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Cell death is a central process for organismal health. Pyroptosis, namely pyroptotic cell death, is recognized as a critical type that disrupts membrane and triggers pro-inflammatory cytokine secretion via gasdermins, providing a robust form of cytolysis. Meanwhile, along with the thorough research, a great deal of evidence has demonstrated the dual effects of pyroptosis in host defense and inflammatory diseases. More importantly, the recent identification of abundant gasdermin-like proteins in bacteria and fungi suggests an ancient origin of pyroptosis-based regulated cell death in the life evolution. In this review, we bring a general overview of pyroptosis pathways focusing on gasdermin structural biology, regulatory mechanisms, and recent progress in induction and inhibition strategies for disease treatment. We look forward to providing an insightful perspective for readers to comprehend the frame and challenges of the pyroptosis field, and to accelerating its clinical application.

Experimental measurement and numerical simulations were carried out for investigating the impact loading behavior of platform decks under regular and irregular wave actions. In the numerical simulation section, a full-scale numerical wave tank was established using STAR-CCM+ software. A decreased tendency can be observed for an increased relative length of platform when the incident wave length is double the deck length. The increased deck height can also decrease impact loading on the platform, which is due to the platform being far away from the incident wave. Impact loading on the deck decreases with the increase in inclination angle, which can be explained by the deck bottom being directly exposed to the incident wave at negative inclination angles. Finally, the variation tendency of impact loading on platform decks under irregular wave actions is similar to that under regular wave actions, including the averaged values and significant values.

The activity and stability of the cytosolic DNA sensor cGAS, a key mediator of innate antiviral immunity and autoimmunity, is fine-tuned by post-translational modifications. Here, the authors demonstrate that the ubiquitin E3 ligase ARIH1 catalyzes the mono-ISGylation of cGAS and promotes its oligomerization in response to viral and self DNA.

Type I R-M systems help establish the prokaryotic DNA methylation landscape and provide protection against invasive DNA. Here, the authors report on detailed structural and molecular mechanisms of a non-canonical type I R-M methyltransferase.

This study focuses on addressing the limitations associated with most chemical derivatization methods commonly used for formaldehyde detection. These methods often suffer from prolonged derivative times (≥30 min) and complex procedures, which hinder their ability to meet the requirements of real-time and accurate sensing. In this research, a novel formaldehyde indicator system based on hyperbranched polyamine molecule was developed, and its mechanism and principles of color change were investigated. The findings revealed that hyperbranched polyamine molecule effectively reacts with formaldehyde, leading to a reduction in electron cloud density in the amine group N and subsequently causing a decrease in pH value. This reaction enables the visualization of formaldehyde detection through changes in the indicator spectrum. Moreover, the spectral variation pattern exhibits a strong linear correlation with the formaldehyde concentration when the PAMAM concentration is optimized. The detection limit of this method was determined to be 1.8 ppm. Notably, the reaction between PAMAM and formaldehyde is almost instantaneous, the color change is insensitive to temperature, and the method demonstrates high selectivity. Overall, this research contributes to the advancement of real-time formaldehyde monitoring technology and provides insights for future developments in this field.

Within planetary gear transmissions (PGTs), mode shapes and eigenfrequencies hold a crucial significance in operational reliability and efficacy. Mode shapes explain the unique motion patterns inherent in PGT systems. Conversely, eigenfrequencies describe the inherent frequencies at which PGT systems undergo vibration or oscillation upon exposure to external forces or disruptions. This research paper presents a comprehensive investigation into the dynamic behavior of a three-stage PGT utilized in medium and heavy trucks. This study introduces the Rayleigh energy method to assess system dynamics, revealing a bounded Rayleigh quotient related to the highest related eigenvalue. Then, this study delves into eigenfrequencies and the mode shape behavior of the adopted PGT model. The eigenfrequencies are identified as encompassing diverse vibrational modes of central components and planet gears. Moreover, a multi-scale analysis of the adopted PGT model is presented by deriving matrices for mass, bearing stiffness, and mesh stiffness. Comparisons with the Rayleigh energy method demonstrate the new approach’s efficiency, exhibiting a low margin of error in the determination of eigenfrequencies. This investigation also highlights the alignment of identified mode shapes with the established literature, detailing the multi-scale approach’s minor deviation in mode shape determination compared to the Rayleigh energy method.

As a by-product of citrus processing, ponkan (Citrus reticulata Blanco, cv. Ponkan) peel residue is a source of high quality dietary fiber (DF). To make a full utilization of this resource and give a better understanding on the probiotic function of its DF, soluble dietary fiber (SDF) and insoluble dietary fiber (IDF) were extracted from ponkan peel residue (after flavonoids were extracted) using an alkaline method, followed by modifications using a composite physical-enzymatic treatment. The in vitro fermentation properties of the modified SDF and IDF (namely, MSDF and MIDF) and their effects on short-chain fatty acids (SCFA) production and changes in the composition of human gut microbiota were investigated. Results showed that MSDF and MIDF both significantly lowered the pH value and enhanced total SCFA content in the broths after fermented for 24 h by fecal inocula (p < 0.05) with better effects found in MSDF. Both MSDF and MIDF significantly reduced the diversity, with more in the latter than the former, and influenced the composition of human gut microbiota, especially increasing the relative abundance of Bacteroidetes and decreasing the ratio of Firmicutes to Bacteroidetes (F/B) value. The more influential microbiota by MSDF were g-Collinsella, p-Actinobacteria and g-Dialister, while those by MIDF were f-Veillonellaceae, c-Negativicutes and f-Prevotellacese. These results suggested that the modified ponkan peel residue DF can be utilized by specific bacteria in the human gut as a good source of fermentable fiber, providing a basis for the exploitation of the citrus by-product.

Wool fabrics are preferred over synthetic and cellulosic fibers by consumers because of their good elasticity, warmth, and high moisture sorption. How to use new materials and new methods to break the bottleneck of high pollution and high energy consumption in wool dyeing and finishing, and develop new functional wool materials has become an urgent need of wool development. In this paper, wool is colored and functionalized with antistatic properties using one-step ecofriendly process by superfine graphene oxide (GO). The results of the assembly mechanism show that the adsorption thermodynamic behavior of GO on wool is more consistent with Langmuir model and the process is exothermic similar to the adsorption of conventional acid dyes on wool fibers. The kinetic behavior results indicated that adsorption behavior of GO on wool was identified, and the phenomenon was more in line with the quasi-secondary dynamics model. The antistatic test results showed that the antistatic performance of the wool fabric that was colored by GO was obviously improved and the half-life of the GO colored wool fabric could be as low as 0.17. The strategy of colored fabrics with GO and imparting additional functionality can provide a basis for the ecological processing and formation of wool fabrics with designed functions.

The bacterial effector MavC can ubiquitinate the host E2 enzyme UBE2N to dampen the host immune response. Here, the authors provide mechanistic insight into this non-canonical ubiquitination machinery and reveal the structural basis for the functional differences between MavC and its close homolog MvcA.

Though significant strides in tumorigenic comprehension and therapy modality have been witnessed over the past decades, glioma remains one of the most common and malignant brain tumors characterized by recurrence, dismal prognosis, and therapy resistance. Immunotherapy advance holds promise in glioma recently. However, the efficacy of immunotherapy varies among individuals with glioma, which drives researchers to consider the modest levels of immunity in the central nervous system, as well as the immunosuppressive tumor immune microenvironment (TIME). Considering the highly conserved property for sustaining energy homeostasis in mammalian cells and repeatedly reported links in malignancy and drug resistance, autophagy is determined as a cutting angle to elucidate the relations between glioma and the TIME. In this review, heterogeneity of TIME in glioma is outlined along with the reciprocal impacts between them. In addition, controversies on whether autophagy behaves cytoprotectively or cytotoxically in cancers are covered. How autophagy collapses from its homeostasis and aids glioma malignancy, which may depend on the cell type and the cellular context such as reactive oxygen species (ROS) and adenosine triphosphate (ATP) level, are briefly discussed. The consecutive application of autophagy inducers and inhibitors may improve the drug resistance in glioma after overtreatments. It also highlights that autophagy plays a pivotal part in modulating glioma and the TIME, respectively, and the intricate interactions among them. Specifically, autophagy is manipulated by either glioma or tumor-associated macrophages to conform one side to the other through exosomal microRNAs and thereby adjust the interactions. Given that some of the crosstalk between glioma and the TIME highly depend on the autophagy process or autophagic components, there are interconnections influenced by the status and well-being of cells presumably associated with autophagic flux. By updating the most recent knowledge concerning glioma and the TIME from an autophagic perspective enhances comprehension and inspires more applicable and effective strategies targeting TIME while harnessing autophagy collaboratively against cancer.

Cyclic GMP-AMP synthase (cGAS) is involved in the modulation of inflammatory responses. Here, the authors present small-molecule inhibitors of human cGAS, characterize their interaction with the protein, and show that the compounds are active in interferon-producing cells including primary human macrophages.

The fatigue performance of the bridge deck significantly affects the safety and durability of the overall steel-concrete composite beam bridge. Based on the vehicle flow information of the highway within 10 years, the fatigue performance of a two-way four-lane steel-concrete composite continuous beam bridge deck is studied in this research. The results indicate that the effect of the wheel track position is negligible for two-way four-lane bridge when the wheel track sways laterally, and the fatigue stress of bridge deck concrete is the most unfavorable while the loading position is 7.0 m away from the bridge center line. The fatigue damage decreases by 30%–40% when the centerline of the lane deviates from the most unfavorable stress position by 1 m. The punching fatigue of the concrete is more sensitive to the changes in slab thickness, and the thickness of the deck concrete slab is recommended to be ≥35 cm.

The experimental work presents results on the fatigue performance of composite beams in the negative moment region and the changes of stiffness and deformation of composite beams under repeated loads; fatigue tests were carried out on two double-layer composite beams. The fatigue performance of composite beams with different reinforcement ratios under complete shear connection and the variation of deflection, strain of the reinforcement, strain of steel beam, and crack growth under fatigue load were obtained. The results showed that the fatigue resistance performance of concrete slab with low reinforcement ratio was much lower than that of concrete slab with high reinforcement ratio whereas, under the fatigue load, the stress of the welding nail in the negative moment region was small and the slip was almost negligible. The degradation of stiffness and the development of cracks were mainly due to the degradation of bond-slip between the concrete and reinforcement. The fatigue failure mode was the fracture of the upper reinforcement in negative moment region. The results obtained in this study are helpful in the design of composite beam.

Summary: Zinc-finger antiviral protein (ZAP) is a host antiviral factor that specifically restricts a wide range of viruses. ZAP selectively binds to CG-dinucleotide-enriched RNA sequences and recruits multiple RNA degradation machines to degrade target viral RNA. However, the molecular mechanism and structural basis for ZAP recognition of specific RNA are not clear. Here, we report the crystal structure of the ZAP N-terminal domain bound to a CG-rich single-stranded RNA, providing the molecular basis for its specific recognition of a CG dinucleotide and additional guanine and cytosine. The four zinc fingers of ZAP adopt a unique architecture and form extensive interactions with RNA. Mutations of both protein and RNA at the RNA-ZAP interacting surface reduce the in vitro binding affinity and cellular antiviral activity. This work reveals the molecular mechanism of ZAP recognition of specific target RNA and also provides insights into the mechanism by which ZAP coordinates downstream RNA degradation processes. : ZAP is a host antiviral factor that specifically restricts a wide range of viruses. Luo et al. determine the structural and molecular basis for the specific recognition of a CG dinucleotide and additional guanine and cytosine by ZAP. Keywords: ▪▪▪

Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.

Abstract The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive “open” to an active “closed” state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.

The previously published version of this Article contained errors in Fig. 6. In panel h the units of the x axis were incorrectly given as mM and should have been given as µM. Also, the IC50s for RU.365, RU.332 and RU.521 within panel h were incorrectly given as mM and should have been given as µM. These errors have been corrected in both the PDF and HTML versions of the Article.

A model to study the effectiveness of potential chemopreventive agents that inhibit neoplastic process by different mechanisms has been used to test the efficacy of seven nitric oxide synthase (NOS) inhibitors. Five selective inducible NOS (iNOS) inhibitors: S-methyl isothiourea (S-MITU), S-2-aminoethyl isothiourea (S-2-AEITU), S-ethyl isothiourea (S-EITU), aminoguanidine (AG), 2-amino-4-methyl pyridine (2AMP), and two non selective general NOS inhibitors: L-N6-(1-iminoethyl) lysine (IEL) and Nω-nitro-L-arginine (NNLA), were tested for efficacy against a carcinogen, benzo[a]pyrene (B[a]P)-induced primary rat tracheal epithelial (RTE) cell transformation assay. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of an NOS inhibitor and the resulting foci at the end of 30 days were scored for inhibition of transformation. The results indicate that all three isothiourea compounds inhibited B[a]Pinduced RTE foci in a dose-dependent manner. SAEITU was the most effective inhibitor with an IC50 (the molar concentration that inhibits transformation by 50%) of 9.1 μM and 100% inhibition at the highest dose tested (30 μM). However, both S-EITU and SMITU showed a maximum percent inhibition of 81% and 100% at 1 mM with an IC50 of 84 and 110 μM, respectively. 2-AMP did not show any dose-dependent response, but was highly effective (57% inhibition) at an intermediate dose of 30 μM and an IC50 of 25 μM. Similar to thiourea compounds, AG exhibited good dose-dependent inhibition with a maximum inhibition of 86% at 1 mM. NNLA and IEL were negative in this assay. Based on the IC50 values, NOS inhibitors were rated for efficacy from high to low as follows: S-2AEITU

Type I DNA methyltransferases contain one specificity subunit (HsdS) and two modification subunits (HsdM). The electron microscopy model of M.EcoKI-M₂S₁ methyltransferase shows a reasonable closed state of this clamp-like enzyme, but the structure of the open state is still unclear. The 1.95 Å crystal structure of the specificity subunit from Thermoanaerobacter tengcongensis (TTE-HsdS) shows an unreported open form inter-domain orientation of this subunit. Based on the crystal structure of TTE-HsdS and the closed state model of M.EcoKI-M₂S₁, we constructed a potential open state model of type I methyltransferase. Mutational studies indicated that two α-helices (aa30-59 and aa466-495) of the TTE-HsdM subunit are important inter-subunit interaction sites in the TTE-M₂S₁ complex. DNA binding assays also highlighted the importance of the C-terminal region of TTE-HsdM for DNA binding by the TTE-M₂S₁ complex. On the basis of structural analysis, biochemical experiments and previous studies, we propose a dynamic opening and closing mechanism for type I methyltransferase.

Rail corrugation is a common characteristic of track wear and exacerbates wheel–rail interaction and accelerates wheel wear and crack propagation. This study focuses on wheel wear and rolling contact fatigue of a metro vehicle under rail corrugation. Firstly, the characteristics of rail corrugation under service conditions are determined by statistical analysis of field data, and rail corrugation is applied to the established vehicle–track coupled dynamics model. Then, the wear index and the work of friction force as indicators of wheel wear are studied. Finally, based on the shakedown map and the criterion of maximum amplitude of shear stress, a simulation analysis of wheel rolling contact fatigue under rail corrugation is carried out. The results show that the increases in superficial fatigue index and accumulated fatigue are respectively 1.52 and 6.16 times in the wavelength range of 30 to 90 mm larger than those in the range of 90 to 210 mm. Furthermore, the cracks more easily occur 2 to 4 mm from the outer surface of wheel and expand along the wheel tread. [ABSTRACT FROM AUTHOR]