Inflammasomes are multiprotein signaling complexes that activate the innate immune system. Canonical inflammasomes recruit and activate caspase-1, which then cleaves and activates IL-1β and IL-18, as ...well as gasdermin D (GSDMD) to induce pyroptosis. In contrast, non-canonical inflammasomes, caspases-4/-5 (CASP4/5) in humans and caspase-11 (CASP11) in mice, are known to cleave GSDMD, but their role in direct processing of other substrates besides GSDMD has remained unknown. Here, we show that CASP4/5 but not CASP11 can directly cleave and activate IL-18. However, CASP4/5/11 can all cleave IL-1β to generate a 27-kDa fragment that deactivates IL-1β signaling. Mechanistically, we demonstrate that the sequence identity of the tetrapeptide sequence adjacent to the caspase cleavage site regulates IL-18 and IL-1β recruitment and activation. Altogether, we have identified new substrates of the non-canonical inflammasomes and reveal key mechanistic details regulating inflammation that may aid in developing new therapeutics for immune-related disorders.
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•Human CASP4/5 directly process IL-18 at D36 to generate the activated cytokine•CASP4/5 cleave IL-1β at D27 into a p27 species that inactivates downstream IL-1R signaling•The tetrapeptide sequence of IL-18 and IL-1β regulates their processing by caspases•CASP11 can process IL-1β into the deactivating p27 species but does not process IL-18
Exconde et al. report that the non-canonical inflammasomes directly process IL-18 and IL-1β. The tetrapeptide sequence regulates IL-18 and IL-1β processing to generate an active or inactive cytokine respectively. These results suggest that the non-canonical inflammasomes directly modulate inflammation and may have a broader substrate repertoire than previously known.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Phosphatidylinositol 3-phosphate (PI(3)P) levels in
correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the
stress response ...was unknown. Here, we used PI3K inhibitors and antimalarial agents to examine the importance of PI(3)P under thermal conditions recapitulating malarial fever. Live cell microscopy using chemical and genetic reporters revealed that PI(3)P stabilizes the digestive vacuole (DV) under heat stress. We demonstrate that heat-induced DV destabilization in PI(3)P-deficient
precedes cell death and is reversible after withdrawal of the stress condition and the PI3K inhibitor. A chemoproteomic approach identified PfHsp70-1 as a PI(3)P-binding protein. An Hsp70 inhibitor and knockdown of PfHsp70-1 phenocopy PI(3)P-deficient parasites under heat shock. Furthermore, PfHsp70-1 downregulation hypersensitizes parasites to heat shock and PI3K inhibitors. Our findings underscore a mechanistic link between PI(3)P and PfHsp70-1 and present a novel PI(3)P function in DV stabilization during heat stress.
The antihistamine clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied ...parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to the Plasmodium falciparum TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight P. falciparum TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a clemastine-induced thermodynamic stabilization of the Plasmodium TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that clemastine reduces levels of the major TRiC substrate tubulin in P. falciparum parasites. In addition, clemastine treatment leads to disorientation of Plasmodium mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively target Plasmodium TRiC-mediated protein folding for malaria intervention.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The apicomplexan parasites
spp. are the causative agents of malaria, a disease that poses a significant global health burden.
spp. initiate infection of the human host by transforming and replicating ...within hepatocytes. This liver stage (LS) is poorly understood compared to other
life stages, which has hindered our ability to target these parasites for disease prevention. We conducted an extensive transcriptome sequencing (RNA-Seq) analysis throughout the
LS, covering as early as 2 h postinfection (hpi) and extending to 48 hpi. Our data revealed that hundreds of genes are differentially expressed at 2 hpi and that multiple genes shown to be important for later infection are upregulated as early as 12 hpi. Using hierarchical clustering along with coexpression analysis, we identified clusters functionally enriched for important liver-stage processes such as interactions with the host cell and redox homeostasis. Furthermore, some of these clusters were highly correlated to the expression of ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding motifs. This finding indicates potential LS targets for these transcription factors, while also hinting at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our work presents a window into the previously undescribed transcriptome of
upon host hepatocyte infection to enable a comprehensive view of the parasite's LS. These findings also provide a blueprint for future studies that extend hypotheses concerning LS gene function in
to human-infective
parasites.
The LS of
infection is an asymptomatic yet necessary stage for producing blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle can prevent clinical malaria, but relatively less is known about the parasite's biology at this stage. Using the rodent model
, we investigated whole-transcriptome changes occurring as early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) have not been accessible before due to the technical challenges associated with liver-stage infections. Our data now provide insights into these early parasite fluxes that may facilitate establishment of infection, transformation, and replication in the liver.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is responsible for over 660 million infections, and more than 6 ...million deaths worldwide. There is an increasing need for more treatment options that addresses SARS-CoV-2 infection and its replication. Innate immune pathways including interferon signaling and inflammatory NF-κB signaling are important players in regulating immune responses, these pathways are often targeted by viral pathogens to enhance viral replication, host immune evasion, and host cell survival. The respiratory tract is the major target for SARS-CoV-2; thus, we are exploring the role of innate immune signaling in regulating infection in these cells. We found that both interferon and NF-κB signaling are induced by SARS-CoV-2 infection as measured by increases in transcription factor localization and gene expression. Moreover, pharmacological inhibition of NF-κB signaling but not interferon signaling blocks SARS CoV-2 infection of these respiratory cells. We are exploring how NF-κB signaling impacts viral infection. Indeed, we found that the activity of the NF-κB pathway is independent of interferon signaling. Further mechanistic studies are underway to define the role of NF-κB in coronavirus infection and suggest that inhibitors of the NF-κB signaling pathway may be a novel pharmacological target for the treatment of SARS-CoV-2.
ABSTRACT The apicomplexan parasites Plasmodium spp. are the causative agents of malaria, a disease that poses a significant global health burden. Plasmodium spp. initiate infection of the human host ...by transforming and replicating within hepatocytes. This liver stage (LS) is poorly understood compared to other Plasmodium life stages, which has hindered our ability to target these parasites for disease prevention. We conducted an extensive transcriptome sequencing (RNA-Seq) analysis throughout the Plasmodium berghei LS, covering as early as 2 h postinfection (hpi) and extending to 48 hpi. Our data revealed that hundreds of genes are differentially expressed at 2 hpi and that multiple genes shown to be important for later infection are upregulated as early as 12 hpi. Using hierarchical clustering along with coexpression analysis, we identified clusters functionally enriched for important liver-stage processes such as interactions with the host cell and redox homeostasis. Furthermore, some of these clusters were highly correlated to the expression of ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding motifs. This finding indicates potential LS targets for these transcription factors, while also hinting at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our work presents a window into the previously undescribed transcriptome of Plasmodium upon host hepatocyte infection to enable a comprehensive view of the parasite’s LS. These findings also provide a blueprint for future studies that extend hypotheses concerning LS gene function in P. berghei to human-infective Plasmodium parasites. IMPORTANCE The LS of Plasmodium infection is an asymptomatic yet necessary stage for producing blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle can prevent clinical malaria, but relatively less is known about the parasite’s biology at this stage. Using the rodent model P. berghei, we investigated whole-transcriptome changes occurring as early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) have not been accessible before due to the technical challenges associated with liver-stage infections. Our data now provide insights into these early parasite fluxes that may facilitate establishment of infection, transformation, and replication in the liver.
Recently, the mobile phones are evolving into mobile multifunctional terminals with the incorporation of various useful functions; the display devices also have advanced in terms of size, design, and ...resolution as a user interface of the mobile phone. Many low power display techniques have been proposed for example dynamic luminance scaling, liquid crystal orientation shift, variable frame refresh, organic LEDs (light emitting diodes) etc. It has been observed that optimizing software alone or hardware alone the solution might not be most optimal. The paper describes the design of a dynamic fuzzy controller based multilayered architecture which is a combination of software and hardware levels to interface between software application layer and physical layer to eventually control the current through LEDs of cell phone and thereby improving battery life depending on user choices and applications running on mobile devices.
Electricity storage system: A Gravity Battery Chaturvedi, D.K.; Yadav, Shubham; Srivastava, Tamanna ...
2020 Fourth World Conference on Smart Trends in Systems, Security and Sustainability (WorldS4),
2020-July
Conference Proceeding
The present energy storage systems such as lead acid batteries or lithium ion batteries have many drawbacks. The most important drawback is their adverse environmental impact, disposal problem, ...efficiency and charging time. We have renewable sources of energy such as solar and wind which can solve the environmental problems to a great extent. We all are aware of the fact about intermittency of wind and solar, hydro has the limitation of space requirement. Resources are free but not always usable and storable. To overcome these problems, a gravity battery is proposed in this paper. These proposed batteries will store the electrical energy in the form of potential energy and when needed this potential energy is converted back into kinetic energy and run a generator to produce electrical energy. A physical prototype is designed, developed and demonstrated in this paper.
The coronavirus disease-2019 (COVID-19) pandemic is a significant threat in the modern era. Clinical studies show that the most common symptom of severe COVID-19 is viral pneumonia-induced acute ...respiratory distress syndrome (ARDS). The underlying mechanisms by which severe respiratory disease syndrome-coronavirus-2 (SARS-CoV-2) results in ARDS and how certain host factors confer an increased risk of developing severe disease remain unknown. Therefore, identifying the distinctive features of this severe and fatal disease and the therapeutic approaches to COVID-19-induced ARDS remains an immediate need to serve as a basis for best practice models of standardized ARDS treatment. This review article aims to comprehensively discuss the immunopathology of ARDS and provides an overview of the precise role of both the innate and adaptive immune system, with emphasis on the current treatment strategies being tested in the COVID-19-induced ARDS patients. This knowledge will supposedly help in revealing further mechanistic insights into understanding COVID-19-induced ARDS.
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