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DPP4 inhibition prevents AKI
(2017)
To investigate and compare the occurrence of inflammatory processes in the sites of disc degeneration in the lumbar and cervical spine by a gene array and subsequent qPCR and to investigate the mechanistic involvement of transient receptor potential channels TRPC6 and TRPV4. The gene expression of inflammatory cytokines and TRP channels was measured in human disc samples obtained from patients undergoing discectomy at the cervical (n = 24) or lumbar (n = 27) spine for degenerative disc disease (DDD) and disc herniation (DH) and analyzed for differences with regard to spinal level, IVD degeneration grade, Modic grade, age, sex, disc region and surgical extent. Aside from genes with known implication in DDD and DH, four previously unreported genes from the interferon and TRP families (IFNA1, IFNA8, IFNB1, TRPC6) could be detected. A correlation between gene expression and age (IL-15) and IVD degeneration grade (IFNA1, IL-6, IL-15, TRPC6), but not Modic grade, was identified. Significant differences were detected between cervical and lumbar discs (IL-15), nucleus and annulus (IL-6, TNF-alpha, TRPC6), single-level and multi-level surgery (IL-6, IL-8) as well as DDD and DH (IL-8), while sex had no effect. Multiple gene-gene pair correlations, either between different cytokines or between cytokines and TRP channels, exist in the disc. This study supports the relevance of IL-6 and IL-8 in disc diseases, but furthermore points toward a possible pathological role of IL-15 and type I interferons, as well as a mechanistic role of TRPC6. With limited differences in the inflammatory profile of cervical and lumbar discs, novel anti-inflammatory or TRP-modulatory strategies for the treatment of disc pathologies may be applicable independent of the spinal region.
Galaxies are surrounded by sizeable gas reservoirs which host a significant amount of metals: the circum-galactic medium (CGM). The CGM acts as a mediator between the galaxy and the extragalactic medium. However, our understanding of how galaxy mergers, a major evolutionary transformation, impact the CGM remains deficient. We present a theoretical study of the effect of galaxy mergers on the CGM. We use hydrodynamical cosmological zoom-in simulations of a major merger selected from the Illustris project such that the z = 0 descendant has a halo mass and stellar mass comparable to the Milky Way. To study the CGM we then re-simulated this system at a 40 times better mass resolution, and included detailed post-processing ionization modelling. Our work demonstrates the effect the merger has on the characteristic size of the CGM, its metallicity, and the predicted covering fraction of various commonly observed gas-phase species, such as H I, C IV, and O VI. We show that merger-induced outflows can increase the CGM metallicity by 0.2-0.3 dex within 0.5 Gyr post-merger. These effects last up to 6 Gyr post-merger. While the merger increases the total metal covering fractions by factors of 2-3, the covering fractions of commonly observed UV ions decrease due to the hard ionizing radiation from the active galactic nucleus, which we model explicitly. Our study of the single simulated major merger presented in this work demonstrates the significant impact that a galaxy interaction can have on the size, metallicity, and observed column densities of the CGM.
This study examines the variations of climate variables and rice yield and quantifies the relationships among them using multiple linear regression, principal component analysis, and support vector machine (SVM) analysis in southwest Nigeria. The climate and yield data used was for a period of 36 years between 1980 and 2015. Similar to the observed decrease (P < 0.001) in rice yield, pan evaporation, solar radiation, and wind speed declined significantly. Eight principal components exhibited an eigenvalue > 1 and explained 83.1% of the total variance of predictor variables. The SVM regression function using the scores of the first principal component explained about 75% of the variance in rice yield data and linear regression about 64%. SVM regression between annual solar radiation values and yield explained 67% of the variance. Only the first component of the principal component analysis (PCA) exhibited a clear long-term trend and sometimes short-term variance similar to that of rice yield. Short-term fluctuations of the scores of the PC1 are closely coupled to those of rice yield during the 1986-1993 and the 2006-2013 periods thereby revealing the inter-annual sensitivity of rice production to climate variability. Solar radiation stands out as the climate variable of highest influence on rice yield, and the influence was especially strong during monsoon and post-monsoon periods, which correspond to the vegetative, booting, flowering, and grain filling stages in the study area. The outcome is expected to provide more in-depth regional-specific climate-rice linkage for screening of better cultivars that can positively respond to future climate fluctuations as well as providing information that may help optimized planting dates for improved radiation use efficiency in the study area.
In assessing adolescent behavior difficulties, parents, teachers, and the adolescents themselves are key informants. However, substantial disagreement has been found between informants. Specifically, children with attention-deficit/hyperactivity disorder (ADHD) tend to overestimate their competencies, also known as "positive (illusionary) bias." This study compared parent, teacher, and adolescent ratings of ADHD and other behavioral symptoms in a sample of 114 adolescents with ADHD. Further, the effect of cross-informant disagreement (CID) on treatment outcomes was investigated in a subsample of 54 adolescents who had undergone a training and coaching intervention. Overall, there was moderate agreement among informants. Parent and adolescent ratings were more strongly correlated with each other than with teacher ratings. The strongest discrepancy was found between teacher and adolescent ratings on prosocial behavior. This discrepancy explained 12% of the variance in parent-rated ADHD symptom severity after the intervention. The treatment was less effective in participants with high teacher-adolescent disagreement on prosocial behavior (d = 0.41) than with low disagreement (d = 0.98). These findings suggest that professionals working with adolescents with ADHD should consider multiple sources of information before initiating treatment and pay attention to cross-informant disagreements because these may indicate a risk of diminished treatment effects.
This article explores the various futures of relations between the European Union (EU) and Ukraine. After distilling two major drivers we construct a future compass in order to conceive of four futures of relations between the EU and Ukraine. Our scenarios aim to challenge deep-rooted assumptions on the EU’s neighbourhood with Ukraine: How will the politico-economic challenges in the European countries influence the EU’s approach towards the East? Will more EU engagement in Ukraine contribute to enduring peace? Does peace always come with stability? Which prospects does the idea of Intermarium have? Are the pivotal transformation players in Ukraine indeed oligarchs or rather small- and medium-sized entrepreneurs? After presenting our scenarios, we propose indicators to know in the years to come, along which path future relations do develop. By unearthing surprising developments we hope to provoke innovative thoughts on Eastern Europe in times of post truth societies, confrontation between states and hybrid warfare.
microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs’ functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein’s active site. Due to their lower molecular weight and, thus, more drug-like chemical structure, the novel inhibitor class may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.
miRNA Targeting Drugs
(2017)
Only 20 years after the discovery of small non-coding, single-stranded ribonucleic acids, so-called microRNAs (miRNAs), as post-transcriptional gene regulators, the first miRNA-targeting drug Miravirsen for the treatment of hepatitis C has been successfully tested in clinical Phase II trials. Addressing miRNAs as drug targets may enable the cure, or at least the treatment of diseases, which presently seems impossible. However, due to miRNAs’ chemical structure, generation of potential drug molecules with necessary pharmacokinetic properties is still challenging and requires a re-thinking of the drug discovery process. Therefore, this chapter highlights the potential of miRNAs as drug targets, discusses the challenges, and tries to give a complete overview of recent strategies in miRNA drug discovery.
Drug target miRNA
(2017)
This volume provides a concise and technical discussion of recently developed approaches to overcome challenges in miRNA drug discovery. Drug Target miRNA: Methods and Protocols explores strategies to overcome pharmacodynamics and pharmacokinetics challenges. These strategies cover anti-sense agents targeting miRNA that are applied in advanced formulations or are chemically optimized to increase delivery; small molecule miRNA modulators to overcome anti-sense agents’ limitations; general enhancers of miRNA maturation; and Argonaute 2 protein and its pharmacokinetic parameters. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.Cutting-edge and thorough, Drug Target miRNA: Methods and Protocols is a valuable resource for anyone interested in the ever-evolving field of miRNA drug discovery.
Preface
(2017)