In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their ...function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
Activation of macrophages and dendritic cells （DCs） by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation （OXPHOS）, similar ...to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-la （HIF-la） plays an important role un- der conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid （TCA） cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-la and pro- motes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.
Black Carbon (BC) may significantly affect nutrient retention and play a key role in a wide range of biogeochemical processes in soils, especially for nutrient cycling. Anthrosols from the Brazilian ...Amazon (ages between 600 and 8700 yr BP) with high contents of biomass‐derived BC had greater potential cation exchange capacity (CEC measured at pH 7) per unit organic C than adjacent soils with low BC contents. Synchrotron‐based near edge X‐ray absorption fine structure (NEXAFS) spectroscopy coupled with scanning transmission X‐ray microscopy (STXM) techniques explained the source of the higher surface charge of BC compared with non‐BC by mapping cross‐sectional areas of BC particles with diameters of 10 to 50 μm for C forms. The largest cross‐sectional areas consisted of highly aromatic or only slightly oxidized organic C most likely originating from the BC itself with a characteristic peak at 286.1 eV, which could not be found in humic substance extracts, bacteria or fungi. Oxidation significantly increased from the core of BC particles to their surfaces as shown by the ratio of carboxyl‐C/aromatic‐C. Spotted and non‐continuous distribution patterns of highly oxidized C functional groups with distinctly different chemical signatures on BC particle surfaces (peak shift at 286.1 eV to a higher energy of 286.7 eV) indicated that non‐BC may be adsorbed on the surfaces of BC particles creating highly oxidized surface. As a consequence of both oxidation of the BC particles themselves and adsorption of organic matter to BC surfaces, the charge density (potential CEC per unit surface area) was greater in BC‐rich Anthrosols than adjacent soils. Additionally, a high specific surface area was attributable to the presence of BC, which may contribute to the high CEC found in soils that are rich in BC.
1. Predictions of the identities and ecological impacts of invasive alien species are critical for risk assessment, but presently we lack universal and standardized metrics that reliably predict the ...likelihood and degree of impact of such invaders (i.e. measurable changes in populations of affected species). This need is especially pressing for emerging and potential future invaders that have no invasion history. Such a metric would also ideally apply across diverse taxonomic and trophic groups. 2. We derive a new metric of invader ecological impact that blends: (i) the classic Functional Response (FR; consumer per capita effect) and Numerical Response (NR; consumer population response) approaches to determining consumer impact, that is, the Total Response (TR = FR × NR), with; (ii) the Tarker-Lonsdale equation' for invader impact, where Impact = Range × Abundance × Effect (per capita effect), into; (iii) a new metric, Relative Impact Potential (RIP), where RIP = FR × Abundance. The RIP metric is an invader/native ratio, where values > 1 predict that invader ecological impact will occur, and increasing values above 1 indicate increasing impact. In addition, the invader/invader RIP ratio allows comparisons of the ecological impacts of different invaders. 3. Across a diverse range of trophic and taxonomic groups, including predators, herbivores, animals and plants (22 invader/native systems with 47 individual comparisons), high-impact invaders were significantly associated with higher FRs compared to native trophic analogues. However, the RIP metric substantially improves this association, with 100% predictive power of high-impact invaders. 4. Further, RIP scores were significantly and positively correlated with two independent ecological impact scores for invaders, allowing prediction of the degree of impact of invasive alien species with the RIP metric. Finally, invader/invader RIP scores were also successful in identifying and associating with higher impacting invasive alien species. 5. Synthesis and applications. The Relative Impact Potential metric combines the per capita effects of invaders with their abundances, relative to trophically analogous natives, and is successful in predicting the likelihood and degree of ecological impact caused by invasive alien species. As the metric constitutes readily measurable features of individuals, populations and species across abiotic and biotic context-dependencies, even emerging and potential future invasive alien species can be assessed. The Relative Impact Potential metric can be rapidly utilized by scientists and practitioners and could inform policy and management of invasive alien species across diverse taxonomic and trophic groups.
The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in ...PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.
Two satellites are currently monitoring surface soil moisture (SM) using L-band observations: SMOS (Soil Moisture and Ocean Salinity), a joint ESA (European Space Agency), CNES (Centre national ...d'études spatiales), and CDTI (the Spanish government agency with responsibility for space) satellite launched on November 2, 2009 and SMAP (Soil Moisture Active Passive), a National Aeronautics and Space Administration (NASA) satellite successfully launched in January 2015. In this study, we used a multilinear regression approach to retrieve SM from SMAP data to create a global dataset of SM, which is consistent with SM data retrieved from SMOS. This was achieved by calibrating coefficients of the regression model using the CATDS (Centre Aval de Traitement des Données) SMOS Level 3 SM and the horizontally and vertically polarized brightness temperatures (TB) at 40° incidence angle, over the 2013–2014 period. Next, this model was applied to SMAP L3 TB data from Apr 2015 to Jul 2016. The retrieved SM from SMAP (referred to here as SMAP_Reg) was compared to: (i) the operational SMAP L3 SM (SMAP_SCA), retrieved using the baseline Single Channel retrieval Algorithm (SCA); and (ii) the operational SMOSL3 SM, derived from the multiangular inversion of the L-MEB model (L-MEB algorithm) (SMOSL3). This inter-comparison was made against in situ soil moisture measurements from >400 sites spread over the globe, which are used here as a reference soil moisture dataset. The in situ observations were obtained from the International Soil Moisture Network (ISMN; https://ismn.geo.tuwien.ac.at/) in North of America (PBO_H2O, SCAN, SNOTEL, iRON, and USCRN), in Australia (Oznet), Africa (DAHRA), and in Europe (REMEDHUS, SMOSMANIA, FMI, and RSMN). The agreement was analyzed in terms of four classical statistical criteria: Root Mean Squared Error (RMSE), Bias, Unbiased RMSE (UnbRMSE), and correlation coefficient (R). Results of the comparison of these various products with in situ observations show that the performance of both SMAP products i.e. SMAP_SCA and SMAP_Reg is similar and marginally better to that of the SMOSL3 product particularly over the PBO_H2O, SCAN, and USCRN sites. However, SMOSL3 SM was closer to the in situ observations over the DAHRA and Oznet sites. We found that the correlation between all three datasets and in situ measurements is best (R>0.80) over the Oznet sites and worst (R=0.58) over the SNOTEL sites for SMAP_SCA and over the DAHRA and SMOSMANIA sites (R=0.51 and R=0.45 for SMAP_Reg and SMOSL3, respectively). The Bias values showed that all products are generally dry, except over RSMN, DAHRA, and Oznet (and FMI for SMAP_SCA). Finally, our analysis provided interesting insights that can be useful to improve the consistency between SMAP and SMOS datasets.
•First application of regression analysis on SMAP L-band TB Observations•Calibration of the regressions using SMOS data (TB and soil moisture SM)•Inter-comparison of SMAP (regressions-based and operational) and SMOS level 3 SM products•Best performances for the two SMAP-based SM products against in situ SM observations
The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules ...Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.
Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory ...macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.
There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus ...erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.
Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related ...neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.
•We analyzed the microstructural changes in rTg4510 and wild type mice at 8.5months.•We correlated microstructural findings with histological measures of tau burden•We compare two diffusion MR models: DTI and NODDI.•Both models revealed changes in tissue microstructure due to tau pathology.•The NODDI metrics demonstrated a good correlation with histological measures of tau burden.
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