Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.

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Membrane-type 1 matrix metalloproteinase (MT1-MMP)/MMP-14 is the activator of progelatinase A (proGelA)/proMMP-2 on the cell surface. However, it was a paradox that a tissue inhibitor of metalloproteinase-2 (TIMP-2), which is an inhibitor of MT1-MMP, is required for proGelA activation by the cells expressing MT1-MMP. In this study, a truncated MT1-MMP having a FLAG-tag sequence at the C terminus (MT1-F) was immobilized onto agarose beads (MT1-F/B) and used to analyze the role of TIMP-2. The proteolytic activity of MT1-F/B against a synthetic peptide substrate was inhibited by TIMP-2 in a dose-dependent manner. In contrast, TIMP-2 promoted the processing of proGelA by MT1-F/B at low concentrations and inhibited it at higher concentrations. TIMP-2 promoted the binding of proGelA to the MT1-F on the beads by forming a trimolecular complex, which was followed by processing of proGelA. A stimulatory effect of TIMP-2 was observed under conditions in which unoccupied MT1-F was still available. Thus, the ternary complex is thought to act as a means to concentrate the substrate to the bead surface and to present it to the neighboring free MT1-F. Matrix metalloproteinases (MMPs)1 are zinc-dependent endopeptidases that play critical roles in the physiological and pathological turnover of extracellular matrix (ECM) by degrading the macromolecules (1-6). MMPs are produced as a zymogen (proMMP) that needs proteolytic activation by eliminating the N-terminal propeptide for the enzymes to function (7). Serine proteases such as plasmin, neutrophil elastase, and trypsin are well known activators for proMMPs. These activators digest the propeptide sequences at the basic amino acid motifs and eventually induce autocatalytic activation (8).However, proGelA lacks such a basic motif and therefore cannot be activated by serine proteinases (9). ProGelA had been reported to be activated by an unknown MMP-like activity on the surface of cancer and fibroblastic cells (10 -15), and we identified MT1-MMP as such an activator on the cell surface (16,17). Three other genes encoding similar enzymes that have a transmembrane domain and a short cytoplasmic tail were identified (18 -20); at least two of them (MT2-MMP and MT3-MMP) activated proGelA in vitro (21).Upon cell-mediated activation, proGelA binds to the cells through its hemopexin-like domain (HLD) (22). Using the HLD of GelA, Strongin et al. (23) isolated TIMP-2 complexed with the activated form of MT1-MMP from the cell membrane extract. We also purified a shaded fragment of MT1-MMP from the culture medium of the human breast carcinoma cell line MDA-MB-231 as a form inhibited by TIMP-2 (24). The Cterminal domain of the TIMP-2 in the complex was available for further complex formation with proGelA through its HLD (trimolecular complex). Strongin et al. also demonstrated that a small amount of TIMP-2 is an essential component for the activation of proGelA on the surface, in contrast to evidence that TIMP-2 is a well established inhibitor for all of the known MMPs. It would thus be of inter...

We discuss two independent, large scale experiments performed in two wave basins of different dimensions in which the statistics of the surface wave elevation are addressed. Both facilities are equipped with a wave maker capable of generating waves with prescribed frequency and directional properties. The experimental results show that the probability of the formation of large amplitude waves strongly depends on the directional properties of the waves. Sea states characterized by long-crested and steep waves are more likely to be populated by freak waves with respect to those characterized by a large directional spreading. DOI: 10.1103/PhysRevLett.102.114502 PACS numbers: 47.35.Bb, 47.55.NÀ An important task in the study of surface gravity waves is the determination of the probability density function of the surface wave elevation. The knowledge of the probability of the occurrence of large amplitude waves is essential for different engineering purposes such as the prediction of wave forces and structural responses or the design of offshore structures. A deep comprehension of the physical mechanisms of the generation of such waves is also a first step towards the development of an operational methodology for the probabilistic forecast of freak waves. It is well known that surface gravity waves obey nonlinear equations and, to date, a universal tool suitable for deriving the probability distribution function of a nonlinear system has not yet been developed. Fortunately, water waves are on average weakly nonlinear [1,2] and solutions can be generally written as power series, where the small parameter, in the case of deep water waves, is the wave steepness ". Strong departure from Gaussian statistics of the surface elevation can be observed if third order nonlinearities are considered. At such order it has been shown numerically [3] and theoretically [4] that, for long-crested waves, a generalization of the Benjamin-Feir instability [5] (or modulational instability [2]) for random spectra can take place [6]. This instability, that corresponds to a quasiresonant four-wave interaction in Fourier space, results in the formation of large amplitude waves (or rogue waves) [7] which affect the statistical properties of the surface elevation (see, for example, [8]). This is particularly true if the ratio between the wave steepness and the spectral bandwidth, known as the Benjamin-Feir Index (BFI), is large [4]. We mention that rogue waves have also been recently observed in optical systems [9] and in acoustic turbulence in He II [10] where giant waves are observed during an inverse cascade process.We emphasize that in many different fields of physics (plasmas [11,12], nonlinear optics [13,14], chargedparticle beam dynamics [15,16]) the modulational instability plays an important role; under suitable physical conditions a nonlinear Schrödinger equation can be derived and the modulational instability can be analyzed directly with this equation [2]. A major question which has to be addressed (and is the subject of the pre...

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The evolution of a random directional wave in deep water was studied in a laboratory wave tank (50 m long, 10 m wide, 5 m deep) utilizing a directional wave generator. A number of experiments were conducted, changing the various spectral parameters (wave steepness 0.05 < ɛ < 0.11, with directional spreading up to 36° and frequency bandwidth 0.2 < δk/k < 0.6). The wave evolution was studied by an array of wave wires distributed down the tank. As the spectral parameters were altered, the wave height statistics change. Without any wave directionality, the occurrence of waves exceeding twice the significant wave height (the freak wave) increases as the frequency bandwidth narrows and steepness increases, due to quasi-resonant wave–wave interaction. However, the probability of an extreme wave rapidly reduces as the directional bandwidth broadens. The effective Benjamin–Feir index (BFIeff) is introduced, extending the BFI (the relative magnitude of nonlinearity and dispersion) to incorporate the effect of directionality, and successfully parameterizes the observed occurrence of freak waves in the tank. Analysis of the high-resolution hindcast wave field of the northwest Pacific reveals that such a directionally confined wind sea with high extreme wave probability is rare and corresponds mostly to a swell–wind sea mixed condition. Therefore, extreme wave occurrence in the sea as a result of quasi-resonant wave–wave interaction is a rare event that occurs only when the wind sea directionality is extremely narrow.

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