Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon ...genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.
Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF). The mechanism of the ...formation of the aggregates in the nucleus remains uncertain. The present study demonstrated that the DNA-binding domain of p53 (p53C) underwent phase separation (PS) on the pathway to aggregation under various conditions. p53C phase separated in the presence of the crowding agent polyethylene glycol (PEG). Similarly, mutant p53C (M237I and R249S) underwent PS; however, the process evolved to a solid-like phase transition faster than that in the case of wild-type p53C. The data obtained by microscopy of live cells indicated that transfection of mutant full-length p53 into the cells tended to result in PS and phase transition (PT) in the nuclear compartments, which are likely the cause of the GoF effects. Fluorescence recovery after photobleaching (FRAP) experiments revealed liquid characteristics of the condensates in the nucleus. Mutant p53 tended to undergo gel- and solid-like phase transitions in the nucleus and in nuclear bodies demonstrated by slow and incomplete recovery of fluorescence after photobleaching. Polyanions, such as heparin and RNA, were able to modulate PS and PT
in vitro
. Heparin apparently stabilized the condensates in a gel-like state, and RNA apparently induced a solid-like state of the protein even in the absence of PEG. Conditions that destabilize p53C into a molten globule conformation also produced liquid droplets in the absence of crowding. The disordered transactivation domain (TAD) modulated both phase separation and amyloid aggregation. In summary, our data provide mechanistic insight into the formation of p53 condensates and conditions that may result in the formation of aggregated structures, such as mutant amyloid oligomers, in cancer. The pathway of mutant p53 from liquid droplets to gel-like and solid-like (amyloid) species may be a suitable target for anticancer therapy.
Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF).
Twisted Laguerre-Gaussian lasers, with orbital angular momentum and characterized by doughnut-shaped intensity profiles, provide a transformative set of tools and research directions in a growing ...range of fields and applications, from super-resolution microcopy and ultra-fast optical communications to quantum computing and astrophysics. The impact of twisted light is widening as recent numerical calculations provided solutions to long-standing challenges in plasma-based acceleration by allowing for high-gradient positron acceleration. The production of ultra-high-intensity twisted laser pulses could then also have a broad influence on relativistic laser-matter interactions. Here we show theoretically and with ab initio three-dimensional particle-in-cell simulations that stimulated Raman backscattering can generate and amplify twisted lasers to petawatt intensities in plasmas. This work may open new research directions in nonlinear optics and high-energy-density science, compact plasma-based accelerators and light sources.
Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms ...and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas.
Geopolymer materials have been gaining ground in the civil construction sector not only for having superior physical properties when compared to conventional cement, but also for being less harmful ...to the environment, since the synthesis of the geopolymer does not release toxic gases or require high energy costs. On the other hand, geopolymer materials like cementitious matrices have low flexural strength and have fragile breakage. To overcome these deficiencies, the insertion of fibers in geopolymeric matrices has been evaluated as a solution. Although most research on this practice focuses on the use of synthetic fibers, the use of natural fibers has been growing and brings as an advantage the possibility of producing an even more ecological material, satisfying the need to create eco-friendly materials that exists today in society. Thus, this paper aimed to, through the evaluation of research available in the literature, understand the behavior of fibers in geopolymer matrices, identify similarities and differences between the performance of geopolymer composites reinforced with natural and synthetic fibers and, understanding that it is possible, point out ways to optimize the performance of these composites.
Electron-positron pair plasmas represent a unique state of matter, whereby there exists an intrinsic and complete symmetry between negatively charged (matter) and positively charged (antimatter) ...particles. These plasmas play a fundamental role in the dynamics of ultra-massive astrophysical objects and are believed to be associated with the emission of ultra-bright gamma-ray bursts. Despite extensive theoretical modelling, our knowledge of this state of matter is still speculative, owing to the extreme difficulty in recreating neutral matter-antimatter plasmas in the laboratory. Here we show that, by using a compact laser-driven setup, ion-free electron-positron plasmas with unique characteristics can be produced. Their charge neutrality (same amount of matter and antimatter), high-density and small divergence finally open up the possibility of studying electron-positron plasmas in controlled laboratory experiments.
Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in ...parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-1 in S. mansoni. SmKI-1 gene suppression in larval stage of S. mansoni robustly impact in parasite development in vitro and in vivo. To determine the ability of SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-1 rescued acetaminophen (APAP)-mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1β secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-1 is a key protein in S. mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases.
Prato cheese, a typical ripened Brazilian cheese, contains high levels of sodium, and the excess intake of this micronutrient is associated with hypertension and cardiovascular diseases. A ...technological alternative to reduce the sodium content in foods is to replace NaCl with KCl and the addition of flavor enhancers. The present study aimed to combine quantitative descriptive analysis (QDA) and temporal dominance of sensations (TDS) to assess the sensory profile of reduced-sodium probiotic prato cheese with the addition of flavor enhancers. Five formulations of probiotic prato cheese were manufactured using 1% (wt/wt) salt as follows: C1 (100% NaCl), C2 (50:50 NaCl:KCl), C3 (50:50 NaCl:KCl + 1% arginine), C4 (50:50 NaCl:KCl + 1% yeast extract), and C5 (50:50 NaCl:KCl + 1% oregano extract). Both methods indicated that the addition of flavor enhancers modified the sensory profile of the reduced-sodium probiotic prato cheese. The QDA revealed that flavor enhancers—in particular, yeast and oregano extract—increased the saltiness of samples C4 and C5, respectively, and that the other flavor enhancer, arginine (sample C3), most modified the attributes of prato cheese. The TDS dominance curves revealed that the addition of yeast extract (sample C4) had a positive effect on cheese flavor because it minimized the bitter taste perception resulting from the addition of potassium chloride. Overall, QDA and TDS used together provided interesting insights for establishing the sensory profile of reduced-sodium probiotic prato cheese.
The presence of biochar with high carbon accumulation capacity and nutrient adsorption is causally associated with archeological soils. Although this type of soil organic matter has been known for a ...long time, the knowledge of its structure and environmental behavior is still limited. This work used Raman spectroscopy to obtain structural information and identify alterations in biochar particles. To this end, we studied biochar particles found in an archaeological site with a temporal window lasting 12451 to 11080 yr cal BP. The molecular, structural and sp2/sp3 characteristics of the charcoal particles were determined at the time of burning and associated with the temperature, time and characteristics of the burnt material. We propose that the process of oxidation of the biochar occurs during the first 2000 years after its genesis. The oxidation process is a reflection of decreases in the number of defects related to sp2 bonds on amorphous carbons and increases in the number of defects associated with ionic impurities, which clearly indicate the interaction between biochar particles and the soil matrix. The data confirm the hypothesis that the persistence of biochar in the environment is due to its graphite structure and suggest that over a 12000 year timeframe, biochar particles undergo several changes that occur in the disordered phase and are rapidly oxidized.
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