MicroRNA-124 Regulates STAT3 Expression and Is Down-regulated in Colon Tissues of Pediatric Patients With Ulcerative Colitis

Background & Aims - Altered levels and functions of microRNAs (miRs) have been associated with inflammatory bowel diseases (IBDs), although little is known about their roles in pediatric IBD. We investigated whether colonic mucosal miRs are altered in children with ulcerative colitis (UC). Methods - We used a library of 316 miRs to identify those that regulate phosphorylation of STAT3 in NCM460 human colonocytes incubated with interleukin-6. Levels of miR-124 were measured by real-time PCR analysis of colon biopsies from pediatric and adult patients with UC and patients without IBD (controls), and of HCT-116 colonocytes incubated with 5-aza-2’-deoxycytidine. Methylation of the MIR124 promoter was measured by quantitative methylation-specific PCR. Results - Levels of phosphorylated STAT3 and the genes it regulates (encoding VEGF, BCL2, BCLXL, and MMP9) were increased in pediatric patients with UC, compared to control tissues. Overexpression of miR-124, let-7, miR-125, miR-26, or miR-101 reduced STAT3 phosphorylation by ≥75% in NCM460 cells; miR-124 had the greatest effect. miR-124 was downregulated specifically in colon tissues from pediatric patients with UC and directly targeted STAT3 mRNA. Levels of miR-124 were decreased whereas levels of STAT3 phosphorylation increased in colon tissues from pediatric patients with active UC, compared to those with inactive disease. Furthermore, levels of miR-124 and STAT3 were inversely correlated in mice with experimental colitis. Downregulation of miR-124 in tissues from children with UC was attributed to hypermethylation of its promoter region. Incubation of HCT-116 colonocytes with 5-aza-2’ deoxycytidine upregulated miR-124 and reduced levels of STAT3 mRNA. Conclusions - MiR-124 appears to regulate the expression of STAT3. Reduced levels of miR-124 in colon tissues of children with active UC appear to increase expression and activity of STAT3, which could promote inflammation and pathogenesis of UC in children

Intercomparison of eddy-covariance software for urban tall-tower sites

Long-term tall-tower eddy-covariance (EC) measurements have been recently established in three European pilot cities as part of the ICOS-Cities project. We conducted a comparison of EC software to ensure a reliable generation of interoperable flux estimates, which is the prerequisite for avoiding methodological biases and improving the comparability of the results. We analyzed datasets covering 5 months collected from EC tall-tower installations located in urbanized areas of Munich, Zurich, and Paris. Fluxes of sensible heat, latent heat, and CO2 were calculated using three software packages (i.e., TK3, EddyPro, and eddy4R) to assess the uncertainty of flux estimations attributed to differences in implemented postprocessing schemes. A very good agreement on the mean values and standard deviations was found across all three sites, which can probably be attributed to a uniform instrumentation, data acquisition, and preprocessing. The overall comparison of final flux time series products showed a good but not yet perfect agreement among the three software packages. TK3 and EddyPro both calculated fluxes with low-frequency spectral correction, resulting in better agreement than between TK3 and the eddy4R workflow with disabled low-frequency spectral treatment. These observed flux discrepancies indicate the crucial role of treating low-frequency spectral loss in flux estimation for tall-tower EC systems.</p

Gene Network Analysis of Bone Marrow Mononuclear Cells Reveals Activation of Multiple Kinase Pathways in Human Systemic Lupus Erythematosus

Background: Gene profiling studies provide important information for key molecules relevant to a disease but are less informative of protein-protein interactions, post-translational modifications and regulation by targeted subcellular localization. Integration of genomic data and construction of functional gene networks may provide additional insights into complex diseases such as systemic lupus erythematosus (SLE). Methodology/Principal Findings: We analyzed gene expression microarray data of bone marrow mononuclear cells (BMMCs) from 20 SLE patients (11 with active disease) and 10 controls. Gene networks were constructed using the bioinformatic tool Ingenuity Gene Network Analysis. In SLE patients, comparative analysis of BMMCs genes revealed a network with 19 central nodes as major gene regulators including ERK, JNK, and p38 MAP kinases, insulin, Ca2+ and STAT3. Comparison between active versus inactive SLE identified 30 central nodes associated with immune response, protein synthesis, and post-transcriptional modification. A high degree of identity between networks in active SLE and non-Hodgkin's lymphoma (NHL) patients was found, with overlapping central nodes including kinases (MAPK, ERK, JNK, PKC), transcription factors (NF-kappaB, STAT3), and insulin. In validation studies, western blot analysis in splenic B cells from 5-month-old NZB/NZW F1 lupus mice showed activation of STAT3, ITGB2, HSPB1, ERK, JNK, p38, and p32 kinases, and downregulation of FOXO3 and VDR compared to normal C57Bl/6 mice. Conclusions/Significance: Gene network analysis of lupus BMMCs identified central gene regulators implicated in disease pathogenesis which could represent targets of novel therapies in human SLE. The high similarity between active SLE and NHL networks provides a molecular basis for the reported association of the former with lymphoid malignancies

What is the future of targeted therapy in rheumatology: biologics or small molecules?

Background: Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved. That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways. Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics.Discussion: TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s. Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy. During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases. In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases. While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis. In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies.Summary: Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases. The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy. © 2014 Mócsai et al.; licensee BioMed Central Ltd

Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions

The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions

Effects of satellite spatial resolution on gross primary productivity estimation through light use efficiency modeling

Terrestrial Gross Primary Productivity (GPP) describes the total amount of CO2 assimilated by plants in an ecosystem during photosynthesis and is considered the largest flux component of the global carbon cycle. One of the most prominent techniques for estimating GPP at ecosystem scale is the Light Use Efficiency (LUE) approach, taking advantage of the spatiotemporal capabilities that satellite data provide. LUE expresses GPP as the product of absorbed photosynthetically active radiation (APAR) and the efficiency (Îμ ) that APAR is converted to biomass. Although satellite imagery is the key component of such models, the effects of image spatial resolution on model performance have not been thoroughly investigated. The emergence of new satellite instruments with enhanced spatial, spectral and temporal capabilities (i.e. Copernicus Sentinels) provides the opportunity for GPP estimation in high spatial resolution and comparison with low resolution GPP products (i.e. MODIS). In this study, a LUE model is applied to three satellite instruments with different spatial resolution: MODIS (500 m), Sentinel-3 (300 m) and Sentinel-2 (10 m). The GPP estimates of the three instruments are compared over six forest sites in Greece: Two deciduous (Quercus sp., Fagus sylvatica), two coniferous (Pinus nigra, Pinus halepensis) and two mixed (Pinus nigra with Fagus sylvatica). The results demonstrate that spatial resolution is not a crucial parameter for LUE modeling in wide, homogenous and fully covered forested areas. The spatial resolution is more important when applying LUE in mixed canopies or partially covered forested areas due to the effects of the different land cover types. To that purpose, Sentinel-2 presents a unique potential for accurate characterization of the land cover type and dynamics, due to the increased spatial resolution and frequent coverage, appearing as a prominent tool for future large scale GPP monitoring. © 2018 SPIE

MODIS PRI performance to track Light Use Efficiency of a Mediterranean coniferous forest: Determinants, restrictions and the role of LUE range

The relationship between the Photochemical Reflectance Index (PRI) and Light Use Efficiency (LUE) is well established at leaf and small canopy scales, but upscaling to ecosystem level is still a challenge. Only few studies have applied satellite-derived PRI to estimate LUE, mostly using MODIS, and although the results are promising, many external factors have been identified affecting PRI performance. The present study investigates determinants and restrictions of MODIS-derived PRI potential to follow the LUE variability of a Mediterranean coniferous forest. Daily and half-hour LUE values were calculated from eddy covariance measurements, dividing GPP by either Photosynthetically Active Radiation (PAR) or the absorbed fraction of PAR (APAR). Also, various PRI datasets were created based on different sensor (Terra, Aqua, Both), reference band (1, 12, 13) and observation/illumination angles. Overall, PRI correlated better with LUE calculated using PAR instead of APAR and Aqua PRI yielded better results than Terra. Restricting acquisitions according to observation/illumination angles improves the PRI:LUE relationship (maximum R2 = 0.512), with backscatter observations yielding the best correlations. Our findings suggest that MODIS-derived PRI is more sensitive to relatively large seasonal LUE changes, but is unable to closely follow severe drought events. Among the tested reference bands, the best results were derived using band 12 (546 - 556 nm), although the optimum reference band seems to depend on viewing conditions. The PRI:LUE relationship was further improved when half-hour LUE of the satellite overpass was used instead of daily LUE. However, it was found that the PRI:LUE relationships for the different datasets were strongly affected by the range of LUE values corresponding to each PRI group, with lower LUE variability resulting to weaker PRI:LUE correlations. LUE range effect should be accounted for in future studies, when different PRI datasets are compared and might explain the contradicting findings in the existing literature. © 202

Multi-Year Monitoring of Deciduous Forests Ecophysiology and the Role of Temperature and Precipitation as Controlling Factors

Two deciduous forest ecosystems, one dominated by Fagus sylvatica and a mixed one with Quercus cerris and Quercus frainetto, were monitored from an ecophysiological perspective during a five-year period, in order to assess seasonal fluctuations, establish links between phenology and ecophysiology, and reveal climatic controls. Field measurements of leaf area index (LAI), chlorophyll content, leaf specific mass (LSM), water potential (Ψ) and leaf photosynthesis (Aleaf) were performed approximately on a monthly basis. LAI, chlorophylls and LSM fluctuations followed a recurrent pattern yearly, with increasing values during spring leaf burst and expansion, relatively stable values during summer and decreasing values during autumn senescence. However, pre-senescence leaf fall and chlorophyll reductions were evident in the driest year. The dynamically responsive Aleaf and Ψ presented considerable inter-annual variation. Both oak species showed more pronounced depressions of Aleaf and Ψ compared to beech, yet the time-point of their appearance coincided and was the same for all species each year. Spring temperature had a positive role in the increasing phase of all ecophysiological processes while rising autumn temperature resulted in retarded senescence. Precipitation showed asymmetric effects on the measured ecophysiological parameters. The between-species differences in responses, climate sensitivity and climate memory are identified and discussed. © 2022 by the authors

Monitoring water stress and fruit quality in an orange orchard under regulated deficit irrigation using narrow-band structural and physiological remote sensing indices

This paper deals with the monitoring of water status and the assessment of the effect of stress on citrus fruit quality using structural and physiological remote sensing indices. Four flights were conducted over a citrus orchard in 2009 using an unmanned aerial vehicle (UAV) carrying a multispectral camera with six narrow spectral bands in the visible and near infrared. Physiological indices such as the Photochemical Reflectance Index (PRI 570), a new structurally robust PRI formulation that uses the 515nm as the reference band (PRI 515), and a chlorophyll ratio (R 700/R 670) were compared against the Normalized Difference Vegetation Index (NDVI), Renormalized Difference Vegetation Index (RDVI) and Modified Triangular Vegetation Index (MTVI) canopy structural indices for their performance in tracking water status and the effects of sustained water stress on fruit quality at harvest. The irrigation setup in the commercial orchard was compared against a treatment scheduled to satisfy full requirements (based on estimated crop evapotranspiration) using two regulated deficit irrigation (RDI) strategies. The water status of the trees throughout the experiment was monitored with frequent field measurements of stem water potential (Ψ x), while titratable acidity (TA) and total soluble solids (TSS) were measured at harvest on selected trees from each irrigation treatment. The high spatial resolution of the multispectral imagery (30cm pixel size) enabled identification of pure tree crown components, extracting the tree reflectance from shaded, sunlit and aggregated pixels. The physiological and structural indices were then calculated from each tree at the following levels: (i) pure sunlit tree crown, (ii) entire crown, aggregating the within-crown shadows, and (iii) simulating a lower resolution pixel, including tree crown, sunlit and shaded soil pixels. The resulting analysis demonstrated that both PRI formulations were able to track water status, except when water stress altered canopy structure. In such cases, PRI 570 was more affected than PRI 515 by the structural changes caused by sustained water stress throughout the season. Both PRI formulations were proven to serve as pre-visual water stress indicators linked to fruit quality TSS and TA parameters (r 2=0.69 for PRI 515 vs TSS; r 2=0.58 vs TA). In contrast, the chlorophyll (R 700/R 670) and structural indices (NDVI, RDVI, MTVI) showed poor relationships with fruit quality and water status levels (r 2=0.04 for NDVI vs TSS; r 2=0.19 vs TA). The two PRI formulations showed strong relationships with the field-measured fruit quality parameters in September, the beginning of stage III, which appeared to be the period most sensitive to water stress and the most critical for assessing fruit quality in citrus. Both PRI 515 and PRI 570 showed similar performance for the two scales assessed (sunlit crown and entire crown), demonstrating that within-crown component separation is not needed in citrus tree crowns where the shaded vegetation component is small. However, the simulation conducted through spatial resampling on tree+soil aggregated pixels revealed that the physiological indices were highly affected by soil reflectance and between-tree shadows, showing that for TSS vs PRI 515 the relationship dropped from r 2=0.69 to r 2=0.38 when aggregating soil+crown components. This work confirms a previous study that demonstrated the link between PRI 570, water stress, and fruit quality, while also making progress in assessing the new PRI formulation (PRI 515), the within-crown shadow effects on the physiological indices, and the need for high resolution imagery to target individual tree crowns for the purpose of evaluating the effects of water stress on fruit quality in citrus. © 2012 International Society for Photogrammetry and Remote Sensing, Inc. (ISPRS).Financial support from the Spanish Ministry of Science and Education (MEC) for the AGL2009-13105 and CONSOLIDER RIDECO (CSD2006-67) projects is gratefully acknowledged.Peer Reviewe