Biology subjects

Kang, Z.

Publications and source records attributed to Kang, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis

Oligodendroglial lineage cells (OLCs) are critical for neuronal support functions, including myelination and remyelination. Emerging evidence reveals their active roles in neuroinflammation, particularly in conditions like Multiple Sclerosis (MS). This study explores the inflammatory translatome of OLCs during the early onset of experimental autoimmune encephalomyelitis (EAE), an established MS model. Using RiboTag-based RNA sequencing in genetically modified Olig2-Cre RiboTag mice, we identified 1,556 upregulated and 683 downregulated genes in EAE OLCs. Enrichment analysis indicated heightened immune-related pathways, such as cytokine signaling, interferon responses, and antigen presentation, while downregulated genes were linked to neuronal development and myelination. Notably, OLCs expressed cytokines/chemokines, and their receptor, highlighting their active involvement in neuroinflammatory signaling. Functional studies demonstrated that interferon-gamma (IFN-{gamma}) signaling in OLCs exacerbates EAE pathology by enhancing antigen presentation and chemokine production, whereas interferon-beta (IFN-{beta}) signaling showed minimal impact. These findings provide novel insights into the inflammatory role of OLCs in EAE and suggest therapeutic potential in targeting OLC-mediated neuroinflammation for MS and related disorders.

neuroscience↗

bioRxiv2024

Single-cell spatial atlas of high-grade serous ovarian cancer unveils MHC class II as a key driver of spatial tumor ecosystems and clinical outcomes

The tumor microenvironment (TME) is a complex network of interactions between malignant and host cells, yet its orchestration in advanced high-grade serous ovarian carcinoma (HGSC) remains poorly understood. We present a comprehensive single-cell spatial atlas of 280 metastatic HGSCs, integrating high-dimensional imaging, genomics, and transcriptomics. Using 929 single-cell maps, we identify distinct spatial domains associated with phenotypically heterogeneous cellular compositions, and demonstrate that immune cell co-infiltration at the tumor-stroma interface significantly influences clinical outcomes. To uncover the key drivers of the tumor ecosystem, we developed CEFIIRA (Cell Feature Importance Identification by RAndom forest), which identified tumor cell-intrinsic MHC-II expression as a critical predictor of prolonged survival, independent of clinicomolecular profiles. Validation with external datasets confirmed that MHC-II-expressing cancer cells drive immune infiltration and orchestrate spatial tumor-immune interactions. Our atlas offers novel insights into immune surveillance mechanisms across HGSC clinicomolecular groups, paving the way for improved therapeutic strategies and patient stratification.

cancer biology↗

bioRxiv2024

An animal model for autoinflammation with infantile enterocolitis

Inflammasomes, particularly NLRC4, play a crucial role in immune responses to intracellular bacterial infections. However, gain-of-function mutations of NLRC4 are linked to severe autoinflammatory diseases, including autoinflammation with infantile enterocolitis (AIFEC). Existing mouse models do not adequately replicate the chronic, unprovoked inflammation observed in AIFEC patients. In this study, we developed a loxP-flanked NLRC4 V341A knock-in (KI) mouse model. Our global NLRC4 V341A KI mice exhibited symptoms closely mirroring those of human AIFEC. These mice demonstrated severe infantile enterocolitis, characterized by heightened intestinal inflammation, compromised intestinal barrier integrity, disrupted gut epithelium, and severe diarrhea, with high mortality within 10 days postnatally. Additionally, they displayed systemic autoinflammation marked by elevated levels of IL-1{beta}, IL-18, and IL-6, alongside cytopenia and hemophagocytosis. In contrast, adult NLRC4 conditional KI mice exhibited autoinflammation with only mild enterocolitis. Since AIFEC is characterized by life-threatening enterocolitis in infancy and recurrent severe autoinflammation throughout life, our conditional NLRC4 KI model effectively recapitulates the clinical features of human AIFEC. Moreover, the NLRC4 V341A-mediated monogenic infantile enterocolitis observed in our model resembles infantile-onset inflammatory bowel disease (IBD), positioning it as a valuable platform for research on very early-onset IBD.

immunology↗

bioRxiv2024

Agent-Based Simulation of Cortical Microtubule Band Movement in the Arabidopsis Zygote

Arabidopsis thaliana zygotes form a circumferential cortical microtubule (CMT) band that moves upward along the longitudinal axis of the cylindrical cell; however, how and why this CMT band moves remain unknown. Based on several recently proposed descriptive feedback mechanisms of CMT reorientation, we hypothesized that a directional cue (DC) changes CMT orientation. We constructed an agent-based simulation model with a DC to observe what happens during CMT formation using different parameters. We determined that the output CMT band can become larger than the input DC zone and identified two types of self-organization processes depending on the parameters used. Furthermore, using well-defined parameters that form a static CMT band, we artificially changed the position of the input DC zone, revealing that CMT band movement requires a DC to move at an appropriate speed.

plant biology↗

bioRxiv2024

Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.

immunology↗

bioRxiv2024

Temporal changes in surface tension guide the accurate asymmetric division of Arabidopsis zygotes

In most plants, the zygote divides asymmetrically to define the body axis. In Arabidopsis thaliana, the zygote undergoes polar elongation maintaining a transverse band of cortical microtubules (MTs), and divides asymmetrically forming another MT band, preprophase band (PPB). How the MT band is maintained at the actively growing cell tip and whether it contributes to PPB formation remain elusive. By combining live-cell imaging and mechanical simulation, we show that zygote elongation induces a temporal change (large material derivative) in surface tension at the growing tip to maintain the MT band, which in turn supports polar elongation. The MT band then guides PPB to determine the cell division site. Therefore, autonomous mechanical feedback between cell elongation and MT organization ensures the zygote division asymmetry.

plant biology↗

bioRxiv2024

A Tough Biointerface in Human Knee Empowered by Dynamic Phase-transforming Minerals in Collagenous Matrix

Joining heterogeneous materials in engineered structures remains a daunting challenge because of stress concentration, often resulting in unexpected failures1,2. Studying the structures in organisms that evolved for centuries provides valuable insights that can be instrumental in addressing this mechanical challenge3-5. The human meniscus root-bone interface is a remarkable example known for its exceptional fatigue resistance, toughness and interfacial adhesion properties throughout its lifespan6-8. We studied the multiscale graded mineralization structure designs within the 30-micron soft-hard interface at the root-bone junction and examined its toughening mechanisms. This graded interface with interdigitated structures and exponential modulus increase exhibits a phase transition from amorphous calcium phosphate (ACP) to gradually matured hydroxyapatite (HAP) crystals, mediated by location-specific distributed biomolecules. In coordination with collagen fibril deformation and reorientation, ACP particles debond with collagen and slide to new positions which enable frictional energy dissipation, and HAP particles arrest cracks. The mineral in transforming phases work synergistically to provide interfacial toughening. The presented biointerface model exemplifies human musculoskeletal systems adaptations to mechanical requirements, offering a blueprint for developing tough interfaces in broad applications.

bioengineering↗

bioRxiv2024

Wheat TaNADPO promotes spot blotch resistance

Bipolaris sorokiniana is a common soil-borne fungal pathogen that can infect various organs of wheat (Triticum aestivum L.), causing diseases such as spot blotch, common root rot, head blight, and black point. The genetic basis of wheat resistance to B. sorokiniana is not yet fully understood. In this study, a natural population of 1,302 global common wheat germplasms was established and inoculated with B. sorokiniana at the seedling stage in a greenhouse. Resistance to spot blotch was assessed, revealing that only about 3.8% of the germplasms exhibited moderate or higher resistance levels. A genome-wide association study (GWAS) using high-density 660K single nucleotide polymorphism (SNP) data identified a region on chromosome 1BL (621.2-674.0 Mb) with 9 SNPs significantly associated (p < 10e-4) with spot blotch resistance, designated as Qsb.hebau-1BL. RNA sequencing and qRT-PCR assays showed that the gene TraesCS1B02G410300, encoding nicotinamide-adenine dinucleotide phosphate-binding oxidoreductase (TaNADPO), was significantly induced by B. sorokiniana. Five SNP variations were found in the promoter region of TaNADPO in wheat lines with or without Qsb.hebau-1BL. Transient expression of TaNADPO in Nicotiana benthamiana leaves showed a cytoplasmic subcellular localization of the fusion protein with a green fluorescent protein (GFP) tag. Wheat transgenic lines overexpressing TaNADPO exhibited significantly enhanced resistance to spot blotch compared to wildtype plants, with higher accumulation of reactive oxygen species (ROS). The knockout EMS mutant of Triticum turgidum NADPO (tdnadpo-K2561, Gln125*) showed significantly reduced resistance to spot blotch and lower ROS accumulation compared to wildtype plants. In summary, TaNADPO has been identified as a crucial gene for resistance to B. sorokiniana, providing valuable insights for developing spot blotch-resistant wheat varieties through molecular breeding techniques.

genetics↗

bioRxiv2024

A viscoelastic-plastic deformation model of hemisphere-like tip growth in Arabidopsis zygotes

Plant zygote cells exhibit tip growth, producing a hemisphere-like tip. To understand how this hemisphere-like tip shape is formed, we revisited a viscoelastic-plastic deformation model that enabled us to simultaneously evaluate the shape, stress, and strain of Arabidopsis (Arabidopsis thaliana) zygote cells undergoing tip growth. Altering the spatial distribution of cell wall extensibility revealed that cosine-type distribution and growth in a normal direction to the surface creates a stable hemisphere-like tip shape. Assuming these as constraints for cell elongation, we determined the best-fitting parameters for turgor pressure and wall extensibility to computationally reconstruct an elongating zygote that retained its hemisphere-like shape using only cell contour data, leading to formulation of non-dimensional growth parameters. Our computational results demonstrate the different morphologies in elongating zygotes through effective non-dimensional parameters.

plant biology↗

bioRxiv2024

Tribus: Semi-automated discovery of cell identities and phenotypes from multiplexed imaging and proteomicdata

MotivationMultiplexed imaging and single-cell analysis are increasingly applied to investigate the tissue spatial ecosystems in cancer and other complex diseases. Accurate single-cell phenotyping based on marker combinations is a critical but challenging task due to (i) low reproducibility across experiments with manual thresholding, and, (ii) labor-intensive ground-truth expert annotation required for learning-based methods. ResultsWe developed Tribus, an interactive knowledge-based classifier for multiplexed images and proteomic datasets that avoids hard-set thresholds and manual labeling. We demonstrated that Tribus recovers fine-grained cell types, matching the gold standard annotations by human experts. Additionally, Tribus can target ambiguous populations and discover phenotypically distinct cell subtypes. Through benchmarking against three similar methods in four public datasets with ground truth labels, we show that Tribus outperforms other methods in accuracy and computational efficiency, reducing runtime by an order of magnitude. Finally, we demonstrate the performance of Tribus in rapid and precise cell phenotyping with two large in-house whole-slide imaging datasets. AvailabilityTribus is available at https://github.com/farkkilab/tribus as an open-source Python package.

bioinformatics↗

bioRxiv2023

Unveiling the A-to-I mRNA editing machinery and its regulation and evolution in fungi

A-to-I mRNA editing occurs during fungal sexual reproduction with an unknown mechanism. Here, we demonstrated that the eukaryotic tRNA-specific heterodimeric deaminase FgTad2-FgTad3, not typically associated with mRNA editing, is responsible for A-to-I mRNA editing in Fusarium graminearum. This editing capacity relies on the interaction between FgTad3 and a sexual stage-specific protein called Ame1. The interaction emerged in Sordariomycetes. Key residues involved in the interaction have been identified. Expression and activity of FgTad2-FgTad3 are regulated through alternative promoters, alternative translation initiation, and post-translational modifications. FgTad2-FgTad3-Ame1 efficiently edits target mRNAs in yeasts, bacteria, and human cells, with significant implications for developing base editors in therapy and agriculture. This study reveals mechanisms, regulation, and evolution of RNA editing in fungi, emphasizing protein-protein interactions in controlling enzyme function.

molecular biology↗

bioRxiv2023

Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy

EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause ATM-mediated slowdown of replication fork progression, accumulation of single-stranded replication gaps, emergence of cytosolic DNA, and increased expression of STING. EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. The effects on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of LIG1, whereas the elevated STING expression and remarkable response to immunotherapy appear mainly elicited by the loss of EHMT2 activity. Depletion of UHRF1, a protein known to be associated with EHMT1/2 and LIG1, also induces STING expression, and depletion of either EHMT2 or UHRF1 leads to demethylation of specific CpG sites in the STING1 promoter, suggestive of a distinct EHMT2-UHRF1 axis that regulates DNA methylation and gene transcription. These results highlight distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors.

cancer biology↗

bioRxiv2023

Using UAV-based temporal spectral indices to dissect changes in the stay green trait in wheat

Stay green (SG) in wheat, a beneficial trait for increasing yield and stress resistance, needs to be supported by analysis of the underlying genetic basis. Spectral reflectance indices (SIs) provide non-destructive tools to evaluate crop temporal senescence. However, few SI-based SG quantification pipelines for analyzing diverse wheat panels in the field are available. Here, we first applied SIs to monitor the senescence dynamics of 565 diverse wheat accessions from anthesis to maturation stages during two field seasons. Based on over 12,000 SIs data set, four SIs (NDVI, GNDVI, NDRE and OSAVI) were selected to develop relative stay green scores (RSGS) and the senescence of wheat populations occurs mainly at four developmental stages stage 1 (S1) to S4, accounting for the final SG indicators. A RSGS-based genome-wide association study identified 47 high-confidence quantitative trait loci (QTL) harboring 3,079 SNPs significantly associated with RSGS and 1,085 corresponding candidate genes in the two seasons; 15 QTL overlapped or were adjacent to known SG-related QTL or genes and the remaining QTL were novel. Finally, we selected three superior candidate genes (TraesCS6B03G0356400, TraesCS2B03G1299500, and TraesCS2A03G1081100) as examples by transcriptomes, gene annotation, and gene-based association analysis for further analysis and found that utilization of superior SG-related variation in China gradually increased following the Green Revolution. The study provides a useful reference for further SG-related gene discovery of favorable variations in diverse wheat panels.

genetics↗

bioRxiv2023

LRRK2 G2019S promotes the development of colon cancer via modulating intestinal inflammation

LRRK2 G2019S is the most prevalent variant associated with Parkinsons disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown. Using a mouse model of colitis-associated cancer (CAC) and LRRK2 G2019S knockin (KI) mice, here we report that LRRK2 G2019S promotes the pathogenesis of colon cancer as evidenced by increased tumor number and tumor size in LRRK2 G2019S KI mice. LRRK2 G2019S promoted intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, we found that LRRK2 G2019S KI mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis. Suppressing the kinase activity of LRRK2 ameliorated the severity of colitis in both LRRK2 G2019S KI and WT mice. At the molecular level, our investigation unveiled that LRRK2 G2019S promotes the production of reactive oxygen species, triggers inflammasome activation, and induces cell necrosis in the gut epithelium in a mouse model of colitis. Collectively, our data provide direct evidence that gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, implicating LRRK2 as a potential target in colon cancer patients with hyper LRRK2 kinase activity.

immunology↗

bioRxiv2022

Population Sequencing Reveals Rht-D1b Contributing the Bigger Seedling Root to Modern Wheat Cultivars

The Green Revolution (GR) has dramatically increased the yield of modern wheat cultivars; however, whether and how GR reshaped the wheat root system remains largely unknown. Here, a large-scale transcriptomic and phenotypical investigation was performed on seedling roots of 406 worldwide bread wheat accessions, showing differential transcriptomes and phenotypes between landrace and modern cultivars, and the GR allele Rht-D1b was the main genetic factor driving this phenotype differential, conferring a significantly larger seedling root to modern cultivars by increasing cell length and root meristem size. In this case, the translational reinitiation of TaRht-D1 underlies Rht-D1bs genetic effects. In contrast, another GR allele, Rht-B1b, has no significant effects on root-related traits, differing from the similar genetic effects of these two GR alleles on reducing plant height. This unexpected effect of Rht-D1b on root systems contributes to a substantially larger root-shoot ratio in modern wheat cultivars. These findings reveal previously overlooked benefits of GR alleles in modern wheat cultivars and provide clues for their future application to form a robust seminal root system.

plant biology↗

bioRxiv2022

Near telomere-to-telomere nuclear phased chromosomes of the dikaryotic wheat fungus Rhizoctonia cerealis

Rhizoctonia cerealis (Rce), which causes sharp eyespot, is one of the most destructive wheat pathogens. However, the genetic and molecular virulence mechanisms of Rce have not been elucidated. As a dikaryotic organism, the haplotype phasing of this fungus has not been completed so far. We applied a haplotype phasing algorithm to generate a high-quality near telomere-to-telomere nuclear-phased genome sequence of Rce strain R0301. Sixteen pairs of chromosomes were assigned to the A and B genomes with a total size of 83 Mb. Based on a dual-time course RNA-seq, 25308 genes were predicted. Genes for steroid biosynthesis and starch and sucrose metabolism were significantly enriched, together with many genes encoding carbohydrate-active enzymes (CAZymes) and secreted effector proteins, which should be involved in infection of wheat plants. Population genomic analysis of 31 isolates collected in China during the last forty years suggests that this population has not undergone substantial differentiation over time. ImportanceThe finished genome reference is the basis of revealing pathogens biology base. Many efforts have been made to produce the chromosome-scale assembly of fungi. However, the reference of many pathogenic fungi is highly fragmented, which prevents the analysis of genome structure variation, evolution and import pathogenicity genes. Here, we assembly the only chromosome-scale haplotype-phased reference of dikaryotic fungus so far. This assembly achieves the gold standard based on many evaluation software, which indicates that the pipeline developed in this study can be applied to assemble references for other dikaryotic organisms. This work can also promote the research on the globes destructive wheat pathogens, sharp eyespot, caused by R. cerealis.

genomics↗

bioRxiv2022

Ascorbic acid derived carbon dots promote circadian rhythm and contribute to attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children, and ADHD patients always display circadian abnormalities. While, the ADHD drugs currently used in clinic have strong side effects, such as psychosis, allergic reactions and heart problems. Here, we demonstrated carbon dots derived from the ascorbic acid (VCDs) could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation. VCDs prolonged the circadian period of zebrafish for more than half an hour. In addition, the amplitude and circadian phase were also changed. The dopamine level was specifically increased, which may be caused by stimulation of the dopaminergic neuron development in the midbrain. Notably, it was found that the serotonin level was not altered by VCDs treatments. Also, the gene transcriptome effects of VCDs were discussed in present work. Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway, which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention. Brief summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/482578v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@198eeforg.highwire.dtl.DTLVardef@1f714f7org.highwire.dtl.DTLVardef@819d8eorg.highwire.dtl.DTLVardef@18ef9cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2021

TaBln1 negatively regulates wheat resistance to stripe rust by reducing Ca2+ influx

Blufensin1 (Bln1) has been identified as a negative regulator of basal defense mechanisms that is unique to the cereal grain crops barley, wheat, and rice. However, the molecular mechanisms through which Blufensin1 regulates the wheat immune response are poorly understood. In this study, we found that TaBln1 is significantly induced by Puccinia striiformis f. sp. tritici (Pst) virulent race CYR31 infection. Knockdown the expression of TaBln1 by virus-induced gene silencing reduced Pst growth and development, and enhanced the host defense response. In addition, TaBln1 was found to physically interact with TaCaM3 on the plasma membrane. Silencing TaCaM3 with virus-induced gene silencing increased fungal infection areas and sporulation and reduced wheat resistance to the Pst CYR23 and CYR31. Moreover, we found that the TaCaM3 transcription level could be induced by treatment with chitin but not flg22. Silencing TaCaM3 decreased the Ca2+ influx induced by chitin, but silencing TaBln1 increased the Ca2+ influx in vivo using a non-invasive micro-test technique. Taken together, we identified the wheat negative regulator TaBln1, which interacts with TaCaM3 to impair Ca2+ influx and inhibits plant defenses. One-sentence summaryTaBln1 negatively regulate wheat resistance to stripe rust possibly due to the interaction with TaCaM3 on the plasma membrane, which impairs the calcium influx modulated by TaCaM3.

pathology↗