Type I interferon regulation by USP18 is a key vulnerability in cancer.

Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics.

Single-Gate In-Transistor Readout of Current Superposition and Collapse Utilizing Quantum Tunneling and Ferroelectric Switching.

In nanostructure assemblies, the superposition of current paths forms microscopic electric circuits, and different circuit networks produce varying results, particularly when utilized as transistor channels for computing applications. However, the intricate nature of assembly networks and the winding paths of commensurate currents hinder standard circuit modeling. Inspired by the quantum collapse of superposition states for information decoding in quantum circuits, the implementation of analogous current path collapse to facilitate the detection of microscopic circuits by modifying their network topology is explored. Here, the superposition and collapse of current paths in gate-all-around polysilicon nanosheet arrays are demonstrated to enrich the computational resources within transistors by engineering the channel length and quantity. Switching the ferroelectric polarization of Hf0.5 Zr0.5 O2 gate dielectric, which drives these transistors out-of-equilibrium, decodes the output polymorphism through circuit topological modifications. Furthermore, a protocol for the single-electron readout of ferroelectric polarization is presented with tailoring the channel coherence. The introduction of lateral path superposition results into intriguing metal-to-insulator transitions due to transient behavior of ferroelectric switching. This ability to adjust the current networks within transistors and their interaction with ferroelectric polarization in polycrystalline nanostructures lays the groundwork for generating diverse current characteristics as potential physical databases for optimization-based computing.

Recent Progress in Conducting Polymer Composite/Nanofiber-Based Strain and Pressure Sensors.

The Conducting of polymers belongs to the class of polymers exhibiting excellence in electrical performances because of their intrinsic delocalized π- electrons and their tunability ranges from semi-conductive to metallic conductive regime. Conducting polymers and their composites serve greater functionality in the application of strain and pressure sensors, especially in yielding a better figure of merits, such as improved sensitivity, sensing range, durability, and mechanical robustness. The electrospinning process allows the formation of micro to nano-dimensional fibers with solution-processing attributes and offers an exciting aspect ratio by forming ultra-long fibrous structures. This review comprehensively covers the fundamentals of conducting polymers, sensor fabrication, working modes, and recent trends in achieving the sensitivity, wide-sensing range, reduced hysteresis, and durability of thin film, porous, and nanofibrous sensors. Furthermore, nanofiber and textile-based sensory device importance and its growth towards futuristic wearable electronics in a technological era was systematically reviewed to overcome the existing challenges.

Optimized protocols for studying the NLRP3 inflammasome and assessment of potential targets of CP-453,773 in undifferentiated THP1 cells.

The NLRP3 inflammasome is a complex multimeric signaling apparatus that regulates production of the pro-inflammatory cytokine IL-1ß. To overcome both the variability among primary immune cells and the limitations of genetic manipulation of differentiated human or murine macrophages, we developed a simplified, reliable and relevant cell-based model for studying the NLRP3 inflammasome using the undifferentiated human myelomonocytic cell line THP1. Undifferentiated THP1 cells constitutively express NLRP3, and NLRP3 inflammasome activation occurred in response to canonical NLRP3 activation stimuli including nigericin, ATP, and urea crystals, culminating in pro-IL-1ß cleavage, extracellular release of mature IL-1ß, and pyroptosis. We used this THP1 cell system to investigate potential targets of the potent, NLRP3 inflammasome selective inhibitor CP-456,773. We optimized a viral shRNA transduction method for gene expression knockdown (KD), and the KD of NLRP3 itself eliminated inflammasome activation and IL-1ß production. NLRP3 inflammasome activation and CP-453,773 pharmacology were not altered in ABCb7- or ABCb10-deficient THP1 cells, eliminating these gene products as candidate pharmacological targets of CP-453,773. For ABCb10, we confirmed our results using CRISPR/CAS9-mediated ABCb10 knockout (KO) THP1 sub-lines. In summary, undifferentiated THP1 cells are fully competent for activation of the NLRP3 inflammasome and production of IL-1ß, without differentiation into macrophages, and we describe optimized KD and KO methodologies to manipulate gene expression in these cells. As an example of the utility of undifferentiated THP1 cells for investigations into the biology of the NLRP3 inflammasome, we have used this cell system to rule out ABCb7 and ABCb10 as potential targets of the NLRP3 inflammasome inhibitor CP-453,773.

SUMO5, a Novel Poly-SUMO Isoform, Regulates PML Nuclear Bodies.

Promyelocytic leukemia nuclear bodies (PML-NBs) are PML-based nuclear structures that regulate various cellular processes. SUMOylation, the process of covalently conjugating small ubiquitin-like modifiers (SUMOs), is required for both the formation and the disruption of PML-NBs. However, detailed mechanisms of how SUMOylation regulates these processes remain unknown. Here we report that SUMO5, a novel SUMO variant, mediates the growth and disruption of PML-NBs. PolySUMO5 conjugation of PML at lysine 160 facilitates recruitment of PML-NB components, which enlarges PML-NBs. SUMO5 also increases polySUMO2/3 conjugation of PML, resulting in RNF4-mediated disruption of PML-NBs. The acute promyelocytic leukemia oncoprotein PML-RARα blocks SUMO5 conjugation of PML, causing cytoplasmic displacement of PML and disruption of PML-NBs. Our work not only identifies a new member of the SUMO family but also reveals the mechanistic basis of the PML-NB life cycle in human cells.