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\"Alonso Berruguete (c. 1488-1561) revolutionized the arts of Renaissance Spain with a dramatic style of sculpture that reflected the decade or more he had spent in Italy while young. Trained as a painter, he traveled to Italy around 1506, where he interacted with Michelangelo and other leading artists. In 1518, he returned to Spain and was appointed court painter to the new king, Charles I. Eventually, he made his way to Valladolid, where he shifted his focus to sculpture, opening a large workshop that produced breathtaking multistory altarpieces (retablos) decorated with sculptures in painted wood. This handsomely illustrated catalogue is the first in English to treat Berruguete's art and career comprehensively. It follows his career from his beginnings in Castile to his final years in Toledo, where he produced his last great work, the marble tomb of Cardinal Juan de Tavera. Enriching the chronological narrative are discussions of important aspects of Berruguete's life and practice: his complicated relationship with social status and wealth; his activity as a draftsman and use of prints; how he worked with his many assistants to create his wood sculptures; and his legacy as an artist\"-- Provided by publisher.

The regulated disruption of the plasma membrane, which can promote cell death, cytokine secretion or both is central to organismal health. The protein gasdermin D (GSDMD) is a key player in this process. GSDMD forms membrane pores that can promote cytolysis and the release of interleukin-1 family cytokines into the extracellular space. Recent discoveries have revealed biochemical and cell biological mechanisms that control GSDMD pore-forming activity and its diverse downstream immunological effects. Here, we review these multifaceted regulatory activities, including mechanisms of GSDMD activation by proteolytic cleavage, dynamics of pore assembly, regulation of GSDMD activities by posttranslational modifications, membrane repair and the interplay of GSDMD and mitochondria. We also address recent insights into the evolution of the gasdermin family and their activities in species across the kingdoms of life. In doing so, we hope to condense recent progress and inform future studies in this rapidly moving field in immunology. Devant and Kagan review the biochemical and cell biological mechanisms that control gasdermin D pore-forming activity and its diverse downstream immunological effects.

Oxidized phospholipids that result from tissue injury operate as immunomodulatory signals that, depending on the context, lead to proinflammatory or anti-inflammatory responses. In this Perspective, we posit that cells of the innate immune system use the presence of oxidized lipids as a generic indicator of threat to the host. Similarly to how pathogen-associated molecular patterns represent general indicators of microbial encounters, oxidized lipids may be the most common molecular feature of an injured tissue. Therefore, microbial detection in the absence of oxidized lipids may indicate encounters with avirulent microorganisms. By contrast, microbial detection and detection of oxidized lipids would indicate encounters with replicating microorganisms, thereby inducing a heightened inflammatory and defensive response. Here we review recent studies supporting this idea. We focus on the biology of oxidized phosphocholines, which have emerged as context-dependent regulators of immunity. We highlight emerging functions of oxidized phosphocholines in dendritic cells and macrophages that drive unique inflammasome and migratory activities and hypermetabolic states. We describe how these lipids hyperactivate dendritic cells to stimulate antitumour CD8+ T cell immunity and discuss the potential implications of the newly described activities of oxidized phosphocholines in host defence.In this Perspective, the authors propose that innate immune detection of oxidized phospholipids, which result from tissue injury, allows the immune system to assess the degree of danger; the detection of oxidized phosphocholines in the presence of pathogen-associated molecular patterns or damage-associated molecular patterns triggers a heightened immune response.

Key Points The innate immune system can detect bacteria by sensing their cell-wall-associated molecules, including lipopolysaccharide, lipoproteins, peptidoglycan and flagellin. Each of these types of molecules is defined as a pathogen-associated molecular pattern (PAMP) and has the capacity to induce inflammatory responses to ensure host defence. Three common themes govern innate immune responses to bacteria. These themes include the use of multiple host receptors to detect individual PAMPs, the use of cytosolic supramolecular organizing centres (SMOCs) to promote inflammation and the use of complementary SMOC-dependent activities to ensure host defence. The best-defined SMOCs are the myddosome, which is assembled on bacterial detection by Toll-like receptors, and the inflammasome, which is assembled on bacterial detection by various cytosolic receptors. Pathogenic and commensal bacteria have evolved mechanisms to avoid recognition by pattern-recognition receptors, particularly by altering the structure of their PAMPs. Multiple evasion strategies are shared by commensals and pathogens alike. The detection of cell wall components has a critical role in the recognition of bacteria and the initiation of host defence. In this Review, Kieser and Kagan discuss common themes associated with the detection of individual bacterial products by diverse receptors of the innate immune system. The receptors of the innate immune system detect specific microbial ligands to promote effective inflammatory and adaptive immune responses. Although this idea is well appreciated, studies in recent years have highlighted the complexity of innate immune detection, with multiple host receptors recognizing the same microbial ligand. Understanding the collective actions of diverse receptors that recognize common microbial signatures represents a new frontier in the study of innate immunity, and is the focus of this Review. Here, we discuss examples of individual bacterial cell wall components that are recognized by at least two and as many as four different receptors of the innate immune system. These receptors survey the extracellular or cytosolic spaces for their cognate ligands and operate in a complementary manner to induce distinct cellular responses. We further highlight that, despite this genetic diversity in receptors and pathways, common features exist to explain the operation of these receptors. These common features may help to provide unifying organizing principles associated with host defence.

Key Points Recent work examining the cell biology of Toll-like receptors (TLRs) illustrates how basic aspects of the cellular machinery contribute to receptor function and regulation. Despite residing on several organelles, all TLRs are first transported to the Golgi complex before being routed to the appropriate location. Bacterium-sensing TLRs probably follow the default secretory pathway from the Golgi to the cell surface, whereas TLRs that detect viral nucleic acids are delivered to endolysosomes by the chaperone Unc93B1. Compartment-specific activity of nucleic acid-sensing TLRs (for example, TLR7 and TLR9) is maintained by compartment-specific cleavage events that generate functional receptors. These cleavage events are probably mediated by lysosomal cathepsins, and consequently nucleic acid-sensing TLRs are only active in endolysosomes. Bacterium-sensing TLRs (such as TLR2 and TLR4) use sorting adaptor proteins to determine the subcellular sites of signal transduction. For TLR4, the sorting adaptors TIRAP (TIR domain-containing adaptor protein) and TRAM (TRIF-related adaptor molecule) function to recruit their downstream signalling machinery to the plasma membrane and endosomes, respectively. Sorting adaptor proteins are positioned in specific intracellular subcompartments by interacting with phosphoinositides. Regulators of phosphoinositide metabolism may therefore control the activity of specific TLR signalling pathways. Endolysosomes seem to be the sole subcompartments that allow a TLR-dependent interferon response. Consequently, the plasma membrane-localized TLR4 must first be internalized into endosomes before the interferon-inducing signalling pathway can be activated. The activation and signalling pathways engaged by Toll-like receptors (TLRs) are determined by their localization in the cell. Here, the authors explain how generic cellular machinery involved in the compartmentalization of receptors and signalling molecules contributes to TLR function and regulation. An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand–receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.

DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP synthase—stimulator of interferon genes) pathway in antigen-presenting cells (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited tumor cell killing and ineffective transfer of stable tumor DNA to APCs. Here we show that liposomes loaded with an optimized ratio of indocyanine green and doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure to ultrasound. LID plus ultrasound enhance the nuclear delivery of doxorubicin, induce tumor mitochondrial DNA oxidation, and promote oxidized tumor mitochondrial DNA transfer to APCs for effective activation of cGAS-STING signaling. Depleting tumor mitochondrial DNA or knocking out STING in APCs compromises the activation of APCs. Furthermore, systemic injection of LID plus ultrasound over the tumor lead to targeted cytotoxicity and STING activation, eliciting potent antitumor T cell immunity, which upon the combination with immune checkpoint blockade leads to regression of bilateral MC38, CT26, and orthotopic 4T1 tumors in female mice. Our study sheds light on the importance of oxidized tumor mitochondrial DNA in STING-mediated antitumor immunity and may inspire the development of more effective strategies for cancer immunotherapy. Chemotherapy-induced cytosolic DNA has been shown to activate the cGAS-STING pathway. Here, the authors demonstrate that the efficacy of low-dose doxorubicin to elicit a STING-mediated anti-tumour immune response can be enhanced by liposomal-loading with indocyanine green, resulting in ultrasound-activatable enhanced nuclear doxorubicin localisation and release of mitochondrial DNA.

Dendritic cells (DCs) use pattern recognition receptors to detect microorganisms and activate protective immunity. These cells and receptors are thought to operate in an all-or-nothing manner, existing in an immunologically active or inactive state. Here, we report that encounters with microbial products and self-encoded oxidized phospholipids (oxPAPC) induce an enhanced DC activation state, which we call \"hyperactive.\" Hyperactive DCs induce potent adaptive immune responses and are elicited by caspase-11, an enzyme that binds oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. Both lipids induce caspase-11–dependent interleukin-1 release, but only LPS induces pyroptosis. The cells and receptors of the innate immune system can therefore achieve different activation states, which may permit context-dependent responses to infection.

Microplastics (less than 5 mm) are a recognized threat to aquatic food webs because they are ingested at multiple trophic levels and may bioaccumulate. In urban coastal environments, high densities of microplastics may disrupt nutritional intake. However, behavioural dynamics and consequences of microparticle ingestion are still poorly understood. As filter or suspension feeders, benthic marine invertebrates are vulnerable to microplastic ingestion. We explored microplastic ingestion by the temperate coral Astrangia poculata . We detected an average of over 100 microplastic particles per polyp in wild-captured colonies from Rhode Island. In the laboratory, corals were fed microbeads to characterize ingestion preference and retention of microplastics and consequences on feeding behaviour. Corals were fed biofilmed microplastics to test whether plastics serve as vectors for microbes. Ingested microplastics were apparent within the mesenterial tissues of the gastrovascular cavity. Corals preferred microplastic beads and declined subsequent offerings of brine shrimp eggs of the same diameter, suggesting that microplastic ingestion can inhibit food intake. The corals co-ingested Escherichia coli cells with microbeads. These findings detail specific mechanisms by which microplastics threaten corals, but also hint that the coral A. poculata , which has a large coastal range, may serve as a useful bioindicator and monitoring tool for microplastic pollution.

In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I–like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP–AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.

Type III interferons have important antiviral functions, but they are poorly described compared to type I interferons. Kagan and colleagues demonstrate that type III interferons are induced on peroxisomes in response to a variety of viral triggers. Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon–independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses.