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A general and efficient [4+1]-annulation of indole-N-carboxamide with cyclopropene has been accomplished in the presence of a chiral cyclopentadienyl rhodium catalyst for the synthesis of imidazo[1,5-a]indole. Introduction of one bulky substituent in the chiral cyclopentadienyl ligand without altering the chirality of the binaphthyl fragment reverses the enantioselectivity of the catalytic reaction. Important features of the method include ligand-controlled enantiodivergence, a base-free and redox-neutral approach, synthetic application, and isolation of the potential intermediate.
Bismuth (III) chloride (BiCl3) has emerged as a powerful and ecofriendly Lewis acid catalyst in modern organic synthesis. Distinguished by its low toxicity, affordability, and environmental compatibility, BiCl3 offers an attractive alternative to conventional metal catalysts. This review compiles and summarizes the significant findings reported to date on the diverse applications of BiCl3 in promoting diverse organic transformations including oxidation, reduction, bond-forming reactions (C-C, C-N, C-P, C-O, C-S, and C-X), and deprotection strategies. Its effectiveness under mild, solvent-free, and even microwave-assisted conditions underscores its potential in green chemistry. The ability of BiCl3 to deliver high yields with good selectivity and reusability positions it as a catalyst of growing importance in sustainable synthetic methodologies.
Optical nanostructures have gained prominence as an efficient tool for bioimaging due to their distinctive capabilities, including tailorable optical features, bright emissions with excellent photostability, and cytocompatibility. In recent years, graphitic carbon nitride (g-C3N4) quantum dots have gained considerable attention within the domains of bioimaging. In this study, an extensive fabrication approach for L-cysteine decorated g-C3N4 quantum dots (L-cys-g-C3N4 QDs) is developed, and their cytotoxicity is investigated in vitro to determine their potential as bioimaging tools. We synthesized g-C3N4 nanostructures by combining thermal polymerization and ultrasonic treatment. The g-C3N4 quantum dots decorated with L-cysteine by EDC/NHS coupling reaction. Afterward, the material was characterized using a range of techniques, including X-ray diffraction, transmission electron microscopy, and photoluminescence spectroscopy. For assessing the cytotoxicity potential of g-C3N4 QDs and L-cys-g-C3N4 QDs, cytotoxicity assays were conducted on breast cancer cell lines using MTT, ethidium bromide/acridine orange staining, and ROS analysis. These results indicate that g-C3N4 QDs and L-cys-g-C3N4 QDs exhibited a non-toxic and biocompatible nature. Compared with g-C3N4 QDs, L-cys-g-C3N4 QDs are highly biocompatible. The fluorescence properties of g-C3N4 were further evaluated to investigate its potential as a bioimaging agent. This revealed g-C3N4 to be a suitable agent for imaging. The study provides insight into the synthesis and biocompatibility of L-cys-g-C3N4 QDs, highlighting their potential for bioimaging applications.
Carboranyl-modified nucleosides are promising boron-10 (10B) delivery agents for boron neutron capture therapy (BNCT), yet methods for directly forming B-C/B-N bonds at unprotected nucleosides are scarce. We report herein two operationally simple, orthogonal strategies for the late-stage installation of carboranyl units at heteroaromatic C(sp2) centers and exocyclic amino groups of native nucleosides, nucleotides, and analogues. The first method uses a visible-light-mediated Minisci-type radical reaction, where 9-meta-carboranyltrifluoroborate serves as a nucleophilic B(9)-vertex radical precursor to selectively forge C(sp2)-B bonds at the C8-position of guanine, C2-position of adenine, and C5-position of uracil. Theoretical calculations revealed that the selectivity for adenosine and uridine is substrate-dependent: in adenosine, C2-selectivity arises from steric repulsion that disfavors C8-addition, whereas in uridine, C5-selectivity is dictated by stabilizing interactions. The second strategy employs Pd-catalyzed Buchwald-Hartwig-type amination to form B-N bonds at the N6-position of adenosine, the N2-position of guanosine, and the N4-position of cytidine. Furthermore, carboranyl groups were successfully incorporated into DNA oligonucleotides at various positions via solid-phase synthesis. To assess their suitability for BNCT applications, 10B-enriched carboranyl-modified oligonucleotides, carboranyl-modified DNA aptamers (Sgc8c) targeting protein tyrosine kinase 7 (PTK7), along with 10B-enriched carboranyl-modified aptamers, were prepared. Cellular uptake studies showed that the aptamer-carborane conjugates effectively recognize and internalize into PTK7-overexpressing HCT116 cells, thereby providing a basis for future exploration of BNCT applications. These methods expand the chemical space of boron-rich nucleos(t)ides and represent a step toward the development of next-generation BNCT agents.
An enantioselective synthetic route to the most active stereoisomer, (8S,9S,16S)-beraprost, through a mild and scalable Yb(OTf)3-catalyzed diastereoselective inverse-electron-demand Diels-Alder/retro-Diels-Alder and Pd(TFA)2-catalyzed aromatization process with a broad substrate scope. In this way, (8S,9S,16S)-beraprost with high stereoselectivity (>99.5%, de) has been successfully synthesized. Moreover, this synthetic route can be produced on a large scale by the API workshop.
Carboxylic acids and their derivatives constitute one of the most diverse and readily accessible classes of synthetic building blocks and are ubiquitous in pharmaceuticals and natural products. Here we report a Pd-catalyzed decarboxylative coupling of hydroxamic acids with aryl electrophiles in which palladium orchestrates both the Lossen rearrangement and the cross-coupling process. This approach enables carboxylic acid derivatives to function as surrogates for primary amines, providing a complementary and powerful route to secondary amines. The reaction is effective across a broad range of hydroxamic acids and aryl (pseudo)halides, including both alkyl and aryl hydroxamic acids as well as aryl chlorides, bromides, and triflates, and exhibits broad functional group compatibility. Mechanistic studies support a dual role of Pd in the catalytic cycle, implicating Pd(II) species as the key promoter of the Lossen rearrangement in addition to the involvement in the C-N coupling step.
The coordination polymers (CPs)/metal-organic frameworks (MOFs) incorporating hetero-bridging ligands have remarkable efficiency and versatility towards fulfilling the objectives of the Sustainable Development Goals (SDGs). In this aspect, two CPs, [Cu2(3-bph)2(adc)4]n (CP1) and [Zn2(3-bph)2(adc)4]n (CP2) (3-bph = (1E,2E)-1,2-bis(pyridin-3-ylmethylene)hydrazine and adc- = 1-adamantanecarboxylate), are characterised, and their significant semiconducting property and selective dye sorption activity are explored. The CPs comprise a secondary building unit (SBU) of a carboxylate-bridging adc- paddle-wheel, [M2(adc)4] (M = Cu(II), Zn(II)), which undergoes pyridyl-N linking by 3-bph to form a 1D chain, where the pyridyl rings undergo π-π interaction to construct a 2D honeycomb-supramolecular network. Interestingly, CP1 demonstrates the selective sorption of methyl red (MR) dye out of four dyes (methylene blue, rhodamine B, methyl red, and methyl orange) with a removal efficiency of 95.37% from aqueous solution within 1 h, whereas CP2 does not show measurable sorption activity. The sorption of CP1 fits the Langmuir isotherm (R2 = 0.9875) and follows pseudo-second-order kinetics, indicating chemisorption on a heterogeneous surface. The DFT calculations using crystallographic parameters determined the band gaps in the semiconducting region (2.39 eV (cal.) and 3.68 eV (exp.) for CP1 and 2.32 eV (cal.) and 3.65 eV (exp.) for CP2). This inspired the measurement of the electrical conductivity from a fabricated Schottky device with thin film electrodes, ITO/CPs/Al. The experiments show that CP2 (5.27 × 10-3 S m-1) has higher electrical conductivity than CP1 (2.72 × 10-3 S m-1) under identical conditions, which explains the superior charge-transport features of CP2 in comparison with CP1. These findings highlight that CP1 serves as a promising material for application as a sustainable MR dye removal agent from wastewater, while both CP1 and CP2 are potential candidates for semiconducting applications.
1,2-Amino alcohols are essential scaffolds in organic synthesis and pharmaceutical development, yet the direct catalytic synthesis of secondary alkylamino alcohol derivatives from alkene precursors remains a significant challenge. Although O-benzoylhydroxylamines are effective aminating reagents, the direct use of primary alkyl amino groups (RNH-X) in amination is still rare. Moreover, existing methods often suffer from poor atom economy due to the generation of stoichiometric byproducts. Herein, we report a tricationic xanthylium-based organophotoredox catalyst that enables primary O-benzoylhydroxylamines to act as bifunctional reagents in the oxyamination of alkenes. This strategy provides direct and regioselective access to 1,2-amino alcohols bearing secondary alkylamine motifs under mild conditions, offering regiocomplementarity to the Sharpless aminohydroxylation. The reaction exhibits broad substrate scope and functional group tolerance, and has been successfully applied to the concise synthesis of natural products. Mechanistic investigations, including control experiments and isotope-labeling studies, support a radical cation pathway involving key alkene oxidation and concerted carbon to nitrogen 1,3-radical acyloxy migration steps. This study establishes tricationic xanthylium salts as powerful organophotoredox catalysts for challenging synthetic transformations.
ZTO/PVA nanocomposite sheets were successfully fabricated using precipitation and sonochemical routes for ZnO and TiO2 nanoparticle synthesis, respectively, followed by solution casting into the PVA matrix. This process ensured uniform dispersion of ZTO nanoparticles within the polymer matrix and was completed without post-mixing thermal calcination, representing an energy-efficient and novel synthesis route. XRD analysis confirmed the incorporation of nanoparticles and revealed an anatase-to-rutile phase transformation of TiO2 after composite formation. XPS spectra confirmed the presence of Zn, O, and Ti LMM signals, indicating the presence of oxide components within the composite structure. Optical analysis showed a significant reduction in the band gap after ZTO incorporation. The indirect band gap decreased from 3.03 eV for pure PVA to 2.93, 2.72, and 2.5 eV for 2, 5, and 8 wt% ZTO/PVA, respectively, while the direct band gap decreased from 4.59 to 2.72 eV at higher filler loading. Photoluminescence results showed a slight red shift for 2 and 5 wt% ZTO/PVA due to interfacial defect states, followed by a blue shift at 8 wt% associated with near-band-edge emission and phase transformation effects. AFM analysis revealed a significant increase in surface roughness from 9.46 to 131.97 nm as ZTO content increased, indicating nanoparticle aggregation and surface heterogeneity. Thermal analysis demonstrated improved thermal stability and multi-step degradation behaviour. Dielectric measurements showed high permittivity at low frequencies due to interfacial polarisation, with non-Debye relaxation behaviour confirmed by Havriliak-Negami and Cole-Cole analysis. Magnetic measurements indicated predominantly non-magnetic behaviour with a slight enhancement after ZTO incorporation. These findings demonstrate that the addition of ZTO effectively tailors the structural, optical, thermal, dielectric, and magnetic properties of PVA nanocomposites, making them promising for multifunctional dielectric and optoelectronic applications.
Halide-based solid electrolytes (HSEs) have garnered substantial interest for all-solid-state batteries (ASSBs) due to their wide electrochemical windows, moderate-to-high room-temperature ionic conductivity, and enhanced air stability over traditional sulfide and oxide-based SEs. This review consolidates recent advances in HSEs, focusing on the link between structure, compositions, and materials properties that influence the transport of lithium-ion (Li-ion) and post-lithium-ion (P-Li-ion) and their stability at the interface. Based on the chemistry of their central metal, HSEs are divided into five classes; key factors influencing ionic conductivity are examined. Nevertheless, despite these benefits, many challenges remain, including interfacial instability, the trade-off between ionic conductivity and electrochemical stability, mechanical challenges, and material costs. The main synthesis methods, mechanochemical, co-melting, and wet-chemical, are investigated for phase formation, scalability, and defect control. The link between synthesis, microstructure, and device-level performance metrics, including critical current density, area-specific resistance, and cycle life, is examined. The strategies, involving bilayer and dual-electrolyte design as well as interface engineering, are analyzed to reduce interfacial resistance and dendrite growth. The applications of HSE in Li-ion and P-Li-ion systems are examined. This review offers a detailed framework and delineates potential research paths to advance scalable, high-performance HSEs for next-generation ASSBs.
Silicon anodes have intrinsically low electronic conductivity and severe volume changes, leading to nonuniform reaction kinetics and progressive structural degradation in both lithium-ion batteries (LIBs) and all-solid-state lithium batteries (ASSLBs). To overcome these limitations, we develop a silicon nanocomposite anode via a scalable and facile synthesis route. The nanocomposite (Si/a-Sn/CoSi2/G/C) consists of ultrafine Si nanocrystallites integrated with a well-deformable, electronically conductive amorphous Sn; a mechanically robust and elastic CoSi2 framework; a highly Li-reversible, electronically conductive, stress-mitigating graphite scaffold; and a highly elastic, electronically conductive PVC-pyrolyzed amorphous carbon shell. This hierarchical and synergistic architecture integrates uniform nanocrystalline Si dispersion, continuous electronic conduction, and mechanically rigid and elastically buffering matrices that accommodate volume expansion, thereby establishing a robust Si nanocomposite anode platform compatible with both LIBs and ASSLBs. The anode has a high reversible capacity, stable long-term cycling performance, high Coulombic efficiency, and improved rate capability. In LIB systems, a Si/a-Sn/CoSi2/G/C|NCM811 full-cell achieves an energy density of 434.4 Wh kg-1 with durable cycling stability. In sulfide-based ASSLB systems employing Li6PS5Cl, the full-cell has an energy density exceeding 300 Wh kg-1, with structural and electrochemical stability. Thus, Si/a-Sn/CoSi2/G/C is a practical and scalable Si-based anode platform for next-generation LIBs and ASSLBs.
α-amylases are indispensable industrial biocatalysts, yet their recombinant production faces significant biochemical and cellular bottlenecks. Recent scientific advancement shifts the paradigm from traditional cloning toward a design-parameter framework, where host selection predominantly Bacillus subtilis, Pichia pastoris, and Aspergillus niger is dictated by secretion capacity, folding landscapes, and metabolic compatibility. While Escherichia coli remains a common host, its lack of efficient extracellular secretion often leads to inclusion body formation and metabolic stress. Advanced strategies are being employed to overcome these limits, including signal peptide optimization, chaperone co-expression, and the fusion of carbohydrate-binding modules (CBMs) to enhance raw-starch degradation. Furthermore, how rational design, aided by artificial intelligence and molecular dynamics simulations, enables the engineering of hyper-thermostable and alkaline-tolerant variants capable of withstanding extreme industrial processing conditions. The advent of CRISPR-Cas technology has further revolutionized the field, allowing for precise genome editing and metabolic rewiring to achieve record-breaking enzyme titers, such as 102,893 U/mL in engineered B. subtilis. By balancing transcriptional levels with enhanced secretion pathways and stress-mitigation systems, modern synthetic biology provides the tools to tailor α-amylases for specific needs, ranging from biofuel production to high-purity malto-oligosaccharide synthesis. Therefore, this comprehensive analysis underscores that reconciling host biology with enzyme biochemistry is essential for meeting global industrial demands.
The genus Pantoea includes species that occupy diverse ecological niches and exhibit significant functional versatility. Historically associated with taxonomic ambiguity within the Enterobacter agglomerans / Erwinia herbicola complex, the advent of genome-based approaches has substantially refined species delineation and evolutionary relationships within the genus. Pantoea species are ubiquitous, occupying environmental, plant, insect and clinical habitats, where they function as mutualists, commensals or opportunistic pathogens. In plant-associated interactions, they contribute to growth promotion, stress tolerance and biocontrol, while also emerging as significant phytopathogens with expanding host ranges and geographical distributions. Their pathogenicity involves multiple mechanisms, including secretion systems, quorum sensing, exopolysaccharide production and toxin synthesis. Strains within the same species may exhibit different lifestyles, complicating efforts to predict ecological function or assess biosafety. This review synthesizes current knowledge on the taxonomy, ecology and functional roles of Pantoea, with an emphasis on insights gained from taxogenomics. Unlike previous reviews, this synthesis integrates taxogenomic advances with ecological and functional data to critically examine lifestyle plasticity within Pantoea and its implications for biosafety and application. It highlights the challenges associated with distinguishing beneficial from pathogenic strains and emphasizes the need for integrative approaches combining genomics, functional assays and host interaction studies. Understanding the ecological and genetic determinants causing lifestyle plasticity in Pantoea is essential for exploiting its beneficial potential while reducing risks to agriculture and human health.
Octahedral Fe(II) complexes with bidentate N-heterocyclic (NHC) ligands are solid candidates for photoactive materials based on first-row transition metals. Despite the remarkable advances in ligand design and excited-state control, the theoretical basis for describing the complexation mechanism from a molecular and electronic point of view is lacking. This work reveals the molecular motions that drive the formation of bidentate [Fe(C^N)3]2+ complexes and how they couple with the electronic structure. Quantum chemistry methods are used to describe the chemical reactions that lead to the [Fe(pyIm)3]2+ (pyIm = pyridine-imidazol-2-ylidene) complex as a model case. The molecular model employed is based on the canonical synthesis using FeCl2 in an organic solvent and a strong Brønsted base to generate the pyIm ligand in situ. The energy profiles indicate that almost all reactivity takes place in the quintet state, whereas the singlet ground state is only populated in the last coordination step. Both d-activated dissociative interchange (Id) and purely dissociative (D) mechanisms compete, although the former is expected to be slightly more favorable. A global description of the coordination mechanism, consistent with the available experimental data, is provided through an analysis of the kinetic competition between the pathways and the thermodynamic stability of the intermediates.
This review aims to address the therapeutic potential of new generation of oncolytic viruses (OVs) for liver cancer with the focus on hepatocellular carcinoma (HCC). We evaluate the therapeutic status of oncolytic virus therapy (OVT) for liver cancer, addresses the research question of how different OVs perform in treating the malignancy, and and analyze the challenges remain in their clinical treatment based on the synthesis of both preclinical and clinical studies investigating various OVs, including Herpes simplex virus (HSV), Adenovirus (AdV), Vaccinia virus (VV), Coxsackievirus (COX), and Newcastle disease virus (NDV). OVs selectively infect and lyse tumor cells, stimulating anti-tumor immunity. HSV and VV have demonstrated high efficacy and safety in studies. Genetically engineered AdV and NDV platforms, especially those expressing immune checkpoint inhibitors or cytokines, show promising anti-tumor activity. Advances in viral engineering and delivery systems have improved tumor selectivity and immune activation. Key challenges identified include host antiviral immunity, delivery efficiency, and optimal patient selection. OVT represents a promising immunotherapeutic strategy for liver cancer. While significant progress has been made in both efficacy and safety through genetic modification, ongoing innovation in viral engineering, combination therapies.
This study aimed to identify and synthesize factors associated with response to digitally collected patient-reported outcome measures (PROMs) among adult patients, to inform efforts to improve response rates. We performed a systematic review of systematic and scoping reviews across five databases. Risk of bias was assessed using A MeaSurement Tool To Assess Systematic Reviews (AMSTAR) and included in a best-evidence synthesis. Additionally, a meta-analysis was conducted using the primary studies from the included reviews that specifically reported on digitally collected PROMs. We identified 43 factors positively, negatively, or not associated with response to digital PROMs, clustered in six domains. Some were modifiable, including the overload or overlap of questions, PROMs irrelevant to the patient, automatic reminders, system usability, and clinicians' follow-up with PROMs. Others were non-modifiable, such as race, language barriers, visual impairments, and comorbidities; many of these factors are shaped by patients' broader social and health-related circumstances and may therefore point to underlying structural or contextual barriers (e.g., limited access to resources, lower literacy, or health-related limitations). Such barriers may ultimately contribute to unequal access to care and are potentially actionable. Factors associated with response to digitally collected PROMs can be clustered into six domains: sociodemographic characteristics, physical health, psychosocial status, PROM characteristics, technological factors, treatment characteristics, and external influences. Although not all factors are directly modifiable, they can inform targeted and tailored interventions to improve response rates across diverse populations and support more equitable access to care. This review provides a structured overview to guide such efforts. Potential interventions could include language simplification, item reduction, follow-up during consultation, tailored reminders, and interface adaptations for patients with specific needs.
Gold nanoparticles (AuNPs) underpin advances across numerous applications, yet most syntheses still rely on added chemical reductants and organic additives, constraining sustainability. Here, we report an aqueous, reductant-free route to AuNPs that leverages hydrophobic interfaces under mild conditions. When NaOH is added to aqueous HAuCl4 to reach basic conditions (pH 10-13), where [Au(OH)4]- predominates, AuNPs form spontaneously upon contact with hydrophobic fluoropolymer surfaces (e.g., PFA) without added reductants or surfactants. In contrast, almost no AuNP formation is observed on hydrophilic glass under otherwise identical conditions, indicating that interfacial rather than bulk properties govern nucleation and growth. Systematic pH tuning revealed that AuNP yield reaches a pronounced maximum at pH ≈ 12 and becomes negligible at very high alkalinity (pH 14), while particle size is tunable by varying HAuCl4 and NaOH concentrations. These results, together with the suppression of AuNP formation at high ionic strength, indicate that interfacial ion distributions, rather than bulk pH alone, play a decisive role in the reaction. A consistent interpretation is that hydrophobic interfaces promote preferential adsorption of OH-, giving rise to an electric double layer (EDL) with an ion distribution distinct from the bulk. Within this nanoscale-confined environment, ultrasmall Au(III) hydroxide-like species may form and, owing to strong size effects, undergo low-temperature transformation to yield AuNPs. These results establish interfacial EDL confinement as a basis for sustainable, reductant-free nanomaterial synthesis and suggest extension of this principle to other aqueous metal systems.
The traditional Haber-Bosch method suffers from harsh conditions and high energy consumption, while electrocatalytic nitrate reduction to ammonia (ENRA) is a green route for ammonia synthesis and can serve as a cathode reaction for Zn-nitrate batteries. Its development is limited by sluggish intermediate hydrogenation and severe hydrogen evolution reaction (HER). Herein, we develop topology-engineered isomeric polyoxometalate (POM)-confined bimetallic metal-organic framework (MOF) electrocatalysts (NH2-MIL-53, -88, -101). Flexible NH2-MIL-88(FeNi) enables tight encapsulation of [PW12O40]3- (PW12) clusters via the "breathing effect", yielding PW12@NH2-MIL-88(FeNi) with synergistically modulated electronic distribution and proton transfer. Combined experimental and theoretical studies reveal that confined PW12 induces electronic redistribution over Fe/Ni centers, concurrently strengthening NO3 - adsorption on Fe and accelerating *NO2 hydrogenation on Ni. Beyond electronic effects, PW12 loosens the rigid hydration layer and forms conjugated acid-base pairs with MOF amino groups, promoting proton diffusion, boosting *NO2 hydrogenation, and suppressing HER. Thus, PW12@NH2-MIL-88(FeNi) achieves an NH3 yield rate of 20.1 mg h-1 mgcat. -1 with a Faradaic efficiency of 98.6% under neutral electrolytes. When used as a cathode in rechargeable Zn-nitrate batteries, it delivers a peak power density of 13.2 mW cm-2. This study establishes a generalizable paradigm for engineering interfacial proton transport and electronic properties via POM confinement in MOFs.
This review summarizes recent evidence on continuous glucose monitoring (CGM) in adults with type 2 diabetes mellitus (T2D), focusing on clinical effectiveness, patient-reported outcomes, disparities in use, and policy and economic considerations. Studies from 2020 to 2025 show that CGM use in T2D is associated with consistent improvements in glycosylated hemoglobin (HbA1c), time in range, and diabetes self-management across insulin and non-insulin treatment regimens. Emerging observational data suggest reductions in mortality and health care utilization, and cost-effectiveness analyses consistently demonstrate that CGM represents a high-value intervention across payer settings. Despite these benefits, CGM uptake remains variable, with persistent disparities by age, race, and ethnicity, insurance coverage, and care setting. CGM is an effective and cost-effective tool for T2D management, but inequities in access limit its impact. Future research should address implementation in safety-net and primary care settings, evaluate over-the-counter CGM, and assess long-term clinical and health system outcomes.
Autoimmune diseases are characterized by the immune system's breakdown of self-tolerance, and manifest as either organ-specific or systemic conditions. Within the target tissues of diverse autoimmune diseases, tertiary lymphoid structures (TLSs) emerge under persistent inflammatory conditions. These pathological, ectopic lymphoid formations serve as sites for sustained antigen presentation, affinity maturation of antibodies, and proliferation /differentiation of B cells, thereby exacerbating local immune-mediated damage. Given their functional significance, TLSs represent promising candidates as diagnostic biomarkers and novel therapeutic targets for autoimmune pathologies. This review synthesizes the current knowledge on the pathological relevance of TLSs, the mechanisms driving their formation and the therapeutic targeting potential, aiming to deepen the understanding of how TLSs influence the immune microenvironment in autoimmune disease pathology.