Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

CCI’s investigation of abuse of dominance: Adjudicatory traits in prima facie opinion

This chapter is premised on the recent judgement delivered by the Delhi High Court (henceforth “DHC”) in Ericsson v CCI.1 This judgement looked at the jurisdiction of the Competition Commission of India (henceforth “CCI”) to investigate alleged abuse of dominance of a holder of standard essential patent (henceforth “SEP”). The jurisdiction of CCI, as suggested by the DHC is independent of any matter pending in a court of law and therefore, the CCI can continue to investigate abuse of dominance complaints

Evolving Huawei framework: SEPs and grant of injunctions

The European Commission in their recent communication paper (COM (2017) 712 final)(EC paper) titled ‘Setting out the EU approach to Standard Essential Patents’ considered the obligations that are cast upon parties during pre-licensing negotiations of SEPs on FRAND terms. The EC paper has derived such obligations from the behavioral criteria as determined by the CJEU in the Huawei judgement. While Huawei provided the general framework, it further evolved through various court decisions in Germany and in the Unwired Planet case. This chapter reflects on the framework developed in the Huawei judgment and shows how this framework has evolved in the post Huawei cases in Germany and UK. The post Huawei cases have tried to adhere to the overall framework provided under Huawei, although there are number of inconsistencies as to specific obligations. From the perceived inconsistences, this chapter concludes on a note that the overall conduct of the parties would play a major role before granting injunctive relief to SEP holders

Differential leaf flooding resilience in Arabidopsis thaliana is controlled by ethylene signaling-activated and age-dependent phosphorylation of ORESARA1

The phytohormone ethylene is a major regulator of plant adaptive responses to flooding. In flooded plant tissues, ethylene quickly increases to high concentrations owing to its low solubility and diffusion rates in water. Ethylene accumulation in submerged plant tissues makes it a reliable cue for triggering flood acclimation responses, including metabolic adjustments to cope with flood-induced hypoxia. However, persistent ethylene accumulation also accelerates leaf senescence. Stress-induced senescence hampers photosynthetic capacity and stress recovery. In submerged Arabidopsis, senescence follows a strict age-dependent pattern starting with the older leaves. Although mechanisms underlying ethylene-mediated senescence have been uncovered, it is unclear how submerged plants avoid indiscriminate breakdown of leaves despite high systemic ethylene accumulation. We demonstrate that although submergence triggers leaf-age-independent activation of ethylene signaling via EIN3 in Arabidopsis, senescence is initiated only in old leaves. EIN3 stabilization also leads to overall transcript and protein accumulation of the senescence-promoting transcription factor ORESARA1 (ORE1) in both old and young leaves during submergence. However, leaf-age-dependent senescence can be explained by ORE1 protein activation via phosphorylation specifically in old leaves, independent of the previously identified age-dependent control of ORE1 via miR164. A systematic analysis of the roles of the major flooding stress cues and signaling pathways shows that only the combination of ethylene and darkness is sufficient to mimic submergence-induced senescence involving ORE1 accumulation and phosphorylation. Hypoxia, most often associated with flooding stress in plants, appears to have no role in these processes. Our results reveal a mechanism by which plants regulate the speed and pattern of senescence during environmental stresses such as flooding. Age-dependent ORE1 activity ensures that older, expendable leaves are dismantled first, thus prolonging the life of younger leaves and meristematic tissues that are vital to whole-plant survival.</p

Genome-Wide Identification of R2R3-MYB Genes and Expression Analyses During Abiotic Stress in

The R2R3-MYB is one of the largest families of transcription factors, which have been implicated in multiple biological processes. There is great diversity in the number of R2R3-MYB genes in different plants. However, there is no report on genome-wide characterization of this gene family in cotton. In the present study, a total of 205 putative R2R3-MYB genes were identified in cotton D genome (Gossypium raimondii), that are much larger than that found in other cash crops with fully sequenced genomes. These GrMYBs were classified into 13 groups with the R2R3-MYB genes from Arabidopsis and rice. The amino acid motifs and phylogenetic tree were predicted and analyzed. The sequences of GrMYBs were distributed across 13 chromosomes at various densities. The results showed that the expansion of the G. Raimondii R2R3-MYB family was mainly attributable to whole genome duplication and segmental duplication. Moreover, the expression pattern of 52 selected GrMYBs and 46 GaMYBs were tested in roots and leaves under different abiotic stress conditions. The results revealed that the MYB genes in cotton were differentially expressed under salt and drought stress treatment. Our results will be useful for determining the precise role of the MYB genes during stress responses with crop improvement

Preliminary design framework for the power gearbox in a contra-rotating open rotor

This study introduces an innovative approach to sizing a differential planetary gearbox for a counter-rotating open rotor application. An updated methodology is proposed for the design of maximum load capacity gears based on the power transmitted, durability and space-envelope requirements of the application. The reported methodology has been validated by comparing the results to published data, demonstrating a maximum difference of 0.6% in geometry. Parametric analyses have also been performed to assess the impact of the design assumptions on gearbox dimensional trends. The proposed methodology enables the assessment of the impact of the preliminary transmission system design on engine performance and general arrangement. The characteristics of the gearset lead to an unequal torque split between output shafts (i.e. the propeller shafts). Given the design assumptions made, the study indicates that valid torque ratios would lie between 1.1 and 1.33. The impact of the torque ratio on the size of the gearbox has been analysed for equal rotational speeds and for different speeds between the output shafts. The study established that the transmission system design needs to be considered prior to selection of the torque ratio at engine design leve

Experimental rig for ice accretion and adhesion strength measurement for air cycle machine system

Air cycle machines (ACM) which are part of the air-conditioning pack in every aircraft, are one such turbomachinery device that can be affected by icing issues particularly at the turbine end. Current ice protection solutions for the air cycle machines use a heating system on the downstream pipe to heat the surface, using electric resistance heaters or hot air coming from the ACM compressor stage. Both solutions require high energy, hence the need to reduce energy consumption through the development of passive energy-saving solutions. Clean Sky 2 ERICE project aims at developing an eco-friendly and cost-effective hydrophobic / ice-phobic solution able to resist ice adhesion in the ACM turbine scroll and its downstream pipe. This paper discusses the implementation of an experimental rig to reproduce the ice formation and accretion conditions within the ACM and a new shear test method to measure the ice adhesion strength on existing and new solutions in the form of coatings. The flow through the ACM turbine exhaust has also been characterized for the first time in published literature. The results from the ice accretion and adhesion tests show that hydrophobic coatings developed for the purposes of ice protection perform better than the current industry baseline material for ACM turbine scroll pipe internal surface. While these coatings could not be used to prevent accretion, they do help in reducing adhesion of ice to the surface.European Union funding: 821301. Clean Sky 2 Joint Undertakin

Performance, environmental, and mobility analysis of large capacity fast rotorcraft configurations for the European regional air traffic market

Fast, large rotorcraft are of interest in the future European air transport system due to their runway independent operation and potential mobility improvements for the passenger. Both a tiltrotor and a coaxial compound concept model were developed for a 70 passenger, 500 NM design mission that would compete with regional fixed-wing aircraft. These models were flown along virtual trajectories representing possible use-cases and assessed for environmental performance in comparison to an in-service baseline aircraft using comparable engine technology levels. Further, the travel time and mobility improvement available to the intermodal transport network through the inclusion of these concept rotorcraft was examined with promising results. Future work is suggested to address the shortfall in environmental performance

Comparative Lipidomics of Azole Sensitive and Resistant Clinical Isolates of Candida albicans Reveals Unexpected Diversity in Molecular Lipid Imprints

Although transcriptome and proteome approaches have been applied to determine the regulatory circuitry behind multidrug resistance (MDR) in Candida, its lipidome remains poorly characterized. Lipids do acclimatize to the development of MDR in Candida, but exactly how the acclimatization is achieved is poorly understood. In the present study, we have used a high-throughput mass spectrometry-based shotgun approach and analyzed the lipidome of genetically matched clinical azole-sensitive (AS) and -resistant (AR) isolates of C. albicans. By comparing the lipid profiling of matched isolates, we have identified major classes of lipids and determined more than 200 individual molecular lipid species among these major classes. The lipidome analysis has been statistically validated by principal component analysis. Although each AR isolate was similar with regard to displaying a high MIC to drugs, they had a distinct lipid imprint. There were some significant commonalities in the lipid profiles of these pairs, including molecular lipid species ranging from monounsaturated to polyunsaturated fatty acid-containing phosphoglycerides. Consistent fluctuation in phosphatidyl serine, mannosylinositolphosphorylceramides, and sterol esters levels indicated their compensatory role in maintaining lipid homeostasis among most AR isolates. Notably, overexpression of either CaCdr1p or CaMdr1p efflux pump proteins led to a different lipidomic response among AR isolates. This study clearly establishes the versatility of lipid metabolism in handling azole stress among various matched AR isolates. This comprehensive lipidomic approach will serve as a resource for assessing strategies aimed at disrupting the functions of Candida lipids, particularly the functional interactions between lipids and MDR determinants