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Endosomal Toll-like receptors (eTLRs) are essential for the sensing of non-self through RNA and DNA detection. Here, using spatiotemporal analysis of vesicular dynamics, super-resolution microscopy studies, and functional assays, we show that endomembrane defects associated with the deficiency of the small GTPase Rab27a cause delayed eTLR ligand recognition, defective early signaling, and impaired cytokine secretion. Rab27a-deficient neutrophils show retention of eTLRs in amphisomes and impaired ligand internalization. Extracellular signal-regulated kinase (ERK) signaling and β2-integrin upregulation, early responses to TLR7 and TLR9 ligands, are defective in Rab27a deficiency. CpG-stimulated Rab27a-deficient neutrophils present increased tumor necrosis factor alpha (TNF-α) secretion and decreased secretion of a selected group of mediators, including interleukin (IL)-10. In vivo, CpG-challenged Rab27a-null mice show decreased production of type I interferons (IFNs) and IFN-γ, and the IFN-α secretion defect is confirmed in Rab27a-null plasmacytoid dendritic cells. Our findings have significant implications for immunodeficiency, inflammation, and CpG adjuvant vaccination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Histological mucosal healing has become a paramount target goal to achieve in the treatment of inflammatory bowel diseases. However, there is still a lack of agreement on the best way to reach this goal, since numerous histological scores are available worldwide., Aims: We investigated whether claudin-2, a member of claudin family involved in the regulation of intestinal tight junctions, might be useful to assess the presence of active disease in patients with inflammatory bowel diseases., Methods: Biopsies from 123 patients with ulcerative colitis, Crohn's disease, infectious colitides and irritable bowel syndrome patients where tested with immunohistochemistry for claudin-2., Results: Claudin-2 appeared to be a very sensitive marker of disease activity in inflammatory bowel diseases, but was negative in the other kinds of patients. In addition, immunohistochemistry for claudin-2 showed good reproducibility by different pathologists., Conclusions: Should these findings be confirmed in more numerous cohorts of patients, and especially in those with minimal or focal residual disease activity, this simple assessment could be useful in the routine daily practice to facilitate the task of pathologists and clinicians in the diagnosis and management of patients with inflammatory bowel diseases., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Build-up/wash-off models were originally developed for small-scale laboratory facilities with uniform properties. The effective translation of these models to catchment scale necessitates the meticulous calibration of model parameters. The present study combines the Mat-SWMM tool with a genetic algorithm (GA) to improve the calibration of build-up and wash-off parameters. For this purpose, Mat-SWMM was modified to equip it with the capacity to provide comprehensive water quality analysis outcomes. Additionally, this research also conducts a comparative examination of two distinct types of objective functions in the optimization. Rather than depending on previous literature, this study undertook a numerical campaign to ascertain an appropriate range for the relevant parameters within the case study, thereby ensuring the optimization algorithm's efficient functionality. This research also implements an integrated event calibration approach, i.e., a novel method that calibrates all rainfall events collectively, thus improving systemic interaction representation and model robustness. The findings indicate that employing this methodology significantly enhances the reliability of the outcomes, thereby establishing a more robust procedure. The first objective function (TSS instantaneous less squared difference function, OF 1), which is widely employed in the literature, was designed to minimize the difference between observed and predicted instantaneous Total Suspended Solids (TSS) concentrations. In contrast, the second function (mass and mass peak consistency function, OF 2) considers integral model outputs, i.e., the overall mass balance, the time of the peak mass flow rate, and its intensity. The analysis of the outputs revealed that both objective functions demonstrated sufficient performance. OF 1 provided slightly better performance in predicting the TSS concentrations, whereas OF 2 demonstrated superior ability in capturing global event characteristics. Notably, the optimal parameter set identified through OF 2 aligned with the physically plausible ranges traditionally recommended in technical manuals for urban catchments. In contrast, OF 1's optimal set necessitated an expansion in the acceptable parameter ranges. Finally, from a computational burden viewpoint, OF 1 demanded a significantly higher number of function evaluations, thus implying an escalating computational cost as the range expands. Conversely, OF 2 necessitated fewer evaluations to converge toward the optimal solution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)