Exosomes derived from lung cancer cells play a critical role in modulating the tumour microenvironment, particularly through their effects on macrophage polarization. We investigated how exosomes from A549 lung adenocarcinoma cells, both unstimulated and stimulated with a toll-like receptor 4 (TLR4) agonist, influence the phenotype and function of THP-1 derived macrophages. We used differential centrifugation and immunobead assay to isolate exosomes. Exosomes from unstimulated A549 cells promoted a mixed M1/M2 macrophage phenotype with a bias towards M2 polarization, while exosomes from TLR4-stimulated A549 cells reduced M2 marker expression without affecting M1 polarization. Both types of exosomes increased macrophage phagocytic capacity compared to PMA-differentiated controls, but TLR4-agonists did not increase it further. These findings provide new insights into how TLR agonist-stimulated lung cancer-derived exosomes shape macrophage phenotypes and functions, with implications for understanding tumour-immune interactions and developing novel therapeutic strategies targeting the tumour microenvironment.

Polymers are promising catalyst supports because of their tunable composition and facile functionality. In this work, a core/shell polydopamine@crosslinked polystyrene support (XP-PDA) was first constructed, and silver nano-clusters were subsequently immobilized via in situ reduction to yield Ag@XP-PDA. Adsorption kinetic and temperature-dependent isotherm tests were conducted to compare the adsorption capacity of the catalysts toward the reactant p-chloronitrobenzene (P-CNB) and its corresponding hydrogenation product p-chloroaniline (P-CAN). At 298 K, Ag@XP-PDA reached adsorption equilibrium within 180 min, with distinct capacities of 38.5 mg g[-1] for P-CNB, whereas only 9.2 mg g[-1] for P-CAN. Increasing the temperature from 298 to 318 K enhanced the adsorption capacity for P-CNB (from 50.3 to 54.1 mg g[-1]) while suppressing that for P-CAN (from 15.3 to 11.6 mg g[-1]). This distinct temperature-dependent adsorption behavior indicates the chemisorption of P-CNB for substrate enrichment. Improved substrate adsorption and product desorption endow Ag@XP-PDA with over 90% P-CAN chemoselectivity at 318 K. Hence, the XP-PDA support enables both the stabilization of Ag nano-clusters and enrichment of the substrate, affording an efficient catalytic system for the selective reduction of P-CNB to P-CAN.

Chalcogenide/silicon monolithic tandem solar cells (SCs) are regarded as promising candidates for next-generation photovoltaic technology. Tunnel oxide passivating contact (TOPCon) technology, with its inherent resilience to high thermal budgets, is well-suited for the bottom cell in such tandems. To further mitigate parasitic light absorption and carrier nonradiative recombination losses in TOPCon when integrated into tandem devices, a wide-bandgap, nitrogen (N)-doped TOPCon structure is adopted in this work. We investigate its thermal stability after a high-temperature preparation process followed by post-annealing (300-600 °C, 10-30 min) on standalone TOPCon samples. The results indicate that Si-Hn bonds in the N-doped TOPCon structure are more prone to breakage during high-temperature processing than those in N-free counterparts, revealing fragile thermal stability. During post-annealing, substantial hydrogen released from the SiNx:H dielectric layer recombines with Si dangling bonds, significantly improving passivation performance. However, excess hydrogen accumulates at the localized Ag-Si contact interface, deactivating dopants and increasing contact resistivity on both sides after post-annealing of SCs, regardless of whether the TOPCon structure contains the N-dopant or not. A subsequent LECO (laser-enhanced contact optimization) treatment effectively reactivates the dopants and largely restores the electrical properties. These findings provide a foundation for optimizing N-doped TOPCon bottom SCs toward future integration into two-terminal monolithic chalcogenide/silicon tandem devices.

Sulfur is a promising high-capacity cathode but suffers from sluggish redox kinetics and severe side reactions in aqueous electrolytes. We introduce pnictogen chalcohalide Bi12.67S18Br2 nanorods (abbreviated as Bi-S-Br) as a multifunctional cathode material that functions as a sulfur/bismuth reservoir and a catalytic redox mediator (RM). By integrating a trace amount of iodide electrolyte additive, we demonstrate a potential pathway, featuring several redox couples with gradient potentials: I[0]/I[-] (0.530 V, RM1) > Bi[3+]/Bi[0] (0.308 V, RM2) > S[0]/S[2-] (0.144 V vs. standard hydrogen electrode), whose stepwise dual mediation accelerates sulfur redox kinetics. The sulfurphilic Bi-S-Br nanorods also strengthen surface Bi-S interfacial interactions, thus localizing active species and suppressing sulfur disproportionation. As a result, Zn||Bi-S-Br cells exhibit synergistic discharge plateaus at 0.66 and 0.59 V and deliver a high specific capacity of 792 mAh gBi-S-Br [-1] at 0.4 A g[-1], with an energy density of 488.2 Wh kg[-1] and a power density of 244.1 W kg[-1], normalized to the Bi-S-Br mass. The practical Zn||Bi-S-Br pouch cell configuration sustains 250 cycles at 0.8 mA cm[-2] with capacity retention of 70.1%. This study elucidated the successive redox mediation strategy for enhanced sulfur redox kinetics, offering a new design principle for high-performance aqueous energy storage systems.

Autophagy is a hallmark of aging, but it has not been exclusively targeted to attenuate aging-related physical dysfunction. Here, we combined Tat-Beclin1 and endurance training to determine its effect on physical function domains in aged male mice. Mice were randomly divided into Control (N = 5), Tat-Beclin1 (TB, 15 mg/kg, 2×/week, N = 9), Exercise (Exe, 70%-maximal-running-speed, 3×/week, N = 9), and TB+Exe (N = 8) for 1 month in 23-month-old male C57BL/6J mice. Animals were assessed for grip strength (GS), endurance capacity (EC) on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). Although no significant interaction was observed, the TB+Exe group showed improvements in GS, EC, and balance and coordination performance, an outcome comparable with additive effects of both therapies. Limited changes were observed in myofiber typing and autophagy markers among groups. A proteomic analysis revealed that TB upregulated biological processes involved in muscle contraction, whereas TB+Exe surprisingly upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. Altogether, combining TB and endurance training elicits additive effects on physical functions of aged male mice and may represent a new approach to attenuate aging-related physical dysfunction.

The abundance of diverse naive CD8[+] T cell clones is essential for broad protection against infection and cancer, but how sex and aging jointly shape this compartment remains poorly understood. Here, using mouse models with supporting human data, we uncover a sex-biased mechanism of immune aging in which early male-biased depletion of naive CD8[+] T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells combines with thymic involution, limiting naive CD8[+] T cell replenishment. These mechanisms led to more rapid lymph node contraction and reduced local naive T cell clone availability in males, limiting cancer antigen recognition. Therapeutic thymus regeneration via androgen ablation repopulated naive CD8[+] T cells in lymph nodes, reinvigorated cancer-specific T cell responses and enhanced responsiveness to immune checkpoint blockade in male mice. These findings reveal the impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged men.

Clinical prediction models are increasingly deployed to support diagnostic and prognostic decisions, making reproducibility essential for assessing their reliability and generalizability. Analytical code supports independent assessment of these processes, yet its availability in the literature remains limited. This scoping review quantifies current practices in sharing analytical code to inform the development of TRIPOD-Code, a reporting guideline for code availability and reproducibility. Here a large-language-model-assisted pipeline was developed to screen articles citing TRIPOD or TRIPOD+AI, extract repository links and assess retrieved repositories against 14 predefined reproducibility-related features. Among 3,967 articles, 482 (12.2%) included code-sharing statements. Sharing prevalence varied widely by journal and country. Repository assessment showed substantial heterogeneity in reproducibility features. These findings underscore the need for clearer expectations beyond code availability, including documentation, dependency specification and executable structure. Strengthening these practices may improve the usability of clinical prediction model studies and support their deployment in real-world clinical settings.

Phosphatidylinositol 3-kinase delta (PI3Kδ) promotes tumour cell growth directly or indirectly by activating immune-suppressive cells. In contrast to previous PI3Kδ inhibitors, roginolisib is a selective, non-ATP competitive inhibitor, which locks PI3Kδ into an inactive state and causes an allosteric modulation. In a First-in-Human dose study, continuous daily dosing of roginolisib was investigated in patients with solid and haematologic malignancies. In Part A, 24 patients received escalating doses of roginolisib. In Part B, 20 mostly pre-treated metastatic uveal melanoma (mUM) patients received a dose associated with continuous PI3Kδ inhibition of >90%. The primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) profile, clinical anti-tumour responses assessments. Exploratory endpoints included immunophenotyping, proteomics, genomics. No Dose Limiting Toxicity or drug related toxicities requiring dose modifications were observed (≥ Grade 3 toxicities: 3/44; 6.8%). In mUM, median Overall Survival (mOS) was 20.8 months (data-cut off December 2023) and 18.4 months (data-cut-off February 2026). mOS in mUM patients with Stable Disease at Week 16 (= Cycle 5) was 28.5 months, while patients who progressed at Week 16 had a median OS of 12.3 months. Roginolisib was safe, had a predictable PK profile, T regulatory cell abundance was decreased while activated CD8[+] T cells increased together with soluble plasma IL-15. ClinicalTrials.gov registration: NCT04328844.

The addition of a benzyloxy group to the adenosine A1R agonist cyclopentyladenosine (CPA) produces a compound (BnOCPA) that selectivity activates A1R signalling via the G protein alpha subunit Gob. In rat hippocampus, BnOCPA inhibits CA3-CA1 synaptic transmission (IC50 65 nM) likely via Gob, with no effect on Goa-mediated postsynaptic membrane electrophysiology at concentrations up to 1 μM. We have investigated how modifications of the benzyloxy group of BnOCPA affects signalling: addition of methoxy group, MBnOCPA, substituting a phenoxy group, PhOCPA; and addition of bromide to the phenoxy group, BPhOCPA. These derivatives, previously shown to be selective A1R agonists, were assessed through inhibition of hippocampal CA3-CA1 synaptic transmission and postsynaptic effects on CA1 pyramidal neurons. All compounds inhibited synaptic transmission and increased paired-pulse facilitation, indicative of presynaptic actions. At a concentration that inhibited synaptic transmission (>75 %), none of the compounds hyperpolarised the resting membrane potential and thus retained the pre- vs postsynaptic selectivity of BnOCPA. Increasing their concentration allowed a measure of the selectivity range. BnOCPA hyperpolarised ∼ 40 % of neurons at 3 μM (∼ 50x the IC50 for synaptic inhibition). For PhOCPA and MBnOCPA, hyperpolarisation, occurred for some neurons, at 1 μM. For BPhOCPA, no hyperpolarisation occurred at concentrations up to 10 μM. Pre-application of the derivatives (at 300 nM) reduced adenosine-mediated hyperpolarisation, showing they bind but do not activate postsynaptic A1Rs. This data shows that modifying the structure of BnOCPA changes the discrimination between different native A1Rs, likely based upon selective activation of G-protein coupling.

Obesity remains a global pandemic and a major driver of metabolic diseases, with current pharmacotherapies often limited by modest efficacy, systemic side effects, high costs, and weight regain after cessation. Targeting dietary lipid digestion via the inhibition of gastrointestinal lipases offers a mechanistically rational and peripherally acting therapeutic strategy. This review provides an updated, quantitative overview of human gastrointestinal lipolysis, emphasizing the sequential and complementary roles of human gastric lipase and human pancreatic lipase in dietary triglyceride absorption. We critically analyze the clinical proof-of-concept provided by Orlistat, the only approved digestive lipase inhibitor, whose utility is constrained by limited efficacy, significant gastrointestinal intolerance, and rare but severe hepatotoxicity. While next-generation systemic therapies like GLP-1 receptor agonists show superior weight loss, their chronic administration and high cost underscore the need for safer, localized alternatives. We systematically review recent strategies for developing superior digestive lipase inhibitors, including structure-based drug design, in silico screening, and bioguided fractionation of natural products (e.g., flavonoid derivatives). Emphasis is placed on the critical design principles required for next-generation inhibitors, including strict luminal confinement, high selectivity for digestive lipases, and controlled, reversible inhibition to improve tolerability. By bridging biochemical insights with pharmacological challenges, this review outlines a roadmap for the development of safer, more effective lipid-targeted therapies to combat obesity.