FoxO6-Mediated TXNIP Induces Lipid Accumulation in the Liver through NLRP3 Inflammasome Activation.

BACKGRUOUND: Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown. METHODS: This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6-null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism. RESULTS: We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1ß through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1ß and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells. CONCLUSION: The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver.

The Potential of Korean Bioactive Substances and Functional Foods for Immune Enhancement.

In this review, we explore the immunomodulatory properties of Korean foods, focusing on ginseng and fermented foods. One notable example is Korean red ginseng, known for its immune system-regulating effects attributed to the active ingredient, ginsenoside. Ginsenoside stimulates immune cells, enhancing immune function and suppressing inflammatory responses. With a long history, Korean red ginseng has demonstrated therapeutic effects against various diseases. Additionally, Korean fermented foods like kimchi, doenjang, chongkukjang, gochujang, vinegar, and jangajji provide diverse nutrients and bioactive substances, contributing to immune system enhancement. Moreover, traditional Korean natural herbs such as Cirsium setidens Nakai, Gomchwi, Beak-Jak-Yak, etc. possess immune-boosting properties and are used in various Korean foods. By incorporating these foods into one's diet, one can strengthen their immune system, positively impacting their overall health and well-being.

Molecular Foundations of Inflammatory Diseases: Insights into Inflammation and Inflammasomes.

Inflammatory diseases are a global health problem affecting millions of people with a wide range of conditions. These diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), osteoarthritis (OA), gout, and diabetes, impose a significant burden on patients and healthcare systems. A complicated interaction between genetic variables, environmental stimuli, and dysregulated immune responses shows the complex biological foundation of various diseases. This review focuses on the molecular mechanisms underlying inflammatory diseases, including the function of inflammasomes and inflammation. We investigate the impact of environmental and genetic factors on the progression of inflammatory diseases, explore the connection between inflammation and inflammasome activation, and examine the incidence of various inflammatory diseases in relation to inflammasomes.

Immune Diseases Associated with Aging: Molecular Mechanisms and Treatment Strategies.

Aging is associated with a decline in immune function, thereby causing an increased susceptibility to various diseases. Herein, we review immune diseases associated with aging, focusing on tumors, atherosclerosis, and immunodeficiency disorders. The molecular mechanisms underlying these conditions are discussed, highlighting telomere shortening, tissue inflammation, and altered signaling pathways, e.g., the mammalian target of the rapamycin (mTOR) pathway, as key contributors to immune dysfunction. The role of the senescence-associated secretory phenotype in driving chronic tissue inflammation and disruption has been examined. Our review underscores the significance of targeting tissue inflammation and immunomodulation for treating immune disorders. In addition, anti-inflammatory medications, including corticosteroids and nonsteroidal anti-inflammatory drugs, and novel approaches, e.g., probiotics and polyphenols, are discussed. Immunotherapy, particularly immune checkpoint inhibitor therapy and adoptive T-cell therapy, has been explored for its potential to enhance immune responses in older populations. A comprehensive analysis of immune disorders associated with aging and underlying molecular mechanisms provides insights into potential treatment strategies to alleviate the burden of these conditions in the aging population. The interplay among immune dysfunction, chronic tissue inflammation, and innovative therapeutic approaches highlights the importance of elucidating these complex processes to develop effective interventions to improve the quality of life in older adults.

Cutibacterium equinum sp. nov., isolated from horse faeces.

Strain CBA3108T is a Gram-positive, non-spore-forming, obligately anaerobic bacterium isolated from horse faecal samples obtained in Jeju Island, Republic of Korea. The cells of CBA3108T are non-motile short rods that have been assessed as catalase-positive and oxidase-negative. Growth of the strain occurs under the following conditions: 25-45 °C (optimum, 35 °C); pH 6-9 (optimum, pH 6); and in the presence of 0-6 % (w/v) NaCl (optimum, 2%). Major fatty acids in the strain include C15 : 0 iso and C15 : 0 iso DMA, while major polar lipids include phosphatidylglycerol, diphosphatidylglycerol and phosphatidylcholine. Based on phylogenetic analysis using 16S rRNA gene sequences, strain CBA3108T forms a phyletic lineage distinct from other closely related species within the genus Cutibacterium. It was found to be most closely related to Cutibacterium avidum ATCC 25577T (98.27 % 16S rRNA gene sequence similarity) and other strains within the genus (≤98.0 %). The genomic DNA G+C content of strain CBA3108T was 63.2 mol%. The in silico DNA-DNA hybridization values of strain CBA3108T with C. avidum ATCC 25577T, C. porci WCA-380-WT-3AT and C. acnes subsp. acnes DSM 1897T were 33.6, 21.7 and 22.7 %, respectively. Its phenotypic, chemotaxonomic and molecular properties support the hypothesis that strain CBA3108T represents a novel species in the genus Cutibacterium, for which we propose the name Cutibacterium equinum sp. nov. The type strain is CBA3108T (=KACC 22889T=JCM 35966T).

From Stoner to local moment magnetism in atomically thin Cr2Te3.

The field of two-dimensional (2D) ferromagnetism has been proliferating over the past few years, with ongoing interests in basic science and potential applications in spintronic technology. However, a high-resolution spectroscopic study of the 2D ferromagnet is still lacking due to the small size and air sensitivity of the exfoliated nanoflakes. Here, we report a thickness-dependent ferromagnetism in epitaxially grown Cr2Te3 thin films and investigate the evolution of the underlying electronic structure by synergistic angle-resolved photoemission spectroscopy, scanning tunneling microscopy, x-ray absorption spectroscopy, and first-principle calculations. A conspicuous ferromagnetic transition from Stoner to Heisenberg-type is directly observed in the atomically thin limit, indicating that dimensionality is a powerful tuning knob to manipulate the novel properties of 2D magnetism. Monolayer Cr2Te3 retains robust ferromagnetism, but with a suppressed Curie temperature, due to the drastic drop in the density of states near the Fermi level. Our results establish atomically thin Cr2Te3 as an excellent platform to explore the dual nature of localized and itinerant ferromagnetism in 2D magnets.

Peptide derived from stromal cell-derived factor 1δ enhances the in vitro expression of osteogenic proteins via bone marrow stromal cell differentiation and promotes bone formation in in vivo models.

Mesenchymal stem cells (MSCs) rely on chemokines and chemokine receptors to execute their biological and physiological functions. Stromal cell-derived factor-1 (SDF-1) is upregulated in injury sites, where it acts as a chemotactic agent, attracting CXCR4-expressing MSCs, which play a pivotal role in the healing and regeneration of tissue throughout the body. Furthermore, SDF-1 expression has been observed in regions experiencing inflammation-induced bone destruction and fracture sites. In this study, we identified a novel peptide called bone-forming peptide-5 (BFP-5), derived from SDF-1δ, which can promote the osteogenesis of MSCs as well as bone formation and healing. Multipotent bone marrow stromal cells treated with BFP-5 showed enhanced alizarin red S staining and higher alkaline phosphatase (ALP) activity. Moreover, ALP and osterix proteins were more abundantly expressed when cells were treated with BFP-5 than SDF-1α. Histology and microcomputed tomography data at 12 weeks demonstrated that both rabbit and goat models transplanted with polycaprolactone (PCL) scaffolds coated with BFP-5 showed significantly greater bone formation than animals transplanted with PCL scaffolds alone. These findings suggest that BFP-5 could be useful in the development of related therapies for conditions associated with bones.

P2-Type Moisture-Stable and High-Voltage-Tolerable Cathodes for High-Energy and Long-Life Sodium-Ion Batteries.

P2-Na0.67Ni0.33Mn0.67O2 represents a promising cathode for Na-ion batteries, but it suffers from severe structural degradation upon storing in a humid atmosphere and cycling at a high cutoff voltage. Here we propose an in situ construction to achieve simultaneous material synthesis and Mg/Sn cosubstitution of Na0.67Ni0.33Mn0.67O2 via one-pot solid-state sintering. The materials exhibit superior structural reversibility and moisture insensitivity. In-operando XRD reveals an essential correlation between cycling stability and phase reversibility, whereas Mg substitution suppressed the P2-O2 phase transition by forming a new Z phase, and Mg/Sn cosubstitution enhanced the P2-Z transition reversibility benefiting from strong Sn-O bonds. DFT calculations disclosed high chemical tolerance to moisture, as the adsorption energy to H2O was lower than that of the pure Na0.67Ni0.33Mn0.67O2. A representative Na0.67Ni0.23Mg0.1Mn0.65Sn0.02O2 cathode exhibits high reversible capacities of 123 mAh g-1 (10 mA g-1), 110 mAh g-1 (200 mA g-1), and 100 mAh g-1 (500 mA g-1) and a high capacity retention of 80% (500 mA g-1, 500 cycles).

Toward High-Performance Mg-S Batteries via a Copper Phosphide Modified Separator.

Magnesium-sulfur (Mg-S) batteries are emerging as a promising alternative to lithium-ion batteries, due to their high energy density and low cost. Unfortunately, current Mg-S batteries typically suffer from the shuttle effect that originates from the dissolution of magnesium polysulfide intermediates, leading to several issues such as rapid capacity fading, large overcharge, severe self-discharge, and potential safety concern. To address these issues, here we harness a copper phosphide (Cu3P) modified separator to realize the adsorption of magnesium polysulfides and catalyzation of the conversion reaction of S and Mg2+ toward stable cycling of Mg-S cells. The bifunctional layer with Cu3P confined in a carbon matrix is coated on a commercial polypropylene membrane to form a porous membrane with high electrolyte wettability and good thermal stability. Density functional theory (DFT) calculations, polysulfide permeability tests, and post-mortem analysis reveal that the catalytic layer can adsorb polysulfides, effectively restraining the shuttle effect and facilitating the reversibility of the Mg-S cells. As a result, the Mg-S cells can achieve a high specific capacity, fast rates (449 mAh g-1 at 0.1 C and 249 mAh g-1 at 1.0 C), and a long cycle life (up to 500 cycles at 0.5 C) and operate even at elevated temperatures.

Transcription Factors as Targets of Natural Compounds in Age-Related Diseases and Cancer: Potential Therapeutic Applications.

Inflammation exacerbates systemic pathophysiological conditions and chronic inflammation is a sustained and systemic phenomenon that aggravates aging that can lead to chronic age-related diseases. These inflammatory phenomena have recently been redefined and delineated at the molecular, cellular, and systemic levels. Many transcription factors that are activated in response to tumor metabolic state have been reported to be regulated by a class of histone deacetylase called sirtuins (SIRTs). Sirtuins play a pivotal role in the regulation of tumor cell metabolism, proliferation, and angiogenesis, including oxidative stress and inflammation. The SIRT1-mediated signaling pathway in diabetes and cancer is the SIRT1/forkhead-box class O (FoxO)/nuclear factor-kappa B (NF-κB) pathway. In this review, we describe the accumulation of SIRT1-, NF-κB-, and FoxO-mediated inflammatory processes and cellular proinflammatory signaling pathways. We also describe the proinflammatory mechanisms underlying metabolic molecular pathways in various diseases such as liver cancer and diabetes. Finally, the regulation of cancer and diabetes through the anti-inflammatory effects of natural compounds is highlighted. Evidence from inflammation studies strongly suggests that cells may be a major source of cytokines secreted during various diseases. A better understanding of the mechanisms that underpin the inflammatory response and palliative role of natural compounds will provide insights into the molecular mechanisms of inflammation and various diseases for potential intervention.

Sargassum horneri (Turner) C. Agardh Extract Regulates Neuroinflammation In Vitro and In Vivo.

Previously, we reported that Sargassum horneri (Turner) C. Agardh (S. horneri) is a brown algae species that exerts anti-inflammatory activity toward murine macrophages. However, the anti-neuroinflammatory effects and the mechanism of S. horneri on microglia cells are still unknown. We investigated the anti-neuroinflammatory effects of S. horneri extract on microglia in vitro and in vivo. In the present study, we found that S. horneri was not cytotoxic to BV-2 microglia cells and it significantly decreased lipopolysaccharide (LPS)-induced NO production. Moreover, S. horneri also diminished the protein expression of iNOS, COX-2, and cytokine production, including IL-1ß, TNF-α, and IL-6, on LPS-stimulated microglia activation. S. horneri elicited anti-neuroinflammatory effects by inhibiting phosphorylation of p38 MAPK and NF-κB. In addition, S. horneri inhibited astrocytes and microglia activation in LPS-challenged mice brain. Therefore, these results suggested that S. horneri exerted anti-neuroinflammatory effects on LPS-stimulated microglia cell activation by inhibiting neuroinflammatory factors and NF-κB signaling.

FoxO Transcription Factors: Applicability as a Novel Immune Cell Regulators and Therapeutic Targets in Oxidative Stress-Related Diseases.

Forkhead box O transcription factors (FoxOs) play an important role in maintaining normal cell physiology by regulating survival, apoptosis, autophagy, oxidative stress, the development and maturation of T and B lymphocytes, and the secretion of inflammatory cytokines. Cell types whose functions are regulated by FoxOs include keratinocytes, mucosal dermis, neutrophils, macrophages, dendritic cells, tumor-infiltrating activated regulatory T (Tregs) cells, B cells, and natural killer (NK) cells. FoxOs plays a crucial role in physiological and pathological immune responses. FoxOs control the development and function of Foxp3+ Tregs. Treg cells and Th17 cells are subsets of CD4+ T cells, which play an essential role in immune homeostasis and infection. Dysregulation of the Th17/Treg cell balance has been implicated in the development and progression of several disorders, such as autoimmune diseases, inflammatory diseases, and cancer. In addition, FoxOs are stimulated by the mitogen-activated protein (MAP) kinase pathway and inhibited by the PI3 kinase/AKT pathway. Downstream target genes of FoxOs include pro-inflammatory signaling molecules (toll-like receptor (TLR) 2, TLR4, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α), chemokine receptors (CCR7 and CXCR2), B-cell regulators (APRIL and BLYS), T-regulatory modulators (Foxp3 and CTLA-4), and DNA repair enzymes (GADD45α). Here, we review the recent progress in our understanding of FoxOs as the key molecules involved in immune cell differentiation and its role in the initiation of autoimmune diseases caused by dysregulation of immune cell balance. Additionally, in various diseases, FoxOs act as a cancer repressor, and reviving the activity of FoxOs forces Tregs to egress from various tissues. However, FoxOs regulate the cytotoxicity of both CD8+ T and NK cells against tumor cells, aiding in the restoration of redox and inflammatory homeostasis, repair of the damaged tissue, and activation of immune cells. A better understanding of FoxOs regulation may help develop novel potential therapeutics for treating immune/oxidative stress-related diseases.

Stabilization of three-dimensional charge order through interplanar orbital hybridization in PrxY1-xBa2Cu3O6+δ.

The shape of 3d-orbitals often governs the electronic and magnetic properties of correlated transition metal oxides. In the superconducting cuprates, the planar confinement of the [Formula: see text] orbital dictates the two-dimensional nature of the unconventional superconductivity and a competing charge order. Achieving orbital-specific control of the electronic structure to allow coupling pathways across adjacent planes would enable direct assessment of the role of dimensionality in the intertwined orders. Using Cu L3 and Pr M5 resonant x-ray scattering and first-principles calculations, we report a highly correlated three-dimensional charge order in Pr-substituted YBa2Cu3O7, where the Pr f-electrons create a direct orbital bridge between CuO2 planes. With this we demonstrate that interplanar orbital engineering can be used to surgically control electronic phases in correlated oxides and other layered materials.

Generic character of charge and spin density waves in superconducting cuprates.

Charge density waves (CDWs) have been observed in nearly all families of copper-oxide superconductors. But the behavior of these phases across different families has been perplexing. In La-based cuprates, the CDW wavevector is an increasing function of doping, exhibiting the so-called Yamada behavior, while in Y- and Bi-based materials the behavior is the opposite. Here, we report a combined resonant soft X-ray scattering (RSXS) and neutron scattering study of charge and spin density waves in isotopically enriched La1.8−xEu0.2SrxCuO4 over a range of doping 0.07≤x≤0.20. We find that the CDW amplitude is temperature independent and develops well above experimentally accessible temperatures. Further, the CDW wavevector shows a nonmonotonic temperature dependence, exhibiting Yamada behavior at low temperature with a sudden change occurring near the spin ordering temperature. We describe these observations using a Landau­Ginzburg theory for an incommensurate CDW in a metallic system with a finite charge compressibility and spin-CDW coupling. Extrapolating to high temperature, where the CDW amplitude is small and spin order is absent, our analysis predicts a decreasing wavevector with doping, similar to Y and Bi cuprates. Our study suggests that CDW order in all families of cuprates forms by a common mechanism.

Characterization of photoinduced normal state through charge density wave in superconducting YBa2Cu3O6.67.

The normal state of high-Tc cuprates has been considered one of the essential topics in high-temperature superconductivity research. However, compared to the high magnetic field study of it, understanding a photoinduced normal state remains elusive. Here, we explore a photoinduced normal state of YBa2Cu3O6.67 through a charge density wave (CDW) with time-resolved resonant soft x-ray scattering, as well as a high magnetic field x-ray scattering. In the nonequilibrium state where people predict a quenched superconducting state based on the previous optical spectroscopies, we experimentally observed a similar analogy to the competition between superconductivity and CDW shown in the equilibrium state. We further observe that the broken pairing states in the superconducting CuO2 plane via the optical pump lead to nucleation of three-dimensional CDW precursor correlation. Ultimately, these findings provide a critical clue that the characteristics of the photoinduced normal state show a solid resemblance to those under magnetic fields in equilibrium conditions.

Thermal-healing of lattice defects for high-energy single-crystalline battery cathodes.

Single-crystalline nickel-rich cathodes are a rising candidate with great potential for high-energy lithium-ion batteries due to their superior structural and chemical robustness in comparison with polycrystalline counterparts. Within the single-crystalline cathode materials, the lattice strain and defects have significant impacts on the intercalation chemistry and, therefore, play a key role in determining the macroscopic electrochemical performance. Guided by our predictive theoretical model, we have systematically evaluated the effectiveness of regaining lost capacity by modulating the lattice deformation via an energy-efficient thermal treatment at different chemical states. We demonstrate that the lattice structure recoverability is highly dependent on both the cathode composition and the state of charge, providing clues to relieving the fatigued cathode crystal for sustainable lithium-ion batteries.

Quantitative proteomic analysis comparing grades ICRS1 and ICRS3 in patients with osteoarthritis.

Osteoarthritis (OA), which is caused by joint damage, is the most common form of arthritis, affecting millions of people worldwide. This damage can accumulate over time, which is why aging is one of the main contributors to joint damage associated with OA. The OA-related proteins that have been reported to date have been identified by the comparative analysis of OA patients with normal controls, following surgical or pharmacological treatment. For the first time, the present study analyzed OA-related proteins in patients with OA according to the International Cartilage Repair Society (ICRS) scale. Changes in protein expression can be observed during the OA process. The present study demonstrated differential protein expression patterns in articular cartilage from ICRS1- and ICRS3-graded OA patients. ICRS grade-matched OA knee samples from 12 OA patients, 6 ICRS grade 1 patients and 6 ICRS3 patients were subjected to proteomic analysis using the LTQ-Orbitrap mass spectrometry system. A total of 231 unique proteins were identified as expressed across the ICRS1 and ICRS3 OA patient groups. Relative differences in protein expression associated with the following classifications were observed: Biological adhesion, cell killing, cellular process, development process and molecular function. Although some of these proteins have been previously reported to be associated with rheumatoid arthritis, including cartilage oligomeric matrix protein, collagen types, angiogenin, complement C5 and CD59 glycoprotein, numerous additional proteins were newly identified, which may further help our understanding of disease pathogenesis. These findings suggested that these proteins may be used to develop novel therapeutic targets for OA.

Bone-Forming Peptide-4 Induces Osteogenic Differentiation and VEGF Expression on Multipotent Bone Marrow Stromal Cells.

Bone morphogenetic proteins (BMPs) have been widely used as treatment for bone repair. However, clinical trials on fracture repair have challenged the effectiveness of BMPs and suggested that delivery of multipotent bone marrow stromal cells (BMSCs) might be beneficial. During bone remodeling and bone fracture repair, multipotent BMSCs differentiate into osteoblasts or chondrocytes to stimulate bone formation and regeneration. Stem cell-based therapies provide a promising approach for bone formation. Extensive research has attempted to develop adjuvants as specific stimulators of bone formation for therapeutic use in patients with bone resorption. We previously reported for the first time bone-forming peptides (BFPs) that induce osteogenesis and bone formation. BFPs are also a promising osteogenic factor for prompting bone regeneration and formation. Thus, the aim of the present study was to investigate the underlying mechanism of a new BFP-4 (FFKATEVHFRSIRST) in osteogenic differentiation and bone formation. This study reports that BFP-4 induces stronger osteogenic differentiation of BMSCs than BMP-7. BFP-4 also induces ALP activity, calcium concentration, and osteogenic factors (Runx2 and osteocalcin) in a dose dependent manner in BMSCs. Therefore, these results indicate that BFP-4 can induce osteogenic differentiation and bone formation. Thus, treatment of multipotent BMSCs with BFP-4 enhanced osteoblastic differentiation and displayed greater bone-forming ability than BMP-7 treatment. These results suggest that BFP-4-stimulated cell therapy may be an efficient and cost-effective complement to BMP-7-based clinical therapy for bone regeneration and formation.

Operando Tailoring of Defects and Strains in Corrugated ß-Ni(OH)2 Nanosheets for Stable and High-Rate Energy Storage.

Nickel hydroxide represents a technologically important material for energy storage, such as hybrid supercapacitors. It has two different crystallographic polymorphs, α- and ß-Ni(OH)2 , showing advantages in either theoretical capacity or cycling/rate performance, manifesting a trade-off trend that needs to be optimized for practical applications. Here, the synergistic superiorities in both activity and stability of corrugated ß-Ni(OH)2 nanosheets are demonstrated through an electrochemical abuse approach. With ≈91% capacity retention after 10 000 cycles, the corrugated ß-Ni(OH)2 nanosheets can deliver a gravimetric capacity of 457 C g-1 at a high current density of 30 A g-1 , which is nearly two and four times that of the regular α- and ß-Ni(OH)2 , respectively. Operando spectroscopy and finite element analysis reveal that greatly enhanced chemical activity and structural robustness can be attributed to the in situ tailored lattice defects and the strain-induced highly curved micromorphology. This work demonstrates a multi-scale defect-and-strain co-design strategy, which is helpful for rational design and tuned fabrication of next-generation electrode materials for stable and high-rate energy storage.

Depth-dependent valence stratification driven by oxygen redox in lithium-rich layered oxide.

Lithium-rich nickel-manganese-cobalt (LirNMC) layered material is a promising cathode for lithium-ion batteries thanks to its large energy density enabled by coexisting cation and anion redox activities. It however suffers from a voltage decay upon cycling, urging for an in-depth understanding of the particle-level structure and chemical complexity. In this work, we investigate the Li1.2Ni0.13Mn0.54Co0.13O2 particles morphologically, compositionally, and chemically in three-dimensions. While the composition is generally uniform throughout the particle, the charging induces a strong depth dependency in transition metal valence. Such a valence stratification phenomenon is attributed to the nature of oxygen redox which is very likely mostly associated with Mn. The depth-dependent chemistry could be modulated by the particles' core-multi-shell morphology, suggesting a structural-chemical interplay. These findings highlight the possibility of introducing a chemical gradient to address the oxygen-loss-induced voltage fade in LirNMC layered materials.