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The bacterium Vibrio vulnificus causes fatal septicemia in humans. Previously, we reported that an extracellular metalloprotease, vEP-45, secreted by V. vulnificus, undergoes self-proteolysis to generate a 34 kDa protease (vEP-34) by losing its C-terminal domain to produce the C-ter100 peptide. Moreover, we revealed that vEP-45 and vEP-34 proteases induce blood coagulation and activate the kallikrein/kinin system. However, the role of the C-ter100 peptide fragment released from vEP-45 in inducing inflammation is still unclear. Here, we elucidate, for the first time, the effects of C-ter100 on inducing inflammation and activating host innate immunity. Our results showed that C-ter100 could activate NF-κB by binding to the receptor TLR4, thereby promoting the secretion of inflammatory cytokines and molecules, such as TNF-α and nitric oxide (NO). Furthermore, C-ter100 could prime and activate the NLRP3 inflammasome (NLRP3, ASC, and caspase 1), causing IL-1β secretion. In mice, C-ter100 induced the recruitment of immune cells, such as neutrophils and monocytes, along with histamine release into the plasma. Furthermore, the inflammatory response induced by C-ter100 could be effectively neutralized by an anti-C-ter100 monoclonal antibody (C-ter100Mab). These results demonstrate that C-ter100 can be a pathogen-associated molecular pattern (PAMP) that activates an innate immune response during Vibrio infection and could be a target for the development of antibiotics. Author summary: This study focused on the specific molecules associated with the pathogenic Vibrio vulnificus that play a role in the initiation of the innate immune responses during infection. The C-domain of vEP-45 and the C-ter100 derived from vEP-45 act as the first signals (as PAMP) to prime the formation of NLRP3 inflammasome, during which they bind to TLR4, thereby activating it (as PRR), leading to the activation of NF-κB signaling pathway to produce a variety of inflammatory cytokines and regulators such as TNF-α and NO, accompanied with the expression of NLRP3 (Fig 1). The formation and activation of NLRP3 inflammasome are triggered by ATP, serving as the second signal and resulting in production of active caspase-1 (Casp 1), which converts pro-IL-1β into IL-1β. Anti-C-ter100 monoclonal antibody (C-ter100Mab) can relieve the inflammatory response by neutralizing both vEP-45 and C-ter100 (Fig 1). Conclusively, C-ter100 functioned as a novel pathogen-associated molecular pattern, potentiating the innate immune system, and thus constituting a new target for the development of antibiotics. We believe that our study makes a significant contribution to the literature because it confirmed the binding between TLR4 and C-ter100 that initiates the innate immune response against Vibrio infection and determined that blocking this binding with C-ter100Mab effectively inhibited vibriosis. These results are important because they further elucidated Vibrio pathogenesis and helped in the designing new treatments and therapies that could control vibriosis. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to examine the influences of creativity, psychological ownership (PO) and perceived organizational support (POS) on knowledge creation, using the integrative systems model of creativity. Design/methodology/approach: A survey was used to collect data from 188 workers in Korean public service organizations. Analyses, including bootstrapping and hierarchical regression analysis, were performed to determine the mediating effect of PO and also the moderating and the moderated mediating effects of POS. Findings: The results showed that PO mediates partially between creativity and knowledge creation and that POS moderates the relationship between PO and knowledge creation. Notably, the moderated mediating effect of POS was only significant when employees had a high level of POS. Practical implications: The findings suggest that creativity dissemination requires employees' social consciousness, collaborative interactions and organizational support. The results imply that human resource development (HRD) practitioners need to cultivate the creativity capacity in the organization. Originality/value: This study discusses the effects of PO and POS on creative performance, which HRD professionals and organizational leaders draw attention to for organizational development. Implications for organizational composition and interventions to enhance creative performance are provided.

INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock‐in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan. METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non‐invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures. RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non‐carriers. Analysis of brain revealed alterations in several enzyme–substrate interactions within the gamma secretase complex prior to adulthood. DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate‐specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression. Highlights: We report the successful generation of genetically engineered marmosets harboring knock‐in point mutations in the PSEN1 gene.PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD‐related biomarkers.Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate‐specific mechanisms that drive disease progression. [ABSTRACT FROM AUTHOR]

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1–5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers. People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy. [ABSTRACT FROM AUTHOR]