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Multi-reference and density functional theory calculations are performed for the diatomic and ligated NpO3+ species. The main goal of this study is to provide insights into the stability of the experimentally synthesized N(CH2CH2NR)3NpO (R = SiiPr3) coordination complex and probe its use as a catalyst for the oxidation of methane. The constructed potential energy curves for NpO3+ showed the presence of three different types of minima (Np3+O, Np4+O−, Np5+O2−) depending on the neptunium–oxygen distance. All these minima are higher in energy than the Np2+ + O+ fragments, and the more stable Np5+O2− form is stabilized only due to the presence of the negatively charged -CH2NR− moiety of the ligand. The C–H bond activation of methane was found to be possible only for the first quintet state of the complex which lies about 30 kcal/mol higher than the ground triplet state.

Secretory polymorphic serine/threonine kinases control pathogenesis of Toxoplasma gondii in the mouse. Genetic studies show that the pseudokinase ROP5 is essential for acute virulence, but do not reveal its mechanism of action. Here we demonstrate that ROP5 controls virulence by blocking IFN-γ mediated clearance in activated macrophages. ROP5 was required for the catalytic activity of the active S/T kinase ROP18, which phosphorylates host immunity related GTPases (IRGs) and protects the parasite from clearance. ROP5 directly regulated activity of ROP18 in vitro, and both proteins were necessary to avoid IRG recruitment and clearance in macrophages. Clearance of both the Δrop5 and Δrop18 mutants was reversed in macrophages lacking Irgm3, which is required for IRG function, and the virulence defect was fully restored in Irgm3(-/-) mice. Our findings establish that the pseudokinase ROP5 controls the activity of ROP18, thereby blocking IRG mediated clearance in macrophages. Additionally, ROP5 has other functions that are also Irgm3 and IFN-γ dependent, indicting it plays a general role in governing virulence factors that block immunity.

Interferon-inducible GTPases of the Immunity Related GTPase (IRG) and Guanylate Binding Protein (GBP) families provide resistance to intracellular pathogenic microbes. IRGs and GBPs stably associate with pathogen-containing vacuoles (PVs) and elicit immune pathways directed at the targeted vacuoles. Targeting of Interferon-inducible GTPases to PVs requires the formation of higher-order protein oligomers, a process negatively regulated by a subclass of IRG proteins called IRGMs. We found that the paralogous IRGM proteins Irgm1 and Irgm3 fail to robustly associate with \"non-self\" PVs containing either the bacterial pathogen Chlamydia trachomatis or the protozoan pathogen Toxoplasma gondii. Instead, Irgm1 and Irgm3 reside on \"self\" organelles including lipid droplets (LDs). Whereas IRGM-positive LDs are guarded against the stable association with other IRGs and GBPs, we demonstrate that IRGM-stripped LDs become high affinity binding substrates for IRG and GBP proteins. These data reveal that intracellular immune recognition of organelle-like structures by IRG and GBP proteins is partly dictated by the missing of \"self\" IRGM proteins from these structures.

Pathologies associated with sarcopenia include decline in muscular strength, lean mass and regenerative capacity. Despite the substantial impact on quality of life, no pharmacological therapeutics are available to counteract the age-associated decline in functional capacity and/or, resilience. Evidence suggests immune-secreted cytokines can improve muscle regeneration, a strategy which we leverage in this study by rescuing the age-related deficiency in Meteorin-like through several in vivo add-back models. Notably, the intramuscular, peptide injection of recombinant METRNL was sufficient to improve muscle regeneration in aging. Using ex vivo media exchange and in vivo TNF inhibition, we demonstrate a mechanism of METRNL action during regeneration, showing it counteracts a pro-fibrotic gene program by triggering TNFα-induced apoptosis of fibro/adipogenic progenitor cells. These findings demonstrate therapeutic applications for METRNL to improve aged muscle, and show Fibro/Adipogenic Progenitors are viable therapeutic targets to counteract age-related loss in muscle resilience. Lee et al. demonstrate the protein Meteorin-like can rejuvenate the body’s immune system to enhance muscle regeneration in old age – in part by inducing the death of pro-fibrotic mesenchymal progenitor cells within the muscle.

Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo . A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-γ). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection. Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. Deletion of PVM-associated GRA3, GRA7, GRA8, and GRA14 or IVN membrane-associated GRA2, GRA9, and GRA12 in the low-virulence type II Prugniaud (Pru) strain induced severe defects in the development of chronic-stage cysts in vivo without affecting the parasite growth rate or the ability to differentiate into cysts in vitro . Acute virulence of the PruΔ gra2 , PruΔ gra3 , and PruΔ gra4 mutants was reduced but not abolished. In contrast, the PruΔ gra12 mutant was avirulent in mice and PruΔ gra12 parasites failed to establish a chronic infection. High-virulence type I strain RHΔ gra12 parasites also exhibited a major defect in acute virulence. In gamma interferon (IFN-γ)-activated macrophages, type I RHΔ gra12 and type II PruΔ gra12 parasites resisted the coating of the PVM with host immunity-related GTPases as effectively as the parental type I RHΔ ku80 and type II PruΔ ku80 strains, respectively. Despite this resistance, Δ gra12 PVs ultimately succumbed to IFN-γ-activated host cell innate immunity. Our findings uncover a key role for GRA12 in mediating resistance to host IFN-γ and reveal that many other IVN membrane-associated GRA proteins, as well as PVM-localized GRA proteins, play important roles in establishing chronic infection. IMPORTANCE Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo . A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-γ). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection.

Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease. Here, we show that the gut microbe Akkermansia muciniphila can mediate negative effects of IFNγ on glucose tolerance. In IFNγ-deficient mice, A. muciniphila is significantly increased and restoration of IFNγ levels reduces A. muciniphila abundance. We further show that IFNγ-knockout mice whose microbiota does not contain A. muciniphila do not show improvement in glucose tolerance and adding back A. muciniphila promoted enhanced glucose tolerance. We go on to identify Irgm1 as an IFNγ-regulated gene in the mouse ileum that controls gut A. muciniphila levels. A. muciniphila is also linked to IFNγ-regulated gene expression in the intestine and glucose parameters in humans, suggesting that this trialogue between IFNγ, A. muciniphila and glucose tolerance might be an evolutionally conserved mechanism regulating metabolic health in mice and humans. Mice deficient in the pro-inflammatory cytokine IFNγ have improved glucose tolerance. Here, the authors show that this effect depends on the gut microbe Akkermansia muciniphila , whose abundance increases in the absence IFNγ, and which is known to have beneficial effects on host metabolism.

Background Concentrations of cadmium (Cd) in the grain of many durum wheats ( Triticum turgidum subsp. durum ) grown in North American prairie soils often exceed international trade standards. Genotypic differences in root-to-shoot translocation of Cd are a major determinant of intraspecific variation in the accumulation of Cd in grain. We tested the extent to which changes in whole-plant Cd accumulation and the distribution of Cd between tissues influences Cd accumulation in grain by measuring Cd accumulation throughout the grain filling period in two near-isogenic lines (NILs) of durum wheat that differ in grain Cd accumulation. Results Roots absorbed Cd and transported it to the shoots throughout the grain filling period, but the low- and high-Cd NILs did not differ in whole-plant Cd uptake. Although the majority of Cd accumulation was retained in the roots, the low- and high-Cd NILs differed substantively in root-to-shoot translocation of Cd. At grain maturity, accumulation of Cd in the shoots was 13% (low-Cd NIL) or 37% (high-Cd NIL) of whole-plant Cd accumulation. Accumulation of Cd in all shoot tissue, including grain, was at least 2-fold greater in the high-Cd NIL at all harvests. There was no net remobilization of shoot Cd pools during grain filling. The timing of Cd accumulation in grain was positively correlated with grain biomass accumulation, and the rate of grain filling peaked between 14 and 28 days post-anthesis, when both NILs accumulated 60% of total grain biomass and 61-66% of total grain Cd content. Conclusions These results show that genotypic variation in root-to-shoot translocation of Cd controls accumulation of Cd in durum wheat grain. Continued uptake of Cd by roots and the absence of net remobilization of Cd from leaves during grain filling support a direct pathway of Cd transport from roots to grain via xylem-to-phloem transfer in the stem.

Immunity-related p47 guanosine triphosphatases (IRG) play a role in defense against intracellular pathogens. We found that the murine Irgm1 (LRG-47) guanosine triphosphatase induced autophagy and generated large autolysosomal organelles as a mechanism for the elimination of intracellular Mycobacterium tuberculosis. We also identified a function for a human IRG protein in the control of intracellular pathogens and report that the human Irgm1 ortholog, IRGM, plays a role in autophagy and in the reduction of intracellular bacillary load.