TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.

The loss of TBK1, or both TBK1 and the related kinase IKKε, results in uncontrolled cell death-driven inflammation. Here, we show that the pathway leading to cell death depends on the nature of the activating signal. Previous models suggest that in steady state, TBK1/IKKε-deficient cells die slowly and spontaneously predominantly by uncontrolled tumor necrosis factor-RIPK1-driven death.

Survey of Clinical Knowledge and Procedural Readiness of Pulmonary Fellows to Start Interventional Pulmonary Fellowship: A Survey of Interventional Pulmonary Fellowship Directors.

Background: Entry into the interventional pulmonary (IP) fellowship requires prerequisite training in pulmonary and critical care medicine (PCCM) fellowship in the United States. IP fellowship has become standardized, but the prerequisite training may be quite variable depending on the learner's exposure to IP during their PCCM fellowship. A survey study was conducted to identify potential foundational knowledge and/or skills gaps of new fellows entering IP fellowships.

NLRP1-dependent activation of Gasdermin D in neutrophils controls cutaneous leishmaniasis.

Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell's killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host.

Gasdermin D is the only Gasdermin that provides protection against acute gut infection in mice.

Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute Typhimurium (Tm) gut infection.

Bronchoscopic Management of COPD and Advances in Therapy.

Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent and morbid disease marked by irreversible structural changes in the lungs. Bronchoscopic therapies have significantly expanded the treatment armamentarium for patients with persistent symptoms by reducing the physiologic detriments of hyperinflation in a less invasive fashion than surgical lung volume reduction. The spectrum of bronchoscopic techniques to reduce hyperinflation includes endobronchial valves, coils, thermal ablation, and biologic sealants.

Detection of Gasdermin Activation and Lytic Cell Death During Pyroptosis and Apoptosis.

Cytosolic pattern recognition receptors trigger pyroptosis by detection of danger- or pathogen-associated molecular patterns. These receptors initiate the assembly of inflammasomes, multimeric protein complexes that drive caspase-1 activation. Active caspase-1 cleaves the proinflammatory cytokines IL-1β and IL-18 and the pore-forming protein gasdermin-D (GSDMD) thereby liberating its N-terminal domain.

How Pyroptosis Contributes to Inflammation and Fibroblast-Macrophage Cross-Talk in Rheumatoid Arthritis.

About thirty years ago, a new form of pro-inflammatory lytic cell death was observed and termed pyroptosis. Only in 2015, gasdermins were defined as molecules that create pores at the plasma membrane and drive pyroptosis. Today, we know that gasdermin-mediated death is an important antimicrobial defence mechanism in bacteria, yeast and mammals as it destroys the intracellular niche for pathogen replication.

Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection.

Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1β release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation.

TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation.

NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation is beneficial during infection and vaccination but, when uncontrolled, is detrimental and contributes to inflammation-driven pathologies. Hence, discovering endogenous mechanisms that regulate NLRP3 activation is important for disease interventions. Activation of NLRP3 is regulated at the transcriptional level and by posttranslational modifications.

Comparative analysis of the coordinated motion of Hsp70s from different organelles observed by single-molecule three-color FRET.

Cellular function depends on the correct folding of proteins inside the cell. Heat-shock proteins 70 (Hsp70s), being among the first molecular chaperones binding to nascently translated proteins, aid in protein folding and transport. They undergo large, coordinated intra- and interdomain structural rearrangements mediated by allosteric interactions.

RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling.

Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defense.

Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.

Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8-dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved.

Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria.

The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic Salmonella or upon cytosolic delivery of LPS.

Cross talk between intracellular pathogens and cell death.

Infections with bacterial pathogens often results in the initiation of programmed cell death as part of the host innate immune defense, or as a bacterial virulence strategy. Induction of host cell death is controlled by an elaborate network of innate immune and cell death signaling pathways and manifests in different morphologically and functionally distinct forms of death, such as apoptosis, necroptosis, NETosis and pyroptosis. The mechanism by which host cell death restricts bacterial replication is highly cell-type and context depended, but its physiological importance is highlighted the diversity of strategies bacterial pathogens use to avoid induction of cell death or to block cell death signaling pathways.

Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD.

Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis.

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis.

Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD).

Pannexin-1 promotes NLRP3 activation during apoptosis but is dispensable for canonical or noncanonical inflammasome activation.

Inflammasomes are multimeric protein complex that assemble in the cytosol upon microbial infection or cellular stress. Upon activation, inflammasomes drive the maturation of proinflammatory cytokines, IL-1β and IL-18, and also activate the pore-forming protein, gasdermin D to initiate a form of lytic cell death known as "pyroptosis". Pannexin-1 is channel-forming glycoprotein that promotes membrane permeability and ATP release during apoptosis; and was implicated in canonical NLRP3 or noncanonical inflammasome activation.

Pannexin-1 channels bridge apoptosis to NLRP3 inflammasome activation.

Apoptosis can promote inflammation by triggering activation of the NLRP3 inflammasome (NLR family, pyrin domain containing 3). However, the molecular mechanisms regulating these processes are ill-defined. We recently reported that pannexin-1 is required to promote NLRP3 inflammasome assembly.

Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly.

Pyroptosis is a form of lytic inflammatory cell death driven by inflammatory caspase-1, caspase-4, caspase-5 and caspase-11. These caspases cleave and activate the pore-forming protein gasdermin D (GSDMD) to induce membrane damage. By contrast, apoptosis is driven by apoptotic caspase-8 or caspase-9 and has traditionally been classified as an immunologically silent form of cell death.

Hemopericardium and Cardiac Tamponade Secondary to Migrated Inferior Vena Cava Filter.

A 73-year-old female presented with cardiogenic shock secondary to hemopericardium and cardiac tamponade. Imaging revealed two fractured legs of an inferior vena cava filter, with one leg within the anterior myocardium of the right ventricle and another penetrating the inferior septum through the middle cardiac vein. Hemopericardium and cardiac tamponade were treated with pericardiocentesis.

Lipid-Coated Zinc Oxide Nanoparticles as Innovative ROS-Generators for Photodynamic Therapy in Cancer Cells.

In the present paper, we use zinc oxide nanoparticles under the excitation of ultraviolet (UV) light for the generation of Reactive Oxygen Species (ROS), with the aim of further using these species for fighting cancer cells in vitro. Owing to the difficulties in obtaining highly dispersed nanoparticles (NPs) in biological media, we propose their coating with a double-lipidic layer and we evaluate their colloidal stability in comparison to the pristine zinc oxide NPs. Then, using Electron Paramagnetic Resonance (EPR) coupled with the spin-trapping technique, we demonstrate and characterize the ability of bare and lipid-coated ZnO NPs to generate ROS in water only when remotely actuated via UV light irradiation.