Vegetation restoration in semi-arid sandy ecosystems can alter soil sulfur cycling not only through changes in sulfur stocks, but also through shifts in the partitioning between organic sulfur and sulfate and their microbial regulation. Here, we investigated soil sulfur pool allocation and sulfur-cycling functional potential along a five-stage vegetation restoration gradient in the Mu Us Sandy Land by integrating sulfur fraction measurements with metagenomic analyses. Vegetation restoration markedly reshaped the soil physicochemical and microbial context, as reflected by lower pH and higher TN, microbial biomass carbon, and enzyme activity in restored soils. In contrast, sulfur pools responded asynchronously: total sulfur and organic sulfur declined substantially from bare sandy land to restored vegetation types, whereas sulfate showed a weaker and comparatively more stable response. At the functional level, dominant sulfur-cycling genes were generally more abundant in bare sandy land, declined across restored vegetation types, and showed only partial recovery in forestland, indicating that restoration reorganized sulfur-cycling functional composition rather than uniformly enhancing sulfur-cycling potential. Taxonomically, dominant sulfur-cycling genes were consistently affiliated mainly with Actinomycetota and Pseudomonadota, but restored vegetation types exhibited more partitioned host compositions, with greater contributions from Acidobacteriota, Chloroflexota, and, for some genes, Thermoproteota. MAG-based analyses further showed that key sulfur-cycling genes were phylogenetically widespread but unevenly distributed across specific host lineages. Co-variation and Mantel analyses showed that sulfur-cycling genes formed coordinated functional modules and were most strongly associated with soil sulfur pools and fractions. Overall, vegetation restoration in the Mu Us Sandy Land primarily reshaped sulfur allocation and sulfur-cycling functional potential rather than promoting simple sulfur accumulation. These findings highlight that sulfur recovery in sandy drylands is better characterized by pool reallocation and functional reorganization.
A key knowledge gap exists in understanding how the decomposition of litter from different halophyte species influences microbial community dynamics in soils. This study addressed this gap through a 180-day laboratory microcosm experiment investigating the effects of leaf litter decomposition from three halophytes (Kalidium cuspidatum, Nitraria tangutorum, and Reaumuria songarica) on soil biogeochemical properties, microbial dynamics, and community compositional constancy. The main research results indicate that at 180 days, the leaf mass loss (Mm) of the three halophytes reached 40.09%-42.89%, and the decomposition constants (k) were all < 0.2. Leaf total nitrogen, lignin, and carbon/nitrogen ratio directly regulated the decomposition process. Decomposition significantly increased soil nutrient pools, including total organic carbon (57.64%-100.12%), total nitrogen (51.92%-129.80%), dissolved organic carbon (44.35%-224.40%), and dissolved organic nitrogen (24.15%-238.58%), relative to bulk soil. Microbial carbon limitation increased by 21.81%-37.99%, while nitrogen limitation was alleviated, as evidenced by a 67.86%-92.28% increase in the vector angle of enzyme stoichiometry. These changes were driven by soil chemistry (explaining 45.47% of the variance) and microbial traits (42.31%-65.77%). Plant litter decomposition reshaped the structure of bacterial and fungal communities while reshaped the structure, which was linked to microbial biomass carbon, β-glucosidase, and alkaline phosphatase (p < 0.05). Furthermore, partial least squares path modeling revealed that plant litter decomposition increased soil organic resources, thereby exacerbating microbial carbon limitation; yet, along with microbial biomass, it also influenced microbial community composition. These results underscore species-specific litter effects on soil-microbe feedbacks in a controlled microcosm, emphasizing the role of resource stoichiometry and enzymatic activity in shaping microbial community in saline ecosystems.
This study aimed to explore the sex-specific regulatory effects of empagliflozin on gut microbiota in male and female diabetic kidney disease (DKD) mice, and to elucidate the underlying renoprotective mechanisms. Four-week-old db/db mice and C57 mice were randomly assigned to six groups. Following 8 weeks of empagliflozin gavage, serum metabolic indices and urinary albumin-to-creatinine ratio (ACR) were measured. Renal pathological alterations were evaluated via hematoxylin-eosin and Masson's trichrome staining. Gut microbiota diversity and community composition were analyzed using 16S rRNA gene sequencing, and Spearman's rank correlation analysis was performed to assess associations between dominant microbial taxa and metabolic/renal parameters. ACR levels were significantly elevated in db/db mice compared to sex-matched C57 controls, with male db/db mice exhibiting significantly higher ACR than females. Empagliflozin significantly reduced ACR in db/db mice, albeit ACR remained significantly higher in males than females post-treatment. Meanwhile, empagliflozin ameliorated glomerular hypertrophy and mesangial proliferation. Pronounced sexual differences were observed in gut microbiota diversity of db/db mice, with female mice displaying significantly higher microbial richness than males. Empagliflozin effectively reshaped gut microbiota composition and alleviated microbial dysbiosis in db/db mice, with these regulatory effects showing distinct sex specificity. Furthermore, several dominant microbial taxa (e.g., Rikenellaceae_RC9_gut_group, Parabacteroides, Klebsiella) were identified to be significantly correlated with ACR, and these correlations were sex-dependent. Empagliflozin significantly reduces ACR levels and modulates gut microbial richness and diversity in db/db mice, with distinct sex-specific effects on microbiota composition. Ultimately, these findings suggest that empagliflozin may exert renoprotective effects in DKD by reshaping gut microbial community structure.
This report presents a 6-year antigen-based surveillance of pediatric viral gastroenteritis in Turkey, revealing substantial epidemiological shifts during and after the coronavirus disease 2019 (COVID-19) pandemic. Adenovirus circulation was strongly affected by COVID-19-related public health restrictions, showing a marked decline during restriction periods. However, rotavirus exhibited a relative increase in 2021 despite ongoing restrictions, followed by a more pronounced rise after the relaxation of measures, aligning with the "immunity debt" hypothesis associated with altered early-life viral exposure. These findings illustrate how pandemic-related interventions reshaped the circulation of enteric viruses and underscore the value of routine rapid antigen testing for detecting post-pandemic resurgences, which is underexplored in the literature. In der vorliegenden Arbeit wird eine 6 Jahre dauernde antigenbasierte Beobachtungsstudie zur pädiatrischen viralen Gastroenteritis in der Türkei vorgestellt, mit dem Ergebnis wesentlicher epidemiologischer Verschiebungen während und nach der COVID-19-Pandemie. Die Verbreitung von Adenoviren war durch Gesundheitsvorschriften aufgrund von COVID-19 stark eingeschränkt – mit einer deutlichen Abnahme während der Phasen mit geltenden Restriktionen. Rotaviren wiesen jedoch im Jahr 2021 trotz weiterhin geltender Restriktionen einen relativen Anstieg auf, mit einem anschließenden deutlicheren Anstieg nach Lockerung der Maßnahmen – in Einklang mit der Hypothese der „Immunitätsschuld“ in Zusammenhang mit veränderter Virusexposition in einem frühen Lebensabschnitt. Diese Ergebnisse zeigen, wie pandemiebezogene Maßnahmen die Verbreitung von Darmviren neu gestalten und unterstreichen den Wert der routinemäßigen schnellen Antigentestung zur Erkennung des postpandemischen Wiederauftretens, das in der Literatur noch zu wenig erforscht ist.
Mining-induced rare earth elements (REEs) pollution in agricultural soil threatens food security, necessitating effective remediation strategies. Foliar-applied nanoparticles (NPs) offer a promising approach, while their potential in alleviating REEs-induced stress in crops remains insufficiently understood, particularly the systemic phytohormone-mediated responses and associated microbiome assembly that are crucial for plant resilience. Here, we demonstrated that SiO2-NPs and MnO2-NPs (0.5 and 1.25 mg/day/plant) significantly promoted lettuce growth (up to 3.02-fold) and reduced REEs accumulation (up to 74.0%/91.2% in roots/shoots). Concurrently, plant nutritional status and photosynthesis activity were improved, with SiO2-NPs specifically contributing to enhanced energy homeostasis. Gene set enrichment analysis (GSEA) revealed that NPs treatments activated plant resistance system, with SiO₂-NPs specifically promoting the biosynthesis of stress resistance-related compounds and MnO₂-NPs tending to regulate phytohormone signal transduction process. Crucially, these transcriptional responses were closely correlated to multiple phytohormones modulated by NPs in both shoots and roots, including auxin and jasmonates, as identified by weighted gene co-expression network analysis (WGCNA). Furthermore, NPs reshaped phyllosphere and rhizosphere microbiomes, such as Pseudomonadota, Cyanobacteriota and Bacillota. Notably, rhizosphere microbiome exhibited a strong correlation with phytohormone levels in shoots and roots, revealing the existence of a hormone-microbiome regulatory network that facilitates whole-plant adaptation to REEs stress. These findings underscore the pivotal role of NPs-induced phytohormonal signaling in coordinating shoot-root stress resistance and modulating microbiome composition under REEs contamination, providing mechanistic insights for developing NPs-based strategies to safeguard food production.
Polyphenols from Saskatoon berry are promising functional ingredients, yet their value depends on stability during processing, digestion, and transepithelial transfer. This study evaluated freeze-dried inulin (INU) and inulin/galactooligosaccharide (INU/GOS) matrices as carriers for purified Saskatoon berry phenolics. Powders containing 5-25% GOS were characterized by SEM, simulated gastrointestinal digestion, Caco-2 transport, antioxidant and anti-inflammatory assays, prebiotic testing, and cytocompatibility assessment. Initial phenolic retention remained high (88.5-92.7%). Digestion markedly reshaped the profile: apparent total polyphenol bioaccessibility reached 106.2-122.6%, anthocyanins were the least stable fraction, and phenolic acids together with selected flavonols dominated the post-digestive pool. Transepithelial transfer was selective; INU90:GOS10 showed the most favorable overall transfer profile, whereas INU80:GOS20 yielded the highest absolute phenolic content after transport. GOS-containing systems improved selected antioxidant, anti-inflammatory, and prebiotic responses, while pure inulin showed the highest cytocompatibility. Overall, carrier composition modulated the post-digestive functionality of Saskatoon berry polyphenols.
Soil salinity is a pervasive abiotic stress that severely constrains global crop productivity, demanding sustainable biotechnological solutions. This study characterized Vreelandella salis strain PAMB 3232ᵀ, a novel species of halophilic endophytic bacterium isolated from the shoot of the halophyte Suaeda maritima. Polyphasic analyses confirmed the taxonomic delineation of PAMB 3232ᵀ. This strain exhibits remarkable halotolerance, sustaining growth in up to 24% (w/v) NaCl. Genomic analysis revealed an enrichment of genes associated with metabolic resilience, particularly those involved in carbohydrate and amino acid metabolism, as well as cofactor and vitamin biosynthesis. Inoculation with strain PAMB 3232ᵀ significantly enhanced growth in Brassica rapa, increasing the shoot fresh weight by 26% under non-saline conditions and by 17.0% under salinity stress (200 mM NaCl). Physiological analyses further indicated enhanced stress tolerance, reflected by improved K+/Na+ homeostasis and reduced malondialdehyde (MDA) accumulation. Moreover, rhizosphere microbiome profiling revealed that inoculation reshaped the rhizosphere microbial community. Under salinity, the rhizosphere network showed increased connectivity and modularity, with Pseudomonadota serving as key hubs and enrichment of beneficial Bacillota. Collectively, these results indicate that V. salis PAMB 3232ᵀ enhances crop salt tolerance via coordinated physiological and microbiome-mediated effects, supporting its potential as a microbial inoculant for salt-affected agriculture.
Characteristic lipid-derived flavors in pre-prepared meat products are often diminished during reheating. This study examined how structural phase transition (SPT)-aligned preheating enhanced the generation of lipid-derived volatile compounds in cooked meat. Volatilomic analysis revealed that SPT-aligned preheating markedly reshaped the lipid-derived volatile profile of cooked Tan lamb meat, with SPT1-aligned preheating effectively enhancing the generation of hexanal, heptanal, 2-pentylfuran, octanal, 3-octanone, 1-octanol and 1-octen-3-ol. Quantitative lipidomics revealed that SPT1-aligned preheating accelerates the hydrolysis of phosphatidylcholine species containing polyunsaturated acyl chains, resulting in the accumulation of C18:2, C20:4, C22:4, C20:3, and C22:5, which are subsequently oxidized during heating to enhance lipid-derived flavor formation in cooked Tan lamb meat. Collectively, these findings illustrate a mechanistic pathway in which SPT1-aligned preheating induces phosphatidylcholine hydrolysis to enhanced generation of lipid-derived volatile compounds, providing a scientific basis for optimizing thermal interventions to improve lipid-derived volatile compounds in cooked meat.
Some probiotic microorganisms have been proven to offer several health benefits. However, there are few reports on lactic acid bacteria with cholesterol-lowering and antioxidant activities in vitro and on their probiotic effects on hosts. This study screened and identified probiotics with cholesterol-lowering activity in vitro and researched their antioxidant activity and probiotic property in vitro, along with their beneficial effects on high-fat diet-induced rats in vivo. The cholesterol-lowering rate in the cell-free supernatant was used to evaluate the cholesterol-lowering activity of isolates. Tolerance to acid and bile salt and antibacterial activity were assessed to investigate their potential probiotic characteristics, and antibiotic susceptibility was evaluated. DPPH and hydroxyl radical scavenging rate of cell-free supernatant was used to evaluate the antioxidant activity in vitro. Body mass, Lee's index, liver index, blood lipid, liver enzymes levels, histological analysis of liver and pancreas, gut microbiota structure, and short-chain fatty acids were used to evaluate the beneficial effects on high-fat diet-induced rats. A strain with 71.2 ± 0.9% cholesterol-lowering rate was screened and identified as Lactobacillus rhamnosus GL68, and its acid and bile salt tolerance were, respectively, 92.1 ± 4.3% and 88.3 ± 3.2%, and it has antibiotic susceptibility. DPPH and hydroxyl radical scavenging rates were 84.6 ± 1.3% and 79.3 ± 1.1%, respectively. Administering L. rhamnosus GL68 to the high-fat diet group significantly reduced weight gain, Lee's index, and liver index by 22.01, 17.71, and 19.35%, respectively. Additionally, it downregulated total cholesterol, total triglycerides, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate aminotransferase levels by 29.88, 52.89, 27.51, 26.10, and 26.27%, respectively. Furthermore, it raised high-density lipoprotein cholesterol levels by 20.03%. Administering L. rhamnosus GL68 upregulated liver superoxide dismutase and glutathione peroxidase levels by 41.39 and 71.02%, respectively. It downregulated liver malondialdehyde levels by 37.82%. Administering L. rhamnosus GL68 ameliorated hepatic inflammation and ballooning degeneration, glandular atrophy, and vesicular degeneration. It also reshaped gut microbiota at the genus level, and showed a positive correlation with short-chain fatty acids in the feces of high-fat diet rats. L. rhamnosus GL68 with cholesterol-lowering and antioxidant activity in vitro can be used as a potential probiotic to administer high-fat diet-induced lipid metabolism disorder and gut microbiota disorders, and alleviate liver and pancreatic damage.
Upconversion nanoparticles (UCNPs) have evolved from niche photophysical systems into multifunctional platforms with growing relevance in biomedicine. Their ability to convert near-infrared (NIR) excitation into higher-energy emission enables deep tissue interrogation with minimal background and high photostability, offering clear advantages over conventional probes. This review revisits the field from a design-oriented perspective, reflecting how recent advances in synthesis, photophysical understanding, and nanoengineering have reshaped the relationship between UCNP structure and biomedical performance. Combining properties and applications highlight how rational control over architecture and interfaces governs functionality in complex biological environments. This evolving framework is discussed across major application domains, alongside emerging directions that extend UCNPs beyond passive imaging toward active and programmable systems. Despite substantial progress, key challenges persist in achieving high brightness under safe excitation, ensuring predictable biological behavior, enabling safe clearance, and improving reproducibility. Addressing these limitations through integrated material and system-level design will be critical for translating UCNPs into reliable biomedical technologies.
Immunotherapy has reshaped cancer treatment, yet its efficacy in many solid tumors remains limited by an immunosuppressive microenvironment and insufficient antigen presentation. As a central gatekeeper of antitumor immunity, the cGAS-STING pathway represents a key axis for converting tumor-intrinsic stress into productive immune priming. Here, we propose an integrated strategy that couples immunogenic tumor cell death with tumor-restricted cGAS-STING activation and adjuvant-amplified innate signaling. Cuproptosis, a recently identified copper-dependent cell-death program, can act as an endogenous trigger of tumor-intrinsic cGAS-STING activation, providing a promising avenue to link cytotoxicity with immune stimulation. We engineered a biomimetic, tumor-responsive nanoplatform (Cu-R837@CM) by co-assembling Cu2+ with the TLR7 agonist R837 and cloaking the core with homologous tumor cell membranes to enhance tumor targeting and intratumoral retention. In vitro, Cu-R837@CM released Cu2+ under acidic conditions, inducing glutathione depletion and ROS accumulation, promoting DLAT aggregation and mitochondrial dysfunction, increasing intracellular 2'3'-cGAMP, and activating cGAS-STING signaling. Concurrently, R837 enhanced dendritic-cell maturation and cytokine production, thereby improving antigen presentation. In vivo, Cu-R837@CM markedly inhibited tumor growth, increased CD4+/CD8+ T-cell infiltration, and remodeled the tumor immune microenvironment toward an antitumor phenotype. Notably, combining Cu-R837@CM with PD-L1 blockade achieved complete tumor regression and significantly prolonged survival. Collectively, Cu-R837@CM offers a clinically translatable nanoadjuvant paradigm that integrates cuproptosis-driven cGAS-STING activation with TLR7 co-stimulation for hepatocellular carcinoma immunotherapy.
CD8⁺ T cells mediate host defense and tumor immunity through specialized differentiation states, yet the regulatory programs that guide these states may also limit their functional potential. Loss-of-function studies have defined many regulators required for T cell differentiation, but they do not readily reveal regulatory activities that emerge only when transcription factors are ectopically expressed outside their native lineage, dosage, or temporal context. Here, we developed single-cell gain-of-functon(GOF) sequencing (scGOF-seq), a multiplexed platform for in vivo mapping of transcription factor overexpression in antigen-specific CD8⁺ T cells across immunocompetent models of infection and cancer. By enforcing expression of canonical T cell regulators, lineage-silenced developmental factors, and temporally restricted transcription factors, scGOF-seq uncovered unexpected in vivo activities. Developmental regulators normally silenced in T cells, including NANOG, SOX2, OCT4 and GATA2, reshaped T cell differentiation in context-dependent ways, with NANOG promoting stemness-associated phenotypes and accumulation during chronic infection. In parallel, sustained cMyc expression outside its native temporal window generated a stem-like, effector-featured state with enhanced metabolic fitness, reduced terminal exhaustion, and profound antigen-dependent expansion exceeding 5,000-fold. Importantly, cMyc GOF maintained cell-cycle checkpoint signatures and demonstrated a strong dependence on antigen presence for proliferation across the tested conditions. scGOF-seq further identified cooperating transcription factor modules that complemented cMyc-driven programs and improved T cell responses in solid tumors. These findings establish systematic GOF perturbation as a framework for uncovering latent and temporally constrained regulatory activities in CD8⁺ T cells and guiding immune-state engineering.
Dicliptera chinensis (L.) Juss. is a herbaceous plant renowned for its anti-inflammatory and antioxidant properties. Previous studies have demonstrated that its polysaccharide (DCP) exerts hepatoprotective effects, yet the underlying mechanism by which DCP alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study investigated the hepatoprotective effects of DCP in high-glucose and high-fat (HHF) diet-induced MASLD mice and AML12 hepatocytes, with a focus on miRNA-mediated regulatory mechanisms. Small RNA sequencing revealed that miR-3073b-5p was significantly upregulated in MASLD. Dual-luciferase reporter assays verified the direct binding of miR-3073b-5p to the 3'UTR of CAMKK2, and RIP assays further confirmed their interaction under physiological conditions. In vivo, DCP administration significantly ameliorated hyperglycemia, dyslipidemia, hepatic steatosis, and oxidative injury. 16S rRNA sequencing and bile acid metabolomics analyses demonstrated that DCP effectively reshaped the gut microbiota composition and restored bile acid metabolic homeostasis. In vitro, DCP downregulated miR-3073b-5p expression, thereby relieving the suppression of CAMKK2, regulating the AMPK/mTOR/Nrf2 signaling axis, restoring autophagy, and counteracting ferroptosis. These findings indicate that DCP alleviates MASLD by regulating miR-3073b-5p/CAMKK2 via the gut microbiota-bile acid axis, positioning it as a promising natural polysaccharide for MASLD therapy and providing a novel molecular target for the targeted intervention of this disease.
Hantaviruses are not emerging pathogens in the strict sense, but their public health relevance is being reshaped by climate change, environmental disruption, land-use change, and increasing human mobility. In Southeast Europe, where Dobrava-Belgrade virus and Puumala virus remain endemic, these infections should no longer be viewed only as sporadic rodent-borne diseases of rural or forested environments. Changing ecological conditions can alter reservoir abundance, virus circulation, and human exposure, while fragmented surveillance and variable diagnostic capacity may obscure the true burden of disease. Although human infection is still driven primarily by environmental exposure to infected rodent excreta, rare person-to-person transmission of Andes virus and recent travel-associated clusters illustrate how traditionally localized zoonoses can acquire wider international relevance. This Opinion argues that hantaviruses should be approached as a climate-sensitive One Health challenge, requiring closer integration of human, veterinary, ecological, and meteorological surveillance. Strengthening regional preparedness is essential before environmental change further expands the conditions for transmission.
Minimally invasive surgery (MIS) has reshaped modern operative care by reducing tissue trauma and accelerating recovery compared with open procedures. Despite extensive research, inconsistencies remain across specialties regarding recovery outcomes and comparative effectiveness, and open surgery remains necessary in selected complex cases where minimally invasive access may be unsuitable or unsafe. This systematic review aimed to evaluate and compare patient recovery following minimally invasive and open surgical approaches. A structured search was conducted across major databases for studies published between 2015 and May 2026, including randomized and observational comparative designs. Data were extracted using a standardized approach and synthesized narratively due to heterogeneity in study designs, surgical procedures, and outcome reporting. Key outcomes included length of hospital stay, postoperative pain, complication rates, operative time, and functional recovery. Findings indicated shorter hospital stay, reduced postoperative pain, and faster recovery in minimally invasive groups, while operative time and cost varied across procedures. Complication profiles favored minimally invasive approaches in many procedures, although differences were procedure-specific. Robotic-assisted approaches did not demonstrate uniform recovery superiority over conventional laparoscopic techniques. MIS enhances short-term recovery and supports improved patient outcomes and healthcare efficiency when applied to appropriate patients and procedures. Conventional open surgery continues to have an important role in technically demanding, advanced, or anatomically complex procedures. Further research should address long-term outcomes, cost-effectiveness, complication-specific endpoints, and technological integration to strengthen evidence-based clinical decision-making across diverse surgical populations and settings.
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults in Western regions, while India reports comparatively lower incidence rates. Bruton's tyrosine kinase (BTK) inhibitors, particularly ibrutinib and acalabrutinib, have reshaped CLL therapy by blocking B-cell receptor signalling pathways essential for malignant B-cell survival. Given the increasing use of BTK inhibitors in routine practice and the limited real-world Indian data, this study evaluates the clinico-safety profile of BTK inhibitors and identifies predictors of response and progression in a pragmatic clinical setting. This was a single-centre ambispective observational study conducted from June 2021 to June 2024 in patients diagnosed with CLL aged 18-70 years. The patients received ibrutinib (420 mg once daily) or acalabrutinib as per availability and physician decision. Among the 93 patients included, most were male and younger than typical Western CLL cohorts. Hematologic recovery rates were high, with normalisation of haemoglobin, platelet count, and leukocyte count seen in the majority within four to seven months of therapy. The overall median progression-free survival (PFS) was 14 months. BTK inhibitors have significantly improved therapeutic outcomes in CLL. Both ibrutinib and acalabrutinib demonstrated meaningful hematologic responses and prolonged disease control. Acalabrutinib showed superior tolerability and better treatment adherence. Expanding access to genomic testing and improving drug availability will be essential to optimise CLL care in India.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, mainly affecting older people. Targeted agents have reshaped first-line (1L) strategies, making real-world evidence important to complement clinical trials. To estimate the incidence of Italian patients initiating first-line CLL therapy (2019-2022) and describe demographics/clinical profile, treatment patterns, adherence, outcomes (overall survival [OS], time to next treatment [TTNT]), and healthcare costs from the perspective of the Italian National Health System (NHS). A retrospective observational study using administrative healthcare databases (~9 million residents) was conducted on CLL patients starting 1L therapy (index-date) for CLL. Baseline characteristics were assessed in the 12 months pre-index; follow-up was ≥12 months. Drug use, adherence (medication possession ratio), dose adjustments, OS, TTNT, and direct costs were analyzed with descriptive and multivariable methods. A total of 1479 patients initiated 1L therapy: 63.9% chemotherapy (CHT), 23.2% ibrutinib, 3.2% acalabrutinib, and 9.7% other regimens. CHT remained common, especially among older and more comorbid patients. Ibrutinib showed lower mortality versus CHT (HR 0.663; p=0.002) and longer TTNT (median not reached). Dose adjustments were frequent; extended refill intervals did not appear to reduce drug survival. Mean annual cost per patient was €38,573, mainly driven by drug acquisition; ibrutinib users had lower hospitalization and outpatient costs than other 1L groups. In Italian practice, ibrutinib was the main targeted 1L option and was associated with improved survival and delayed progression versus CHT. Despite higher drug costs, reduced hospital-based resource use suggests favourable overall clinical and economic impact.
Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through posttranslational modifications remains unclear. Methods: We used house dust mite (HDM)-induced asthmatic mice with multiomics analyses (metabolomics, posttranslational modification-proteomics, and chromatin immunoprecipitation sequencing) and validated findings through gene editing and adeno-associated virus interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. Phosphoenolpyruvate carboxykinase 2 (PCK2) succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered polyglutamine-binding protein 1 (PQBP1) lactylation at K223, enabling protein arginine methyltransferase 5 (PRMT5)/WD repeat domain 77 complex inhibition. This erased H4R3me2s repressive marks from proinflammatory gene promoters, particularly mitogen-activated protein kinase pathway genes, causing transcriptional derepression. Airway epithelium-specific Pqbp1 knockout reduced inflammation, goblet cell hyperplasia, and T helper 2 responses. Pck2-short hairpin RNA or oxamate treatment ameliorated asthmatic pathology. Conclusion: We identified a PCK2-lactate-PQBP1-PRMT5 axis linking metabolic reprogramming to epigenetic dysregulation in asthma. PCK2-K100 succinylation drives lactate accumulation, inducing PQBP1-K223 lactylation that inhibits PRMT5 and activates inflammatory genes, representing a therapeutic target for asthma.
Cannabis use is increasing globally, yet the immunological effects of Δ9-tetrahydrocannabinol (THC), the main intoxicating component of cannabis, remain incompletely understood. Given prior evidence that endocannabinoid signaling influences helminth immunity and type 2 inflammation, we investigated how sustained THC exposure alters immune responses to the helminth Nippostrongylus brasiliensis (Nb), which infects the lung and small intestine of mice. C57BL/6J mice were treated with THC (5 mg/kg/day) or vehicle for 14 days prior to helminth infection and assessed for parasite burden, innate immune cell and T cell responses, and transcriptional changes in lung eosinophils and macrophages. THC exposure did not significantly alter infection-associated weight loss or helminth burden; however, THC selectively restrained infection-induced circulating eosinophils and monocytes while increasing regulatory T cells. T cell activation assays showed reduced TNFα and IFNγ secretion in splenocytes from THC-treated infected mice. Bulk RNA sequencing showed that THC shifted lung eosinophils and CD11c⁺ lung macrophage-enriched cells from inflammatory, fibrotic, and costimulatory pathways toward stress and metabolic-adaptive transcriptional programs. Within the infected macrophage-enriched population, THC reduced CD80 expression while increasing MHC class II and antigen presentation-associated genes, suggesting a potential shift in macrophage-mediated T cell activation. Consistent with altered inflammatory and tissue remodeling-associated programs, immunofluorescent staining showed that THC mitigated infection-associated loss of lung collagen. Collectively, these findings indicate that THC reshapes the immune response to helminth infection by restraining innate and T cell effector responses while altering lung eosinophil and macrophage activation programs. THC reshapes helminth-induced type 2 inflammation by restraining inflammatory leukocyte responses and reprogramming lung eosinophils and macrophages.
Neutrophils are central mediators of innate defense in bone marrow, where infection rapidly reshapes local hematopoietic and immune niches. Here, we identify a subset of Mrgpra2+ neutrophils that supports antimicrobial immunity through neutrophil extracellular trap (NET) formation during bone marrow infection. Using a murine Staphylococcus aureus marrow infection model, we show that Mrgpra2 is enriched in neutrophil precursors and supports their survival and effector activation under infectious stress. Single-cell and bulk transcriptomics show that Mrgpra2+ neutrophils exhibit a transcriptional program enriched for NET formation and inflammatory signaling. Mechanistically, Mrgpra2 and TNFR signals converge on a PLC-Ca2+-PKC-NADPH oxidase axis to drive reactive oxygen species (ROS)-dependent NET release while preserving neutrophil viability. In vivo, Mrgpra2 deficiency impairs bacterial clearance, exacerbates tissue injury, and reduces the therapeutic benefit of β-defensin. These findings define a marrow neutrophil pathway that couples infection-derived signals with controlled NET deployment to preserve bone marrow immune homeostasis.