Biology subjects

Ru, Y.

Publications and source records attributed to Ru, Y..

8 recordsLinked to original sources

bioRxiv2026

Anti-IL1RAP Antibodies for Pan-Inhibition of IL-1 Family Cytokine Signaling in Inflammatory Diseases and Oncology

The interleukin-1 (IL-1) superfamily of cytokines--comprising the IL-1, IL-33, and IL-36 subfamilies--orchestrates a vast array of innate and adaptive immune responses. While physiological activation of these pathways is essential for host defense and tissue repair, their chronic dysregulation is pathognomonic of a broad spectrum of autoimmune diseases and malignancies. Current therapeutic modalities largely rely on the neutralization of single cytokines, an approach often limited by the functional redundancy and compensatory signaling loops inherent to the IL-1 superfamily. The Interleukin-1 Receptor Accessory Protein (IL1RAP) serves as an obligatory co-receptor for IL-1, IL-33, and IL-36 subfamilies, functioning as a molecular bottleneck for pro-inflammatory signaling. Herein, we report the development and comprehensive characterization of two humanized monoclonal antibodies, DXP-006 and DXP-106, which target a unique epitope on domain 2 of IL1RAP. Cryo-electron microscopy studies at 3.55 [A] resolution reveal that these antibodies lock the critical c2d2 loop of IL1RAP, sterically occluding its recruitment to IL-1R1, ST2 and IL-36R binary complexes and potently blockade IL-1, IL33, and IL-36 signaling. DXP-006, engineered with a half-life-extended and effector-silenced Fc, exerts profound efficacy in murine models of psoriasis, superior to the clinical benchmark bimekizumab. Conversely, DXP-106, engineered with a defucosylated Fc to enhance antibody-dependent cellular cytotoxicity, exhibits potent antitumor activity in non-small cell lung cancer xenografts. These findings position DXP-006 and DXP-106 as ideal therapeutics for IL-1 family-driven autoimmunity and IL1RAP-positive cancers. One Sentence SummaryAnti-IL1RAP antibodies block multiple IL-1 family cytokines simultaneously, showing superior efficacy in inflammation and cancer models.

immunology↗

bioRxiv2024

Oligomerization of PRMT1 Regulated RNA-Binding Protein Cascade Promotes Pancreatic Ductal Adenocarcinoma

PRMT1 is the predominant type I protein arginine methyltransferase responsible for generating monomethylarginine and asymmetric dimethylarginine (MMA and ADMA) in various protein substrates. It regulates numerous biological processes, including RNA metabolism, mRNA splicing, DNA damage repair, and chromatin dynamics. The crystal structure of rat PRMT1 has been previously reported as a homodimer; however, higher-order oligomeric species of human PRMT1 have been observed in vivo, and their structural basis remains elusive. In this study, we present the cryo-EM structure of human PRMT1 in its oligomeric form, revealing novel interfaces crucial for PRMT1 self-assembly and normal function. PRMT1 shows a strong preference for intrinsically disordered RGG/RG motifs, which are commonly found in RNA-binding proteins (RBPs), highlighting its critical role in regulating RNA metabolism. In vitro studies indicate that disrupting PRMT1 oligomerization impairs its binding affinity for RGG motif substrates, thereby reducing arginine methylation levels on these substrates. This finding emphasizes the essential role of the oligomeric state of PRMT1 in its function with RGG motif-containing RBPs. In vivo, the loss of PRMT1 oligomerization leads to decreased global ADMA levels in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits PDAC tumor growth. Collectively, we propose that PRMT1 oligomerization, rather than mere dimerization, is sufficient for PRMT1-driven PDAC tumor growth, offering novel insights into the potential therapeutic targeting of PRMT1 oligomeric forms in PDAC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/627716v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1ed6232org.highwire.dtl.DTLVardef@1c9e688org.highwire.dtl.DTLVardef@3e2c43org.highwire.dtl.DTLVardef@1cbf33e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Transcriptional and Metabolic Mechanism of Carbon Dots Enhancing Rice Growth and Resistance by Promoting Root

Increasing climate change and pollutant discharge induce constant challenges to crops, while crops are vulnerable to environmental and pollutant stresses. In this study, a carbon dots (CDs) was developed that significantly increased rice seedling growth, and successfully reduced the inhibition of heavy metal cadmium (Cd), salt (NaCl), and herbicide 2,4-D stresses on rice seedling growth by pre-spraying. The root of rice seedlings responded specifically to CDs exposure, with significant improvements in root biomass, architecture, cell wall thickness, mechanical strength, and metabolic vitality. Metabolomics and transcriptomics were combined to reveal the regulatory mechanism of CDs in rice seedlings. Transcriptome analysis indicated that CDs upregulated genes related to cytokinin, jasmonic acid, salicylic acid, MAPK signaling pathway, calcium homeostasis, and peroxidase, and downregulated those related to auxin, abscisic acid, and ethylene. Metabolomic analysis suggested CDs improved the metabolites related to antioxidant (betalain, ascorbate, aldarate, and glutathione), formation of cell wall, plasma membrane, xylem, and root cortex (phenylpropanoids biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, and sphingolipid), and energy metabolism (nicotinate, nicotinamide, glyoxylate, dicarboxylate, and nitrate cycle) in rice seedlings. Therefore, pre-spraying CDs reprogrammed stress signaling pathways and enhanced adaptive responses in rice seedlings, ultimately increasing growth potential and stress resistance. This study presents a promising nano-bio-stimulant of CDs for crop resilience in the context of increasing climate change and contributes to sustainable agriculture.

physiology↗

bioRxiv2024

Transcriptomic landscape of human induced pluripotent stem cell-derived osteogenic differentiation identifies a regulatory role of KLF16

Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses, KLF16 emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression of Klf16 in vitro inhibited osteogenic differentiation and mineralization, while Klf16+/- mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such as KLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.

molecular biology↗

bioRxiv2023

Adenosine Kinase regulates Sleep Timing and the Homeostatic Sleep Response through Distinct Molecular Pathways

Sleep behaviour is broadly regulated by two drives, the circadian (Process C), which is orchestrated by the suprachiasmatic nuclei (SCN), and controls sleep timing, and the homeostatic (Process S), which controls sleep amount and the response to sleep deprivation (Borbely et al., 2016). However, the molecular pathways that mediate their independent effects, and their interactions remain unclear. Adenosine is an important integrator of both processes (Bjorness & Greene, 2009; Jagannath et al., 2021, 2022), such that adenosine levels track and modulate wakefulness, whilst adenosine signalling inhibits the circadian response to light. Therefore, we studied the sleep/circadian behaviour, and cortical and SCN transcriptomic profiles of a mouse model overexpressing Adenosine Kinase (Adk-Tg) (Fedele et al., 2005), (Palchykova et al., 2010). We found that overall, the Adk-Tg mouse slept less and showed lower amplitude circadian rhythms with an altered sleep/wake distribution across the 24h day, which correlated with changes in transcription of synaptic signalling genes that would shift the excitatory/inhibitory balance. In addition, the Adk-Tg mouse showed a reduced level of ERK phosphorylation, and attenuation of DNA repair related pathways. After sleep deprivation, however, the Adk-Tg mouse significantly increased relative to wildtype, immediate early gene expression levels including of Arc, but paradoxically reduced ERK phosphorylation. Thus, baseline sleep levels and timing are regulated by ERK signalling, whereas the response to sleep loss is mediated by the alteration of the transcriptomic landscape independently of ERK.

molecular biology↗

bioRxiv2023

Single-cell transcriptomic analysis of pea shoot development and cell-type-specific responses to boron deficiency

Understanding how nutrient stress impacts plant growth is fundamentally important to the development of approaches to improve crop production under nutrient limitation. Here we applied single-cell RNA sequencing to shoot apices of Pisum sativum grown under boron (B) deficiency. We identified up to fifteen cell clusters based on the clustering of gene expression profiles and verified cell identity with cell-type-specific marker gene expression. Different cell types responded differently to B deficiency. Specifically, the expression of photosynthetic genes in mesophyll cells (MCs) was down-regulated by B deficiency, consistent with impaired photosynthetic rate. Furthermore, the down-regulation of stomatal development genes in guard cells (GCs), including homologs of MUTE and TOO MANY MOUTHS, correlated with a decrease in stomatal density under B deficiency. We also constructed the developmental trajectory of the shoot apical meristem (SAM) cells and a transcription factor (TF) interaction network. The developmental progression of SAM to MC was characterized by up-regulation of genes encoding histones and chromatin assembly and remodeling proteins including homologs of FASCIATA1 (FAS1) and SWITCH DEFECTIVE/SUCROSE NON-FERMENTABLE (SWI/SNF) complex. However, B deficiency suppressed their expression, which helps to explain impaired SAM development under B deficiency. These results represent a major advance over bulk-tissue RNA-seq analysis in which cell-type-specific responses are lost and hence important physiological responses to B deficiency are missed. The reported approach and resources have potential applications well beyond P. sativum species and could be applied to various legumes to improve their adaptability to multiple nutrient or abiotic stresses.

plant biology↗

bioRxiv2023

ZBP1-mediated macrophage necroptosis inhibits ASFV replication

African swine fever (ASF) is an infectious disease characterized by hemorrhagic fever, highly pathogenic, and severe mortality in domestic pigs caused by the African swine fever virus (ASFV). ASFV is a large DNA virus and primarily infects porcine monocyte macrophages. The interaction between ASFV and host macrophages is the major reason for gross pathological lesions caused by ASFV. Necroptosis is an inflammatory programmed cell death and plays an important immune role during virus infection. However, whether and how ASFV induces macrophage necroptosis and what effect of necroptosis signaling on host immunity and ASFV infection remains unknown. This study uncovered that ASFV activates the necroptosis signaling in the spleen, lung, liver, and kidney from ASFV-infected pigs. And macrophage necroptosis also was induced by ASFV infection in vitro. Further evidence showed that the macrophage necroptosis is independent of TNF--RIPK1 or TLR-TRIF pathway but depends on Z-DNA binding protein 1 (ZBP1). ASFV infection upregulates the expression of ZBP1 and RIPK3 to consist of the ZBP1-RIPK3-MLKL necrosome and further activates macrophage necroptosis. Subsequently, multiple Z-DNA sequences were predicted to be present in the ASFV genome. And the Z-DNA signals were further confirmed to be present and colocalized with ZBP1 in the cytoplasm and nucleus of ASFV-infected cells. Moreover, ZBP1-mediated macrophage necroptosis caused the extracellular release of proinflammatory cytokines TNF- and IL-1{beta} induced by ASFV infection. Finally, we demonstrated that ZBP1-mediated necroptosis signaling significantly inhibits ASFV replication in host macrophages. Our findings uncovered a novel mechanism by which ASFV induces macrophage necroptosis by facilitating Z-DNA accumulation and ZBP1 necrosome assembly, providing significant insights into the pathogenesis of ASFV infection. ImportanceASFV infection causes an acute, febrile, hemorrhagic, and severely lethal disease in swine, which seriously threatens the global porcine industry. Understanding the interaction mechanism between ASFV and host macrophages during infection is essential for elucidating the pathogenesis of ASFV. To our knowledge, this study revealed the interaction mechanism between ASFV infection and host macrophage necroptosis. The results showed that ASFV infection induces macrophage necroptosis through ZBP1 activation instead of the TNF--RIPK1 or TLR-TRIF pathway. ASFV infection promotes Z-DNA accumulation, which causes ZBP1-RIPK3-MLKL necrosome assembly and macrophage necroptosis. The ZBP1-mediated necroptosis signaling facilitates the extracellular release of proinflammatory cytokines, inhibiting ASFV replication in host macrophages. This study found a new interaction mechanism between ASFV and host macrophages, which may help understand the pathogenesis caused by ASFV infection.

microbiology↗

bioRxiv2020

Identifying therapeutic drug targets for rare and common forms of short stature

While GWAS of common diseases has delivered thousands of novel genetic findings, prioritizing genes for translation to therapeutics has been challenging. Here, we propose an approach to resolve that issue by identifying genes that have both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). Bidirectionality is a desirable feature of the best targets because it implies both a causal role on the phenotype in one direction and that modulating the target activity might be safe and therapeutically beneficial in the other. We used height, a highly heritable trait and a model of complex diseases, to test our approach. Using 34,231 individuals with exome sequence data and height, we identified five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants significantly increased risk for idiopathic short stature (ISS) (OR=2.75, p= 3.99x10-8). These genes are key members of the only two pathways successfully targeted for short stature: Growth Hormone/Insulin-like growth factor 1 axis and C-type Natriuretic peptide (CNP) for Achondroplasia, a monogenic form of dwarfism. We assayed a subset of NPR2 mutations and identified those with elevated (GoF) and diminished (LoF) activity and found that a polygenic score for height modulates the penetrance of pathogenic variants. We also demonstrated that adding exogenous CNP (encoded by NPPC) rescues the NPR2 haploinsufficiency molecular phenotype in a CRISPR-engineered cell line, thus validating its potential therapeutic treatment for inherited forms of short stature. Finally, we found that these BEST targets increase the probability of success in clinical trials above and beyond targets with other genetic evidence. Our results show the value of looking for bidirectional effects to identify and validate drug targets.

genetics↗