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\"When Batman discovers a mysterious package containing DNA test results proving that he is not Damian Wayne's biological father, the Dark Knight sets his sights on his son's true father--Deathstroke! But Damian Wayne can't really be Slade Wilson's son--can he? And who sent the package--and why? The ultimate custody battle ensues as the World's Greatest Detective and the World's Deadliest Assassin clash in this instant classic!\"-- Provided by publisher.

Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases 1 – 4 . During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro −1 ), we identify unexpected beneficial effects of the Pyro −1 secretome. First, we noted that the Pyro −1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro −1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro −1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E 2 (PGE 2 ), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE 2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301 + macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically. Defining the composition of the secretome of pyroptotic macrophages reveals the involvement of the component factors in wound healing.

Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis 1 . Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract 2 . A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component 3 – 6 , but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella , and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment. Intestinal microorganisms exploit nutrients released by apoptotic gut epithelial cells for growth.

is a common causative agent of infectious intestinal and systemic disease and has been extensively studied for several decades. Yet, much of pathogenicity remains a mystery due in part to the highly complex virulence and adaptation strategies at the pathogen's disposal. One of the more influential tools within the field, an attenuated deficient strain, has been used for many years to probe the host immune response that would otherwise be impossible with a fully virulent strain. Now, new work by Rooke et al. (J. L. Rooke, E. C. A. Goodall, K. Pullela, R. Da Costa, et al., mBio 15:e03319-23, 2024, https://doi.org/10.1128/mbio.03319-23) utilizes in-depth transposon-directed insertion-site sequencing to elucidate the contribution of genes to fitness within isogenic wild-type and -deficient strains. Specifically, Rooke et al. demonstrate that the deletion of the gene leads to iron-dependent membrane instability, raising several exciting new ideas surrounding biology and therapeutic strategies.

Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts.

Little is known about how immigrants participate in politics and whether they transform political engagement in contemporary democracies. This study investigates whether citizenship (as opposed to being foreign-born) affects political and civic engagement beyond the voting booth. It is argued that citizenship should be understood as a resource that enhances participation and helps immigrants overcome socialization experiences that are inauspicious for political engagement. The analysis of the European Social Survey data collected in nineteen European democracies in 2002–03 reveals that citizenship has a positive impact on political participation. Moreover, citizenship is a particularly powerful determinant of un-institutionalized political action among individuals who were socialized in less democratic countries. These findings have important implications for debates over the definition of and access to citizenship in contemporary democracies.

The synthetic biology research community describes a standard language for exchanging designs of biological 'parts'. The re-use of previously validated designs is critical to the evolution of synthetic biology from a research discipline to an engineering practice. Here we describe the Synthetic Biology Open Language (SBOL), a proposed data standard for exchanging designs within the synthetic biology community. SBOL represents synthetic biology designs in a community-driven, formalized format for exchange between software tools, research groups and commercial service providers. The SBOL Developers Group has implemented SBOL as an XML/RDF serialization and provides software libraries and specification documentation to help developers implement SBOL in their own software. We describe early successes, including a demonstration of the utility of SBOL for information exchange between several different software tools and repositories from both academic and industrial partners. As a community-driven standard, SBOL will be updated as synthetic biology evolves to provide specific capabilities for different aspects of the synthetic biology workflow.

Microorganisms use genetic circuits to integrate environmental information. We have constructed a synthetic AND gate in the bacterium Escherichia coli that integrates information from two promoters as inputs and activates a promoter output only when both input promoters are transcriptionally active. The integration occurs via an interaction between an mRNA and tRNA. The first promoter controls the transcription of a T7 RNA polymerase gene with two internal amber stop codons blocking translation. The second promoter controls the amber suppressor tRNA supD . When both components are transcribed, T7 RNA polymerase is synthesized and this in turn activates a T7 promoter. Because inputs and outputs are promoters, the design is modular; that is, it can be reconnected to integrate different input signals and the output can be used to drive different cellular responses. We demonstrate this modularity by wiring the gate to integrate natural promoters (responding to Mg 2+ and AI‐1) and using it to implement a phenotypic output (invasion of mammalian cells). A mathematical model of the transfer function is derived and parameterized using experimental data. Synopsis Cells can be ‘programmed’ by building DNA encoding a series of instructions. Some recent examples include strains of E. coli that have been programmed to record images of light, form two‐dimensional patterns, and oscillate like a clock. Logic gates form the core of electronic computing and are an essential component of complex programs. An AND gate integrates two input signals into a single output. If both inputs are ON, then the output is ON. If either or both inputs are OFF, then the output is OFF. AND gates are particularly important to program a bacterium to respond to a microenvironment that is not well defined by a single signal (i.e., high glucose AND low salt). To incorporate a genetic circuit into a larger program, it is critical that it be able to be connected to different inputs and outputs. Bacteria ‘see’ their environment using genetic sensors that respond to different stimuli. These sensors can regulate gene expression by activating a promoter. We have constructed a genetic AND gate that uses such promoters as inputs (Figure 1 ). One promoter leads to the transcription of an mRNA encoding a transcriptional activator. However, stop codons are placed in the activator gene so that the mRNA alone is not sufficient to produce active protein. Only when a tRNA is transcribed from the second input promoter will the activator be produced. Thus, only when the two input promoters are active, the activator will turn on an output promoter. This genetic architecture produces an AND gate with near‐digital behavior (Figure 2 ). Further, we demonstrate that different input promoters, representing different environmental stimuli, can be connected to this circuit. Genetic parts are used to construct a near‐digital AND gate Two input promoters are integrated to activate a single output promoter The circuit is modular and can be connected to different inputs and outputs A mathematical model is developed that describes how the circuit integrates information

The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients.