Cylindrical TGR as early radiological predictor of RLT progression in GEPNETs: a proof of concept.

This study aims to assess the predictive capability of cylindrical Tumor Growth Rate (cTGR) in the prediction of early progression of well-differentiated gastro-entero-pancreatic tumours after Radio Ligand Therapy (RLT), compared to the conventional TGR. Fifty-eight patients were included and three CT scans per patient were collected at baseline, during RLT, and follow-up. RLT response, evaluated at follow-up according to RECIST 1.1, was calculated as a percentage variation of lesion diameters over time (continuous values) and as four different RECIST classes. TGR between baseline and interim CT was computed using both conventional (approximating lesion volume to a sphere) and cylindrical (called cTGR, approximating lesion volume to an elliptical cylinder) formulations. Receiver Operating Characteristic (ROC) curves were employed for Progressive Disease class prediction, revealing that cTGR outperformed conventional TGR (area under the ROC equal to 1.00 and 0.92, respectively). Multivariate analysis confirmed the superiority of cTGR in predicting continuous RLT response, with a higher coefficient for cTGR (1.56) compared to the conventional one (1.45). This study serves as a proof of concept, paving the way for future clinical trials to incorporate cTGR as a valuable tool for assessing RLT response.

Assessing LLIN distribution implementation using evidence-informed intervention core elements: a qualitative study in a resource-constrained setting.

BACKGROUND: The National Malaria Elimination Programme implements the mass LLIN Distribution Campaigns in Ghana. Implementation science promotes the systematic study of social contexts, individual experiences, real-world environments, partnerships, and stakeholder consultations regarding the implementation of evidence-informed interventions. In this paper, we assess the core elements of the mass LLIN distribution campaign in a resource constrained setting to learn best implementation practices. Three core domains were assessed through the application of Galbraith's taxonomy (i.e., implementation, content, and pedagogy) for evidence-informed intervention implementation. METHODS: Six districts in two regions (Eastern and Volta) in Ghana participated in this study. Fourteen Focus Group Discussions (FGDs) were conducted across these communities. Eligible participants were purposively sampled considering age, occupation, gender, and care giving for children under 5 years and household head roles. All audio-recorded FGDs were transcribed verbatim, data was assessed and coded through deductive and inductive processes. NVivo software version 13 was used for the coding process. Themes were refined, legitimized, and the most compelling extracts selected to produce the results. RESULTS: Sixty-nine (69) caregivers of children under 5 years and sixty (60) household heads participated in the FGDs. All caregivers were females (69), whilst household heads included more males (41). Core elements identified under implementation domain of the LLIN distribution campaign in Ghana include the registration and distribution processes, preceded by engagement with traditional authorities and continuous involvement of community health volunteers during implementation. For pedagogy domain, core elements include delivery of intervention through outreaches, illustrations, demonstrations, and the use of multiple communication channels. Core elements realized within the content domain include information on effective malaria prevention, and provision of information to enhance their self-efficacy. Yet, participants noted gaps (e.g., misuse) in the desired behavioural outcome of LLIN use and a heavy campaign focus on women. CONCLUSION AND RECOMMENDATIONS: Although the implementation of the mass LLIN distribution campaigns exhibit components of core elements of evidence informed interventions (implementation, content and pedagogy), it has not achieved its desired behavioural change intentions (i.e. continuous LLIN use). Future campaigns may consider use of continuous innovative pedagogical approaches at the community level and lessons learnt from this study to strengthen the implementation process of evidence-based health interventions. There is also the need for standardization of core elements to identify the number of core elements required within each domain to achieve efficacy. ETHICAL APPROVAL: Ethical clearance was obtained from the Ghana Health Service Ethics Review Committee (GHS-ERC: 002/06/21) before the commencement of all data collection.

Synthetic CT generation for pelvic cases based on deep learning in multi-center datasets.

BACKGROUND AND PURPOSE: To investigate the feasibility of synthesizing computed tomography (CT) images from magnetic resonance (MR) images in multi-center datasets using generative adversarial networks (GANs) for rectal cancer MR-only radiotherapy. MATERIALS AND METHODS: Conventional T2-weighted MR and CT images were acquired from 90 rectal cancer patients at Peking University People's Hospital and 19 patients in public datasets. This study proposed a new model combining contrastive learning loss and consistency regularization loss to enhance the generalization of model for multi-center pelvic MRI-to-CT synthesis. The CT-to-sCT image similarity was evaluated by computing the mean absolute error (MAE), peak signal-to-noise ratio (SNRpeak), structural similarity index (SSIM) and Generalization Performance (GP). The dosimetric accuracy of synthetic CT was verified against CT-based dose distributions for the photon plan. Relative dose differences in the planning target volume and organs at risk were computed. RESULTS: Our model presented excellent generalization with a GP of 0.911 on unseen datasets and outperformed the plain CycleGAN, where MAE decreased from 47.129 to 42.344, SNRpeak improved from 25.167 to 26.979, SSIM increased from 0.978 to 0.992. The dosimetric analysis demonstrated that most of the relative differences in dose and volume histogram (DVH) indicators between synthetic CT and real CT were less than 1%. CONCLUSION: The proposed model can generate accurate synthetic CT in multi-center datasets from T2w-MR images. Most dosimetric differences were within clinically acceptable criteria for photon radiotherapy, demonstrating the feasibility of an MRI-only workflow for patients with rectal cancer.

Reparative effects after low-dose radiation exposure: Inhibition of atherosclerosis by reducing NETs release.

OBJECTIVE: The cardiovascular system effects of environmental low-dose radiation exposure on radiation practitioners remain uncertain and require further investigation. The aim of this study was to initially investigate and explore the mechanisms by which low-dose radiation may contribute to atherosclerosis through a multi-omics joint comprehensive basic experiment. METHODS: We used WGCNA and differential analyses to identify shared genes and potential pathways between radiation injury and atherosclerosis sequencing datasets, as well as tissue transcriptome immune infiltration level extrapolation and single-cell transcriptome data correction using the CIBERSORT deconvolution algorithm. Animal models were constructed by combining a high-fat diet with 5 Gy γ-ray whole-body low-dose ionizing radiation. The detection of NETs release was validated by enzyme-linked immunosorbent assay. RESULTS: Analysis reveals shared genes in both datasets of post-irradiation and atherosclerosis, suggesting that immune system neutrophils may be a key node connecting radiation to atherosclerosis. NETs released by neutrophil death can influence the development of atherosclerosis. Animal experiments showed that the number of neutrophils decreased (P < 0.05) and the concentration of NETs reduced after low-dose radiation compared with the control group, and the concentration of NETs significantly increased (P < 0.05) in the HF group. Endothelial plaques were significantly increased in the high-fat feed group and significantly decreased in the low-dose radiation group compared with the control group. CONCLUSIONS: Long-term low-dose ionizing radiation exposure stimulates neutrophils and inhibits their production of NETs, resulting in inhibition of atherosclerosis.

Long-Lasting Insecticidal Net Coverage and Utilization in Burla Town of Sambalpur District: A Cross-Sectional Study.

Background Vector-borne diseases continue to significantly contribute to mortality and morbidity, especially in developing nations. Vector management is a key pillar in combating these diseases, and long-lasting insecticidal nets (LLINs) are cost-effective tools. The Government of India, under the National Vector Borne Disease Control Programme (NVBDCP), has distributed LLINs for free to increase coverage and utilization. This study aims to estimate the coverage and utilization of LLINs in Burla town. Method This cross-sectional study was conducted from October to December 2022 in Burla town of Sambalpur in Odisha, India. The estimated sample size was 510 households, assuming 50% coverage. Multi-stage cluster sampling was adopted to select the Anganwadi centers and households. A pretested questionnaire was utilized for data collection by trained personnel through Epicollect5 (Centre for Genomic Pathogen Surveillance, Oxford, UK). Logistic regression was used to identify predictors for LLIN usage. Results The survey covered 516 households with 2,541 individuals and 1,165 nets. Household-level coverage was 94.2%, and regular utilization was 45.74%. Skin reactions (35.7%) were the most common reason for non-usage, followed by low mosquito density (12%). Logistic regression showed that the number of rooms (adjusted odds ratio (AOR) = 0.663, p = 0.012), number of bed nets (AOR = 2.757, p < 0.001), knowledge of malaria (AOR = 2.92, p = 0.04), adopting other measures for mosquito control (AOR = 0.295, p < 0.001), and washing the net (AOR = 1.92, p = 0.028) significantly predicted sleeping under mosquito net. Conclusion Our study has depicted high coverage of LLINs in Burla town, but utilization needs further improvement. Counseling regarding proper use can decrease the skin reactions responsible for non-usage. Regular health education programs are required to emphasize the benefits of LLIN use, along with regular monitoring and supervision.

Ion channel profiles of extraocular motoneurons and internuclear neurons in human abducens and trochlear nuclei.

Introduction: Extraocular muscles are innervated by two anatomically and histochemically distinct motoneuron populations: motoneurons of multiply-innervated fibers (MIF), and of singly-innervated fibers (SIF). Recently, it has been established by our research group that these motoneuron types of monkey abducens and trochlear nuclei express distinct ion channel profiles: SIF motoneurons, as well as abducens internuclear neurons (INT), express strong Kv1.1 and Kv3.1b immunoreactivity, indicating their fast-firing capacity, whereas MIF motoneurons do not. Moreover, low voltage activated cation channels, such as Cav3.1 and HCN1 showed differences between MIF and SIF motoneurons, indicating distinct post-inhibitory rebound characteristics. However, the ion channel profiles of MIF and SIF motoneurons have not been established in human brainstem tissue. Methods: Therefore, we used immunohistochemical methods with antibodies against Kv, Cav3 and HCN channels to (1) examine the human trochlear nucleus in terms of anatomical organization of MIF and SIF motoneurons, (2) examine immunolabeling patterns of ion channel proteins in the distinct motoneurons populations in the trochlear and abducens nuclei. Results: In the examination of the trochlear nucleus, a third motoneuron subgroup was consistently encountered with weak perineuronal nets (PN). The neurons of this subgroup had -on average- larger diameters than MIF motoneurons, and smaller diameters than SIF motoneurons, and PN expression strength correlated with neuronal size. Immunolabeling of various ion channels revealed that, in general, human MIF and SIF motoneurons did not differ consistently, as opposed to the findings in monkey trochlear and abducens nuclei. Kv1.1, Kv3.1b and HCN channels were found on both MIF and SIF motoneurons and the immunolabeling density varied for multiple ion channels. On the other hand, significant differences between SIF motoneurons and INTs were found in terms of HCN1 immunoreactivity. Discussion: These results indicated that motoneurons may be more variable in human in terms of histochemical and biophysiological characteristics, than previously thought. This study therefore establishes grounds for any histochemical examination of motor nuclei controlling extraocular muscles in eye movement related pathologies in the human brainstem.

Design patterns for the construction of computational biological models.

Computational biological models have proven to be an invaluable tool for understanding and predicting the behaviour of many biological systems. While it may not be too challenging for experienced researchers to construct such models from scratch, it is not a straightforward task for early stage researchers. Design patterns are well-known techniques widely applied in software engineering as they provide a set of typical solutions to common problems in software design. In this paper, we collect and discuss common patterns that are usually used during the construction and execution of computational biological models. We adopt Petri nets as a modelling language to provide a visual illustration of each pattern; however, the ideas presented in this paper can also be implemented using other modelling formalisms. We provide two case studies for illustration purposes and show how these models can be built up from the presented smaller modules. We hope that the ideas discussed in this paper will help many researchers in building their own future models.

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.

A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

No Evidence of Neutrophil Response Modulation in Goats after Immunization against Paratuberculosis with a Heat-Inactivated Vaccine.

Neutrophils are believed to play a role in the initial stages of paratuberculosis, and it has recently been demonstrated that vaccination can modulate their function via priming or through epigenetic and metabolic reprogramming (training). Modulation of the neutrophil response against Mycobacterium avium subspecies paratuberculosis (Map) through vaccination has been demonstrated in a rabbit model but not in ruminants. Therefore, in the present work, the effect of vaccination on the response of caprine neutrophils against Map was studied. Neutrophils were isolated from non-vaccinated (n = 7) and Gudair®-vaccinated goat kids (n = 7), before vaccination and 30 days post-vaccination. Then, several neutrophil functions were quantified ex vivo: cell-free and anchored neutrophil extracellular trap (NET) release, phagocytosis, and the differential expression of several cytokines and TLR2. The induction of cell-free NETosis and TLR2 expression by Map is reported for the first time. However, vaccination showed no significant effect on any of the functions studied. This suggests that the protection conferred by Gudair® vaccination is based on mechanisms that are independent of the neutrophil function modulation. Further research into the impact of alternative vaccination strategies or the paratuberculosis infection stage on ruminant neutrophil function could provide valuable insights into its role in paratuberculosis.

Decreased extrasynaptic δ-GABAA receptors in PNN-associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD-associated anxiety correlated with modulation of extrasynaptic δ-subunit-containing GABAA receptors (δ-GABAARs) in experimental mouse models of AD. EXPERIMENTAL APPROACH: We combined behavioural experimental paradigms to measure cognition performance, and anxiety with neuroanatomy and molecular biology, using familial knock-in (KI) mouse models of AD that harbour ß-amyloid (Aß) precursor protein App (AppNL-F) with or without humanized microtubule-associated protein tau (MAPT), age-matched to wild-type control mice at three different age windows. RESULTS: AppNL-F KI and AppNL-F/MAPT AD models showed a similar magnitude of cognitive decline and elevated magnitude of anxiety correlated with neuroinflammatory hallmarks, including triggering receptor expressed on myeloid cells 2 (TREM2), reactive astrocytes and activated microglia consistent with accumulation of Aß, tau and down-regulation of Wnt/ß-catenin signalling compared to aged-matched WT controls. In both the CA1 region of the hippocampus and dentate gyrus, there was an age-dependent decline in the expression of δ-GABAARs selectively expressed in parvalbumin (PV)-expressing interneurons, encapsulated by perineuronal nets (PNNs) in the AD mouse models compared to WT mice. In vivo positive allosteric modulation of the δ-GABAARs, using a δ-selective-compound DS2, decreased the level of anxiety in the AD mouse models, which was correlated with reduced hallmarks of neuroinflammation, and 'normalisation' of the expression of δ-GABAARs. CONCLUSIONS: Our data show that the δ-GABAARs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals.

Gene Regulation of Neutrophils Mediated Liver and Lung Injury through NETosis in Acute Pancreatitis.

Acute pancreatitis (AP) is one of the most common gastrointestinal emergencies, often resulting in self-digestion, edema, hemorrhage, and even necrosis of pancreatic tissue. When AP progresses to severe acute pancreatitis (SAP), it often causes multi-organ damage, leading to a high mortality rate. However, the molecular mechanisms underlying SAP-mediated organ damage remain unclear. This study aims to systematically mine SAP data from public databases and combine experimental validation to identify key molecules involved in multi-organ damage caused by SAP. Retrieve transcriptomic data of mice pancreatic tissue for AP, lung and liver tissue for SAP, and corresponding normal tissue from the Gene Expression Omnibus (GEO) database. Conduct gene differential analysis using Limma and DEseq2 methods. Perform enrichment analysis using the clusterProfiler package in R software. Score immune cells and immune status in various organs using single-sample gene set enrichment analysis (ssGSEA). Evaluate mRNA expression levels of core genes using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Validate serum amylase, TNF-α, IL-1ß, and IL-6 levels in peripheral blood using enzyme-linked immunosorbent assay (ELISA), and detect the formation of neutrophil extracellular traps (NETs) in mice pancreatic, liver, and lung tissues using immunofluorescence. Differential analysis reveals that 46 genes exhibit expression dysregulation in mice pancreatic tissue for AP, liver and lung tissue for SAP, as well as peripheral blood in humans. Functional enrichment analysis indicates that these genes are primarily associated with neutrophil-related biological processes. ROC curve analysis indicates that 12 neutrophil-related genes have diagnostic potential for SAP. Immune infiltration analysis reveals high neutrophil infiltration in various organs affected by SAP. Single-cell sequencing analysis shows that these genes are predominantly expressed in neutrophils and macrophages. FPR1, ITGAM, and C5AR1 are identified as key genes involved in the formation of NETs and activation of neutrophils. qPCR and IHC results demonstrate upregulation of FPR1, ITGAM, and C5AR1 expression in pancreatic, liver, and lung tissues of mice with SAP. Immunofluorescence staining shows increased levels of neutrophils and NETs in SAP mice. Inhibition of NETs formation can alleviate the severity of SAP as well as the levels of inflammation in the liver and lung tissues. This study identified key genes involved in the formation of NETs, namely FPR1, ITGAM, and C5AR1, which are upregulated during multi-organ damage in SAP. Inhibition of NETs release effectively reduces the systemic inflammatory response and liver-lung damage in SAP. This research provides new therapeutic targets for the multi-organ damage associated with SAP.

Co-existing Neuroendocrine Tumors in the Ileum and Pancreas: A Clinico-Pathological Challenge.

Ileal (I) and pancreatic (Pan) neuroendocrine tumors (NETs) are among the most common digestive neuroendocrine neoplasms (NENs). Coexisting NETs at both sites are rare, and establishing the primary or metastatic nature of the two lesions may be crucial for the appropriate treatment. We reviewed all the clinical reports of patients with INETs or PanNETs, diagnosed and treated in our ENETS Center of Excellence between 2012 and 2022. We selected patients with a history of synchronous or metachronous neuroendocrine (NE) lesions at the ileum and pancreas. For those with available histological samples from both sites, an immunohistochemistry (IHC) analysis for CDX2, Islet1, and serotonin has been performed. We found seven patients with NET in both the ileum and pancreas. F to M ratio was 4:3, and the median age at first diagnosis was 54 years (42-79). Five cases had synchronous lesions; in 2 cases, PanNETs were diagnosed respectively 8 and 56 months, after INETs. In four patients, with available histological samples from both the sites, a pathologic review and the IHC analysis have been performed, identifying three different scenarios: (i) primary INET metastatic to the pancreas, (ii) primary PanNET metastatic to the ileum, and (iii) synchronous primary PanNET and INET. In our experience, coexisting ileal and pancreatic NENs are rare occurrences. A multidisciplinary evaluation case-by-case and, whenever feasible, a comprehensive histopathological examination are needed to distinguish between metastatic and primary disease, in order to properly treat the patient.

Combined Insults of a MASH Diet and Alcohol Binges Activate Intercellular Communication and Neutrophil Recruitment via the NLRP3-IL-1ß Axis in the Liver.

Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1ß via NLRP3 activation and that IL-1ß acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.

Characteristics of Neutrophil Migration and Function in Acute Inflammation Induced by Zymosan and Carrageenan in the Mice Air Pouch Model.

Deciphering the complex and redundant process of acute inflammation remains challenging. The failure of numerous clinical trials assessing anti-inflammation agents which had promising preclinical effects inevitably questions the validity of current animal models of inflammation. This study aimed to better understand the process of immune inflammatory response and to select more suitable models to evaluate the effect of potential anti-inflammatory drugs. Zymosan and λ-carrageenan are the most used representatives of particulate and soluble irritants that trigger acute inflammation in the air pouch inflammation model. When zymosan was used, the number of exudate cells first increased at 4 h-8 h, followed by a drop at 12 h-24 h. While, the changes in number of leukocytes in peripheral blood and proportion of neutrophils in bone marrow have the opposite trend. Meanwhile, neutrophils released neutrophil extracellular traps (NETs) to clean zymosan particles. In contrast, the cell migration response to carrageenan increased during 4 h to 24 h, no obvious NETs were observed, and the number of leukocytes in peripheral blood increased and the proportion of neutrophils in bone marrow decreased slightly. This study indicated that although both zymosan and carrageenan are sterile irritants, the characteristics of the inflammatory response induced by each other were different. In the acute phase of inflammation, zymosan-stimulated neutrophils were mobilized, recruited, and engulfed, and then died by NETs. Carrageenan stimulated the production of cytokines/chemokines by neutrophils or macrophages, but did not lead to an obvious death by releasing NETs.

Blocking the TRAIL-DR5 Pathway Reduces Cardiac Ischemia-Reperfusion Injury by Decreasing Neutrophil Infiltration and Neutrophil Extracellular Traps Formation.

PURPOSE: Acute myocardial infarction (AMI) is a leading cause of mortality. Neutrophils penetrate injured heart tissue during AMI or ischemia-reperfusion (I/R) injury and produce inflammatory factors, chemokines, and extracellular traps that exacerbate heart injury. Inhibition of the TRAIL-DR5 pathway has been demonstrated to alleviate cardiac ischemia-reperfusion injury in a leukocyte-dependent manner. However, it remains unknown whether TRAIL-DR5 signaling is involved in regulating neutrophil extracellular traps (NETs) release. METHODS: This study used various models to examine the effects of activating the TRAIL-DR5 pathway with soluble mouse TRAIL protein and inhibiting the TRAIL-DR5 signaling pathway using DR5 knockout mice or mDR5-Fc fusion protein on NETs formation and cardiac injury. The models used included a co-culture model involving bone marrow-derived neutrophils and primary cardiomyocytes and a model of myocardial I/R in mice. RESULTS: NETs formation is suppressed by TRAIL-DR5 signaling pathway inhibition, which can lessen cardiac I/R injury. This intervention reduces the release of adhesion molecules and chemokines, resulting in decreased neutrophil infiltration and inhibiting NETs production by downregulating PAD4 in neutrophils. CONCLUSION: This work clarifies how the TRAIL-DR5 signaling pathway regulates the neutrophil response during myocardial I/R damage, thereby providing a scientific basis for therapeutic intervention targeting the TRAIL-DR5 signaling pathway in myocardial infarction.

Systematic review of the impacts of US Social Safety Nets on child maltreatment.

INTRODUCTION: Children living in poverty are at an increased risk for maltreatment. Social safety net (SSN) programs with anti-poverty objectives may reduce child maltreatment through pathways such as reduced food insecurity, lessened caregiver stress, and improved caregiving behaviors and ability to meet children's basic needs. The objective of this study is to conduct a systematic review of evidence on the ability of SSN programs to reduce child maltreatment in the United States (US). METHODS: This systematic review was conducted using PRISMA protocol. Among studies published between 1996-2022, the initial search returned 1,873 articles, and 27 papers were included in the final analysis. Abstracts were identified primarily on June 24th, 2022, and extraction and synthesis of data was conducted in 2022-2023. RESULTS: Of the 27 papers assessed, 16 studies found that SSN programs were protective against child maltreatment. Three of the reviewed studies found no effect of safety net programs, four studies presented mixed findings, and four studies found adverse impacts in terms of child maltreatment outcomes. When restricting to high-quality studies only, 10 out of 12 found protective impacts and none found adverse impacts on child maltreatment. DISCUSSION: SSNs are associated with protective effects against child maltreatment. Expansion of SSN programs would likely have positive benefits beyond poverty-related objectives, including reducing incidence of child maltreatment.

Exosomal miRNA-26b-5p from PRP suppresses NETs by targeting MMP-8 to promote diabetic wound healing.

The utilization of platelet-rich plasma (PRP) has exhibited potential as a therapeutic approach for the management of diabetic foot ulcers (DFUs). However, it is currently not well understood how the diabetic environment may influence PRP-derived exosomes (PRP-Exos) and their potential impact on neutrophil extracellular traps (NETs). This study aims to investigate the effects of the diabetic environment on PRP-Exos, their communication with neutrophils, and the subsequent influence on NETs and wound healing. Through bulk-seq and Western blotting, we confirmed the increased expression of MMP-8 in DFUs. Additionally, we discovered that miRNA-26b-5p plays a significant role in the communication between DFUs and PRP-Exos. In our experiments, we found that PRP-Exos miR-26b-5p effectively improved diabetic wound healing by inhibiting NETs. Further tests validated the inhibitory effect of miR-26b-5p on NETs by targeting MMP-8. Both in vitro and in vivo experiments showed that miRNA-26b-5p from PRP-Exos promoted wound healing by reducing neutrophil infiltration through its targeting of MMP-8. This study establishes the importance of miR-26b-5p in the communication between DFUs and PRP-Exos, disrupting NETs formation in diabetic wounds by targeting MMP-8. These findings provide valuable insights for developing novel therapeutic strategies to enhance wound healing in individuals suffering from DFUs.

Assessment of Potential and Techno-Economic Performance of Solid Sorbent Direct Air Capture with CO2 Storage in Europe.

Direct air capture with CO2 storage (DACCS) is among the carbon dioxide removal (CDR) options, with the largest gap between current deployment and needed upscaling. Here, we present a geospatial analysis of the techno-economic performance of large-scale DACCS deployment in Europe using two performance indicators: CDR costs and potential. Different low-temperature heat DACCS configurations are considered, i.e., coupled to the national power grid, using waste heat and powered by curtailed electricity. Our findings reveal that the CDR potential and costs of DACCS systems are mainly driven by (i) the availability of energy sources, (ii) the location-specific climate conditions, (iii) the price and GHG intensity of electricity, and (iv) the CO2 transport distance to the nearest CO2 storage location. The results further highlight the following key findings: (i) the limited availability of waste heat, with only Sweden potentially compensating nearly 10% of national emissions through CDR, and (ii) the need for considering transport and storage of CO2 in a comprehensive techno-economic assessment of DACCS. Finally, our geospatial analysis reveals substantial differences between regions due to location-specific conditions, i.e., useful information elements and consistent insights that will contribute to assessment and feasibility studies toward effective DACCS implementation.