Dobrá díla jsou plodem dobrého charakteru a protože je chvályhodnější příčina než následek, chval více dobrý charakter bez vzdělání než vzdělance bez charakteru.

Leonardo da Vinci

Literatura

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Podívejte se do Langmuir

Cover image by Jessica T. Wen. The coffee ring effect is a common phenomenon where a droplet of colloid solution evaporates on a surface and creates a ring structure. We employ this mechanism as a simple and effective method for biomolecular concentration and combine it with a sensitive aptamer sensing scheme for protein detection. This illustration depicts the detection process. A blood sample is mixed with an aptamer beacon solution and incubated for 30 min. Target proteins in the mixture bind to the aptamer beacons, causing them to fluoresce. A droplet of the mixture is dispensed onto a hydrophobic-treated microscope slide and allowed to dry. The aptamer-protein complexes are concentrated in the coffee ring spots and the resulting fluorescence signal is measured using fluorescent microscopy. Coffee ring-concentrated complexes produce fluorescence signals up to 40 times larger compared to those suspended in liquid droplets. Further, the intensity of the fluorescence signal is proportional to the concentration of protein in the sample. For more information, see “Coffee Ring Aptasensor for Rapid Protein Detection” by Jessica T. Wen, Chih-Ming Ho, and Peter B. Lillehoj on pages 8440–8446 View the article.

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Current Protocols

V rámci řešení projektu MENDELU RESEARCH LIBRARY http://mereli.mendelu.cz/ byl na webových stránkách http://www.mendelu.cz/cz/sluzby_sz/icuk/databaze zpřístupněn nový elektronický informační zdroj a to Wiley Current Protocols
http://onlinelibrary.wiley.com/browse/publications?type=labprotocols. Jedná se o trvalý nákup Current Protocols publikovaných 2013-2017.

Prima ZOOM

Metalothionein information servis (27 T)

Title: Sulfur mustard causes oxidative stress and depletion of antioxidants in muscles, livers, and kidneys of Wistar rats
Author(s): Pohanka, Miroslav; Stetina, Rudolf; Svobodova, Hana; et al.
Source: DRUG AND CHEMICAL TOXICOLOGY Volume: 36 Issue: 3 Pages: 270-276 DOI: 10.3109/01480545.2012.710629 Published: JUL 2013

Title: Dysfunctions of the translational machinery in digestive glands of mussels exposed to mercury ions
Author(s): Pytharopoulou, Sofia; Kournoutou, Georgia G.; Leotsinidis, Michel; et al.
Source: AQUATIC TOXICOLOGY Volume: 134 Pages: 23-33 DOI: 10.1016/j.aquatox.2013.02.014 Published: JUN 15 2013
Mercury is an element naturally occurring in the biosphere, but is also released into the environment by human activities, such as mining, smelting, and industrial discharge. Mercury is a biologically harmful element and any exposure of living organisms mainly due to contamination, can cause severe or even lethal side effects. In every form detected, elemental, inorganic, or organic, mercury exhibits toxicity associated with induced oxidative stress. Although the genotoxicity of mercury has been well demonstrated in mussels, little is known about its toxic effects on the translational machinery at the molecular level. To investigate possible effects, we exposed the common mussel Mytilus galloprovincialis in seawater supplemented by 30 mu g/L Hg2+ for 15 days. We observed that Hg2+ was significantly accumulated in the digestive glands of mussels, reaching a level around 80 mu g/g tissue (dry weight) at the 15th day of exposure. Exposure of mussels to Hg2+ resulted in failure of redox homeostasis, as reflected on lipid peroxidation levels and superoxide dismutase activity in glands, and micronucleus frequency in gills. Extracts from digestive glands after 15-day exposure to Hg2+ exhibited decreased tRNA aminoacylation ability and, moreover, a 70% reduction in the ability of 40S ribosomal subunits to form the 48S initiation ribosomal complex. A similar reduction was detected in the ability of ribosomes to translocate peptidyl-tRNA from the A-site to the P-site, an observation coinciding with the notion that regulation of protein synthesis by Hg2+ mainly occurs at the initiation and elongation stages of translation. A-site binding, peptidyl transferase activity, and termination of peptide chain synthesis underwent less pronounced but measurable reductions, a finding which explains why poly(Phe)-synthesis in ribosomes isolated from exposed mussels is reduced by 70%. In conclusion, Hg2+ apart from being a genotoxic ion acts as a modulator of protein synthesis in mussels, an observation probably related with its ability to induce oxidative stress. (C) 2013 Elsevier B.V. All rights reserved. Accession Number: WOS:000319647800004

Title: Mechanical Ventilation Injury and Repair in Extremely and Very Preterm Lungs
Author(s): Brew, Nadine; Hooper, Stuart B.; Zahra, Valerie; et al.
Source: PLOS ONE Volume: 8 Issue: 5 Article Number: e63905 DOI: 10.1371/journal.pone.0063905 Published: MAY 21 2013
Background: Extremely preterm infants often receive mechanical ventilation (MV), which can contribute to bronchopulmonary dysplasia (BPD). However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood. Aim: To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs.
Methods: Extremely preterm lambs (0.75 of term) were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term) lungs 24 h after MV to assess molecular injury and repair responses.
Results: 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment.
Conclusions: Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm

Title: Effects of Zinc Supplementation on Antioxidant Status and Lipid Peroxidation in Hemodialysis Patients
Author(s): Mazani, Mohammad; Argani, Hassan; Rashtchizadeh, Nadereh; et al.
Source: JOURNAL OF RENAL NUTRITION Volume: 23 Issue: 3 Pages: 180-184 DOI: 10.1053/j.jrn.2012.08.012 Published: MAY 2013
Objectives: This study was designed to determine the effects of zinc supplementation on oxidative stress in hemodialysis (HD) patients through evaluating total antioxidant capacity (TAC), whole blood glutathione peroxidase (GSH) level, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) level.
Design and Setting: Double-blinded randomized controlled trialfrom October 2006 to December 2007 at Tabriz Imam Khomeini Hospital.
Subjects: Sixty-five HD patients were randomly enrolled into 2 groups.
Intervention: Patients received placebo in group A and zinc (100 mg/day) in group B for 2 months. After a washout period for 2 months, the groups were crossed over and the study was continued for an additional 2 months.
Main outcome measures: Serum zinc concentration was measured using atomic absorption spectrophotometry. TAC, GSH level, and SOD activity were determined by commercial enzyme-linked immunosorbent assay kits. MDA level was measured using a thiobarbituric acid method.
Results: The levels of serum zinc, TAC, GSH (P .001 for all), and SOD activity (P .001 for group A and P = .003 for group B) significantly increased after zinc supplementation whereas the serum level of MDA decreased after the same period (P = .003 for group A and P .001 for group B).
Conclusions: Zinc supplementation for 2 months improved the serum levels of zinc, antioxidant status, and lipid peroxidation in HD patients. (c) 2013 by the National Kidney Foundation, Inc. All rights reserved.

Title: The proteomics of heavy metal hyperaccumulation by plants
Author(s): Visioli, Giovanna; Marmiroli, Nelson
Source: JOURNAL OF PROTEOMICS Volume: 79 Pages: 133-145 DOI: 10.1016/j.jprot.2012.12.006 Published: FEB 21 2013

Title: Sulfide ions as modulators of metal-thiolate cluster size in a plant metallothionein
Author(s): Huber, Tamara; Freisinger, Eva
Source: DALTON TRANSACTIONS Volume: 42 Issue: 24 Pages: 8878-8889 DOI: 10.1039/c3dt32438a Published: 2013

Title: Phytase inclusion in pig diets improves zinc status but its effect on copper availability is inconsistent
Author(s): Bikker, P.; van Diepen, J. Th. M.; Binnendijk, G. P.; et al.
Source: JOURNAL OF ANIMAL SCIENCE Volume: 90 Supplement: 4 Pages: 197-199 DOI: 10.2527/jas53907 Published: DEC 2012

Influenza

Title: Effects of the Protonation State of the Catalytic Residues and Ligands Upon Binding and Recognition in Targeted Proteins of HIV-1 and Influenza Viruses
Author(s): Nunthaboot, Nadtanet; Rungrotmongkol, Thanyada; Aruksakunwong, Ornjira; et al.
Source: CURRENT PHARMACEUTICAL DESIGN Volume: 19 Issue: 23 Pages: 4276-4290 Published: JUL 2013

Title: Identification of the first synthetic inhibitors of the type II transmembrane serine protease IMPRSS2 suitable for inhibition of influenza virus activation
Author(s): Meyer, Daniela; Sielaff, Frank; Hammami, Maya; et al.
Source: BIOCHEMICAL JOURNAL Volume: 452 Pages: 331-343 DOI: 10.1042/BJ20130101 Part: 2 Published: JUN 1 2013
TMPRSS2 (transmembrane serine proteinase 2) is a multidomain type II transmembrane senile protease that cleaves the surface glycoprotein HA (haemagglutinin) of influenza viruses with a monobasic cleavage site, which is a prerequisite for virus fusion and propagation. Furthermore, it, activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS-CoV (severe acute respiratory syndrome coronavirus). Increased TMPRSS2 expression was also described in several tumour entities. Therefore TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in Escherichia coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases. Two inhibitor types were identified which inhibit TMPRSS2 in the nanomolar range. The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety at the P1 position, whereby some of these analogues possess inhibition constants of approximately 20 nM. An improved potency was found for a second type derived from sulfonylated 3-amindinophenylalanylamide derivatives. The most potent derivative of this series inhibits TMPRSS2 with a K-i value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. On the basis of the inhibitor studies, a series of new fluorogenic substrates containing a D-arginine residue at the P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.

Title: Heterogeneity in antibody range and the antigenic drift of influenza A viruses
Author(s): Parisi, Andrea; Lopes, Joao S.; Nunes, Ana; et al.
Source: ECOLOGICAL COMPLEXITY Volume: 14 Special Issue: SI Pages: 157-165 DOI: 10.1016/j.ecocom.2012.12.001 Published: JUN 2013
In this paper we explore the consequences of a heterogeneous immune response in individuals on the evolution of a rapidly mutating virus. We show that several features of the incidence and phylogenetic patterns typical of influenza A may be understood in this framework. In our model, limited diversity and rapid drift of the circulating viral strains result from the interplay of two interacting subpopulations with different types of immune response, narrow or broad, upon infection. The subpopulation with the narrow immune response acts as a reservoir where consecutive mutations escape immunity and can persist. Strains with a number of accumulated mutations escape immunity in the other subpopulation as well, causing larger epidemic peaks in the whole population, and reducing strain diversity. Overall, our model produces a modulation of epidemic peak heights and patterns of antigenic drift consistent with reported observations, suggesting an underlying mechanism for the evolutionary epidemiology of influenza, in particular, and other infectious diseases, more generally. (C) 2013 Elsevier B.V. All rights reserved.

Title: Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells
Author(s): Khare, Drirh; Godbole, Nachiket M.; Pawar, Shailesh D.; et al.
Source: EUROPEAN JOURNAL OF NUTRITION Volume: 52 Issue: 4 Pages: 1405-1415 DOI: 10.1007/s00394-012-0449-7 Published: JUN 2013
Influenza viruses infect airway epithelial cells, causing respiratory distress. Immune defense is maintained by chemokine/cytokine secretions from airway epithelial cells. While moderate inflammatory response protects from ill effects, hyper-inflammatory response promotes the pathogenesis. High circulating levels of vitamin D are known to mitigate effects of infectious diseases, including respiratory infectious diseases. The question whether and how vitamin D treatment pre-/post-viral exposure modulates inflammatory response is not clear. The present study was undertaken to understand autophagy/apoptosis balance and chemokine/cytokine response to influenza A (H1N1) infection by pre- and post-1, 25-dihydroxyvitamin D3 (1,25[OH]2 D3)[calcitriol] treatment of human lung A549 epithelial cells.
Influenza A (H1N1) virus was propagated in A549 cell line, titrated using hemagglutination assay, and was used to assess effect of calcitriol. After confirming that 100 nM of calcitriol fails to clear virus, A549 cells were either pre-treated (16 h) with 100 nM or post-treated with 30 nM of 1,25[OH]2 D3 of virus inoculation (1 h). Cells after incubation at 37 A degrees C under 5 % CO2 for 48 h were collected and subjected to RNA and protein extraction. Measurements of viability, influenza M protein, and molecular parameters of cell death and inflammatory response were performed.
We report that treatment of these cells with 100/30 nM of 1,25[OH]2 D3 prior to/or post-H1N1 exposure does not affect viral clearance but significantly reduces autophagy and restores increased apoptosis seen on H1N1 infection back to its constitutive level. However, it significantly decreases the levels of H1N1-induced TNF-alpha (tumor necrosis factor-alpha), IFN-beta (interferon-beta), and IFN-stimulated gene-15 (ISG15). 1,25[OH]2 D3 treatment prior to/or post-H1N1 infection significantly down-regulates IL-8 as well as IL-6 RNA levels. These results demonstrate that calcitriol treatment suppresses the H1N1-induced transcription of the chemokines RANTES and IL-8 in epithelial cells.
The findings provide support for the initiation of vitamin D supplementation program to VDD populations in reducing the severity of influenza.

Title: Replication and Immunogenicity of Swine, Equine, and Avian H3 Subtype Influenza Viruses in Mice and Ferrets
Author(s): Baz, Mariana; Paskel, Myeisha; Matsuoka, Yumiko; et al.
Source: JOURNAL OF VIROLOGY Volume: 87 Issue: 12 Pages: 6901-6910 DOI: 10.1128/JVI.03520-12 Published: JUN 2013
Abstract: Interleukin-22 (IL-22) has redundant, protective, or pathogenic functions during autoimmune, inflammatory, and infectious diseases. Here, we addressed the potential role of IL-22 in host defense and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that retinoic acid receptor-related orphan receptor-gamma t (ROR gamma t)-positive alpha beta and gamma delta T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as 2 days postinfection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22-deficient animals had enhanced lung injuries and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection, where it limits lung inflammation and subsequent bacterial superinfections.

Title: Interleukin-22 Reduces Lung Inflammation during Influenza A Virus Infection and Protects against Secondary Bacterial Infection
Author(s): Ivanov, Stoyan; Renneson, Joelle; Fontaine, Josette; et al.
Source: JOURNAL OF VIROLOGY Volume: 87 Issue: 12 Pages: 6911-6924 DOI: 10.1128/JVI.02943-12 Published: JUN 2013
Abstract: Interleukin-22 (IL-22) has redundant, protective, or pathogenic functions during autoimmune, inflammatory, and infectious diseases. Here, we addressed the potential role of IL-22 in host defense and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that retinoic acid receptor-related orphan receptor-gamma t (ROR gamma t)-positive alpha beta and gamma delta T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as 2 days postinfection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22-deficient animals had enhanced lung injuries and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection, where it limits lung inflammation and subsequent bacterial superinfections. Accession Number: WOS:000319508600035

Title: Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1
Author(s): Kallfass, Carsten; Lienenklaus, Stefan; Weiss, Siegfried; et al.
Source: JOURNAL OF VIROLOGY Volume: 87 Issue: 12 Pages: 6925-6930 DOI: 10.1128/JVI.00283-13 Published: JUN 2013
Abstract: The innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-beta-coding region. IFN-beta-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-beta responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c(+) cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-beta at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.

Title: Structure of a Classical Broadly Neutralizing Stem Antibody in Complex with a Pandemic H2 Influenza Virus Hemagglutinin
Author(s): Dreyfus, Cyrille; Ekiert, Damian C.; Wilson, Ian A.
Source: JOURNAL OF VIROLOGY Volume: 87 Issue: 12 Pages: 7149-7154 DOI: 10.1128/JVI.02975-12 Published: JUN 2013
Abstract: We report the structural characterization of the first antibody identified to cross-neutralize multiple subtypes of influenza A viruses. The crystal structure of mouse antibody C179 bound to the pandemic 1957 H2N2 hemagglutinin (HA) reveals that it targets an epitope on the HA stem similar to those targeted by the recently identified human broadly neutralizing antibodies. C179 also inhibits the low-pH conformational change of the HA but uses a different angle of approach and both heavy and light chains.

Title: Transduction of Ferret Airways with Avian Influenza Virus Hemagglutinin Pseudotyped Equine Infectious Anemia Virus Vector
Author(s): Yan, Ziying; Patel, Manij; Sun, Xingshen; et al.
Conference: 16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) Location: Salt Lake City, UT Date: MAY 15-18, 2013
Sponsor(s): Amer Soc Gene & Cell Therapy (ASGCT)
Source: MOLECULAR THERAPY Volume: 21 Supplement: 1 Pages: S206-S206 Meeting Abstract: 535 Published: JUN 2013

Title: Glycosylations in the Globular Head of the Hemagglutinin Protein Modulate the Virulence and Antigenic Properties of the H1N1 Influenza Viruses
Author(s): Medina, Rafael A.; Stertz, Silke; Manicassamy, Balaji; et al.
Source: SCIENCE TRANSLATIONAL MEDICINE Volume: 5 Issue: 187 Article Number: 187ra70 DOI: 10.1126/scitranslmed.3005996 Published: MAY 29 2013 Abstract: With the global spread of the 2009 pandemic H1N1 (pH1N1) influenza virus, there are increasing worries about evolution through antigenic drift. One way previous seasonal H1N1 and H3N2 influenza strains have evolved over time is by acquiring additional glycosylations in the globular head of their hemagglutinin (HA) proteins; these glycosylations have been believed to shield antigenically relevant regions from antibody immune responses. We added additional HA glycosylation sites to influenza A/Netherlands/602/2009 recombinant (rpH1N1) viruses, reflecting their temporal appearance in previous seasonal H1N1 viruses. Additional glycosylations resulted in substantially attenuated infection in mice and ferrets, whereas deleting HA glycosylation sites from a pre-pandemic virus resulted in increased pathogenicity in mice. We then more directly investigated the interactions of HA glycosylations and antibody responses through mutational analysis. We found that the polyclonal antibody response elicited by wild-type rpH1N1 HA was likely directed against an immunodominant region, which could be shielded by glycosylation at position 144. However, rpH1N1 HA glycosylated at position 144 elicited a broader polyclonal response able to cross-neutralize all wild-type and glycosylation mutant pH1N1 viruses. Moreover, mice infected with a recent seasonal virus in which glycosylation sites were removed elicited antibodies that protected against challenge with the antigenically distant pH1N1 virus. Thus, acquisition of glycosylation sites in the HA of H1N1 human influenza viruses affected not only their pathogenicity and ability to escape from polyclonal antibodies elicited by previous influenza virus strains but also their ability to induce cross-reactive antibodies against drifted antigenic variants.

Title: Structural Comparison of the Wild-Type and Drug-Resistant Mutants of the Influenza A M2 Proton Channel by Molecular Dynamics Simulations
Author(s): Gu, Ruo-Xu; Liu, Limin Angela; Wang, Yong-Hua; et al.
Source: JOURNAL OF PHYSICAL CHEMISTRY B Volume: 117 Issue: 20 Pages: 6042-6051 DOI: 10.1021/jp312396q Published: MAY 23 2013
Abstract: The influenza A M2 channel in the viral envelope is a pH-regulated proton channel that is crucial for viral infection and replication. Amantadine and rimantadine are two M2 inhibitors that have been widely used as anti-influenza drugs. However, due to naturally occurring drug-resistant mutations, their inhibition ability has gradually decreased. These drug-resistant mutations are found at various positions on the transmembrane domain of the M2 protein and could be categorized to three types: mutations close to the drug-binding site located at the pore-facing positions (V27A, A30T, S31N, and G34E); mutations at the interhelical interfaces at the N-terminal half of the channel (L26F); and mutations outside the drug-binding site lying at the interhelical interfaces (L38F, D44A). Investigating the structures and the M2-inhibitor interactions of these mutants would illuminate drug inhibition and drug resistance mechanisms and guide the design of novel anti influenza drugs targeting these drug-resistant mutants. In this study, we chose four mutations at different positions (V27A, S31N, L26F, L38F) and conducted molecular dynamics simulations on both the apo-form and the drug-bound forms. The protein structures as well as the water structure in the channel pore were analyzed. Stable water clusters facilitating drug binding were found. Both the protein pore radius profiles and the structure of the water clusters were sensitive to the mutations. Based on our simulations, we compared the structures of the mutated proteins and proposed possible mechanisms for drug resistance of these mutations.

Title: Sequence-Specific and Visual Identification of the Influenza Virus NS Gene by Azobenzene-Tethered Bis-Peptide Nucleic Acid
Author(s): Kaihatsu, Kunihiro; Sawada, Shinjiro; Nakamura, Shota; et al.
Source: PLOS ONE Volume: 8 Issue: 5 Article Number: e64017 DOI: 10.1371/journal.pone.0064017 Published: MAY 21 2013
Abstract: To rapidly and specifically identify highly virulent influenza virus strains, we prepared an azobenzene-tethered hairpin-type peptide nucleic acid, bisPNA-AZO, which has a complementary sequence against a highly conserved genomic RNA sequence within the ribonucleoprotein complex of the 2009 pandemic influenza A virus, H1N1 subtype. bisPNA-AZO recognizes the conserved virus genome sequence in a sequence-specific manner. Immobilization of bisPNA-AZO on a plate allowed capture of the target virus gene and the generation of a visual colour signal.

Title: The Influenza Virus Protein PB1-F2 Interacts with IKK beta and Modulates NF-kappa B Signalling
Author(s): Reis, Ana Luisa; McCauley, John W.
Source: PLOS ONE Volume: 8 Issue: 5 Article Number: UNSP e63852 DOI: 10.1371/journal.pone.0063852 Published: MAY 21 2013
Abstract: PB1-F2, a protein encoded by a second open reading frame of the influenza virus RNA segment 2, has emerged as a modulator of lung inflammatory responses but the molecular mechanisms underlying this are only poorly understood. Here we show that PB1-F2 inhibits the activation of NF-kappa B dependent signalling pathways in luciferase reporter assays. PB1-F2 proteins from four different viruses interact with IKK beta in yeast two-hybrid assays and by co-immunoprecipitation. PB1-F2 expression did not inhibit IKK beta kinase activity or NF-kappa B translocation into the nucleus, but NF-kappa B binding to DNA was severely impaired in PB1-F2 transfected cells as assessed by Electrophoretic Mobility Shift Assay. Neither the N-terminal 57 amino acid truncated forms nor the C-terminus of PB1-F2 were able to inhibit NF-kB dependent signalling, indicating that the full length protein is necessary for the inhibition.

Title: Phosphorylation Drives an Apoptotic Protein to Activate Antiapoptotic Genes PARADIGM OF INFLUENZA A MATRIX 1 PROTEIN FUNCTION
Author(s): Halder, Umesh Chandra; Bhowmick, Rahul; Mukherjee, Tapasi Roy; et al.
Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 288 Issue: 20 Pages: 14554-14568 DOI: 10.1074/jbc.M112.447086 Published: MAY 17 2013
Abstract: During infection, viral proteins target cellular pathways that regulate cellular innate immune responses and cell death. We demonstrate that influenza A virus matrix 1 protein (M1), an established proapoptotic protein, activates nuclear factor-kappa B member RelB-mediated survival genes (cIAP1, cIAP2, and cFLIP), a function that is linked with its nuclear translocation during early infection. Death domain-associated protein 6 (Daxx) is a transcription co-repressor of the RelB-responsive gene promoters. During influenza virus infection M1 binds to and stabilizes Daxx protein by preventing its ubiquitination and proteasomal degradation. Binding of M1 with Daxx through its Daxx binding motif prevents binding of RelB and Daxx, resulting in up-regulation of survival genes. This interaction also prevents promoter recruitment of DNA methyltransferases (Dnmt1 and Dnmt3a) and lowers CpG methylation of the survival gene promoters, leading to the activation of these genes. Thus, M1 prevents repressional function of Daxx during infection, thereby exerting a survival role. In addition to its nuclear localization signal, translocation of M1 to the nucleus depends on cellular kinase-mediated phosphorylation as the protein kinase C inhibitor calphostin C effectively down-regulates virus replication. The study reconciles the ambiguity of dual antagonistic function of viral protein and potentiates a possible target to limit virus infection.

Title: Effect of avian influenza A H5N1 infection on the expression of microRNA-141 in human respiratory epithelial cells
Author(s): Lam, Wai-Yip; Yeung, Apple Chung-Man; Ngai, Karry Lei-Ka; et al.
Source: BMC MICROBIOLOGY Volume: 13 Article Number: 104 DOI: 10.1186/1471-2180-13-104 Published: MAY 10 2013
Abstract: Background: Avian influenza remains a serious threat to human health. The consequence of human infection varies markedly among different subtypes of avian influenza viruses. In addition to viral factors, the difference in host cellular response is likely to play a critical role. This study aims at elucidating how avian influenza infection perturbs the host's miRNA regulatory pathways that may lead to adverse pathological events, such as cytokine storm, using the miRNA microarray approach.
Results: The results showed that dysregulation of miRNA expression was mainly observed in highly pathogenic avian influenza A H5N1 infection. We found that miR-21*, miR-100*, miR-141, miR-574-3p, miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection. Interestingly, we demonstrated that miR-141, which was more highly induced by H5N1 than by H1N1 (p 0.05), had an ability to suppress the expression of a cytokine - transforming growth factor (TGF)-beta 2. This was supported by the observation that the inhibitory effect could be reversed by antagomiR-141.
Conclusions: Since TGF-beta 2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules, and previous report showed that only seasonal influenza H1N1 (but not the other avian influenza subtypes) could induce a persistent expression of TGF-beta 2, we speculate that the modulation of TGF-beta 2 expression by different influenza subtypes via miR-141 might be a critical step for determining the outcome of either normal or excessive inflammation progression.

Title: Influenza virus resistance to neuraminidase inhibitors
Author(s): Samson, Melanie; Pizzorno, Andres; Abed, Yacine; et al.
Source: ANTIVIRAL RESEARCH Volume: 98 Issue: 2 Pages: 174-185 DOI: 10.1016/j.antiviral.2013.03.014 Published: MAY 2013
Abstract: In addition to immunization programs, antiviral agents can play a major role for the control of seasonal influenza epidemics and may also provide prophylactic and therapeutic benefits during an eventual pandemic. The purpose of this article is to review the mechanism of action, pharmacokinetics and clinical indications of neuraminidase inhibitors (NAIs) with an emphasis on the emergence of antiviral drug resistance. There are two approved NAIs compounds in US: inhaled zanamivir and oral oseltamivir, which have been commercially available since 1999-2000. In addition, two other NAIs, peramivir (an intravenous cyclopentane derivative) and laninamivir (a long-acting NAI administered by a single nasal inhalation) have been approved in certain countries and are under clinical evaluations in others. As for other antivirals, the development and dissemination of drug resistance is a significant threat to the clinical utility of NAIs. The emergence and worldwide spread of oseltamivir-resistant seasonal A(H1N1) viruses during the 2007-2009 seasons emphasize the need for continuous monitoring of antiviral drug susceptibilities. Further research priorities should include a better understanding of the mechanisms of resistance to existing antivirals, the development of novel compounds which target viral or host proteins and the evaluation of combination therapies for improved treatment of severe influenza infections, particularly in immunocompromised individuals. This article forms part of a symposium in Antiviral Research on "Treatment of influenza: targeting the virus or the host." (C) 2013 Elsevier B.V. All rights reserved.

Title: Combination of MEK inhibitors and oseltamivir leads to synergistic antiviral effects after influenza A virus infection in vitro
Author(s): Haasbach, Emanuel; Hartmayer, Carmen; Planz, Oliver
Source: ANTIVIRAL RESEARCH Volume: 98 Issue: 2 Pages: 319-324 DOI: 10.1016/j.antiviral.2013.03.006 Published: MAY 2013

Title: Sublingual administration of Lactobacillus rhamnosus affects respiratory immune responses and facilitates protection against influenza virus infection in mice
Author(s): Lee, Yu-Na; Youn, Ha-Na; Kwon, Jung-Hoon; et al.
Source: ANTIVIRAL RESEARCH Volume: 98 Issue: 2 Pages: 284-290 DOI: 10.1016/j.antiviral.2013.03.013 Published: MAY 2013

Title: Host Restrictions of Avian Influenza Viruses: In Silico Analysis of H13 and H16 Specific Signatures in the Internal Proteins
Author(s): Tonnessen, Ragnhild; Hauge, Anna G.; Hansen, Elisabeth F.; et al.
Source: PLOS ONE Volume: 8 Issue: 4 Article Number: UNSP e63270 DOI: 10.1371/journal.pone.0063270 Published: APR 30 2013

Title: Broadly Protective Adenovirus-Based Multivalent Vaccines against Highly Pathogenic Avian Influenza Viruses for Pandemic Preparedness
Author(s): Vemula, Sai V.; Ahi, Yadvinder S.; Swaim, Anne-Marie; et al.
Source: PLOS ONE Volume: 8 Issue: 4 Article Number: UNSP e62496 DOI: 10.1371/journal.pone.0062496 Published: APR 30 2013

Title: Effectiveness of MF59 (TM) Adjuvanted Influenza A(H1N1)pdm09 Vaccine in Risk Groups in the Netherlands
Author(s): Wijnans, Leonoor; Dieleman, Jeanne; Voordouw, Bettie; et al.
Source: PLOS ONE Volume: 8 Issue: 4 Article Number: e63156 DOI: 10.1371/journal.pone.0063156 Published: APR 30 2013

Title: Isolation of Recombinant Phage Antibodies Targeting the Hemagglutinin Cleavage Site of Highly Pathogenic Avian Influenza Virus
Author(s): Dong, Jinhua; Sakurai, Akira; Nomura, Namiko; et al.
Source: PLOS ONE Volume: 8 Issue: 4 Article Number: e61158 DOI: 10.1371/journal.pone.0061158 Published: APR 5 2013

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