Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA), originally developed for type 2 diabetes mellitus and obesity, have attracted considerable attention in rheumatology due to their pleiotropic effects. Accumulating evidence indicates that GLP-1RA not only indirectly reduce inflammation through weight loss and metabolic improvement, but also directly act on GLP-1 receptors expressed on immune cells and musculoskeletal cells, exerting anti-inflammatory and tissue-protective effects independent of weight reduction. In recent years, several large real-world studies and randomized controlled trials have shown that GLP-1RA may improve disease activity and reduce cardiovascular events and mortality in osteoarthritis, rheumatoid arthritis (RA), psoriasis/psoriatic arthritis, and systemic lupus erythematosus (SLE). However, the available evidence has notable limitations: most studies are retrospective, with limited sample sizes; different GLP-1RA are often analyzed as a single class; the weight-loss effect is difficult to dissociate from direct anti-inflammatory action; and randomized controlled trials in non-obese, non-diabetic rheumatic patients are lacking. This review systematically summarizes the molecular mechanisms and clinical evidence of GLP-1RA in rheumatic diseases (including RA, psoriasis/psoriatic arthritis, osteoarthritis, and SLE), and based on this, the authors' perspective is put forward: currently, GLP-1RA should only be recommended for rheumatic patients with overweight/obesity or type 2 diabetes who also have high cardiovascular risk. Future research should prioritize head-to-head comparisons of different GLP-1RA, mechanistic studies independent of weight loss, and exploration of combination strategies. It is believed that GLP-1RA hold promise to usher in a new era of "metabolic-immune" synergistic intervention in rheumatology, but their benefits and risks must be carefully evaluated.

Inflammation is a fundamental protective response, yet its chronic form drives many non-communicable diseases. Conventional anti-inflammatory drugs carry significant side effects, prompting interest in natural alternatives such as pectin polysaccharides (PPs), which are generally recognized as safe, structurally diverse, and anti-inflammatory in preclinical models. This narrative review offers a comprehensive overview of anti-inflammatory PPs, from sources to functions. We discuss conventional and emerging green methods and their effects on yield, structural integrity, and bioactivity. Anti-inflammatory mechanisms are systematically covered, including modulation of canonical signaling pathways, cytokine networks, immune cell functions, oxidative stress, and gut microbiota-host crosstalk. Structure-activity relationships (SAR) are summarized across multiple scales. Source and extraction method influence PPs anti-inflammatory activity and structural properties, including molecular weight (Mw), monosaccharide composition, degree of esterification (DE), branching, and advanced conformation. Emerging techniques, such as physical wave-assisted, enzyme-assisted, and deep eutectic solvent, can maximize extraction efficiency while preserving structural integrity. PPs act through multimodal pathways, including modulation of gut microbiota, inhibition of key inflammatory signaling cascades, and enhancement of intestinal barrier integrity. Despite progress in elucidating structure-function relationships, challenges remain in conducting high-quality clinical trials, and translating PPs into functional foods or therapeutics is hindered by inconsistent product characterization, unclear dose-response relationships, and limited understanding of human-specific efficacy.

Bacterial symbionts play crucial roles in mosquito development and other features. Increasing evidence suggests that exposure to insecticides can modulate mosquito-associated microbiota, with potential implications for vector control strategies. The goal of this study was to compare the bacterial communities of Culex quinquefasciatus from a laboratory-susceptible (S) strain and a resistant (R) strain to the microbial larvicide Lysinibacillus sphaericus, and a field-collected sample (F) was included as an external reference. Additionally, we assessed whether larval exposure to L. sphaericus influences microbiota structure in laboratory strains. Our results revealed distinct bacterial composition across developmental stages and mosquito groups. Larvae from the S strain exhibited lower bacterial diversity compared to F samples, with Wolbachia and Thorsellia dominant taxonomic signatures, respectively. S females showed significantly higher bacterial diversity, with a marked reduction in Wolbachia relative abundance. In contrast, R and F females showed no changes. Within laboratory strains L. sphaericus treatment had a minor influence on the community of resistant individuals that kept a stable community dominated by Wolbachia throughout the life stages. In contrast S females surviving from larvicide exposure displayed a significant microbiota remodeling with enhanced diversity. Our findings indicate that L. sphaericus resistance phenotype seems to have a limiting effect of diversity found in both life stages, while susceptible females surviving L. sphaericus exposure showed a marked restructuring. Our results suggest that microbiota may act as a relevant component of the set of mosquito responses to microbial larvicides, suggesting modulation of the bacterial communities with potential effects on mosquito biology.

During an immune response, metabolism changes dramatically. Metabolites are oxidized to power immune cell functions, serve as building blocks for proliferation, and act as effectors to regulate pathogen or host cells. Though metabolic changes in cultured cells have been studied extensively, metabolism changes in vivo are less understood. Here, we measured metabolomic changes across six mouse tissues in three models of immune activation: CpG-DNA cytokine storm, lymphocytic choriomeningitis virus infection, and polyI:C viral mimetic injection; and carried out metabolomics in cultured macrophages activated with different stimuli. We found most metabolomic changes were exclusive to either inflamed tissues or cultured macrophages, although itaconate was strongly induced in both contexts. We then mechanistically dissected the role of the soluble sialic acid N-glycolylneuraminic acid, which is highly induced in inflamed tissues yet only modestly in cultured macrophages. This metabolite increases in tissues in different models of inflammation, and the analogous human metabolite, N-acetylneuraminic acid, rises in human patients experiencing inflammation. We found that N-glycolylneuraminic acid is produced in CD11b+ myeloid cells by cleavage of protein-bound sialic acid. However, blocking its production did not affect CpG-DNA liver inflammation or LCMV infection in mice. Therefore, these experiments identify soluble sialic acid as a conserved biomarker of inflammation in mice and humans and highlight the differences in metabolism between in vitro and in vivo models of inflammation.

The Warburg effect drives cancer cells to rely preferentially on glycolysis, resulting in diminished mitochondrial oxidative phosphorylation (OXPHOS). This metabolic phenotype limits the ability of excess copper (Cu) ions to trigger cuproptosis in dysfunctional mitochondria, leading to suboptimal therapeutic outcomes. Therefore, remodeling tumor energy metabolism to counteract the Warburg effect represents a pivotal strategy to enhance cuproptosis efficacy. Herein, we developed a Cu(I)-stabilized metal-organic framework nanoplatform (CuTz-1) encapsulated by Azurin (CuTz-1@Azurin) as a cuproptosis sensitizer. Mechanistically, Azurin increases p53 protein levels by intercepting MDM2-mediated ubiquitin-proteasome degradation. Elevated p53 subsequently inhibits pyruvate kinase M2 (PKM2) activity, suppressing glycolysis, while simultaneously promoting mitochondrial OXPHOS-collectively shifting cellular metabolism from glycolysis toward mitochondrial respiration and sensitizing tumor cells to Cu-induced proteotoxic stress. In addition, CuTz-1@Azurin triggers oxidative stress via reactive oxygen species (ROS) generation and glutathione (GSH) depletion, which act together with p53-mediated apoptosis to suppress tumor growth. Meanwhile, the oxidation of Cu(I) to paramagnetic Cu(II) enables real-time monitoring of the therapeutic process by magnetic resonance imaging (MRI). Both in vitro and in vivo results demonstrate good antitumor performance of CuTz-1@Azurin. This study highlights the potential of Azurin-mediated metabolic regulation as a promising strategy to potentiate cuproptosis for combined cancer therapy.

Environmental nitrogen pollution resulting from various sources (e.g., industrial/municipal wastewater and agricultural runoff) poses a tough global challenge. Traditional approaches for transforming nitrogenous contaminants to inert N2 are often restricted by large operational costs, high energy dependence, and severe reaction bottlenecks. Recently, the discovery of direct mechanobiological activation has inspired a new frontier emerged, highlighting the potential to promote nitrogen conversion via an unprecedented abiotic-biotic synergy enabled by ferroelectric and piezoelectric materials. While previous reviews have focused on either bioelectrochemical nitrogen transformation or piezocatalytic nitrogen conversion, there is no comprehensive discussion that integrates these two domains and elucidates their interfacial coupling mechanisms. This review is aimed to fill this gap by critically examining this synergistic paradigm. We dissect how these materials function dually: they act as abiotic catalysts that form localized electric fields and reactive species, directly activating nitrogen molecules, and simultaneously as biotic stimulators that electronically interface with microbes, enhancing their metabolic denitrification pathways. How this synergy breaks conventional limitations is elaborated. The abiotic pathway can generate favorable microenvironments or intermediates used by the biotic pathway, while microbial activity in turn prevents catalyst fouling. However, practical application requires addressing the critical challenge of energy mismatch with ambient environments. Thus, key emerging strategies are assessed, including photo-mechanical synergy using sunlight as the primary power source while weak mechanical forces restrict charge recombination, and flexoelectric effects that harvest energy from low-frequency non-uniform strains. Harnessing this abiotic-biotic synergy through next-generation concepts can offer a transformative method for sustainable nitrogen remediation.

Research examining artificial intelligence's (AI) role in food choice largely asks whether AI helps people make better decisions, treating it as an information source that improves the accuracy or personalization of recommendations. We suggest that this framing captures one point on a broader continuum of how AI impacts food decisions. AI can act, often simultaneously, as an advisor consulted for information, a decision partner that actively shares in constructing the choice, or an ambient influence that shapes what appears desirable and available before deliberate choice begins. As AI becomes more conversational and more embedded across the food environment, this continuum is increasingly populated in less visible regions, yet the field remains concentrated on the advisor role. We focus on the decision-partner role, where AI participates in value construction, goal clarification, attribute weighting, and choice justification, raising questions about agency, responsibility, and delegation. We articulate four mechanisms that describe this participation, namely preference offloading, responsibility reallocation, confidence calibration, and food-decision skill erosion. Because food choice is frequent, often habitual, and commonly involves trade-offs among hedonic and utilitarian goals, it is an ideal domain in which these process-level effects can compound. We draw on evidence from consumer psychology, automation research, and cognitive science, noting where boundary conditions remain untested in food contexts, and close with a research agenda organized around agency, reliance, responsibility, confidence, and cognitive effort. When AI shares in constructing a food choice, the values being optimized may no longer be entirely the consumer's own.

Nitric oxide (NO) and gibberellin (GA) antagonistically regulate plant cell elongation. Here, we report an unexpected observation that NO confers partial GA-insensitivity on hypocotyl elongation in Arabidopsis thaliana. We identify GASA13 and GASA14 as essential downstream specificity filters underlying this phenomenon. Loss-of-function of GASA13 or GASA14 converted the NO-mediated inhibition from a partially GA-insensitive state to a fully GA-reversible state, as revealed by hypocotyl phenotyping analyses. Both GASA proteins showed increased protein accumulation upon NO treatment and decreased accumulation upon GA treatment, while their transcript levels were also regulated by DELLA. Hormone profiling showed that NO modulated bioactive GA levels in a GASA-dependent manner. Transcriptomic analysis revealed that wild-type plants exhibited a focused NO response, whereas gasa13 and gasa14 mutants displayed broad, diffuse transcriptional signatures, indicating a loss of signal specificity. Further analysis of GA metabolic and cell wall-related genes supported the model that GASA13 and GASA14 restrict NO-induced transcriptional changes to a precise growth-suppressive program. We propose that GASA13 and GASA14 act as downstream transcriptional specificity filters that channel NO signals into a focused output, conferring partial GA-insensitivity. This work uncovers a novel regulatory layer of NO-GA crosstalk beyond DELLA stabilization, and provides a mechanistic framework for understanding how plants achieve signal specificity during growth regulation.

Isolated severe traumatic brain injury (TBI) is associated with high mortality and long-term morbidity, especially in low- and middle-income countries (LMICs). Despite promising results using pharmacological and non-pharmacological therapies in the experimental setting, no clinical trials have demonstrated robust efficacy. We aimed to investigate the effect of antisecretory factor (Salovum®) on 30-day mortality in adult patients with severe TBI. This was a prospective, double-blind, placebo-controlled phase 2 trial, conducted from September 2017 to February 2022 in a tertiary trauma centre (university hospital) in Cape Town, South Africa (www.clinicaltrials.gov: NCT03339505). The participants were adults with isolated severe TBI (Glasgow Coma Score 6-8), receiving intracranial pressure (ICP) monitoring and neurointensive care. Participants were administered either Salovum® (freeze-dried egg yolk powder enriched with the active compound antisecretory factor) or placebo (freeze dried egg yolk powder) via the nasogastric tubing, dosed according to weight (10-17 g/4 h) and initiated at 32.9 h ± 10.7 h (mean ± standard deviation) post-injury. Study drug or placebo were administered until the ICP monitor was removed or for a maximum of 5 days. The primary outcome of this trial was 30-day mortality and secondary outcome measures were therapy intensity level (TIL) and ICP. One hundred participants aged 18-61 were included, with 49 and 51 patients in the treatment and control groups, respectively. Most patients were male (96%) and the mean age was 33 years. The 30-day mortality rate was 20% in the treatment group and 39% in the control group, yielding a relative risk ratio of 0.52 (confidence interval: 0.271-0.997) and a P-value of 0.040 (chi-square test). TIL and ICP were similar in both groups. No significant adverse events were noted. Antisecretory factor significantly reduced 30-day mortality in severe TBI in an LMIC environment. Further studies investigating the mechanisms by which antisecretory factor act are warranted. The safety, easy administration and marked efficacy of antisecretory factor support exploration in multicentre randomized controlled trials.

Despite enormous expenditures in the research field, the electron-doped side of nickelate superconductors remains uncharted territory. Substituting the trivalent rare-earth cations by a tetravalent one hitherto failed. Here, we demonstrate by first-principles calculations a disorder-free route to electron dope Ruddlesden-Popper nickelates. When intercalating wide-band-gap insulating layers such as LaXO_{3} (X=Al, Ga, Sc) into La_{2}NiO_{4}, the extra (LaO)^{+} layers act as electron donors, releasing carriers into the Ni-3d orbitals. This electron doping puts La_{2}NiO_{4}:La_{2}AlO_{4} naturally in the optimal region for d_{x^{2}-y^{2}}-wave superconductivity with T_{c} exceeding 50 K. The same concept also allows us to electron dope La_{3}Ni_{2}O_{7}, the superconductor in the limelight.

Rho-like GTPases from plants (ROPs) constitute a plant-specific subfamily of Rho-family small GTPases. The Rho family is conserved among all eukaryotic cells, and includes the Rho, Rac and Cdc42 subfamilies found in fungi and animals. Like other GTPases, ROPs act as molecular switches that cycle between the inactive GDP-bound and active GTP-bound states, and are typically involved in cell signaling. Functional studies have demonstrated that ROPs play key roles in regulating processes such as the establishment of cell polarity, polar growth of cells (e.g., pollen tubes and root hairs), cell shape formation, and cell wall patterning. These processes depend upon cytoskeletal dynamics and vesicular trafficking, which are commonly regulated by Rho-family GTPases in many organisms. However, in plants, the upstream input and downstream regulatory outputs are highly diverse, and ROPs have evolved distinct regulatory mechanisms and specialized functions adapted to plant-specific processes, such as hormone signaling, stress responses, meristem maintenance, and tropic growth. Evolutionary analysis shows that ROPs are highly conserved in land plants, and are encoded by a small gene family, whose members can be functionally redundant or distinct. Thus, distinct ROPs can serve as major players in different cellular systems, allowing a shared regulatory mechanism to diversify into cell type-specific functions. By comparing representative models of polarized cell growth, we highlight how multiple ROPs regulate both shared and cell type-specific signaling pathways and discuss how ROPs achieve functional diversity and serve as targets of genetic manipulation for potential applications in synthetic biology and agriculture.

As pressure on urban water resources grows, roof-harvested rainwater is increasingly used for drinking and domestic purposes. However, changing roof infrastructure and expanding vulnerable populations may be introducing under-recognised public health risks. This study assessed the microbiological and physicochemical quality of domestic roof-harvested rainwater across Adelaide and the Adelaide Hills, South Australia. One hundred rainwater tanks were sampled, and 97 households completed a survey on rainwater use, system characteristics, wildlife presence and rooftop solar infrastructure. Most households used rainwater for drinking (67%) and gardening (76%), and 62% had rooftop solar panels. Quantitative PCR detected enteric and opportunistic pathogens in a proportion of tanks, including Campylobacter jejuni (13%), Pseudomonas aeruginosa (12%), Salmonella spp. (10%) and Shigella spp. (3%), with pathogens also present in tanks used for drinking. Between 1 and 4% of tanks exceeded Australian Drinking Water Guideline health values for cadmium, iron, manganese, lead and arsenic, while 1-11% exceeded aesthetic values for zinc, manganese, aluminium and sodium. In unadjusted analyses, elevated metal concentrations were associated with solar panel presence (p = 0.004) and tank type (p = 0.004). However, multivariable analysis adjusting for tank material showed that households with solar panels had lower odds of elevated metal concentrations (aOR = 0.265, p = 0.026), while metal tank construction was associated with increased odds of elevated metal concentrations (p = 0.031). These findings indicate that domestic rainwater systems can act as reservoirs of microbial and chemical hazards with potential implications for human health. As climate change and water insecurity increase reliance on alternative water sources, understanding and managing these risks will become increasingly important. Further research is needed to examine how evolving roof infrastructure affects contamination pathways and emerging risks, including antimicrobial resistance, within domestic rainwater systems.