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The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β and IL-18. Gain-of-function variants in the gene encoding NLRP3 (also called cryopyrin) lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening and automated analysis of 534 NLRP3 variants from the international INFEVERS registry and the ClinVar database. This resource captures the effect of NLRP3 variants on ASC speck formation spontaneously, at low temperature, after inflammasome stimulation and with the specific NLRP3 inhibitor MCC950. Most notably, our analysis facilitated the updated classification of NLRP3 variants in INFEVERS. Structural analysis suggested multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex and promoting oligomerization of the pyrin domain. Furthermore, we identified pathogenic variants that can hypersensitize the activation of NLRP3 in response to nigericin and cold temperature exposure. We also found that most CAPS-related NLRP3 variants can be inhibited by MCC950; however, NLRP3 variants with changes to proline affecting helices near the inhibitor binding site are resistant to MCC950, as are variants in the pyrin domain, which likely trigger activation directly with the pyrin domain of ASC. Our findings could help stratify the CAPS population for NLRP3 inhibitor clinical trials and our automated methodologies can be implemented for molecules with a different mechanism of activation and in laboratories worldwide that are interested in adding new functionally validated NLRP3 variants to the resource. Overall, our study provides improved diagnosis for patients with CAPS, mechanistic insight into the activation of NLRP3 and stratification of patients for the future application of targeted therapeutics., Competing Interests: Competing interests: S.L.M. is the Vice President of Discovery Biology of NRG Therapeutics and scientific advisor for Odyssey Therapeutics. M.G. is a scientific advisor to BioAge Labs. The other authors declare no competing interests., (© 2025. The Author(s).)

Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Laparoscopic cholecystectomy is the gold standard in the treatment of symptomatic gallstones. The large number of gallbladders removed every year is not fully consistent with the excessively high incidence of iatrogenic bile duct injury (IBDI). Several strategies have been suggested to reduce this risk. Among them, the use of extra biliary anatomic structures, such as the Rouvière's sulcus, as a landmark to guide the surgeon during dissection has been proposed as a means to prevent IBDI. The main aim of the present paper is the evaluation of the prevalence of Rouvière's sulcus (RS) and its anatomic variants in a given population., Materials and Methods: This observational, cross-sectional, and multicenter study has been conducted at the Department of Digestive and Emergency Surgery of the "Azienda Ospedaliera Santa Maria," Terni (Italy), at the Department of Surgical Sciences of the "Azienda Ospedaliera Perugia," Perugia (Italy) and at the Department of Emergency and Trauma Surgery of the "Policlinico Umberto I," Rome (Italy). Intraoperative images of 111 patients undergoing laparoscopic cholecystectomy were analyzed to identify the presence and type of RS, according to the Singh-Prasad classification and the Dahmane classification., Results: RS was present in 93 (83.8%) patients. Singh-Prasad type 1A is present in 48.4% of patients, type 1B in 25.8%, type 2 in 12.9% and type 3 in 12.9%. Dahmane's open type is present in 48.4% of patients and fused type in 51.6%., Conclusion: Due to its high prevalence, RS can be used as an anatomic landmark and probably reduces the incidence of IBDI during laparoscopic cholecystectomy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Despite advances in medicine and antimicrobial research, viral infections continue to pose a major threat to human health. While major strides have been made in generating vaccines and small molecules to combat emerging pathogens, new modalities of treatment are warranted in diseases where there is a lack of treatment options, or where treatment cannot fully eradicate pathogens, as in HIV infection. Cellular therapies, some of which are FDA approved for treating cancer, take advantage of our developing understanding of the immune system, and harness this knowledge to enhance, or direct, immune responses toward infectious agents. As with cancer, viruses that evade immunity, do so by avoiding immune recognition or by redirecting the cellular responses that would eradicate them. As such, infusing virus specific immune cells has the potential to improve patient outcomes and should be investigated as a potential tool in the arsenal to fight infection. The present manuscript summarizes key findings made using cellular therapies for the treatment of viral infections, focusing on the potential that these strategies might have in controlling disease., Competing Interests: Declarations. Competing interests: J. L. R is a scientific co-founder and holds equity in BlueWhale Bio and is a scientific advisor and received research funding from Kite Pharma, a Gilead company. The other authors declare no competing interests., (© 2024. The Author(s).)