Dihydromyricetin ameliorates experimental ulcerative colitis by inhibiting neutrophil extracellular traps formation via the HIF-1α/VEGFA signaling pathway.

Dihydromyricetin (DHM), which has various biological functions, possesses therapeutic potential for ulcerative colitis (UC). Neutrophil extracellular traps (NETs) and their components play a crucial role in several pathological processes in UC. However, whether DHM alleviates UC by regulating NETs remains unclear. Mice with dextran sulfate sodium (DSS)-induced acute colitis were treated with DHM at different concentrations, and the severity of colitis was evaluated by assessing body weight, colon length, histological scores, cytokine production, and epithelial barrier integrity. To quantify and visualize NETs, the expression of cell free-DNA (cf-DNA) in serum and Cit-H3 in colonic tissue was analyzed via western blotting and immunofluorescence analysis. HL-60 cells and mouse bone marrow-derived neutrophils (BMDNs) were used to evaluate the effects of DHM on NETs in vitro. NETs were treated with DHM at varying concentrations or DNase I and used to repair the intestinal epithelial barrier in a Caco-2/HIEC-6 cell monolayer model. Furthermore, the genes targeted by DHM through neutrophils for alleviating UC were identified by screening online databases, and the results of network pharmacological analysis were verified via western blotting and quantitative real-time polymerase chain reaction. DHM alleviated DSS-induced colitis in mice by reversing weight loss, increased DAI score, colon length shortening, enhanced spleen index, colonic pathological damage, cytokine production, and epithelial barrier loss in a dose-dependent manner. In addition, it inhibited the formation of NETs both in vivo and in vitro. Based on the results of network pharmacological analysis, DHM may target HIF-1α and VEGFA through neutrophils to alleviate UC. Treatment with PMA increased the expression of HIF-1α and VEGFA in D-HL-60 cells and BMDNs, whereas treatment with DHM or DNase I reversed this effect. Treatment with DMOG, an inhibitor of HIF prolyl hydroxylase (HIF-PH), counteracted the suppressive effects of DHM on NETs formation in D-HL-60 cells and BMDNs. Accordingly, it partially counteracted the protective effects of DHM on the intestinal epithelial barrier in Caco-2 and HIEC-6 cells. These results indicated that DHM alleviated DSS-induced UC by regulating NETs formation via the HIF-1α/VEGFA signaling pathway, suggesting that DHM is a promising therapeutic candidate for UC.

Sex Differences of Neutrophil Extracellular Traps on Lipopolysaccharide-Stimulated Human Neutrophils.

Objective: Sex differences exist in sepsis, but the commitment of neutrophils to these differences remains unclear. Neutrophil extracellular traps (NETs) function to remove pathogens, yet excessive NETs release can contribute to organ damage. This study explores effects of the gender hormones on endotoxin-induced NETs using neutrophils from both male and female sources. Methods: Blood samples were collected from healthy volunteers. Isolated neutrophils were seeded in collagen-coated cell culture plates, and NETs were induced by lipopolysaccharide (LPS) treatment. After 15 minutes of LPS treatment, 17ß-estradiol (0.03-272.4 ng/mL), testosterone enanthate (0.01-10 ng/mL), dimethyl sulfoxide, or ethanol (vehicle control) was added to the plates. These were incubated for three hours at 37°C with 5% CO2. Neutrophil extracellular traps formation was assessed using immunofluorescence staining. Results: Lipopolysaccharide-induced NETs formation was significantly greater in females than in males. In male-derived neutrophils, 17ß-estradiol at above the blood concentrations significantly suppressed LPS-induced NETs. No effect was seen while using testosterone enanthate to NETs at any concentration. In female-derived neutrophils, 17ß-estradiol, which was near to the highest concentration of non-pregnant women's blood, tended to increase NETs. Testosterone enanthate, which was near to female blood concentration, significantly promoted NETs. Conclusions: Sex differences existed in LPS-induced NETs of human neutrophil. In males, high concentrations of 17ß-estradiol administration may have a suppressive effect on excessive NETs during infection. In females, endogenous gender hormones may promote NETs during infection. Sex differences in neutrophils may need to be considered in organ damage owing to NETs excess such as sepsis.

Comparing the cost-effectiveness of drones, camera trapping and passive acoustic recorders in detecting changes in koala occupancy.

Quantifying the cost-effectiveness of alternative sampling methods is crucial for efficient biodiversity monitoring and detection of population trends. In this study, we compared the cost-effectiveness of three novel sampling methods for detecting changes in koala (Phascolarctos cinereus) occupancy: thermal drones, passive acoustic recorders and camera trapping. Specifically, we fitted single-season occupancy-detection models to data recorded from 46 sites in eight bioregions of New South Wales, Australia, between 2018 and 2022. We explored the effect of weather variables on daily detection probability for each method and, using these estimates, calculated the statistical power to detect 30%, 50% and 80% declines in koala occupancy. We calculated power for different combinations of sites (1-200) and repeat surveys (2-40) and developed a cost model that found the cheapest survey design that achieved 80% power to detect change. On average, detectability of koalas was highest with one 24-h period of acoustic surveys (0.32, 95% CI's: 0.26, 0.39) compared to a 25-ha flight of drone surveys (0.28, 95% 0.15, 0.48) or a 24-h period of camera trapping consisting of six cameras (0.019, 95% CI's: 0.014, 0.025). We found a negative quadratic relationship between detection probability and air temperature for all three methods. Our power and cost analysis suggested that 148 sites surveyed with acoustic recorders deployed for 14 days would be the cheapest method to sufficiently detect a 30% decline in occupancy with 80% power. We recommend passive acoustic recorders as the most efficient sampling method for monitoring koala occupancy compared to cameras or drones. Further comparative studies are needed to compare the relative effectiveness of these methods and others when the monitoring objective is to detect change in koala abundance over time.

Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2.

Immune escape is the main reason that immunotherapy is ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) that can promote immune escape of HCC. Mechanistically, we demonstrated that NETs up-regulated CD73 expression through activating Notch2 mediated nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate immune escape of HCC. In addition, we found the similar results in mouse HCC models by hydrodynamic plasmid transfection. The treatment of deoxyribonuclease I (DNase I) could inhibit the action of NETs and improve the therapeutic effect of anti-programmed cell death protein 1 (PD-1). In summary, our results revealed that targeting of NETs was a promising treatment to improve the therapeutic effect of anti-PD-1.

Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.

Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. In vitro and in vivo experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.

IL-8 Induces Neutrophil Extracellular Trap Formation in Severe Thermal Injury.

Neutrophil extracellular traps (NETs) have a dual role in the innate immune response to thermal injuries. NETs provide an early line of defence against infection. However, excessive NETosis can mediate the pathogenesis of immunothrombosis, disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) in sepsis. Recent studies suggest that high interleukin-8 (IL-8) levels in intensive care unit (ICU) patients significantly contribute to excessive NET generation. This study aimed to determine whether IL-8 also mediates NET generation in patients with severe thermal injuries. IL-8 levels were measured in serum samples from thermally injured patients with ≥15% of the total body surface area (TBSA) and healthy controls (HC). Ex vivo NET generation was also investigated by treating isolated neutrophils with serum from thermal injured patients or normal serum with and without IL-8 and anti-IL-8 antibodies. IL-8 levels were significantly increased compared to HC on days 3 and 5 (p < 0.05) following thermal injury. IL-8 levels were also significantly increased at day 5 in septic versus non-septic patients (p < 0.001). IL-8 levels were also increased in patients who developed sepsis compared to HC at days 3, 5 and 7 (p < 0.001), day 10 (p < 0.05) and days 12 and 14 (p < 0.01). Serum containing either low, medium or high levels of IL-8 was shown to induce ex vivo NETosis in an IL-8-dependent manner. Furthermore, the inhibition of DNase activity in serum increased the NET-inducing activity of IL-8 in vitro by preventing NET degradation. IL-8 is a major contributor to NET formation in severe thermal injury and is increased in patients who develop sepsis. We confirmed that DNase is an important regulator of NET degradation but also a potential confounder within assays that measure serum-induced ex vivo NETosis.

The Multifaceted Complexity of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS): A Case Report Highlighting Atypical Gastrointestinal Manifestations.

BACKGROUND: Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder stemming from mutations in the TNFRSF1A gene affecting the tumor necrosis factor receptor (TNFR)-1. These mutations lead to dysregulated inflammatory responses, primarily mediated by augmented interleukin (IL)-1ß release. CASE PRESENTATION: We present the case of a 29-year-old woman with a history of recurrent febrile episodes, abdominal pain, and joint manifestations, eventually diagnosed with TRAPS following genetic testing revealing a heterozygous R92Q mutation in TNFRSF1A. Further genetic examinations unveiled additional clinically significant mutations, complicating the clinical picture. Our patient exhibited delayed colonic transit time and right colonic amyloidosis, a rare complication. Surgical intervention was required for overwhelming intestinal obstruction, revealing mucosal atrophy and dense lymphocytic infiltrates on histological examination. DISCUSSION: Gastrointestinal involvement in TRAPS is common but can present diagnostic challenges. Following colon resection, histological examination revealed amyloid deposition, underscoring the importance of a comprehensive evaluation of these patients. Isolated colic amyloidosis has significant diagnostic and prognostic implications, warranting cautious monitoring and tailored management strategies. Treatment of TRAPS typically involves anti-inflammatory agents such as IL-1 inhibitors, with our patient experiencing clinical improvement on anakinra and canakinumab. CONCLUSION: This case report emphasizes the diverse manifestations of TRAPS and the importance of recognizing gastrointestinal complications, particularly isolated colic amyloidosis. Comprehensive evaluation, including histological examination, is crucial for identifying atypical disease presentations and guiding management decisions. Continued research is needed to elucidate the underlying mechanisms and optimize treatment strategies for TRAPS and its associated complications.

The role of neutrophil extracellular traps in ß-methylamino L-alanine-induced liver injury in mice.

The non-protein amino acid ß-N-methylamino-L-alanine (BMAA), produced by cyanobacteria, has been recognized as a neurotoxin. L-serine as an antagonist of BMAA can effectively alleviate BMAA-induced neurotoxicity. Although BMAA has long been emphasized as a neurotoxin, with the emergence of BMAA detected in a variety of algae in freshwater around the world and its clear biological enrichment effect, it is particularly important to study the non-neurotoxic adverse effects of BMAA. However, there is only limited evidence to support the ability of BMAA to cause oxidative damage in the liver. The exact molecular mechanism of BMAA-induced liver injury is still unclear. The formation of neutrophil extracellular traps (NETs) is a 'double-edged sword' for the organism, excessive formation of NETs is associated with inflammatory diseases of the liver. Our results innovatively confirmed that BMAA was able to cause the formation of NETs in the liver during the liver injury. The possible mechanism may associated with the regulation of ERK/p38 and cGAS/STING signaling pathways. The massive formation of NETs was able to exacerbate the BMAA-induced oxidative stress and release of inflammatory factors in the mice liver. And the removal of NETs could alleviate this injury. This article will bring a new laboratory evidence for BMAA-induced non-neurotoxicity and immunotoxicity.

The role of anti-citrullinated protein antibody in pathogenesis of RA.

Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.

tRF-His-GTG-1 enhances NETs formation and interferon-α production in lupus by extracellular vesicle.

BACKGROUND: Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE. METHODS: We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay. RESULTS: Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P < 0.005). We demonstrated that SLE patient-derived immune complexes (ICs) induced platelet activation, followed by pEVs release. ICs-triggered NETs formation was significantly enhanced in the presence of pEVs through Toll-like receptor (TLR) 8 activation. Increased levels of tRF-His-GTG-1 in pEVs and neutrophils of SLE patients were associated with disease activity. tRF-His-GTG-1 interacted with TLR8 to prime p47phox phosphorylation in neutrophils, resulting in reactive oxygen species production and NETs formation. Additionally, tRF-His-GTG-1 modulated NF-κB and IRF7 activation in neutrophils upon TLR8 engagement, resulting IL-1ß, IL-8, and interferon-α upregulation, respectively. CONCLUSIONS: The level of tRF-His-GTG-1 was positively correlated with NETs formation in SLE patients; tRF-His-GTG-1 inhibitor could efficiently suppress ICs-triggered NETs formation/hyperactivation, which may become a potential therapeutic target.

Neutrophils and platelets are key members in the immunopathogenesis of SLE. EVs play a key role in intercellular communication. Abnormal NETs formation promotes vascular complications and organ damage in SLE patients. tsRNA is a novel regulatory small non-coding RNA and participates in diverse pathological processes. Herein, we showed that SLE patient-derived ICs activates platelets directly, followed by intracellular tRF-His-GTG-1 upregulation, which is loaded into pEVs. The pEV-carried tRF-His-GTG-1 could interact with TLR8 in neutrophils, followed by activation of the downstream signaling pathway, including p47phox-NOX2-ROS, which causes NETs enhancement, while IRF7 promotes the expression of IFN-α. The tRF-His-GTG-1 inhibitor could suppress efficiently SLE ICs-induced NETs formation and pEVs primed NETs enhancement. This study offers new molecular machinery to explain the association between the platelets-derived tsRNAs, pEVs, and hyperactive NETs formation in lupus. tRF-His-GTG-1 may serve as a potential therapeutic target and help to advance our understanding of tsRNAs in SLE pathogenesis.

Using motion-detection cameras to monitor foraging behaviour of individual butterflies.

The activity of many animals follows recurrent patterns and foraging is one of the most important processes in their daily activity. Determining movement in the search for resources and understanding temporal and spatial patterns in foraging has therefore long been central in behavioural ecology. However, identifying and monitoring animal movements is often challenging. In this study we assess the use of camera traps to track a very specific and small-scale interactions focused on the foraging behaviour of Heliconiini butterflies. Data on floral visitation was recorded using marked individuals of three pollen-feeding species of Heliconius (H. erato, H. melpomene and H. sara), and two closely related, non-pollen feeding species (Dryas iulia and Dryadula phaetusa) in a large outdoor insectary. We demonstrate that camera traps efficiently capture individual flower visitation over multiple times and locations and use our experiments to describe some features of their spatial and temporal foraging patterns. Heliconiini butterflies showed higher activity in the morning with strong temporal niche overlap. Differences in foraging activity between males and females was observed with females foraging earlier than males, mirroring published field studies. Some flowers were more explored than others, which may be explained by butterflies foraging simultaneously affecting each other's flower choices. Feeding was grouped in short periods of intense visits to the same flower, which we refer to as feeding bouts. Heliconius also consistently visits the same flower, while non-Heliconius visited a greater number of flowers per day and their feeding bouts were shorter compared with Heliconius. This is consistent with Heliconius having more stable long-term spatial memory and foraging preferences than outgroup genera. More broadly, our study demonstrates that camera traps can provide a powerful tool to gather information about foraging behaviour in small insects such as butterflies. © 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.

Neutrophil extracellular traps-related lncRNAs prognostic signature for gastric cancer and immune infiltration: potential biomarkers for predicting overall survival and clinical therapy.

Gastric cancer (GC) is one of the most common digestive tract malignant tumors in the world. At the time of initial diagnosis, it frequently presents with local or distant metastasis, contributing to poor prognosis in patients. Neutrophil extracellular traps (NETs) constitute a mechanism employed by neutrophils that is intricately associated with tumor progression, prognosis, and response to immunotherapy and chemotherapy. Despite this, the specific involvement of NETs-related long non-coding RNAs (lncRNAs) in gastric cancer remains unclear. A prognostic model for NETs-related lncRNAs was constructed through correlation analysis, COX regression analysis, and least absolute shrinkage and selection operator regression (LASSO) analysis. The predictive performance of the model was assessed using Kaplan-Meier survival curves, receiver operating characteristic (ROC) curves, facilitating the exploration of the relationship between disease onset and prognosis in gastric cancer. Additionally, differences in the tumor microenvironment and response to immunotherapy among gastric cancer patients across high- and low-risk groups were analyzed. Furthermore, a prognostic nomogram integrating the risk score with relevant clinicopathological parameters was developed. The prognostic prediction model for gastric cancer, derived from NETs-related lncRNAs in this study, demonstrates robust prognostic capabilities, serving as a valuable adjunct to traditional tumor staging. This model holds promise in offering novel guidelines for the precise treatment of gastric cancer, thereby potentially improving patient outcomes.

Using applied social science disciplines to implement creative outdoor cat management solutions and avoid the trap of one-size-fits-all policies.

In the United States, policy conflicts have prevented successful population-level management of outdoor cats for decades. Wildlife conservation professionals have sought widespread use of humane dispatch (i.e., lethal culling applied humanely), whereas cat welfare professionals have promoted trap-neuter-return (TNR) (cats are trapped, neutered, and returned to the outdoors). These conflicts represent a policy panacea trap, which we argue drives many conservation conflicts. In these situations, the focus on defending a one-size-fits-all policy fails to account for the value differences that shape the different understandings of the problem and desired outcomes associated with each policy, as well as complexities in the social-ecological system. Over the past 5 years, a group of wildlife conservation and cat welfare professionals codeveloped a set of products that have started to be used to help organizations break out of the policy panacea trap. We used a case study to illustrate how efforts grounded in applied social science disciplines, such as science communication, social-ecological systems, and conservation marketing, can help identify a more robust set of policy options tailored to local management and cultural contexts for successful implementation. Shifting the focus to embrace a shared understanding of the broader system helped us identify areas for collaboration, broaden the policy toolbox, and allow space for policy tools originally framed as opposing panaceas. This work helped prepare all parties to have difficult but productive discussions and address shared policy needs. We suggest that many value-based conservation conflicts would benefit from similar efforts that use applied social science to transform how conflict is addressed, moving beyond policy panaceas that end in stalemate to develop shared understandings of context-specific policies, and to identify opportunities for creative cooperation that yield real conservation progress.

Uso de las disciplinas aplicadas de las ciencias sociales para implementar soluciones creativas de manejo de gatos callejeros y evitar la trampa de las políticas universales Resumen Durante décadas, los conflictos entre políticas han evitado un manejo exitoso a nivel poblacional de los gatos callejeros en los Estados Unidos. Los profesionales de la conservación silvestre han buscado el uso extenso de los sacrificios con humanidad, mientras que los profesionales del bienestar felino han promovido la captura­esterilización­liberación (CEL) de los gatos. Estos conflictos representan una trampa panacea de políticas, la cual argumentamos causa muchos conflictos de conservación. En estas situaciones, el enfoque en defender una política universal no logra considerar la diferencia de valores que forman los diferentes entendimientos del problema y los resultados deseados que se asocian con cada política, así como las complejidades dentro del sistema socio­ecológico. A lo largo de los últimos cinco años, un grupo de profesionales de la conservación silvestre y del bienestar felino desarrollaron en conjunto una serie de productos que han comenzado a ayudar a las organizaciones a salir de la trampa panacea de políticas. Usamos un estudio de caso para ilustrar cómo los esfuerzos cimentados en las disciplinas aplicadas de las ciencias sociales (p. ej.: las ciencias de la comunicación, los sistemas socio­ecológicos y el marketing de la conservación) pueden ayudar a identificar un conjunto más sólido de opciones de políticas personalizadas para el manejo local y los contextos culturales para tener una implementación exitosa. El cambio de enfoque para aceptar el entendimiento compartido del sistema más amplio nos ayudó a identificar áreas de colaboración, a ampliar las herramientas para las políticas y a permitirle espacio a las herramientas formuladas originalmente como panaceas contrarias. Este trabajo ayudó a que todas las partes se prepararan para tener discusiones difíciles pero productivas y para abordar las necesidades compartidas de las políticas. Sugerimos que muchos conflictos de conservación basados en los valores se beneficiarían de un esfuerzo similar que use las ciencias sociales aplicadas para transformar cómo se aborda el conflicto, llegando más allá de las panaceas de políticas que terminan en un punto muerto para el desarrollo del entendimiento compartido de políticas específicas al contexto, y para identificar las oportunidades de cooperación creativa que producen un progreso real de la conservación.

The neutrophil extracellular traps in neurological diseases: An update.

Neutrophil extracellular traps released by neutrophils are web-like DNA structures adhered to granulin proteins with bactericidal activity and can be an important mechanism for preventing pathogen dissemination or eliminating microorganisms. However, they also play important roles in diseases of other systems, such as the central nervous system. We tracked the latest advances and performed a review based on published original and review articles related to neutrophil extracellular traps and neurological diseases. Generally, neutrophils barely penetrate the blood-brain barrier into the brain parenchyma, but when pathological changes such as infection, trauma, or neurodegeneration occur, neutrophils rapidly infiltrate the central nervous system to exert their defensive effects. However, neutrophils may adversely affect the host when they uncontrollably release neutrophil extracellular traps upon persistent neuroinflammation. This review focused on recent advances in understanding the mechanisms and effects of neutrophil extracellular traps release in neurological diseases, and we also discuss the role of molecules that regulate neutrophil extracellular traps release in anticipation of clinical applications in neurological diseases.

A model-based analysis for trapping suspended sediment in stormwater inlets of urban drainage network.

Raised awareness of environmental constraints in recent decades has led stormwater management to incorporate quality components and focus on the treatment of urban runoff water at pollutant source areas. This study evaluated the impact of a developed type of sediment trap, installed into stormwater inlets, on the total suspended solids (TSS) load in an urban city center catchment in Finland. The objective was to outline a modelling approach to assess efficiency of the traps to treat TSS originating from different land uses (green areas, pavement, parking, roof, street, and other areas not belonging to the main land uses). A Storm Water Management Model (SWMM) parametrization of a 5.87 ha catchment in the Lahti city center, Finland was utilized as the computation engine. The model had separate subcatchments for each land use, allowing the use of literature-based Event Mean Concentrations (EMC) to estimate the TSS pollutant washoff for the land uses. A method to assess the individual stormwater inlet pollutant loads and potential removal effect of the sediment traps was introduced. The hydrological and TSS load simulations covered a period of 6 months. The stormwater network inlets installed with sediment traps were ranked according to their potential removal of TSS. One out of five EMC sets was selected to be representative of the urban land uses in the study site (green areas 75 mg/l, pavement 46 mg/l, parking 44 mg/l, roof 20 mg/l, street 64 mg/l, other 46 mg/l). The simulation results showed the influence of land uses on the pollutant load and revealed the optimal set of locations for the sediment traps. Additionally, the effect of regular maintenance intervals on the pollutant load, given a maximum storage capacity of the traps, was explored. The results showed a large variation in TSS removal depending on the inlets chosen for the sediment traps, with removal rates ranging from about 0 % to 10 % of catchment TSS load. The maximum TSS removal was 63 %, which was the reported efficiency of the traps. These results highlighted the need for an informed decision when selecting trap locations. Streets and parking lots were the largest TSS contributors, with stormwater inlets on streets being the desired sediment trap locations. While the absolute level of simulated TSS load was found to be dependent on the EMCs, the ranking of sediment trap locations was similar for the simulations with different EMC data sets.

Neutrophil extracellular traps in cancer.

Neutrophil extracellular traps (NETs), which consist of chromatin DNA studded with granule proteins, are released by neutrophils in response to both infectious and sterile inflammation. Beyond the canonical role in defense against pathogens, the extrusion of NETs also contributes to the initiation, metastasis, and therapeutic response of malignant diseases. Recently, NETs have been implicated in the development and therapeutic responses of various types of tumors. Although extensive work regarding inflammation in tumors has been reported, a comprehensive summary of how these web-like extracellular structures initiate and propagate tumor progression under the specific microenvironment is lacking. In this review, we demonstrate the initiators and related signaling pathways that trigger NETs formation in cancers. Additionally, this review will outline the current molecular mechanisms and regulatory networks of NETs during dormant cancer cells awakening, circulating tumor cells (CTCs) extravasation, and metastatic recurrence of cancer. This is followed by a perspective on the current and potential clinical potential of NETs as therapeutic targets in the treatment of both local and metastatic disease, including the improvement of the efficacy of existing therapies.

Machine learning based on metabolomics unveils neutrophil extracellular trap-related metabolic signatures in non-small cell lung cancer patients undergoing chemoimmunotherapy.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the primary form of lung cancer, and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease. However, the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies. Consequently, it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments. AIM: To identify the metabolic signatures associated with neutrophil extracellular traps (NETs) and chemoimmunotherapy efficacy in NSCLC patients. METHODS: In total, 159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled. We first investigated the characteristics influencing clinical efficacy. Circulating levels of NETs and cytokines were measured by commercial kits. Liquid chromatography tandem mass spectrometry quantified plasma metabolites, and differential metabolites were identified. Least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and random forest algorithms were employed. By using plasma metabolic profiles and machine learning algorithms, predictive metabolic signatures were established. RESULTS: First, the levels of circulating interleukin-8, neutrophil-to-lymphocyte ratio, and NETs were closely related to poor efficacy of first-line chemoimmunotherapy. Patients were classed into a low NET group or a high NET group. A total of 54 differential plasma metabolites were identified. These metabolites were primarily involved in arachidonic acid and purine metabolism. Three key metabolites were identified as crucial variables, including 8,9-epoxyeicosatrienoic acid, L-malate, and bis(monoacylglycerol)phosphate (18:1/16:0). Using metabolomic sequencing data and machine learning methods, key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy. CONCLUSION: The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.

Identification of organs of origin of macrophages that produce presepsin via neutrophil extracellular trap phagocytosis.

Presepsin (P-SEP) is a specific biomarker for sepsis. Monocytes produce P-SEP by phagocytosing neutrophil extracellular traps (NETs). Herein, we investigated whether M1 macrophages (M1 MΦs) are the primary producers of P-SEP after NET phagocytosis. We co-cultured M1 MΦs and NETs from healthy participants, measured P-SEP levels in the culture medium supernatant, and detected P-SEP using western blotting. When NETs were co-cultured with M1 MΦs, the P-SEP level of the culture supernatant was high. Notably, we demonstrated, for the first time, the intracellular kinetics of P-SEP production by M1 MΦs via NET phagocytosis: M1 MΦs produced P-SEP intracellularly 15 min after NET phagocytosis and then released it extracellularly. In a sepsis mouse model, the blood NET ratio and P-SEP levels, detected using ELISA, were significantly increased (p < 0.0001). Intracellular P-SEP analysis via flow cytometry demonstrated that lung, liver, and kidney MΦs produced large amounts of P-SEP. Therefore, we identified these organs as the origin of M1 MΦs that produce P-SEP during sepsis. Our data indicate that the P-SEP level reflects the trend of NETs, suggesting that monitoring P-SEP can be used to both assess NET-induced organ damage in the lungs, liver, and kidneys during sepsis and determine treatment efficacy.

The role of P-selectin/PSGL-1 in regulating NETs as a novel mechanism in cerebral ischemic injury.

In recent years, substantial advancements have been made in understanding the pathophysiology of ischemic stroke. Despite these developments, therapeutic options for cerebral ischemia remain limited due to stringent time windows and various contraindications. Consequently, there has been a concentrated effort to elucidate the underlying mechanisms of cerebral ischemic injury. Emerging research indicates that neutrophil extracellular traps (NETs) exacerbate inflammation and damage in ischemic brain tissue, contributing to neuronal cell death. The inhibition of NETs has shown potential in preventing thrombosis and the infiltration of immune cells. Central to the formation of NETs are P-selectin and its ligand, P-selectin glycoprotein ligand-1 (PSGL-1), which represent promising therapeutic targets. This review explores the detrimental impact of P-selectin, PSGL-1, and NETs on cerebral ischemia. Additionally, it delineates the processes by which P-selectin and PSGL-1 stimulate NETs production and provides evidence that blocking these molecules reduces NETs formation. This novel insight highlights a potential therapeutic avenue that warrants further investigation by researchers in the field.

Genetic ablation of myeloid integrin α9 attenuates early atherosclerosis.

Integrin α9ß1 is known to stabilize leukocyte adhesion to the activated endothelium. We determined the role of myeloid cell α9ß1 in early atherosclerosis in two models: α9MyeKOApoe-/- or the Ldlr-/- mice transplanted with bone marrow (BM) from α9Mye-KO mice fed a high-fat "Western" diet for four weeks. α9Mye-KOApoe-/- mice exhibited reduced early lesions in the aortae and aortic sinuses (p<0.05 vs. α9WT Apoe-/- mice). Similar results were obtained in α9Mye-KO BM→Ldlr-/- mice (p<0.05 vs α9WT BM→Ldlr-/- mice). Reduced early atherosclerosis in α9Mye-KOApoe-/- mice was associated with decreased neutrophil and neutrophil extracellular traps (NETs) content in the aortic lesions (p<0.05 vs. α9WTApoe-/-). VCAM-1-stimulated neutrophils from α9Mye-KO mice exhibited reduced adhesion, transmigration, and NETs formation (NETosis) (p<0.05 vs. α9WT neutrophils). Reduced NETosis was associated with decreased ERK phosphorylation, PAD4, and H3Cit expression. In summary, genetic ablation of myeloid cell-specific α9 reduces early atherosclerosis, most likely by reducing neutrophil adhesion, transmigration, and NETosis.