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Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. Notch signalling plays important roles in many developmental processes, making it difficult to name a tissue or a developing organ that does not depend on Notch function at one stage or another. Thus, dysregulation of Notch signalling is associated with many developmental defects and various pathological conditions, including cancer. Although many recent advances have been made to reveal different aspects of the Notch signalling mechanism and its intricate regulation, there are still many unanswered questions related to how the Notch signalling pathway functions in so many developmental events. The same pathway can be deployed in numerous cellular contexts to play varied and critical roles in an organism's development and this is only possible because of the complex regulatory mechanisms of the pathway. In this review, we provide an overview of the mechanism and regulation of the Notch signalling pathway along with its multifaceted functions in different aspects of development and disease. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) secretes extracellular vesicles (EVs) containing a variety of proteins, lipoproteins, and lipoglycans. While emerging evidence suggests that EVs contribute to tuberculosis pathogenesis, the factors and molecular mechanisms involved in mycobacterial EV production have not been identified. In this study, we use a genetic approach to identify Mtb proteins that mediate vesicle release in response to iron limitation and antibiotic exposure. We uncover a critical role for the isoniazid‐induced, dynamin‐like proteins, IniA and IniC, in mycobacterial EV biogenesis. Further characterization of a Mtb iniA mutant shows that the production of EVs enables intracellular Mtb to export bacterial components into the extracellular environment to communicate with host cells and potentially modulate the immune response. The findings advance our understanding of the biogenesis and functions of mycobacterial EVs and provide an avenue for targeting vesicle production in vivo. Synopsis: The iron‐regulated, dynamin‐like proteins IniAC promote the production and release of extracellular vesicles from Mycobacterium tuberculosis.Induction of iniAC expression in response to infection‐relevant conditions such as iron limitation or antibiotic exposure is associated with enhanced release of mycobacterial extracellular vesicles (MEVs).Inactivation of the dynamin‐like proteins iniAC abrogates MEV production and is associated with impaired vesicle‐mediated, mycobactin‐dependent iron acquisition, and export of bacterial products out of infected macrophages via extracellular vesicles. [ABSTRACT FROM AUTHOR]

Background: Research and clinical outcomes that matter to people with lived experience can significantly differ from those outcomes studied by researchers. To inform a future Cochrane review of suicide and self‐harm prevention interventions, we aimed to work with young people with relevant lived experience to agree on priority outcomes. Design: Four participatory codesign workshops were completed across two sites (New Zealand, United Kingdom) with 28 young people in total. We iteratively adapted the methods over the course of the study. Results: 'Improved coping' and 'safer/more accepting environment to disclose' were the final top‐rated outcomes. 'Reduction of self‐harm' was considered a low priority as it could be misleading, stigmatizing and was considered a secondary consequence of other improvements. In contrast to typical research outcomes, young people emphasized the diversity of experience, the dynamic nature of improvement and holistic and asset‐based framing. Methodologically, dialogue using design materials (personas) to thematically explore outcomes was effective in overcoming the initial challenge of disparate quantitative ratings. Discussion: The results will directly inform the development of a Cochrane review, enabling identification of whether and how outcomes of most importance to young people are measured in trials. Rather than producing discrete measurable outcomes that could be easily added to the systematic review, the young people challenged the academic conceptualization of outcomes, with implications for future evidence synthesis and intervention research, and for future codesign. Patient or Public Contribution: Young people with lived experience were codesigners of the outcomes, and their feedback informed iterative changes to the study methods. [ABSTRACT FROM AUTHOR]

Notch signaling is an evolutionarily conserved pathway that is widely used for multiple cellular events during development. Activation of the Notch pathway occurs when the ligand from a neighboring cell binds to the Notch receptor and induces cleavage of the intracellular domain of Notch, which further translocates into the nucleus to activate its downstream genes. The involvement of the Notch pathway in diverse biological events is possible due to the complexity in its regulation. In order to maintain tight spatiotemporal regulation, the Notch receptor, as well as its ligand, undergoes a series of physical and biochemical modifications that, in turn, helps in proper maintenance and fine‐tuning of the signaling outcome. Ubiquitination is the post‐translational addition of a ubiquitin molecule to a substrate protein, and the process is regulated by E3 ubiquitin ligases. The present review describes the involvement of different E3 ubiquitin ligases that play an important role in the regulation and maintenance of proper Notch signaling and how perturbation in ubiquitination results in abnormal Notch signaling leading to a number of human diseases. [ABSTRACT FROM AUTHOR]

Toll pathway is the center for the function of immune system in both Drosophila and mammals. Toll pathway in Drosophila gets activated upon binding of the ligand Spätzle to the receptor, Toll, triggering a series of proteolytic cascade culminating into the activation of the NF‐κB factors Dorsal and/or Dif (Dorsal‐related immunity factor). Inappropriate activation of the Toll pathway is often associated with systemic inflammation phenotype in the absence of infection, and thus, it is important to understand the regulation of Toll signaling. Deltex (Dx) is a context‐dependent regulator of Notch signaling and has been linked with cell‐mediated immunity in the mammalian system lately. However, the unambiguous role of Dx in humoral and cell‐mediated immunity is yet to be explored. Our study unravels the novel role of Dx in Toll pathway activation. Gain of function of dx in Drosophila larvae results in increased melanotic mass formation and increased lamellocyte production. Our results also reveal the nuclear accumulation of transcription factors Dorsal and Dif and expression of Toll‐associated antimicrobial peptides (AMP) in Dx over‐expression background. Further, we also tried to elucidate the role of Dx in JNK‐independent Toll activation. Here we present Dx as a novel candidate in the regulation of Toll pathway. [ABSTRACT FROM AUTHOR]

JNK signaling is a highly conserved signaling pathway that regulates a broad spectrum of cellular processes including cell proliferation, migration, and apoptosis. In Drosophila, JNK signaling is activated by binding of the tumor necrosis factor (TNF) Eiger to its receptor Wengen, and a conserved signaling cascade operates that culminates into activation of dual phosphatase Puckered thereby triggering apoptosis. The tumor necrosis factor receptor (TNFR) associated factor 6 (TRAF6) is an adaptor protein, which transduces the signal from TNFRs and Toll‐like receptor/interleukin‐1 receptor superfamily to induce a wide spectrum of cellular responses. TRAF6 also acts as the adaptor protein that mediates Eiger/JNK signaling in Drosophila. In a genetic interaction study, deltex (Dx) was identified as a novel interactor of TRAF6. Dx is well known to regulate Notch signaling in a context‐dependent manner. Our data suggest that combinatorial action of Dx and TRAF6 enhances the Dx‐induced wing nicking phenotype by inducing caspase‐mediated cell death. Co‐expression of Dx and TRAF6 also results in enhanced invasive behavior and perturbs the normal morphology of cells. The cooperative action of Dx and TRAF6 is attributed to JNK activation, which also leads to ectopic wingless (Wg) and decapentaplegic (Dpp) expression. Our results also reveal that the endocytic pathway component Rab7 may play a pivotal role in the regulation of Dx–TRAF6‐mediated activation of JNK signaling. Here, we present the fact that Dx and TRAF6 together activate JNK signaling in an Eiger‐independent mechanism. [ABSTRACT FROM AUTHOR]