Biology subjects

Wang, D.

Publications and source records attributed to Wang, D..

At least 343 records · Page 19Linked to original sources

bioRxiv2024

Targeting Diffuse Midline Glioma with a novel anti-CD99 Antibody

Diffuse midline gliomas (DMGs) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. We identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+DMGs. We found that the increased expression of CD99 in K27M+DMGs was a result of the onco-histone K27M mutation. In K27M+DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation, indicating an oncogenic role of CD99 enabled by blocking differentiation. We then developed a novel therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope, and evaluated its antitumor efficacy in preclinical models of K27M+DMG. 10D1 suppressed DMG growth in vitro and in vivo by inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficiency and xenograft survival, providing a strong justification for its clinical development as a therapy for DMGs. Statement of SignificanceThis study emphasizes that CD99 overexpression occurs due to the H3K27M mutation in Diffuse Midline Gliomas (DMGs). This heightened expression suppresses apoptosis, inhibits differentiation, and induces radio-resistance in DMGs. This research justifies using a novel CD99 antibody alone or combined with radiation therapy in human pediatric clinical trials.

cancer biology↗

bioRxiv2024

Engineered Migrasomes: A Robust, Thermally Stable Vaccination Platform

The increasing ability of pathogens and tumor cells to evade immune detection underscores the urgent need for novel vaccine platforms leveraging diverse biological mechanisms. Additionally, logistical challenges associated with cold-chain transportation significantly limit vaccine accessibility, especially in resource-limited regions. Recently, we identified migrasomes, specialized organelles generated during cell migration, which are inherently stable and enriched with immune-modulating molecules. To address the low yield of natural migrasomes, we engineered migrasome-like vesicles (eMigrasomes) using hypotonic shock combined with cytoskeletal disruption to enhance vesicle formation. The biogenesis of eMigrasomes relies on the core migrasome machinery, faithfully recapitulating the biophysical attributes of native migrasomes while significantly improving production efficiency. We demonstrate that eMigrasomes loaded with a model antigen elicit potent antibody responses and maintain structural integrity and immunogenic potential at room temperature. Furthermore, eMigrasomes displaying the SARS-CoV-2 Spike protein induce robust humoral immune responses, providing effective protection against viral infection. Our findings highlight the potential of utilizing migrasome biology and hypotonic shock-driven vesicle generation as an innovative, stable, and broadly accessible vaccine platform.

cell biology↗

bioRxiv2024

Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven Medulloblastoma

MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines, we identified the Mediator-associated kinase CDK8 as the top dependence for MYC-driven MB. Loss of CDK8 markedly reduces MYC expression and impedes MB growth. Mechanistically, we demonstrate that CDK8 depletion suppresses ribosome biogenesis and mRNA translation. CDK8 regulates occupancy of phospho-Polymerase II at specific chromatin loci facilitating an epigenetic alteration that promotes transcriptional regulation of ribosome biogenesis. Additionally, CDK8-mediated phosphorylation of 4EBP1 plays a crucial role in initiating eIF4E-dependent translation. Targeting CDK8 effectively suppresses cancer stem and progenitor cells, characterized by increased ribosome biogenesis activity. We also report the synergistic inhibition of CDK8 and mTOR in vivo and in vitro. Overall, our findings establish a connection between transcription and translation regulation, suggesting a promising therapeutic approach targets multiple points in the protein synthesis network for MYC-driven MB.

cancer biology↗

bioRxiv2024

Testing a Method for Quantifying Microplastic Content in Mytilus californianus

With the proliferation of microplastics within the environment, there has been an increased need to quantify them within organic tissues of aquatic species. Several studies have examined the potential role of mussels in filtering these contaminants, prompting interest in characterizing uptake and retention of microplastics in these species. There are a variety of methods to isolate and quantify microplastics, including density separation, enzymatic digestion, and filtration. The applicability of a combined digestion and ultrasonic bath methodology in isolating microplastics from the California mussel (Mytilus californianus Conrad, 1837) was investigated. Microplastics were added to 20-gallon tanks at 0 g (control) 8 mg. Mussel tissues from each tank were digested using potassium hydroxide solutions. These digestions were subjected to vacuum filtration and a sonication bath, then treated with a mixture of sodium hypochlorite and nitric acid. It was found that this method successfully removed organic tissue from the mussels while leaving dyed microplastics intact. The latter were quantified using fluorescent microscopy. This proof-of-principle experiment indicates that this technique can be applied to further studies on environmental impact and retention of microplastics in mussels and may also have utility for other shellfish.

zoology↗

bioRxiv2024

DeepPrep: An accelerated, scalable, and robust pipeline for neuroimaging preprocessing empowered by deep learning

Neuroimaging has entered the era of big data. However, the advancement of preprocessing pipelines falls behind the rapid expansion of data volume, causing significant computational challenges. Here, we present DeepPrep, a pipeline empowered by deep learning and workflow manager. Evaluated on over 55,000 scans, DeepPrep demonstrates a 11-fold acceleration, exceptional scalability, and robustness compared to the current state-of-the-art pipeline, providing a promising solution to meet the scalability requirements of neuroimaging.

neuroscience↗

bioRxiv2024

TabHLH27 orchestrates root growth and drought tolerance to enhance water use efficiency in wheat

Cultivating high-yield wheat under limited water resources is essential for sustainable agriculture in semiarid regions. Amid water scarcity, plants activate drought response signaling, yet the delicate balance between drought tolerance and development remains unclear. Through genome-wide-association study (GWAS) and transcriptome profiling, we identified a wheat atypical basic helix-loop-helix (bHLH) transcription factor (TF), TabHLH27-A1, as a promising quantitative trait locus (QTL) candidate for both relative root dry weight (DW.R%) and spikelet number per spike (SPS) in wheat. TabHLH27-A1/B1/D1 knockout reduced wheat drought tolerance, yield, and water use efficiency (WUE). TabHLH27-A1 exhibited rapid induction with PEG treatment, gradually declining over days. It activated stress response genes such as TaCBL8-B1 and TaCPI2-A1 while inhibiting root growth genes like TaSH15-B1 and TaWRKY70-B1 under short-term PEG stimulus. The distinct transcriptional regulation of TabHLH27-A1 involved diverse interacting factors such as TaABI3-D1 and TabZIP62-D1. Natural variations of TabHLH27-A1 influences its transcriptional responses to drought stress, with TabHLH27-A1Hap-II associated with stronger drought tolerance, larger root system, more spikelets, and higher WUE in wheat. Significantly, the elite TabHLH27-A1Hap-II was selected during the breeding process in China, and introgression of TabHLH27-A1Hap-II allele improves drought tolerance and grain yield, especially under water-limited conditions. Our study highlights TabHLH27-A1s role in balancing root growth and drought tolerance, providing a genetic manipulation locus for enhancing WUE in wheat.

genetics↗

bioRxiv2024

Super Pangenome of Grapevines Empowers Improvement of the Oldest Domesticated Fruit

Grapevine (Vitis) is the oldest domesticated fruit crop with great cultural and economic importance. Here, we assemble and annotate haplotype-resolved genomes of 72 Vitis accessions including 25 wild and 47 cultivated grapevines, and a haplotype-resolved complete genome of V. vinifera. Coalescent phylogenomics of 142 haplotype genomes disentangles the mysterious hybridization history of grapevines, revealing enormous genetic diversity among species. Pangenome analysis together with phenotyping data reveals that European cultivars, more susceptible to the most destructive disease downy mildew (DM), had a smaller repertoire of disease resistance genes of NLR family. Through extensive structural variation (SV) characterization, phenotyping, transcriptome profiling of 113 Vitis accessions, and SV-eQTL analysis, we have identified over 79 SVs and their relevant genes significantly associated with DM resistance, exemplified by a lysine histidine transporter, VvLHT8. This haplotype-resolved complete genome and pangenome of Vitis genus will accelerate grapevine breeding and enrich our understanding of the evolution and biology of grapevines.

plant biology↗

bioRxiv2024

Blockade of Interleukin-6 (IL-6) Signaling in Dedifferentiated Liposarcoma (DDLPS) Decreases Mouse Double Minute 2 (MDM2) Oncogenicity via Alternative Splicing

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

molecular biology↗

bioRxiv2024

LXA4 promotes the browning of white adipose through miR-133a-3p/SIRT1 pathway

Lipoxin A4 (LXA4) promotes the browning of white adipose and energy consumption. The specific mechanism of which involved in white adipose browning is less clear. A high-fat diet (HFD) mouse model was constructed. Different groups of mice were treated with LXA4 accordingly. The body weight of mouse, subcutaneous and visceral fat, and food intake were recorded. The effect of LXA4 was examined by observing changes in pathology, serum insulin and lipid accumulation indices. The effects of LXA4/miR-133a-3p/Sirtuin1 on lipid droplet formation, fat browning-related genes, and the insulin receptor-AKT pathway in cells were examined after induction of adipocyte differentiation in 3T3-L1 precursors. At the cellular level, LXA4 promoted lipid droplet formation, expressions of fat browning genes and activation of the insulin receptor-AKT pathway in differentiated 3T3-L1 cells. MiR-133a-3p agomir partially offset the effects of LXA4. SIRT1 was a downstream target gene of miR-133a-3p, participating in the promotive effects of LXA4 on fat browning. LXA4 promotes white adipose browning and relieves insulin resistance through miR-133a-3p/SIRT1 pathway.

biochemistry↗

bioRxiv2024

Targeted Dab2 Restoration: A Novel Approach for Enhanced Wound Healing in Diabetic Conditions

Diabetes mellitus can cause impaired and delayed wound healing, leading to lower extremity amputations; however, the mechanisms underlying the regulation of vascular endothelial growth factor (VEGF)-dependent angiogenesis remain uncertain and could reveal new therapeutic targets. In our study, the molecular underpinnings of endothelial dysfunction in diabetes were investigated, focusing on the roles of Disabled-2 (Dab2) and Forkhead Box M1 (FoxM1) in VEGF receptor 2 (VEGFR2) signaling and endothelial cell (EC) function. Bulk RNA-sequencing analysis identified significant downregulation of Dab2 in high concentrations glucose treated primary mouse skin ECs, simulating hyperglycemic conditions in diabetes mellitus. In diabetic mice with a genetic EC deficiency of Dab2 angiogenesis was reduced in vivo and in vitro when compared with wild-type mice. Restoration of Dab2 expression by injected mRNA-containing lipid nanoparticles rescued impaired angiogenesis and wound healing in diabetic mice. At the same time, FoxM1 was downregulated in skin ECs subjected to high glucose conditions as determined by RNA-sequencing analysis. FoxM1 was found to bind to the Dab2 promoter, regulating its expression and influencing VEGFR2 signaling. The FoxM1 inhibitor FDI-6 reduced Dab2 expression and phosphorylation of VEGFR2. These findings indicate that restoring Dab2 expression through targeted therapies can enhance angiogenesis and wound repair in diabetes. To explore this therapeutic potential, we tested LyP-1-conjugated lipid nanoparticles (LNPs) containing Dab2 or control mRNAs to target ECs and found the former significantly improved wound healing and angiogenesis in diabetic mice. This study provides evidence of the crucial roles of Dab2 and FoxM1 in diabetic endothelial dysfunction and establishes targeted delivery as a promising treatment for diabetic vascular complications.

cell biology↗

bioRxiv2024

Screening and assessment of functional variants by regulatory features from epigenomic data in livestock species

BackgroundUnderstanding the functional impact of genetic variants is essential for advancing animal genomics and improving livestock breeding. Variants that disrupt transcription factor (TF) motifs provide a means to assess functional potential, but the lack of TF ChIP-seq data for farm animals presents a challenge. ResultsTo address this, we curated nearly 900 epigenomic datasets from 10 farm animal species and annotated eight regulatory regions to assess how variants affect TF motifs. Over 127 million candidate functional variants were classified into five functional confidence categories across the species. Variants with high confidence were enriched in eQTLs and trait-associated SNPs, showing greater potential to affect gene expression and phenotypes. Incorporating these functional variants into genomic prediction models improved the accuracy of Estimated Breeding Values (EBVs). Active variants also revealed trait-related tissues, and single-cell RNA sequencing (scRNA-seq) identified the cell types most associated with production traits. To facilitate research, we developed the Integrated Functional Mutation (IFmut) platform, enabling users to explore variant functions easily. Our study provides a flexible platform and resource for studying genomic variation in farm animals, setting a new standard for research and breeding strategies. ConclusionThe results indicated that evaluating functional potential by annotating and categorizing variants that interfere with transcription factor motifs can help elucidate changes in gene expression and phenotype. By focusing on high-confidence variants enriched in eQTL and trait-associated SNPs, it improves the accuracy of genomic predictions in research and breeding strategies.

genomics↗

bioRxiv2024

Large-scale multi-omics analyses identified root-microbiome associations underlying plant nitrogen nutrition

The microbiome determines the performance and fitness of the host plant. Nevertheless, the causal interaction between host genetic variation, gene regulation and the impact of the microbiome on the host phenotype remain unknown. Here we generated 1,341 paired root transcriptome, rhizosphere microbiome and root ionome samples and performed a multi-omics analyses of the host-microbe association at the root-soil interface using 175 rapeseeds (Brassica napus L.) resequenced ecotypes at two field environments. We observed the highest statistically explained variance for root nitrogen uptake among natural ionomic variation by overall transcriptome-wide gene expression and microbial abundance variation. Moreover, we identified significant genome-wide associations for 203 highly heritable amplicon sequence variants (ASVs) at multiple genetic loci regulated by eQTL hotspots associated with nitrogen metabolism components. These associations involved a central bacterial genus (Sphingopyxis), which plays a dominant role on gene regulatory effect on its variation regulated by eQTL hotspots. In addition, we performed high-throughput bacterial cultivation from rapeseed roots and subjected Sphingopyxis to whole genome sequencing. Finally, targeted metabolite profiling and confocal imaging assays demonstrated a host-microbiome regulatory effect on Sphingopyxis established by lateral root development and plant nitrogen nutrition. In summary, our integrative approach reveals the genetic basis of host-microbiome trait associations in the transcriptional, nutritional and environmental domains and suggests that the microbiome might have causal effects on root development with implications towards the breeding of nutrient-efficient crops.

plant biology↗

bioRxiv2024

XBB.1.5 monovalent booster improves antibody binding and neutralization against emerging SARS-CoV-2 Omicron variants

The rapid emergence of divergent SARS-CoV-2 variants has led to an update of the COVID-19 booster vaccine to a monovalent version containing the XBB.1.5 spike. To determine the neutralization breadth following booster immunization, we collected blood samples from 24 individuals pre- and post-XBB.1.5 mRNA booster vaccination ([~]1 month). The XBB.1.5 booster improved both neutralizing activity against the ancestral SARS-CoV-2 strain (WA1) and the circulating Omicron variants, including EG.5.1, HK.3, HV.1, XBB.1.5 and JN.1. Relative to the pre-boost titers, the XBB.1.5 monovalent booster induced greater total IgG and IgG subclass binding, particular IgG4, to the XBB.1.5 spike as compared to the WA1 spike. We evaluated antigen-specific memory B cells (MBCs) using either spike or receptor binding domain (RBD) probes and found that the monovalent booster largely increases non-RBD cross-reactive MBCs. These data suggest that the XBB.1.5 monovalent booster induces cross-reactive antibodies that neutralize XBB.1.5 and related Omicron variants.

immunology↗

bioRxiv2024

Individualized functional connectivity markers associated with motor and mood symptoms of Parkinson's disease

Parkinsons disease (PD) is a complex neurological disorder characterized by many motor and non-motor symptoms. While most studies focus on the motor symptoms of the disease, it is important to identify markers that underlie different facets of the disease. In this case-control study, we sought to discover reliable, individualized functional connectivity markers associated with both motor and mood symptoms of PD. Using functional MRI, we extensively sampled 166 patients with PD (64 women, 102 men; mean age=61.8 years, SD=7.81) and 51 healthy control participants (32 women, 19 men; mean age=55.68 years, SD=7.62). We found that a model consisting of 44 functional connections predicted both motor (UPDRS-III: Pearson r=0.21, FDR-adjusted p=0.006) and mood symptoms (HAMD: Pearson r=0.23, FDR-adjusted p=0.006; HAMA: Pearson r=0.21, FDR-adjusted p=0.006). Two sets of connections contributed differentially to these predictions. Between-network connections, mainly connecting the sensorimotor and visual large-scale functional networks, substantially contributed to the prediction of motor measures, while within-network connections in the insula and sensorimotor network contributed more so to mood prediction. The middle to posterior insula region played a particularly important role in predicting depression and anxiety scores. We successfully replicated and generalized our findings in two independent PD datasets. Taken together, our findings indicate that sensorimotor and visual network markers are indicative of PD brain pathology, and that distinct subsets of markers are associated with motor and mood symptoms of PD.

neuroscience↗

bioRxiv2024

ViraLM: Empowering Virus Discovery through the Genome Foundation Model

MotivationViruses, with their ubiquitous presence and high diversity, play pivotal roles in ecological systems and have significant implications for public health. Accurately identifying these viruses in various ecosystems is essential for comprehending their variety and assessing their ecological influence. Metagenomic sequencing has become a major strategy to survey the viruses in various ecosystems. However, accurate and comprehensive virus detection in metagenomic data remains difficult. Limited reference sequences prevent alignment-based methods from identifying novel viruses. Machine learningbased tools are more promising in novel virus detection but often miss short viral contigs, which are abundant in typical metagenomic data. The inconsistency in virus search results produced by available tools further highlights the urgent need for a more robust tool for virus identification. ResultsIn this work, we develop a Viral Language Model, named ViraLM, to identify novel viral contigs in metagenomic data. By employing the latest genome foundation model as the backbone and training on a rigorously constructed dataset, the model is able to distinguish viruses from other organisms based on the learned genomic characteristics. We thoroughly tested ViraLM on multiple datasets and the experimental results show that ViraLM outperforms available tools in different scenarios. In particular, ViraLM improves the F1-score on short contigs by 22%. AvailabilityThe source code of ViraLM is available via: https://github.com/ChengPENG-wolf/ViraLM. Contactyannisun@cityu.edu.hk

bioinformatics↗

bioRxiv2024

Transcriptomic and epigenetic responses shed light on soybean resistance to Phytophthora sansomeana

Phytophthora root rot caused by oomycete pathogens in the Phytophthora genus poses a significant threat to soybean productivity. While resistance mechanisms against Phytophthora sojae have been extensively studied in soybean, the molecular basis underlying immune responses to Phytophthora sansomeana remains unclear. We investigated transcriptomic and epigenetic responses of two resistant (Colfax and NE2701) and two susceptible (Williams 82 and Senaki) soybean lines at four time points (2, 4, 8, and 16 hours post inoculation, hpi) after P. sansomeana inoculation. Comparative transcriptomic analyses revealed a greater number of differentially expressed genes (DEGs) upon pathogen inoculation in resistant lines, particularly at 8 and 16 hpi, predominantly associated with ethylene and reactive oxygen species-mediated defense pathways. Moreover, DE transposons were predominantly up-regulated after inoculation and enriched near genes in Colfax. A long non-coding RNA (lncRNA) within the mapped region of the resistance gene exhibited exclusive up-regulation in the resistant lines after inoculation, potentially regulating two flanking LURP-one-related genes. Furthermore, DNA methylation analysis revealed increased CHH methylation levels in lncRNAs after inoculation, with delayed responses in Colfax compared to Williams 82. Overall, our results provide comprehensive insights into soybean responses to P. sansomeana, highlighting potential roles of lncRNAs and epigenetic regulation in plant defense.

plant biology↗

bioRxiv2024

Individual connectivity-based parcellations reflect functional properties of human auditory cortex

Neuroimaging studies of the functional organization of human auditory cortex have focused on group-level analyses to identify tendencies that represent the typical brain. Here, we mapped auditory areas of the human superior temporal cortex (STC) in 30 participants by combining functional network analysis and 1-mm isotropic resolution 7T functional magnetic resonance imaging (fMRI). Two resting-state fMRI sessions, and one or two auditory and audiovisual speech localizer sessions, were collected on 3-4 separate days. We generated a set of functional network-based parcellations from these data. Solutions with 4, 6, and 11 networks were selected for closer examination based on local maxima of Dice and Silhouette values. The resulting parcellation of auditory cortices showed high intraindividual reproducibility both between resting state sessions (Dice coefficient: 69-78%) and between resting state and task sessions (Dice coefficient: 62-73%). This demonstrates that auditory areas in STC can be reliably segmented into functional subareas. The interindividual variability was significantly larger than intraindividual variability (Dice coefficient: 57%-68%, p<0.001), indicating that the parcellations also captured meaningful interindividual variability. The individual-specific parcellations yielded the highest alignment with task response topographies, suggesting that individual variability in parcellations reflects individual variability in auditory function. Connectional homogeneity within networks was also highest for the individual-specific parcellations. Furthermore, the similarity in the functional parcellations was not explainable by the similarity of macroanatomical properties of auditory cortex. Our findings suggest that individual-level parcellations capture meaningful idiosyncrasies in auditory cortex organization.

neuroscience↗

bioRxiv2024

Neurophysiological Correlates of Phase-Specific Enhancement of Motor Memory Consolidation via Slow-Wave Closed-Loop Targeted Memory Reactivation

Memory consolidation can be enhanced during sleep using targeted memory reactivation (TMR) and closed-loop (CL) acoustic stimulation on the up-phase of slow oscillations (SOs). Here, we tested whether applying TMR at specific phases of the SOs (up vs. down vs. no reactivation) could influence the behavioral and neural correlates of motor memory consolidation in healthy young adults. Results showed that up- (as compared to down-) state cueing resulted in greater performance improvement. Sleep electrophysiological data indicated that up-stimulated SOs exhibited higher amplitude and greater peak-nested sigma power. Task-related functional magnetic resonance images revealed that up-state cueing strengthened activity in - and segregation of - striato-motor and hippocampal networks; and that these modulations were related to the beneficial effect of TMR on sleep features and performance. Overall, these findings highlight the potential of CL-TMR to induce phase-specific modulations of motor performance, sleep oscillations and brain responses during motor memory consolidation.

neuroscience↗