Subsurface lithoautotrophic microbial ecosystems (SLiMEs) under oligotrophic conditions are typically supported by H 2 . Methanogens and sulfate reducers, and the respective energy processes, are thought to be the dominant players and have been the research foci. Recent investigations showed that, in some deep, fluid-filled fractures in the Witwatersrand Basin, South Africa, methanogens contribute <5% of the total DNA and appear to produce sufficient CH 4 to support the rest of the diverse community. This paradoxical situation reflects our lack of knowledge about the in situ metabolic diversity and the overall ecological trophic structure of SLiMEs. Here, we show the active metabolic processes and interactions in one of these communities by combining metatranscriptomic assemblies, metaproteomic and stable isotopic data, and thermodynamic modeling. Dominating the active community are four autotrophic β-proteobacterial genera that are capable of oxidizing sulfur by denitrification, a process that was previously unnoticed in the deep subsurface. They co-occur with sulfate reducers, anaerobic methane oxidizers, and methanogens, which each comprise <5% of the total community. Syntrophic interactions between these microbial groups remove thermodynamic bottlenecks and enable diverse metabolic reactions to occur under the oligotrophic conditions that dominate in the subsurface. The dominance of sulfur oxidizers is explained by the availability of electron donors and acceptors to these microorganisms and the ability of sulfur-oxidizing denitrifiers to gain energy through concomitant S and H 2 oxidation. We demonstrate that SLiMEs support taxonomically and metabolically diverse microorganisms, which, through developing syntrophic partnerships, overcome thermodynamic barriers imposed by the environmental conditions in the deep subsurface.active subsurface environment | metabolic interactions | sulfur-driven autotrophic denitrifiers | syntrophy | inverted biomass pyramid M icroorganisms living in deep-subsurface ecosystems acquire energy through chemosynthesis and carbon from organic or inorganic sources. Whereas heterotrophs use dissolved organic carbon (DOC) transported from the surface and/or produced in situ, detrital organic deposits buried along with the sediments, and hydrocarbons migrating into petroleum reservoirs, chemolithoautotrophs fix dissolved inorganic carbon (DIC). In oligotrophic systems, subsurface lithoautotrophic microbial ecosystems (SLiMEs) (1) that are fueled by H 2 support the occurrence of autotrophic methanogens, acetogens, and sulfate reducers (2-5). These environments can host highly diverse communities, consisting mostly of prokaryotes, but also multicellular microeukaryotes and viral particles (6-13). Due to the limitation of available nutrients and energy substrates in the oligotrophic subsurface, it is reasonable to hypothesize that subsurface inhabitants with diverse functional traits cooperate syntrophically to maximize energy yield SignificanceMicroorganisms are known to live in the deep ...

Mesangial cells-mediated glomerulonephritis is a frequent cause of end-stage renal disease. Here, we show that celastrol is effective in treating both reversible and irreversible mesangioproliferative glomerulonephritis in rat models, but find that its off-target distributions cause severe systemic toxicity. We thus target celastrol to mesangial cells using albumin nanoparticles. Celastrol-albumin nanoparticles crosses fenestrated endothelium and accumulates in mesangial cells, alleviating proteinuria, inflammation, glomerular hypercellularity, and excessive extracellular matrix deposition in rat anti-Thy1.1 nephritis models. Celastrol-albumin nanoparticles presents lower drug accumulation than free celastrol in off-target organs and tissues, thereby minimizing celastrol-related systemic toxicity. Celastrol-albumin nanoparticles thus represents a promising treatment option for mesangioproliferative glomerulonephritis and similar glomerular diseases.

RFP-Man-NLCs provided an alternative strategy for selectively delivering rifampicin to alveolar macrophages.

It has been reported that the susceptibility of insect herbivores to entomoviruses is affected by phytochemicals ingested during the acquisition of viral inoculum on the foliage of host plants. However, the relationship between this susceptibility and phytochemicals is poorly understood. To test this hypothesis of plant‐mediated effects on this susceptibility, we measured the effects of foliage from three plants, soybeans (Glycine max), collards (Brassica oleracea) and water convolvuluses (Ipomoea aquatica), on the susceptibility of larval beet armyworm (Spodoptera exigua) to nucleopolyhedrovirus (NPV), and analysed six foliar chemicals (total phenolics, peroxidase [POD], catalase [CAT], superoxide dismutase [SOD], endochitinase and exochitinase) in the three plants, respectively. The results of exponential modelling indicated that the LD50s (median lethal dose) of NPV to larvae increased with the increase in both phenolics and POD but declined with the increase in four other foliar chemicals, while the opposite trend was found between median lethal time (LT50) of NPV and the six foliar chemicals. This study reveals that phenolics and POD decrease host susceptibility to the entomoviruses and that CAT, SOD, endochitinase and exochitinase increase this susceptibility.

Pseudomonas aeruginosa (PA)-induced keratitis is one of the most common and destructive bacterial diseases. The pathogenesis of PA infections is closely associated with excessive inflammatory responses. Nucleotide oligomerization domain (NOD)-like receptor (NLR) family with caspase activation and recruitment domain (CARD) containing 3 (NLRC3) protein has been implicated as a negative regulator of inflammation and antiviral response, but the role of NLRC3 in PA-induced keratitis has not been described. In the present study, we investigated the effects of NLRC3 in PA-induced keratitis and explored the underlying mechanism. We found that the expression of NLRC3 was decreased in mouse corneas and macrophages after PA infection. Overexpr-ession of NLRC3 significantly attenuated disease progression, inhibited the activation of nuclear factor-κB signaling and decreased the production of pro-inflammatory cytokines after PA infection. Furthermore, overexpression of NLRC3 promoted K48-linked polyubiquitination and degradation of interleukin-1 receptor-associated kinase 1 (IRAK1). Taken together, we demonstrated that NLRC3 has an anti-inflammatory effect on PA-induced keratitis, which may provide an improved understanding of host resistance to PA infection.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammatory cell infiltration, synovial inflammation, and cartilage destruction. Proliferative fibroblast-like synoviocytes (FLS) play crucial roles in both propagation of inflammation and joint damage because of their production of great amount of proinflammatory cytokines and proteolytic enzymes. In this study, we investigate the role of TRAF-interacting protein (TRIP) in regulating inflammatory process in RA-FLS. TRIP expression was attenuated in RA-FLS compared with osteoarthritis- (OA-) FLS. Overexpression of TRIP significantly inhibited the activation of NF-κB signaling and decreased the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in TNFα-stimulated RA-FLS. Furthermore, TRIP was found to interact with transforming growth factor β-activated kinase 1 (TAK1) and promoting K48-linked polyubiquitination of TAK1 in RA-FLS. Our results demonstrate that TRIP has anti-inflammatory effects on RA-FLS and suggest TRIP as a potential therapeutic target for human RA.

Pseudomonas aeruginosa (PA)-induced keratitis is a rapidly progressive ocular infectious disease that often leads to inflammatory epithelial edema, stromal infiltration, tissue destruction, corneal ulceration, and vision loss. In this study, we investigate the role of tripartite motif 8 (TRIM8) in regulating the inflammatory process of PA-induced keratitis. The expression of TRIM8 was increased in mouse corneas and in vitro-cultured macrophages after PA infection. Knockdown of the expression of TRIM8 significantly inhibited the activation of NF-κB signaling and decreased the production of pro-inflammatory cytokines both in vivo and in vitro after infected with PA. Furthermore, we investigated the potential mechanism and we found after PA infection that TRIM8 could promote K63-linked polyubiquitination of transforming growth factor β-activated kinase 1 (TAK1), leading to the activation of TAK1 and enhanced inflammatory responses. Taken together, we demonstrated that TRIM8 has pro-inflammatory effect on PA-induced keratitis and suggest TRIM8 as a potential therapeutic target for keratitis.

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