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Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases. Disulfiram is an FDA-approved drug for treating alcoholism. Wu and colleagues show that disulfiram can be repurposed to efficiently inhibit pyroptosis by specifically blocking gasdermin-mediated pore formation.

Natural killer (NK) cells kill infected, transformed and stressed cells when an activating NK cell receptor is triggered 1 . Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1 , the most evolutionarily ancient NK cell receptor 2 , 3 . Blockage of NKp46 inhibits NK killing of many cancer targets 4 . Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death 5 , 6 , flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of  CALR , the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1 -deficient human (and Ncr1 -deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells. NKp46 recognizes externalized calreticulin, which translocates from the ER to the cell membrane during ER stress, indicating a danger-associated molecular pattern that eliminates ER-stressed cells.

Inflammasomes are multi-protein signalling scaffolds that assemble in response to invasive pathogens and sterile danger signals to activate inflammatory caspases (1/4/5/11), which trigger inflammatory death (pyroptosis) and processing and release of pro-inflammatory cytokines (1,2). Inflammasome activation contributes to many human diseases, including inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer's disease, and sepsis, the often fatal response to systemic infection (3-6). The recent identification of the pore-forming protein gasdermin D (GSDMD) as the final pyroptosis executioner downstream of inflammasome activation presents an attractive drug target for these diseases (7-11). Here we show that disulfiram, a drug used to treat alcohol addiction (12), and Bay 11-7082, a previously identified NF-kappaB inhibitor (13), potently inhibit GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1beta secretion in human and mouse cells. Moreover, disulfiram, administered at a clinically well-tolerated dose, inhibits LPS-induced septic death and IL-1beta secretion in mice. Both compounds covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation (8,14). Inflammatory caspases employ Cys active sites, and many previously identified inhibitors of inflammatory mediators, including those against NLRP3 and NF-kappaB, covalently modify reactive cysteine residues (15). Since NLRP3 and noncanonical inflammasome activation are amplified by cellular oxidative stress (16-22), these redox-sensitive reactive cysteine residues may regulate inflammation endogenously, and compounds that covalently modify reactive cysteines may inhibit inflammation by acting at multiple steps. Indeed, both disulfiram and Bay 11-7082 also directly inhibit inflammatory caspases and pleiotropically suppress multiple processes in inflammation triggered by both canonical and noncanonical inflammasomes, including priming, puncta formation and caspase activation. Hence, cysteine-reactive compounds, despite their lack of specificity, may be attractive agents for reducing inflammation.

Natural killer cells (NK) are a first line of immune defense to eliminate infected, transformed and stressed cells by releasing cytotoxic granules1. NK activation is controlled by the balance of signals transmitted by activating and inhibitory receptors but activating receptor engagement is required to trigger cytotoxicity. The activating receptor NKp46, encoded by the NCR1 gene, is expressed by virtually all NK cells and is the most evolutionarily ancient NK receptor. NKp46 plays a major role in NK recognition of cancer cells, since NKp46 blocking antibodies potently inhibit NK killing of many cancer targets2,3. Although a few viral, fungal and soluble host ligands4 have been identified, the endogenous cell-surface ligand of this important activating NK receptor is unknown. Here we show that NKp46 recognizes and is activated by the P-domain of externalized calreticulin (ecto-CRT). CRT, normally localized to the ER, translocates to the cell surface during ER stress and is a hallmark of chemotherapy-treated dying cancer cells that induce an immune response (immunogenic cell death, ICD)5. NKp46 caps with ecto-CRT in NK immune synapses formed with ecto-CRT-bearing target cells. ER stress, induced by ZIKV infection, ICD-causing chemotherapy drugs and some senescence activators, externalizes CRT and triggers NKp46 signaling. NKp46-mediated killing is inhibited by CRT knockout or knockdown or anti-CRT antibodies and is enhanced by ectopic expression of GPI-anchored CRT. NCR1/Ncr1-deficient human and mouse NK are impaired in killing ZIKV-infected, ER-stressed, and senescent cells and cancer cells that endogenously or ectopically express ecto-CRT. Importantly, NKp46 recognition of ecto-CRT controls the growth of B16 melanoma and RAS-driven lung cancer in mouse models and enhances tumor-infiltrating NK degranulation and cytokine secretion. Thus, ecto-CRT is a danger-associated molecular pattern (DAMP) that is an endogenous NKp46 ligand that promotes innate immune elimination of ER-stressed cells.

The Earth’s diffuse auroral precipitation provides the major source of energy input into the nightside upper atmosphere and acts as an essential linkage of the magnetosphere-ionosphere coupling. Resonant wave-particle interactions play a dominant role in the scattering of injected plasma sheet electrons, leading to the diffuse auroral precipitation. We review the recent advances in understanding the origin of the diffuse aurora and in quantifying the exact roles of various magnetospheric waves in producing the global distribution of diffuse auroral precipitation and its variability with the geomagnetic activity. Combined scattering by upper-and lower-band chorus accounts for the most intense inner magnetospheric electron diffuse auroral precipitation on the nightside. Dayside chorus can be responsible for the weaker dayside electron diffuse auroral precipitation. Pulsating auroras, the dynamic auroral structures embedded in the diffuse aurora, can be mainly caused by modulation of the excitation of lower band chorus due to macroscopic density variations in the magnetosphere. Electrostatic electron cyclotron harmonic waves are an important or even dominant cause for the nightside electron diffuse auroral precipitation beyond ∼ 8 R e and can also contribute to the occurrence of the pulsating aurora at high L -shells. Scattering by electromagnetic ion cyclotron waves could quite possibly be the leading candidate responsible for the ion precipitation (especially the reversed-type events of the energy-latitude dispersion) in the regions of the central plasma sheet and ring current. We conclude the review with a summary of current understanding, outstanding questions, and a number of suggestions for future research.

The stability of single-atom catalysts is critical for their practical applications. Although a high temperature can promote the bond formation between metal atoms and the substrate with an enhanced stability, it often causes atom agglomeration and is incompatible with many temperature-sensitive substrates. Here, we report using controllable high-temperature shockwaves to synthesize and stabilize single atoms at very high temperatures (1,500–2,000 K), achieved by a periodic on–off heating that features a short on state (55 ms) and a ten-times longer off state. The high temperature provides the activation energy for atom dispersion by forming thermodynamically favourable metal–defect bonds and the off-state critically ensures the overall stability, especially for the substrate. The resultant high-temperature single atoms exhibit a superior thermal stability as durable catalysts. The reported shockwave method is facile, ultrafast and universal (for example, Pt, Ru and Co single atoms, and carbon, C3N4 and TiO2 substrates), which opens a general route for single-atom manufacturing that is conventionally challenging.

Human activities, especially increased nutrient loads that set in motion a cascading chain of events related to eutrophication, accelerate development of hypoxia (lower oxygen concentration) in many areas of the world's coastal ocean. Climate changes and extreme weather events may modify hypoxia. Organismal and fisheries effects are at the heart of the coastal hypoxia issue, but more subtle regime shifts and trophic interactions are also cause for concern. The chemical milieu associated with declining dissolved oxygen concentrations affects the biogeochemical cycling of oxygen, carbon, nitrogen, phosphorus, silica, trace metals, and sulfide as observed in water column processes, shifts in sediment biogeochemistry, and increases in carbon, nitrogen, and sulfur, as well as shifts in their stable isotopes, in recently accumulated sediments.

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic—termed post-acute sequelae of SARS-CoV-2 (PASC)—are rapidly evolving into a major public health concern 1 – 3 . While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses 3 – 6 and/or impaired organ recovery 7 – 9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune–epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8 + T cell–macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8 + T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention 10 , we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease. CD8 + T cell–macrophage interactions have a central role in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia in a mouse model of long COVID.