Modulation of nontypeable Haemophilus influenza-induced inflammation in the pathogenesis of otitis media by curcumin

Otitis media (OM) is the most common childhood bacterial infection, and leading cause of conductive hearing loss. Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen causing OM. During infection, epithelial cells act as the first line of defense by secreting numerous pro-inflammatory mediators including C-X-C motif chemokine ligand 5 (CXCL5) and mucin 5AC (MUC5AC). While appropriate inflammatory responses are critical for the containment and removal of the invading pathogen, excess inflammation can lead to tissue damage, impaired mucociliary clearance and be detrimental to the host. Therefore, inflammatory responses must be tightly regulated. Current therapies for OM are ineffective due to the emergence of antibiotic-resistant NTHi strains and risk of side effects with prolonged use of immunosuppressant drugs. Therefore, therapeutic strategies that increase the levels of endogenous negative regulators of inflammation while leaving the positive pathways intact are gaining prominence. Thus, understanding the underlying molecular mechanisms regulating inflammation is critical for developing effective therapeutic strategies. Despite the importance of CXCL5 chemokine in mediating inflammation, the signaling cascade mediating its up-regulation in OM remains largely unknown. Here we show that NTHi up-regulates CXCL5 expression by activating IKKβ-IκBα and p38 MAPK pathways via NF-κB nuclear translocation-dependent and -independent mechanism in middle ear epithelial cells. We also show that MKP-1 is a negative regulator of NTHi-induced CXCL5 expression. We further demonstrated the translational significance of these findings by reporting for the first time that curcumin, derived from Curcuma longa plant suppressed CXCL5 expression by direct inhibition of IKKβ phosphorylation, and inhibition of p38 MAPK via induction of negative regulator, MKP-1. Next, we show that curcumin also suppressed NTHi-induced MUC5AC expression via up-regulation of MKP-1, demonstrating for the first time the efficacy and pleiotropic anti-inflammatory action of curcumin to suppress NTHi-induced inflammatory responses in OM model. Finally, we demonstrate for the first time that MKP-1 protein undergoes lysine 63 (K63)-linked polyubiquitination, suggesting the importance of post-translational modification on MKP-1 activity. We also show that curcumin enhanced K63-linked polyubiquitination of MKP-1. Since K63-linked polyubiquitination mediates non-degradative molecular functions such as protein-protein interactions, protein trafficking and regulation of signal transduction events, our findings suggest a new mechanism of action of curcumin on MKP-1. Taken together our study demonstrates the therapeutic potential of curcumin in treating NTHi-induced OM by modulating the expression and activity of negative regulator MKP-1

The Reactive Carbonyl Methylglyoxal Suppresses Vascular KATP Channels by MRNA Destabilization

Diabetes mellitus is characterized by hyperglycemia, oxidative stress and excessive production of intermediary metabolites including methylglyoxal (MGO), a reactive carbonyl. MGO can readily interact with proteins, lipids and DNA, and cause an imbalance of the cellular antioxidant system leading to carbonyl stress. The effects of MGO can be devastating if the targeted molecules are responsible for the maintenance of membrane potentials and ionic homeostasis. Here we show that MGO disrupts the vascular isoform of ATP-sensitive K+ (KATP) channels by acting on the mRNAs of Kir6.1 and SUR2B subunits thereby regulating vascular tone. Our results show that the 3’ untranslated region (UTR) of Kir6.1 mRNA and the coding region of SUR2B mRNA are targeted by MGO causing a disruption of vascular KATP channels. The destabilization of the mRNAs of KATP channel can in turn affect K+ homeostasis of vascular smooth muscles as well as vascular responses to circulating vasodilators and vasoconstrictors

Effectiveness of body–mind–spirit intervention on well‐being, functional impairment and quality of life among depressive patients – a randomized controlled trial

Aim The aim of the study was to examine the efficacy of body–mind–spirit Intervention in improving the outcomes (well-being, quality of life and functional impairment) among depressive patients. Background Depressive disorders lead to significant dysfunction, disability and poor quality of life among sufferers. Body–mind–spirit intervention has been associated with improvements in the outcomes; however, few studies have examined this among depressive patients. Design True experimental pre–post equivalent groups design was adopted with longitudinal measurement of outcomes. Methods Participants were 120 adult depressive patients visiting the psychiatric outpatient department in a District Hospital in India. The participants were randomly assigned to either the body–mind–spirit group or the treatment-as-usual group between July 2011–January 2013. The treatment-as-usual group (n = 64) received only routine treatment (antidepressants and structured psycho-education) in the hospital. The body–mind–spirit group (n = 56) received four weekly body–mind–spirit group sessions in addition to the routine treatment. Outcome measures on depression, well-being, functional impairment and quality of life were evaluated for both groups at baseline and at four follow-up assessments in the 1st, 2nd, 3rd and 6th month. Treatment effects of the body–mind–spirit intervention were analysed by repeated-measures analysis of covariance. Findings Compared with the treatment-as-usual group, the body–mind–spirit group showed significant reduction in depression and functional impairment, and significant improvement in the well-being and quality of life scores over the 6-month study period. Conclusion The present findings provided evidence for the effectiveness of integrating a complementary therapy such as the body–mind–spirit intervention with conventional treatment in improving prospective outcomes among the depressive patients.postprin

Asymmetric Information in Cattle Auction: The Problem of Revaccinations

The authors acknowledge the help of Chris Boessen, Glenn Grimes, Joe Horner, Robert Larson, K.C. Olson, and Kurt Richter. This revision is dated July 2004.The paper analyzes the problem of asymmetric information between buyers and sellers in cattle auctions. An illustration is made regarding the vaccinations that the animals receive. Buyers do not know and cannot verify if sellers have vaccinated their animals forcing them to consider revaccination. Revaccination is only a part of the broader problem of information asymmetry that includes other quality issues and costs that can be saved, thereby increasing the welfare of both buyers and sellers. Structural characteristics of ranching, traditions and consumers' preferences are taken into account and a wider approach is attempted to explain the persistence of the problem in light of potential institutional solutions. We argue for a comprehensive empirical study of the incidence and impacts of buyer revaccination.This research was supported in part by the Missouri Agricultural Experiment Station

Stress Inducible Overexpression of AtHDG11 Leads to Improved Drought and Salt Stress Tolerance in Peanut (Arachis hypogaea L.)

Peanut is an important oilseed and food legume cultivated as a rain-fed crop in semi-arid tropics. Drought and high salinity are the major abiotic stresses limiting the peanut productivity in this region. Development of drought and salt tolerant peanut varieties with improved yield potential using biotechnological approach is highly desirable to improve the peanut productivity in marginal geographies. As abiotic stress tolerance and yield represent complex traits, engineering of regulatory genes to produce abiotic stress-resilient transgenic crops appears to be a viable approach. In the present study, we developed transgenic peanut plants expressing an Arabidopsis homeodomain-leucine zipper transcription factor (AtHDG11) under stress inducible rd29A promoter. A stress-inducible expression of AtHDG11 in three independent homozygous transgenic peanut lines resulted in improved drought and salt tolerance through up-regulation of known stress responsive genes (LEA, HSP70, Cu/Zn SOD, APX, P5CS, NCED1, RRS5, ERF1, NAC4, MIPS, Aquaporin, TIP, ELIP) in the stress gene network, antioxidative enzymes, free proline along with improved water use efficiency traits such as longer root system, reduced stomatal density, higher chlorophyll content, increased specific leaf area, improved photosynthetic rates, and increased intrinsic instantaneous WUE. Transgenic peanut plants displayed high yield compared to non-transgenic plants under both drought and salt stress conditions. Holistically, our study demonstrates the potentiality of stress-induced expression of AtHDG11 to improve the drought, salt tolerance in peanut

Econometric modeling of tobacco exports in the milieu of changing global and national policy regimes: repercussions on the Indian tobacco sector

IntroductionTobacco, an important commercial crop, plays a crucial role in farmers' incomes and livelihoods to a sizable population and contributes significant exchange earnings to the Indian economy. Currently, India is the second-largest tobacco producer after China, with a production of 758 million kg (13% of global production) and exports of ~190 million kg of tobacco (9% of global tobacco export volume). However, there are uncertainties surrounding the tobacco sector, such as growing public health and environmental issues associated with tobacco production and consumption and changing national and international tobacco-related policy regimes. In this context, the current study investigates the determinants of tobacco exports and geographical shifts in export destinations over the years.MethodsThe statistical models employed are co-integration, and vector error-correlation models to test the short-run and long-run dynamics relationship between tobacco exports and the explanatory variables, and the Markov chain approach to find out geographical shifts in export destinations.Results and discussionThe econometric model estimated the relationship between the tobacco export volume with domestic production, export price, and global demand for Indian tobacco, and investigated the geographical shift in export destinations of tobacco in the context of changing global and national policy regimes on the sector. The econometric modeling framework confirms that there exists a statistically significant relationship between Indian tobacco export demand, domestic production, export price, and world demand for Indian tobacco. The geographical shift was evident in major export destinations during the post-WHO-FCTC (Framework Convention on Tobacco Control) regime. The model findings direct that India should take advantage of the export price, and global demand for tobacco as India ratified WHO-FCTC; there is no scope for horizontal expansion of the area under tobacco. This modeling framework aids as a tool to direct and explore the possible options with a greater emphasis on export-centric farming system in tobacco production by augmenting crop compliance and quality to meet the standards of international markets

The Role of FeNO in Cough Management : A Randomised Controlled Trial

This abstract is funded by: Observational & Pragmatic Research Institute Pte Ltd, and Circassia Presented at thematic poster session: A34 ASTHMA CLINICAL STUDIES I Sunday 20th MayPeer reviewedPostprin

Disruption of TLR3 Signaling Due to Cleavage of TRIF by the Hepatitis A Virus Protease-Polymerase Processing Intermediate, 3CD

Toll-like receptor 3 (TLR3) and cytosolic RIG-I-like helicases (RIG-I and MDA5) sense viral RNAs and activate innate immune signaling pathways that induce expression of interferon (IFN) through specific adaptor proteins, TIR domain-containing adaptor inducing interferon-β (TRIF), and mitochondrial antiviral signaling protein (MAVS), respectively. Previously, we demonstrated that hepatitis A virus (HAV), a unique hepatotropic human picornavirus, disrupts RIG-I/MDA5 signaling by targeting MAVS for cleavage by 3ABC, a precursor of the sole HAV protease, 3Cpro, that is derived by auto-processing of the P3 (3ABCD) segment of the viral polyprotein. Here, we show that HAV also disrupts TLR3 signaling, inhibiting poly(I:C)-stimulated dimerization of IFN regulatory factor 3 (IRF-3), IRF-3 translocation to the nucleus, and IFN-β promoter activation, by targeting TRIF for degradation by a distinct 3ABCD processing intermediate, the 3CD protease-polymerase precursor. TRIF is proteolytically cleaved by 3CD, but not by the mature 3Cpro protease or the 3ABC precursor that degrades MAVS. 3CD-mediated degradation of TRIF depends on both the cysteine protease activity of 3Cpro and downstream 3Dpol sequence, but not 3Dpol polymerase activity. Cleavage occurs at two non-canonical 3Cpro recognition sequences in TRIF, and involves a hierarchical process in which primary cleavage at Gln-554 is a prerequisite for scission at Gln-190. The results of mutational studies indicate that 3Dpol sequence modulates the substrate specificity of the upstream 3Cpro protease when fused to it in cis in 3CD, allowing 3CD to target cleavage sites not normally recognized by 3Cpro. HAV thus disrupts both RIG-I/MDA5 and TLR3 signaling pathways through cleavage of essential adaptor proteins by two distinct protease precursors derived from the common 3ABCD polyprotein processing intermediate

Molecular insights on the interference of simplified lung surfactant models by gold nanoparticle pollutants

YesInhaled nanoparticles (NPs) are experienced by the first biological barrier inside the alveolus known as lung surfactant (LS), a surface tension reducing agent, consisting of phospholipids and proteins in the form of the monolayer at the air-water interface. The monolayer surface tension is continuously regulated by the alveolus compression and expansion and protects the alveoli from collapsing. Inhaled NPs can reach deep into the lungs and interfere with the biophysical properties of the lung components. The interaction mechanisms of bare gold nanoparticles (AuNPs) with the LS monolayer and the consequences of the interactions on lung function are not well understood. Coarse-grained molecular dynamics simulations were carried out to elucidate the interactions of AuNPs with simplified LS monolayers at the nanoscale. It was observed that the interactions of AuNPs and LS components deform the monolayer structure, change the biophysical properties of LS and create pores in the monolayer, which all interfere with the normal lungs function. The results also indicate that AuNP concentrations >0.1 mol% (of AuNPs/lipids) hinder the lowering of the LS surface tension, a prerequisite of the normal breathing process. Overall, these findings could help to identify the possible consequences of airborne NPs inhalation and their contribution to the potential development of various lung diseases.University of Technology Sydney (UTS) FEIT Research Scholarship, UTS IRS (S.I.H.), 2018 Blue Sky scheme–Suvash Saha (Activity 2232368), N.S.G is supported by the Vice-Chancellor fellowship funded by QUT