IL-23 tunes inflammatory functions of human mucosal-associated invariant T cells

IL-23 signaling plays a key role in the pathogenesis of chronic inflammatory and infectious diseases, yet the cellular targets and signaling pathways affected by this cytokine remain poorly understood. We show that IL-23 receptors are expressed on the large majority of human mucosal-associated invariant T (MAIT), but not of conventional T cells. Protein and transcriptional profiling at the population and single cell level demonstrates that stimulation with IL-23 or the structurally related cytokine IL-12 drives distinct functional profiles, revealing a high level of plasticity of MAIT cells. IL-23, in particular, affects key molecules and pathways related to autoimmunity and cytotoxic functions. Integrated analysis of transcriptomes and chromatin accessibility, supported by CRISPR-Cas9 mediated deletion, shows that AP-1 transcription factors constitute a key regulatory node of the IL-23 pathway in MAIT cells. In conclusion, our findings indicate that MAIT cells are key mediators of IL-23 functions in immunity to infections and chronic inflammatory diseases

Synthesis and Functional Development of Metal–Phenolic Network Films

© 2025 Tianzheng WangMetal-organic frameworks (MOFs) are of broad scientific and industrial interest due to their unique hybrid physicochemical properties arising from organic ligands and metal ions. The structural characteristics of organic ligands—whether flexible or rigid—significantly influence their coordination networks, thereby determining MOF morphologies, properties, and applications. Amorphous MOFs typically derived from flexible ligands, offer versatile substrate-coating capabilities but often exhibit limited control over morphologies, pore sizes, and thickness. In contrast, crystalline MOFs fabricated from rigid ligands possess well-defined pore structures, while their coating compatibility with diverse substrates is often restricted. This thesis focuses on precisely engineering MOF properties and functions by integrating amorphous and crystalline coordination networks, specifically by developing novel metal-phenolic networks (MPNs) consisting of metal ions and natural phenolic ligands. First, a universal approach for crystalline MOF coating is developed by utilizing amorphous MPN interfaces, enabling controlled assembly on a wide variety of particle and planar substrates for different applications (e.g., gas separation). Second, a robust and versatile method for MPN film growth via liquid-liquid interfacial assembly is introduced, accommodating both flexible and rigid phenolic ligands. The resulting interfacial assembled MPN films exhibit tunable physicochemical properties (e.g., thickness and morphology), possess microporous structures, and can be integrated with diverse functional components (e.g., polymers and nanoparticles) to achieve desired properties (e.g., wettability, conductive, and antibacterial properties). Finally, a novel class of reversible conduction switching materials based on MPN films is discovered, which leverages thermally induced crystalline coordination networks with electronic correlations. These MPN films show ultrahigh resistivity in the insulating state but relatively high Hall mobility in the conductive state, along with tunable transition temperatures and scalable production capability. Collectively, these studies provide insights into the interplay between amorphous and crystalline coordination networks, advance MPN assembly strategies, and expand their potential applications across multiple fields, including environmental science, materials science, and electronics

The relationship between ON–OFF function and OCT structural and angiographic parameters in early diabetic retinal disease

PURPOSE: This study measured associations between ON and OFF functional indicators and structural optical coherence tomography (OCT) and OCT angiography (OCTA) markers in diabetic retinal disease. METHODS: Fifty-four participants with type 1 or type 2 diabetes (mean age = 34.1 years; range 18-60) and 48 age-matched controls (mean age = 35.4 years, range 18-59) underwent visual psychophysical testing, OCT and OCTA retinal imaging. Psychophysical tasks measuring (A) contrast increment and decrement sensitivity and (B) response times to increment and decrement targets were assessed as surrogate measures of ON and OFF retinal ganglion cell function. RESULTS: The group with diabetes had worse foveal contrast increment and decrement thresholds (p = 0.04) and were slower to search for increment and decrement targets relative to controls (p = 0.009). Individuals with diabetes had a less circular foveal avascular zone (FAZ) (p < 0.001) but did not differ from controls in foveal vessel density and FAZ area. Functional and structural outcome measures related to the peripheral retina were also comparable between those with and without diabetes. Functional responses to increments and decrements were not significantly correlated with FAZ circularity or vessel density in individuals with diabetes. CONCLUSIONS: Diabetic retinal disease results in impaired performance on measures of inferred ON and OFF pathway function in addition to vascular deficits measurable with OCTA. Future longitudinal studies may determine the temporal relationship between these deficits, and whether they predict future diabetic retinopathy

A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: A Single-Arm Clinical Trial of Feasibility

PURPOSE: To assess the feasibility of a second-generation (44-channel) suprachoroidal retinal prosthesis for provision of functional vision in recipients with end-stage retinitis pigmentosa (RP) over 2.7 years. DESIGN: Prospective, single-arm, unmasked interventional clinical trial. PARTICIPANTS: Four participants, with advanced RP and bare-light perception vision. METHODS: The 44-channel suprachoroidal retinal prosthesis was implanted in the worse-seeing eye. Device stability, functionality, and adverse events were investigated at approximately 12-week intervals up to 140 weeks (2.7 years) postdevice activation. MAIN OUTCOME MEASURES: Serious adverse event (SAE) reporting, visual response outcomes, functional vision outcomes, and quality-of-life outcomes. RESULTS: All 4 participants (aged 39-66 years, 3 males) were successfully implanted in 2018, and there were no device-related SAEs over the duration of the study. A mild postoperative subretinal hemorrhage was detected in 2 recipients, which cleared spontaneously within 2 weeks. OCT confirmed device stability and position under the macula. Improvements in localization abilities were demonstrated for all 4 participants in screen-based, tabletop, and orientation and mobility tasks. In addition, 3 of 4 participants recorded improvements in motion discrimination and 2 of 4 participants recorded substantial improvements in spatial discrimination and identification of tabletop objects. Participants reported their unsupervised use of the device included exploring new environments, detecting people, and safely navigating around obstacles. A positive effect of the implant on participants' daily lives in their local environments was confirmed by an orientation and mobility assessor and participant self-report. Emotional well-being was not impacted by device implantation or usage. CONCLUSIONS: The completed clinical study demonstrates that the suprachoroidal prosthesis raises no safety concerns and provides improvements in functional vision, activities of daily living, and observer-rated quality of life. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Cultivar-specific wheat-associated bacterial communities and metabolites in response to nitrogen deficiency

Background and Aims: Nitrogen (N) deficiency in soil constrains plant growth, which beneficial soil bacterial communities may potentially alleviate. However, there is limited knowledge of the plant-bacteria interactions of wheat cultivars with different N-use efficiency (NUE) under N deficiency. Methods: We investigated the responses of soil and root endosphere bacterial communities as well as root metabolites of two wheat cultivars (cv. Mace and Gladius) with reported high and low NUE, respectively, using a glasshouse experiment and a hydroponic experiment with three N levels. Results: The rhizosphere bacterial community of Mace shifted under N deficiency but not in its root endosphere. Conversely, the rhizosphere bacterial community of Gladius remained unchanged under N deficiency but shifted in its root endosphere. The metagenomic analysis illustrated increased detection of genes related to bacterial growth and motility in the rhizosphere of Mace, but not of Gladius, under N deficiency. A four-fold increase in octadecanoic acid in the root of Mace, but not Gladius, under N deficiency, suggesting the potential role of octadecanoic acid in shaping the rhizobacterial community in Mace with higher reported NUE. Conclusion: Our study highlights the divergent responses of wheat-associated microorganisms and root metabolites to N deficiency in the two cultivars. We found that wheat cultivars with higher NUE increased octadecanoic acid secretion, potentially shaping the rhizobacterial communities and enhancing their growth under N-limited conditions

Costs and Benefits of the Melbourne Mobile Stroke Unit Compared with Standard Ambulance: Causal Analysis Using Observational Linked Data

BACKGROUND: Evidence of the cost implications and health outcomes associated with the use of mobile stroke units (MSU) is required to support their utilization. We aimed to evaluate the causal effect of the use of an MSU compared with a standard ambulance on hospitalization costs and 90- to 180-day health outcomes. METHODS: Causal effect estimation was performed using patient-level data from a cohort of patients with stroke in 2018 identified from the Australian Stroke Clinical Registry (Victoria) and Melbourne MSU. These data were linked to Ambulance Victoria and government-held administrative data sets. In total, linked data from 8657 patients were available. Propensity score matching was used to define comparator groups within a target trial framework. Costs included emergency department and hospital admission costs in the first 180 days after stroke. Multivariable regression analyses of the matched data were used to compare costs and outcomes (mortality and modified Rankin Scale) between MSU and standard ambulance groups. RESULTS: The target trial sample included 96 patients transported by the MSU (intervention) and 198 patients transported by standard ambulance services (control). Of these, the mean age was 76 years and 157 (53%) were men. A greater proportion of patients received mechanical thrombectomy in the intervention group than the control group (40% versus 23%; P<0.001). The adjusted hospital costs were $17 949 greater in the intervention group than the control group (95$4682-$31 214; P=0.01). Patients in intervention group doubled the odds of achieving nondisability (modified Rankin Scale scores of 0-1, adjusted odds ratio of 2.11 [95% CI, 1.07-4.18]) and halved the mortality rate (adjusted hazard ratio, 0.53 [95% CI, 0.32-0.86]) within 90 to 180 days poststroke compared with the control group. CONCLUSIONS: There are important cost implications and improved outcomes from using the MSU that are likely related to increased provision of reperfusion therapy

Association of chemotherapy dose intensity and age with outcomes in patients with Ewing's family sarcoma

BACKGROUND: Ewing's family sarcoma (EFS) is an aggressive malignancy with a peak incidence in adolescents. Multimodal treatment involves surgery and/or radiotherapy, and chemotherapy typically with VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide). There is a paucity of data for the treatment of adults, with protocols extrapolated from the pediatric setting. This study aimed to assess patterns of care, chemotherapy tolerability across age groups, and outcomes from four Australian sarcoma centers. METHODS: ANZSA ACCORD sarcoma database and medical records were used to identify and collect data of patients aged ≥ 10 years with EFS who received VDC/IE between 2010 and 2020. Survival outcomes were analyzed based on chemotherapy received dose intensity (RDI). Clinical predictors of RDI were explored using logistic regression. RESULTS: Of 146 patients with EFS, 76 received VDC/IE. The majority had localized disease (65%). Seventy-one percent completed scheduled chemotherapy, with some requiring dose reduction (29%), delay > 7 days (65%), or cycle omission (4%). Hematological toxicity was the main reason for dose reduction/delay. Fifty-seven percent patients achieved an acceptable RDI ≥85%. Compared to those aged 10-19, the odds ratio for acceptable RDI aged 40-59 was 0.20 (95% CI 0.04-0.86, p = 0.04). RDI was an independent prognostic factor for overall survival, after accounting for age, gender, Ewing's type, primary site, and stage (adjusted HR 0.25 [95% CI 0.10-0.63], p = 0.004). CONCLUSION: Survival outcomes in EFS were associated with chemotherapy RDI. Older adults more commonly required dose reduction or early cessation of treatment due to toxicity. VDC/IE chemotherapy should be carefully tailored in adults > 40 years

Systems serology analysis shows IgG1 and IgG3 memory responses six years after one dose of quadrivalent HPV vaccine

The WHO has given a permissive recommendation for an off-label one-dose human papillomavirus (HPV) vaccine schedule to prevent cervical cancer, based on evidence of comparable protection to two or three doses of vaccine. While neutralizing antibodies are thought to be the primary mechanism of protection, the persistence of immunity and whether other antibody-mediated mechanisms of protection are involved is unclear. Using systems serology, we investigated HPV antibody responses in serum from Fijian girls who were unvaccinated or received one, two or three doses of quadrivalent HPV vaccine six years earlier. We also evaluated their HPV antibody responses 28 days following a dose of bivalent HPV vaccine. After six years, one dose induced lower antibody concentrations but similar antibody profiles and phagocytic function as two or three doses. Following bivalent vaccine, antibody concentrations, particularly IgG1/IgG3, antibody profiles and phagocytic function were similar between previously vaccinated girls, indicating immune memory after one dose. Cross-reactive antibody responses against non-vaccine genotypes (HPV31/33/45/52/58) were lower following one dose than two or three doses. These findings provide novel insights into serological immunity and recall responses following one-dose HPV vaccination

Optimised modular anti-FLAG CAR T cells for solid tumor therapy

Objectives: Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of B cell malignancies and show promise in other diseases, including autoimmune disorders and cardiac injury. However, broader application, particularly in solid tumours, is limited by challenges such as antigen escape and tumour heterogeneity. This study aimed to develop an anti-FLAG CAR capable of engaging FLAG-tagged secondary reagents, providing a flexible and adaptable targeting strategy. Methods: We engineered a humanised anti-FLAG CAR to engage FLAG-tagged secondary reagents. The initial construct exhibited tonic signalling, which was addressed through structural optimisation. Therapeutic efficacy was assessed in solid tumour mouse models expressing either FLAG or a FLAG-tagged secondary targeting reagent. Results: The initial anti-FLAG CAR showed functional activity but exhibited tonic signalling and exhaustion, limiting its therapeutic utility. Structural optimisation significantly reduced exhaustion and improved T cell persistence and functionality. The optimised CAR T cells effectively inhibited tumour growth in models using either FLAG- engineered tumour cells or a FLAG-tagged secondary targeting reagent. Conclusion: Our findings underscore the importance of CAR design in minimising exhaustion and enhancing therapeutic efficacy. This work supports a modular CAR T cell platform with the potential to overcome tumour antigen heterogeneity and immune evasion in solid cancers