Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Knockout of integrin αvß6 protects against renal inflammation in chronic kidney disease by reduction of pro-inflammatory macrophages.

Integrin αvß6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvß6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvß6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvß6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvß6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvß6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvß6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvß6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvß6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvß6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvß6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvß6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvß6 in renal inflammation, providing a solid rationale for the use of αvß6 inhibition to treat kidney inflammation and fibrosis.

Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression.

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.

Identification and characterization of a PL35 GAGs lyase with 4-O-sulfated N-acetylgalactosamine (A-type)-rich structures producing property.

Glycosaminoglycan (GAG) lyases are important tools for investigating the structure of GAGs and preparing low-molecular-weight GAGs. The PL35 family, a recently established polysaccharide lyase family, should be further investigated. In this study, we discovered a new GAG lyase, CHa1, which belongs to the PL35 family. When expressed heterologously in Escherichia coli (BL21), CHa1 exhibited high expression levels and solubility. The optimal activity was observed in Tris-HCl buffer (pH 7.0) or sodium phosphate buffer (pH 8.0) at 30 °C. The specific activities towards HA, CSA, CSC, CSD, CSE, and HS were 3.81, 13.03, 36.47, 18.46, 6.46, and 0.50 U/mg protein, respectively. CHa1 digests substrate chains randomly that acting as an endolytic lyase and shows a significant preference for GlcA-containing structures, prefers larger oligosaccharides (≥UDP8) and can generate a series of oligosaccharides composed mainly of the A unit when digesting CSA. These oligosaccharides include ΔC-A, ΔC-A-A, ΔC-A-A-A, ΔC-A-A-A-A, and ΔC-A-A-A-A-A. The residues Tyr257 and His421 play crucial roles in the catalytic process, and Ser211, Asn212, Asn213, Trp214, Gln216, Lys360, Arg460 and Gln462 may participate in the binding process of CHa1. This study on CHa1 contributes to our understanding of the PL35 family and provides valuable tools for investigating the structure of GAGs.

A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3ß/ß-catenin Signaling.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3ß (p-GSK-3ß), thereby promoting ß-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic ß-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

Group 3 Innate Lymphoid Cells Exacerbate Lupus Nephritis by Promoting B Cell Activation in Kidney Ectopic Lymphoid Structures.

Group 3 innate lymphoid cells (ILC3s) represent a new population in immune regulation, yet their role in lupus nephritis (LN) remains elusive. In the present work, systemic increases in ILC3s, particularly in the kidney, are observed to correlate strongly with disease severity in both human and murine LN. Using MRL/lpr lupus mice and a nephrotoxic serum-induced LN model, this study demonstrates that ILC3s accumulated in the kidney migrate predominantly from the intestine. Furthermore, intestinal ILC3s accelerate LN progression, manifested by exacerbated autoimmunity and kidney injuries. In LN kidneys, ILC3s are located adjacent to B cells within ectopic lymphoid structures (ELS), directly activating B cell differentiation into plasma cells and antibody production in a Delta-like1 (DLL1)/Notch-dependent manner. Blocking DLL1 attenuates ILC3s' effects and protects against LN. Altogether, these findings reveal a novel pathogenic role of ILC3s in B cell activation, renal ELS formation and autoimmune injuries during LN, shedding light on the therapeutic value of targeting ILC3s for LN.

Nitrogen and Chlorine Co-doped Carbon Dots as a Highly Selective and Sensitive Fluorescent Probe for Sensing of PH, Tetracycline Detection and Cell Imaging.

Carbon dots have been widely focused on the field of sensing and detection due to their excellent optical property. Herein, novel orange fluorescent nitrogen and chlorine co-doped carbon dots (N,Cl-CDs) are obtained by one-pot hydrothermal method using o-phenylenediamine and neutral red. Based on the inner filter effect, the prepared N,Cl-CDs can be innovatively developed as an effective "signal-off" multifunctional sensing platform for sensitive determination of tetracycline. The proposed sensor was utilized to realize the determination of tetracycline in Rirver water samples/milk samples (λex = 390 nm, λem = 606 nm) with satisfactory recoveries and relative standard deviations. The linear range of are 0.05 to 45 µM and 45 to135 µM, and detection limit is 3.9 nM (3σ/m). Meanwhile, the luminescent intensity of N,Cl-CDs was reduced gradually when pH changed continuously from 12 to 2, showing a pH-responsive fluorescence property with two linear ranges of pH 3-7 and pH 7-10. In addition, due to the characteristics of low toxicity and excellent biocompatibility, the N, Cl-CDs were also used in the imaging of oocystis cells, which is hopeful to realize the detection of tetracycline in living cells.

Robust, Flame-Retardant, and Anti-Corrosive Waterborne Polyurethane Enabled by a PN Synergistic Flame-Retardant Containing Benzimidazole and Phosphinate Groups.

Waterborne polyurethanes (WPUs) have attracted great interest owing to their environmentally friendly properties, and are wildly applied in production and daily life. However, waterborne polyurethanes are flammable. Up to now, the challenge remains to prepare WPUs with excellent flame resistance, high emulsion stability, and outstanding mechanical properties. Herein, a novel flame-retardant additive, 2-hydroxyethan-1-aminium (2-(1H-benzo[d]imidazol-2-yl)ethyl)(phenyl)phosphinate (BIEP-ETA) has been synthesized and applied to improve the flame resistance of WPUs, which has both phosphorus nitrogen synergistic effect and the ability to form hydrogen bonds with WPUs. The WPU blends (WPU/FRs) exhibited a positive fire-retardant effect in both the vapor and condensed phases, with significantly improved self-extinguishing performance and reduced heat release value. Interestingly, thanks to the good compatibility between BIEP-ETA and WPUs, WPU/FRs not only have higher emulsion stability, but also have better mechanical properties with synchronously improved tensile strength and toughness. Moreover, WPU/FRs also exhibit excellent potential as a corrosion-resistant coating.

The synthesis of N-doped carbon dots for visual differentiating and detection of tetracyclines.

N-doped carbon dots (N-CDs) were synthesized from L-glutamine and triethanolamine using a one-step hydrothermal method. The N-CDs emitting blue fluorescence had selective responses to tetracyclines (TCs) and could be used as a fluorescent probe to realize the quantitative detection and qualitative analysis of TCs. A method for the determination of TCs using the N-CDs in actual samples was successfully established. The recovery rate was maintained at 97.50-105.60%, and the relative standard deviation (RSD) was less than 3%. In addition, TCs can be visually distinguished using filter paper by the different fluorescence colours (light green, dark blue, and yellow-green) of the N-CDs/TCs system under ultraviolet light. This study provides a relatively simple method to detect and identify TCs.

Hydrothermal Synthesis of Polyethyleneimine Modified Carbon Quantum Dots for Sensitively Detection of Cobalt Ions.

In this work, fluorescent carbon quantum dots (CQDs) was prepared using natural on ions as carbon source with hydrothermal method and it was modified with polyethyleneimine (PEI). The properties of PEI modified CQDs (PEI-CQDs) were characterized by fluorescence, infrared spectroscopy and ultraviolet method, the morphology characteristics of PEI-CQDs was observed by transmission electron microscope. The results shown that the fluorescence excitation and emission wavelength were at 340 nm/462 nm, respectively. The fluorescence quantum yield was 8.68%, the average diameter of the PEI-CQDs was 2.82 nm. The infrared showed that the PEI-CQDs contained hydroxyl and amino groups on its surface. The Co2+ has selective quenching effects on fluorescence of PEICQDs, PEI-CQDs can be used for detection and analysis of Co2+ in samples. The limit of detection and linear range of Co2+ using the PEI-CQDs as fluorescence probe are 0.048 µM and 0.05-11 µM, respectively. The recovery was in the range of 97.00-100.64%. Moreover, the PEI-CQDs are also successfully utilized for monitoring the Co2+ content of tap water.

An Occlusion Compensation Learning Framework for Improving the Rendering Quality of Light Field.

Occlusions are common phenomena in light field rendering (LFR) technology applications. The 3-D spatial structures of some features may be missing or incorrect when capturing some samples due to occlusion discontinuities. Most prior works on LFR, however, have neglected occlusions from other objects in 3-D scenes that do not participate in the capturing and rendering of the light field. To improve rendering quality, this report proposes an occlusion probability learning framework (OPLF) based on a deep Boltzmann machine (DBM) to compensate for the occluded information. In the OPLF, an occlusion probability density model is applied to calculate the visibility scores, which are modeled as hidden variables. Additionally, the probability of occlusion is related to the visibility, the camera configuration (i.e., position and direction), and the relationship between the occlusion object and occluded object. Furthermore, a deep probability model based on the OPLF is used for learning the occlusion relationship between the camera and object in multiple layers. The proposed OPLF can optimize the LFR quality. Finally, to verify the claimed performance, we also compare the OPLF with the most advanced occlusion theory and light field reconstruction algorithms. The experimental results show that the proposed OPLF outperforms other known occlusion quantization schemes.

A signal-processing framework for occlusion of 3D scene to improve the rendering quality of views.

Occlusions will reduce the performance of systems in many computer vision applications with discontinuous surfaces of 3D scenes. We explore a signal-processing framework of occlusions based on the light ray visibility to improve the rendering quality of views. An occlusion field (OCF) theory is derived by calculating the relationship between the occluded light rays and the nonoccluded light rays to quantify the occlusion degree (OCD). The OCF framework can describe the various in-scene information captured by the changes in the camera configuration (i.e., position and direction) through a quantitative description of the occlusion information. From a spectral analysis of the OCF, we mathematically derive analytical functions to determine the changing relationship between the scene and the camera configuration. A reconstruction filter can be designed to achieve interference cancellation and compensate for the missing information caused by the occlusions. Our measurements of different occlusions using this OCF framework included both synthetic and actual scenes. The experimental results show that the proposed OCF framework can improves the rendering quality of views and outperforms other known occlusion quantization schemes in a complex scene.

Frequency analysis of light field sampling for texture information.

Light field sampling (LFS) theory can properly reduce minimum sampling rate while ensuring that novel views are not distorted for image-based rendering (IBR). The minimum sampling rate is determined by spectral support of light field. The spectral support of light field has studied the influence of the following factors: the minimum depth and the maximum depth, non-Lambertian reflections, whether the scene surfaces are flat, maximum frequency of painted signals. In this paper, we further perfect the light field spectrum analysis from the quantitative description of scene texture information based on the existing spectrum analysis theory. The quantification of texture information can be interactively refined via detected regional entropy. Thus, we can derive a spectral analytical function of light field with respect to texture information. The new function allows the spectral support of light field to be analyzed and estimated for different texture information associated with scene objects. In this way, we limit the spectral analysis problems of light field to those of a simpler signal. We show that this spectral analysis approach can be easily extended to arbitrary scene complexity levels, as we simplify the LFS of complex scenes to a plane. Additionally, the spectral support of light field broadens as the plane texture information becomes more complex. We present experimental results to demonstrate the performance of LFS with texture information, verify our theoretical analysis, and extend our conclusions on the optimal minimum sampling rate.