Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.

Anti-staphylococcal activity of C-methyl flavanones from propolis of Australian stingless bees (Tetragonula carbonaria) and fruit resins of Corymbia torelliana (Myrtaceae)

Propolis of Australian stingless bees (Tetragonula carbonaria, Meliponini) originating from Corymbia torelliana (Myrtaceae) fruit resins was tested for its antimicrobial activities as well as its flavonoid contents. This study aimed at the isolation, structural elucidation and antibacterial testing of flavanones of C. torelliana fruit resins that are incorporated into stingless bee propolis. Flavanones of this study were elucidated by spectroscopic and spectrometric methods including UV, 1D and 2D NMR, EI-MS, ESI-MS and HR-MS. The results indicated known C-methylated flavanones namely, 1 (2S)-cryptostrobin, its regioisomer 2 (2S)- stroboponin, 3 (2S)- cryptostrobin 7-methyl ether, and 6 (2S)- desmethoxymatteucinol, and known flavanones 4 (2S)- pinostrobin and 5 (2S)- pinocembrin as markers for C. torelliana fruit resins and one propolis type. Ethanolic preparations of propolis were shown to be active against Staphylococcus aureus (ATCC 25923) and to a lesser extent against Pseudomonas aeruginosa (ATCC 27853). C. torelliana flavanones inhibited the growth of S. aureus therefore contributing to the antibacterial effects observed for Australian stingless bee propolis extracts.

Fractal and complex network analyses of protein molecular dynamics

Based on protein molecular dynamics, we investigate the fractal properties of energy, pressure and volume time series using the multifractal detrended fluctuation analysis (MF-DFA) and the topological and fractal properties of their converted horizontal visibility graphs (HVGs). The energy parameters of protein dynamics we considered are bonded potential, angle potential, dihedral potential, improper potential, kinetic energy, Van der Waals potential, electrostatic potential, total energy and potential energy. The shape of the h(q)h(q) curves from MF-DFA indicates that these time series are multifractal. The numerical values of the exponent h(2)h(2) of MF-DFA show that the series of total energy and potential energy are non-stationary and anti-persistent; the other time series are stationary and persistent apart from series of pressure (with H≈0.5H≈0.5 indicating the absence of long-range correlation). The degree distributions of their converted HVGs show that these networks are exponential. The results of fractal analysis show that fractality exists in these converted HVGs. For each energy, pressure or volume parameter, it is found that the values of h(2)h(2) of MF-DFA on the time series, exponent λλ of the exponential degree distribution and fractal dimension dBdB of their converted HVGs do not change much for different proteins (indicating some universality). We also found that after taking average over all proteins, there is a linear relationship between 〈h(2)〉〈h(2)〉 (from MF-DFA on time series) and 〈dB〉〈dB〉 of the converted HVGs for different energy, pressure and volume.

Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2-ASK1 apoptosis pathways and oxidative stress is mitigated by Srx-Nrf2 anti-oxidant system

Atmospheric pressure gas plasma (AGP) generates reactive oxygen species (ROS) that induce apoptosis in cultured cancer cells. The majority of cancer cells develop a ROS-scavenging anti-oxidant system regulated by Nrf2, which confers resistance to ROS-mediated cancer cell death. Generation of ROS is involved in the AGP-induced cancer cell death of several colorectal cancer cells (Caco2, HCT116 and SW480) by activation of ASK1-mediated apoptosis signaling pathway without affecting control cells (human colonic sub-epithelial myofibroblasts; CO18, human fetal lung fibroblast; MRC5 and fetal human colon; FHC). However, the identity of an oxidase participating in AGP-induced cancer cell death is unknown. Here, we report that AGP up-regulates the expression of Nox2 (NADPH oxidase) to produce ROS. RNA interference designed to target Nox2 effectively inhibits the AGP-induced ROS production and cancer cell death. In some cases both colorectal cancer HT29 and control cells showed resistance to AGP treatment. Compared to AGP-sensitive Caco2 cells, HT29 cells show a higher basal level of the anti-oxidant system transcriptional regulator Nrf2 and its target protein sulfiredoxin (Srx) which are involved in cellular redox homeostasis. Silencing of both Nrf2 and Srx sensitized HT29 cells, leads to ROS overproduction and decreased cell viability. This indicates that in HT29 cells, Nrf2/Srx axis is a protective factor against AGP-induced oxidative stress. The inhibition of Nrf2/Srx signaling should be considered as a central target in drug-resistant colorectal cancer treatments.

Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK

Background Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy. Method We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer. Result We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo. Conclusion Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

William James, Sciences of Mind, and Anti-imperial Discourse

In the past few decades, the humanities and social sciences have developed new methods of reorienting their conceptual frameworks in a “world without frontiers.” In this book, Bernadette M. Baker offers an innovative approach to rethinking sciences of mind as they formed at the turn of the twentieth century, via the concerns that have emerged at the turn of the twenty-first. The less-visited texts of Harvard philosopher and psychologist William James provide a window into contemporary debates over principles of toleration, anti-imperial discourse, and the nature of ethics. Baker revisits Jamesian approaches to the formation of scientific objects including the child mind, exceptional mental states, and the ghost to explore the possibilities and limits of social scientific thought dedicated to mind development and discipline formation around the construct of the West.

DC-SIGN and alpha 2,6-sialylated IgG Fc interaction is dispensable for the anti-inflammatory activity of IVIg on human dendritic cells

Intravenous immunoglobulin (IVIg) is widely used to treat autoimmune diseases. Several mutually nonexclusive mechanisms are proposed to explain the beneficial effects of IVIg in patients (1, 2). Lately, Ravetch and colleagues (3) demonstrate that anti-inflammatory activity of IVIg is mediated mainly by antibodies that contain terminal _2,6-sialic acid linkages at the Asn297-linked glycan of Fc region.

Efficient Output-Sensitive Construction of Reeb Graphs

The Reeb graph tracks topology changes in level sets of a scalar function and finds applications in scientific visualization and geometric modeling. This paper describes a near-optimal two-step algorithm that constructs the Reeb graph of a Morse function defined over manifolds in any dimension. The algorithm first identifies the critical points of the input manifold, and then connects these critical points in the second step to obtain the Reeb graph. A simplification mechanism based on topological persistence aids in the removal of noise and unimportant features. A radial layout scheme results in a feature-directed drawing of the Reeb graph. Experimental results demonstrate the efficiency of the Reeb graph construction in practice and its applications.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab2) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab2 was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab2 resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab2, which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab2. It provides evidence that Ab2 is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

On the cubicity of bipartite graphs

A unit cube in k-dimension (or a k-cube) is defined as the Cartesian product R-1 x R-2 x ... x R-k, where each R-i is a closed interval on the real line of the form [a(j), a(i), + 1]. The cubicity of G, denoted as cub(G), is the minimum k such that G is the intersection graph of a collection of k-cubes. Many NP-complete graph problems can be solved efficiently or have good approximation ratios in graphs of low cubicity. In most of these cases the first step is to get a low dimensional cube representation of the given graph. It is known that for graph G, cub(G) <= left perpendicular2n/3right perpendicular. Recently it has been shown that for a graph G, cub(G) >= 4(Delta + 1) In n, where n and Delta are the number of vertices and maximum degree of G, respectively. In this paper, we show that for a bipartite graph G = (A boolean OR B, E) with |A| = n(1), |B| = n2, n(1) <= n(2), and Delta' = min {Delta(A),Delta(B)}, where Delta(A) = max(a is an element of A)d(a) and Delta(B) = max(b is an element of B) d(b), d(a) and d(b) being the degree of a and b in G, respectively , cub(G) <= 2(Delta' + 2) bar left rightln n(2)bar left arrow. We also give an efficient randomized algorithm to construct the cube representation of G in 3 (Delta' + 2) bar right arrowIn n(2)bar left arrow dimension. The reader may note that in general Delta' can be much smaller than Delta.

Cubicity of threshold graphs

We show that the cubicity of a connected threshold graph is equal to inverted right perpendicularlog(2) alpha inverted left perpendicular, where alpha is its independence number.

Characterisation of k-Variegated Graphs, k greater-than-or-equal-to 3

A graph is said to be k-variegated if its vertex set can be partitioned into k equal parts such that each vertex is adjacent to exactly one vertex from every other part not containing it. Bednarek and Sanders [1] posed the problem of characterizing k-variegated graphs. V.N. Bhat-Nayak, S.A. Choudum and R.N. Naik [2] gave the characterization of 2-variegated graphs. In this paper we characterize k-variegated graphs for k greater-or-equal, slanted 3.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab(2)) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab(2) was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab(2) resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab(2), which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab(2). It provides evidence that Ab(2) is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

Representation of functional dependencies in relational databases using linear graphs

Functional dependencies in relational databases are investigated. Eight binary relations, viz., (1) dependency relation, (2) equipotence relation, (3) dissidence relation, (4) completion relation, and dual relations of each of them are described. Any one of these eight relations can be used to represent the functional dependencies in a database. Results from linear graph theory are found helpful in obtaining these representations. The dependency relation directly gives the functional dependencies. The equipotence relation specifies the dependencies in terms of attribute sets which functionally determine each other. The dissidence relation specifies the dependencies in terms of saturated sets in a very indirect way. Completion relation represents the functional dependencies as a function, the range of which turns out to be a lattice. Depletion relation which is the dual of the completion relation can also represent functional dependencies and similarly can the duals of dependency, equipotence, and dissidence relations. The class of depleted sets, which is the dual of saturated sets, is defined and used in the study of depletion relations.