16 research outputs found
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Rising powers, UN Security Council reform, and the failure of rhetorical coercion
Despite repeated calls for reform, the UN Security Council has as yet resisted to satisfy the demands of a group of rising powers – Brazil, Germany, India, and Japan (G4) – for a permanent seat. We focus on one strategy of institutional adaptation to power shifts mentioned in the introductory article to this special issue and examine why the G4’s rhetorical coercion strategy has failed to resonate with the Council’s permanent members and the wider UN membership. Looking at the key debate on Security Council reform in the General Assembly in 2005, we examine the justifications the G4 have offered to support their proposal and whether these have been accepted as legitimate by UN member states. We show that the G4’s rhetorical coercion strategy has failed to resonate with the targeted audience because the G4 have justified their demand strongly in terms of how their material contributions would enhance the UN’s performance. In contrast, the G4’s opponents provided justifications predominantly based on fair and democratic procedures, generating higher levels of expressed support. The importance of procedural fairness is consistent with findings in social psychology and challenges the prominent argument that performance is the main path to legitimacy for international institutions
Disulfiram inhibits neutrophil extracellular trap formation protecting rodents from acute lung injury and SARS-CoV-2 infection.
Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram -an FDA-approved drug for alcohol use disorder- dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for COVID-19 patients. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in two rodent models of lung injury for which treatment options are limited
Human TLR8 Senses RNA From Plasmodium falciparum-Infected Red Blood Cells Which Is Uniquely Required for the IFN-γ Response in NK Cells
During blood-stage malaria, the innate immune system initiates the production of pro-inflammatory cytokines, including IFN-γ, that are critical to host defense and responsible for severe disease. Nonetheless, the innate immune pathways activated during this process in human malaria remain poorly understood. Here, we identify TLR8 as an essential sensor of Plasmodium falciparum-infected red blood cells (iRBC). In human immune cells, iRBC and RNA purified from iRBC were detected by TLR8 but not TLR7 leading to IFN-γ induction in NK cells. While TLR7 and 9 have been shown to lead to IFN-γ in mice, our data demonstrate that TLR8 was the only TLR capable of inducing IFN-γ release in human immune cells. This unique capacity was mediated by the release of IL-12p70 and bioactive IL-18 from monocytes, the latter via a hitherto undescribed pathway. Altogether, our data are the first reported activation of TLR8 by protozoan RNA and demonstrate both the critical role of TLR8 in human blood-stage malaria and its unique functionality in the human immune system. Moreover, our study offers important evidence that mouse models alone may not be sufficient to describe the human innate immune response to malaria
A novel direct coupling of simultaneous thermal analysis (STA) and Fourier transform-infrared (FT-IR) spectroscopy
The mbo Operon Is Specific and Essential for Biosynthesis of Mangotoxin in Pseudomonas syringae
Mangotoxin is an antimetabolite toxin produced by certain Pseudomonas syringae pv. syringae strains. This toxin is an oligopeptide that inhibits ornithine N-acetyl transferase, a key enzyme in the biosynthesis of ornithine and arginine. Previous studies have reported the involvement of the putative nonribosomal peptide synthetase MgoA in virulence and mangotoxin production. In this study, we analyse a new chromosomal region of P. syringae pv. syringae UMAF0158, which contains six coding sequences arranged as an operon (mbo operon). The mbo operon was detected in only mangotoxin-producing strains, and it was shown to be essential for the biosynthesis of this toxin. Mutants in each of the six ORFs of the mbo operon were partially or completely impaired in the production of the toxin. In addition, Pseudomonas spp. mangotoxin non-producer strains transformed with the mbo operon gained the ability to produce mangotoxin, indicating that this operon contains all the genetic information necessary for mangotoxin biosynthesis. The generation of a single transcript for the mbo operon was confirmed and supported by the allocation of a unique promoter and Rho-independent terminator. The phylogenetic analysis of the P. syringae strains harbouring the mbo operon revealed that these strains clustered together
Adaptive survival mechanisms and growth limitations of small-stature herb species across a plant diversity gradient
Several biodiversity experiments have shown positive effects of species richness on aboveground biomass production, but highly variable responses of individual species. The well-known fact that the competitive ability of plant species depends on size differences among species, raises the question of effects of community species richness on small-stature subordinate species. We used experimental grasslands differing in species richness (1-60 species) and functional group richness (one to four functional groups) to study biodiversity effects on biomass production and ecophysiological traits of five small-stature herbs (Bellis perennis, Plantago media, Glechoma hederacea, Ranunculus repens and Veronica chamaedrys). We found that ecophysiological adaptations, known as typical shade-tolerance strategies, played an important role with increasing species richness and in relation to a decrease in transmitted light. Specific leaf area and leaf area ratio increased, while area-based leaf nitrogen decreased with increasing community species richness. Community species richness did not affect daily leaf carbohydrate turnover of V. chamaedrys and P. media indicating that these species maintained efficiency of photosynthesis even in low-light environments. This suggests an important possible mechanism of complementarity in such grasslands, whereby smaller species contribute to a better overall efficiency of light use. Nevertheless, these species rarely contributed a large proportion to community biomass production or achieved higher yields in mixtures than expected from monocultures. It seems likely that the allocation to aboveground plant organs to optimise carbon assimilation limited the investment in belowground organs to acquire nutrients and thus hindered these species from increasing their performance in multi-species mixtures
When public principals give up control over private agents: The new independence of ICANN in internet governance
l-Threonine Export: Use of Peptides To Identify a New Translocator from Corynebacterium glutamicum
Bacterial mechanisms for the uptake of peptides and their hydrolysis to amino acids are known in great detail, whereas much less is known about the fates of the peptide-derived amino acids. We show that the addition of l-threonine-containing di- or tripeptides results in reduction of the growth of Corynebacterium glutamicum, with concomitant high intracellular accumulation of l-threonine to up to 130 mM. Using transposon mutagenesis and isolation of mutants with increased Thr peptide sensitivity, nine open reading frames (ORFs) were identified, almost all encoding hypothetical proteins of unknown function. Three ORFs encode membrane proteins. Their individual functional characterizations in the wild-type background led to the identification of thrE. Upon thrE overexpression, growth is no longer sensitive to the presence of the Thr peptide, and l-threonine is exported at a rate of 3.8 nmol min(−1) mg of dry weight(−1), whereas the rate of export of a thrE inactivation mutant is reduced to 1.1 nmol min(−1) mg of dry weight(−1). In addition to l-threonine, l-serine is also a substrate for the exporter. The exporter exhibits nine predicted transmembrane-spanning helices with long charged C and N termini and with an amphipathic helix present within the N terminus. All these data suggest that the carrier encoded by thrE serves to export small molecules such as l-threonine and that the carrier is a prototype of a new translocator family. Homologues of ThrE are present in Mycobacterium tuberculosis and Streptomyces coelicolor
Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy
Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose “reprogramming” of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy