Kuqin). A special flavonoid was observed to show especially high mass intensity in the cork region, and its spatial distribution was regarded as a reflection of cork development. Interxylary corks were found to be successively formed in the root of S. baicalensis. After the continuous formation of interxylary corks, root tissues were divided into different parts by interxylary corks, including the non-decayed part, slightly decayed part and severely decayed part. Interestingly, pharmaceutically important flavonoids presented different accumulation tendencies in tissues of different decaying degrees. Owing to the non-targeted analytical function of mass spectrometry imaging, the holistic difference of chemical composition of decayed and non-decayed tissues of Kuqin was deciphered. To our knowledge, this is the first experiment that maps out the successive formation of interxylary corks in S. baicalensis using mass spectrometry imaging. Also, our research successfully correlates plant anatomy with the spatial distribution of phytochemicals, which sets a good example for the exploration of plant science from the dimension of spatial information.

biochemistry↗

bioRxiv2023

DePARylation is critical for S phase progression and cell survival

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

cancer biology↗