Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Single-cell sequencing of the retina shows that LDHA regulates pathogenesis of autoimmune uveitis.

Autoimmune uveitis (AU) is a severe disorder causing poor vision and blindness. However, the cellular dynamics and pathogenic mechanisms underlying retinal injury in uveitis remain unclear. In this study, single-cell RNA sequencing of the retina and cervical draining lymph nodes in experimental autoimmune uveitis mice was conducted to identify the cellular spatiotemporal dynamics and upregulation of the glycolysis-related gene LDHA. Suppression of LDHA can rescue the imbalance of T effector (Teff) cells/T regulator (Treg) cells under inflammation via downregulation of the glycolysis-PI3K signaling circuit and inhibition of the migration of CXCR4+ Teff cells towards retinal tissue. Furthermore, LDHA and CXCR4 are upregulated in the peripheral blood mononuclear cells of Vogt-Koyanagi-Harada patients. The LDHA inhibitor suppresses CD4+ T cell proliferation in humans. Therefore, our data indicate that the autoimmune environment of uveitis regulates Teff cell accumulation in the retina via glycolysis-associated LDHA. Modulation of this target may provide a novel therapeutic strategy for treating AU.

Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis.

Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell-cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.

Scalable Precise Nanofilm Coating and Gradient Al Doping Enable Stable Battery Cycling of LiCoO2 at 4.7†V.

The quest for smart electronics with higher energy densities has intensified the development of high-voltage LiCoO2 (LCO). Despite their potential, LCO materials operating at 4.7 V faces critical challenges, including interface degradation and structural collapse. Herein, we propose a collective surface architecture through precise nanofilm coating and doping that combines an ultra-thin LiAlO2 coating layer and gradient doping of Al. This architecture not only mitigates side reactions, but also improves the Li+ migration kinetics on the LCO surface. Meanwhile, gradient doping of Al inhibited the severe lattice distortion caused by the irreversible phase transition of O3-H1-3-O1, thereby enhanced the electrochemical stability of LCO during 4.7 V cycling. DFT calculations further revealed that our approach significantly boosts the electronic conductivity. As a result, the modified LCO exhibited an outstanding reversible capacity of 230 mAh g-1 at 4.7 V, which is approximately 28 % higher than the conventional capacity at 4.5 V. To demonstrate their practical application, our cathode structure shows improved stability in full pouch cell configuration under high operating voltage. LCO exhibited an excellent cycling stability, retaining 82.33 % after 1000 cycles at 4.5 V. This multifunctional surface modification strategy offers a viable pathway for the practical application of LCO materials, setting a new standard for the development of high-energy-density and long-lasting electrode materials.

Intravitreal dexamethasone implants facilitate the management of refractory Behçet's uveitis with vasculitis.

To investigate the efficacy and safety of dexamethasone (DEX) implant, Ozurdex ®, as an adjunctive treatment for refractory Behçet's uveitis (BU), a total of 61 patients (80 eyes) were included in this cross-sectional study and divided into the non-DEX and DEX groups. After >12 months of treatment, the improvement in the fluorescein angiography score and vitritis score was significantly higher in the DEX group than in the non-DEX group. Although the posterior capsule opacification score was exacerbated, the rate of low-dose systemic glucocorticoid was higher and the relapse times were fewer in the DEX group. Therefore, Ozurdex® is an effective and safe option for patients with BU that are refractory to systemic immunosuppressant treatments by controlling vasculitis, stabilizing vitreous inflammation, preventing recurrence, and reducing daily glucocorticoid doses.

Single-Cell Analysis Reveals the Heterogeneity of Monocyte-Derived and Peripheral Type-2 Conventional Dendritic Cells.

Dendritic cells (DCs) are critical for pathogen recognition and Ag processing/presentation. Human monocyte-derived DCs (moDCs) have been extensively used in experimental studies and DC-based immunotherapy approaches. However, the extent of human moDC and peripheral DCs heterogeneity and their interrelationship remain elusive. In this study, we performed single-cell RNA sequencing of human moDCs and blood DCs. We identified seven subtypes within moDCs: five corresponded to type 2 conventional DCs (cDC2s), and the other two were CLEC10A+CD127+ cells with no resemblance to any peripheral DC subpopulations characterized to date. Moreover, we defined five similar subtypes in human cDC2s, revealed the potential differentiation trajectory among them, and unveiled the transcriptomic differences between moDCs and cDC2s. We further studied the transcriptomic changes of each moDC subtype during maturation, demonstrating SLAMF7 and IL15RA as maturation markers and CLEC10A and SIGLEC10 as markers for immature DCs. These findings will enable more accurate functional/developmental analyses of human cDC2s and moDCs.

Confined Thermolysis for Oriented N-Doped Carbon Supported Pd toward Stable Catalytic and Energy Storage Applications.

Carbon-based nanomaterials have been widely utilized in catalysis and energy-related fields due to their fascinating properties. However, the controllable synthesis of porous carbon with refined morphology is still a formidable challenge due to inevitable aggregation/fusion of resulted carbon particles during the high-temperature synthetic process. Herein, a hierarchically oriented carbon-structured (fiber-like) composite is fabricated by simultaneously taking advantage of a confined pyrolysis strategy and disparate bond environments within metal-organic frameworks (MOFs). In the resultant composite, the oriented carbon provides a fast mass (molecule/ion/electron) transfer efficiency; the doping-N atoms can anchor or act as active sites; the mesoporous SiO2 (mSiO2 ) shell not only effectively prevents the derived carbon or active metal nanoparticles (NPs) from aggregation or leaching, but also acts as a "polysulfide reservoir" in the Li-S batteries to suppress the "shuttle" effect. Benefiting from these advantages, the synthesized composite Pd@NDHPC@mSiO2 (NDHPC means N-doped hierarchically porous carbon) exhibits extremely high catalytic activity and stability toward the one-pot Knoevenagel condensation-hydrogenation reaction. Furthermore, the oriented NDHPC@mSiO2 manifests a boosted capacity and cycling stability in Li-S batteries compared to the counterpart that directly pyrolyzes without silica protection. This report provides an effective strategy of fabricating hierarchically oriented carbon composites for catalysis and energy storage applications.

Solvent-Free Synthesis of Uniform MOF Shell-Derived Carbon Confined SnO2 /Co Nanocubes for Highly Reversible Lithium Storage.

Tin dioxide (SnO2 ) has attracted much attention in lithium-ion batteries (LIBs) due to its abundant source, low cost, and high theoretical capacity. However, the large volume variation, irreversible conversion reaction limit its further practical application in next-generation LIBs. Here, a novel solvent-free approach to construct uniform metal-organic framework (MOF) shell-derived carbon confined SnO2 /Co (SnO2 /Co@C) nanocubes via a two-step heat treatment is developed. In particular, MOF-coated CoSnO3 hollow nanocubes are for the first time synthesized as the intermediate product by an extremely simple thermal solid-phase reaction, which is further developed as a general strategy to successfully obtain other uniform MOF-coated metal oxides. The as-synthesized SnO2 /Co@C nanocubes, when tested as LIB anodes, exhibit a highly reversible discharge capacity of 800 mAh g-1 after 100 cycles at 200 mA g-1 and excellent cycling stability with a retained capacity of 400 mAh g-1 after 1800 cycles at 5 A g-1 . The experimental analyses demonstrate that these excellent performances are mainly ascribed to the delicate structure and a synergistic effect between Co and SnO2 . This facile synthetic approach will greatly contribute to the development of functional metal oxide-based and MOF-assisted nanostructures in many frontier applications.

Regulation of Interface Ion Transport by Electron Ionic Conductor Construction toward High-Voltage and High-Rate LiNi0.5Co0.2Mn0.3O2 Cathodes in Lithium Ion Battery.

Simultaneously achieving high-energy-density and high-power-density is a crucial yet challenging objective in the pursuit of commercialized power batteries. In this study, atomic layer deposition (ALD) is employed combined with a coordinated thermal treatment strategy to construct a densely packed, electron-ion dual conductor (EIC) protective coating on the surface of commercial LiNi0.5Co0.2Mn0.3O2 (NCM523) cathode material, further enhanced by gradient Al doping (Al@EIC-NCM523). The ultra-thin EIC effectively suppresses side reactions, thereby enhancing the stability of the cathode-electrolyte interphase (CEI) at high-voltages. The EIC's dual conduction capability provides a potent driving force for Li+ transport at the interface, promoting the formation of rapid ion deintercalation pathways within the Al@EIC-NCM523 bulk phase. Moreover, the strategic gradient doping of Al serves to anchor the atomic spacing of Ni and O within the structure of Al@EIC-NCM523, curbing irreversible phase transitions at high-voltages and preserving the integrity of its layered structure. Remarkably, Al@EIC-NCM523 displays an unprecedented rate capability (114.7 mAh g-1 at 20 C), and a sustained cycling performance (capacity retention of 74.72% after 800 cycles at 10 C) at 4.6 V. These findings demonstrate that the proposed EIC and doping strategy holds a significant promise for developing high-energy-density and high-power-density lithium-ion batteries (LIBs).