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Most Cited Antiviral Research Articles
The most cited articles published since 2011, extracted from Scopus.
Favipiravir (T-705), a novel viral RNA polymerase inhibitorYousuke Furuta | Brian B. Gowen | Kazumi Takahashi | Kimiyasu Shiraki | Donald F. Smee | Dale L. Barnard
Volume 100, Issue 2, October 2013, Pages 446-454
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5′-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies. © 2013 Elsevier B.V. All rights reserved.
Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal modelLisa Oestereich | Anja Lüdtke | Stephanie Wurr | Toni Rieger | César Muñoz-Fontela | Stephan Günther
Volume 105, Issue 1, January 2014, Pages 17-21
Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are associated with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide derivative T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4 log units with an IC90 of 110 μM. Mice lacking the type I interferon receptor (IFNAR-/-) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochemical parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever. © 2014 The Authors. Published by Elsevier B.V.
Influenza virus resistance to neuraminidase inhibitorsMélanie Samson | Andrés Pizzorno | Yacine Abed | Guy Boivin
Volume 98, Issue 2, May 2013, Pages 174-185
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". © 2013 Elsevier B.V.
Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversityDennis A. Bente | Naomi L. Forrester | Douglas M. Watts | Alexander J. McAuley | Chris A. Whitehouse | Mike Bray
Volume 100, Issue 1, September 2013, Pages 159-189
Crimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case numbers, case fatality rates and all CCHFV strains on GenBank. © 2013 Elsevier B.V. All rights reserved.
Chikungunya fever: Epidemiology, clinical syndrome, pathogenesis and therapySimon Djamel Thiberville | Nanikaly Moyen | Laurence Dupuis-Maguiraga | Antoine Nougairede | Ernest A. Gould | Pierre Roques | Xavier de Lamballerie
Volume 99, Issue 3, September 2013, Pages 345-370
Chikungunya virus (CHIKV) is the aetiological agent of the mosquito-borne disease chikungunya fever, a debilitating arthritic disease that, during the past 7. years, has caused immeasurable morbidity and some mortality in humans, including newborn babies, following its emergence and dispersal out of Africa to the Indian Ocean islands and Asia. Since the first reports of its existence in Africa in the 1950s, more than 1500 scientific publications on the different aspects of the disease and its causative agent have been produced. Analysis of these publications shows that, following a number of studies in the 1960s and 1970s, and in the absence of autochthonous cases in developed countries, the interest of the scientific community remained low. However, in 2005 chikungunya fever unexpectedly re-emerged in the form of devastating epidemics in and around the Indian Ocean. These outbreaks were associated with mutations in the viral genome that facilitated the replication of the virus in Aedes albopictus mosquitoes. Since then, nearly 1000 publications on chikungunya fever have been referenced in the PubMed database. This article provides a comprehensive review of chikungunya fever and CHIKV, including clinical data, epidemiological reports, therapeutic aspects and data relating to animal models for in vivo laboratory studies. It includes Supplementary Tables of all WHO outbreak bulletins, ProMED Mail alerts, viral sequences available on GenBank, and PubMed reports of clinical cases and seroprevalence studies. © 2013 Elsevier B.V.
Ten years of dengue drug discovery: Progress and prospectsSiew Pheng Lim | Qing Yin Wang | Christian G. Noble | Yen Liang Chen | Hongping Dong | Bin Zou | Fumiaki Yokokawa | Shahul Nilar | Paul Smith | David Beer | Julien Lescar | Pei Yong Shi
Volume 100, Issue 2, October 2013, Pages 500-519
To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the Singapore Economic Development Board. One of NITD's missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we review the progress in dengue drug discovery made at NITD as well as the major discoveries made by academia and other companies. Four strategies have been pursued to identify inhibitors of DENV through targeting both viral and host proteins: (i) HTS (high-throughput screening) using virus replication assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along the developmental process from hit finding to clinical candidate, many inhibitors did not advance beyond the stage of hit-to-lead optimization, due to their poor selectivity, physiochemical or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs, NITD-008 and Balapiravir, entered preclinical animal safety study and clinic trial, but both were terminated due to toxicity and lack of potency, respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under clinical trial; its clinical efficacy remains to be determined. The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery. Though challenging, we are optimistic that this continuous, concerted effort will lead to an effective dengue therapy. © 2013 Elsevier B.V. All rights reserved.
The flavivirus NS1 protein: Molecular and structural biology, immunology, role inpathogenesis and application asadiagnostic biomarker.David A. Muller | Paul R. Young
Volume 98, Issue 2, April 2013, Pages 192-208
The flavivirus nonstructural glycoprote in NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since i twas first reported in 1970 as a viral antigen cir- culating in the sera ofdengue-infected patients.All flavivirus NS1 genes share ahigh degree ofhomology, encoding a352-amino- acid polypeptide that has amolecular weight of46-55kDa,depending on its gly- cosylat ion status.NS1 exists in multiple oligomeric forms and isfound indifferent cellular locations:a cell membrane-bound form inassociation wit hvirus-induced intracellular vesicular compartments,on the cell surface and asasoluble secreted hexameric lipoparticl e.Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays anessential cofactor role in rep- lication. Although this makes NS1 anideal target for inhibitor design,the precise nature ofits cofactor function has yet to be elucidated.Aplethora of potential interacting partners have been identified,par- ticularly for the secreted form ofNS1,with many being implicated in immune evasion strategies. Secreted and cell-surface-assoc iated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host.Finally,NS1 is also an important biomarker for early diagnosis of disease.In this article,we provide an overview of these some what disparate areas of research,drawing together the wealth of data generated over more than 40years of study of this fascinating protein. © 2013 Elsevier B.V. All rights reserved.
Post-exposure efficacy of Oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse modelSophie J. Smither | Lin S. Eastaugh | Jackie A. Steward | Michelle Nelson | Robert P. Lenk | Mark S. Lever
Volume 104, Issue 1, April 2014, Pages 153-155
Filoviruses cause disease with high case fatality rates and are considered biological threat agents. Licensed post-exposure therapies that can be administered by the oral route are desired for safe and rapid distribution and uptake in the event of exposure or outbreaks. Favipiravir or T-705 has broad antiviral activity and has already undergone phase II and is undergoing phase III clinical trials for influenza. Here we report the first use of T-705 against Ebola virus. T-705 gave 100% protection against aerosol Ebola virus E718 infection; protection was shown in immune-deficient mice after 14 days of twice-daily dosing. T-705 was also shown to inhibit Ebola virus infection in cell culture. T-705 is likely to be licensed for use against influenza in the near future and could also be used with a new indication for filovirus infection. © 2014 Elsevier B.V. All rights reserved.
Update on hepatitis C virus resistance to direct-acting antiviral agentsEva Poveda | David L. Wyles | Álvaro Mena | José D. Pedreira | Ángeles Castro-Iglesias | Edward Cachay
Volume 108, Issue 1, January 2014, Pages 181-191
Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g.; genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19-48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6-12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e.; null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study. © 2014 Elsevier B.V. All rights reserved.
Molecular basis of human immunodeficiency virus type 1 drug resistance: Overview and recent developmentsLuis Menéndez-Arias
Volume 98, Issue 1, April 2013, Pages 93-120
The introduction of potent combination therapies in the mid-90s had a tremendous effect on AIDS mortality. However, drug resistance has been a major factor contributing to antiretroviral therapy failure. Currently, there are 26 drugs approved for treating human immunodeficiency virus (HIV) infections, although some of them are no longer prescribed. Most of the available antiretroviral drugs target HIV genome replication (i.e. reverse transcriptase inhibitors) and viral maturation (i.e. viral protease inhibitors). Other drugs in clinical use include a viral coreceptor antagonist (maraviroc), a fusion inhibitor (enfuvirtide) and two viral integrase inhibitors (raltegravir and elvitegravir). Elvitegravir and the nonnucleoside reverse transcriptase inhibitor rilpivirine have been the most recent additions to the antiretroviral drug armamentarium. An overview of the molecular mechanisms involved in antiretroviral drug resistance and the role of drug resistance-associated mutations was previously presented (Menéndez-Arias, L., 2010. Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res. 85, 210-231). This article provides now an updated review that covers currently approved drugs, new experimental agents (e.g. neutralizing antibodies) and selected drugs in preclinical or early clinical development (e.g. experimental integrase inhibitors). Special attention is dedicated to recent research on resistance to reverse transcriptase and integrase inhibitors. In addition, recently discovered interactions between HIV and host proteins and novel strategies to block HIV assembly or viral entry emerge as promising alternatives for the development of effective antiretroviral treatments. © 2013 Elsevier B.V.
Antiviral therapy of hepatitis C in 2014: Do we need resistance testing?Maximilian David Schneider | Christoph Sarrazin
Volume 105, Issue 1, January 2014, Pages 64-71
The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1-3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9-48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4-64 weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." © 2014 Elsevier B.V. All rights reserved.
The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1Vanessa Pirrone | Brian Wigdahl | Fred C. Krebs
Volume 90, Issue 3, June 2011, Pages 168-182
Infection by the human immunodeficiency virus type 1 (HIV-1) is an ordered, multistep process involving binding and entry, reverse transcription, integration, viral gene transcription, translation, processing, and finally assembly. Numerous therapeutic and preventive compounds, which are currently available for clinical use or are under preclinical and clinical development, act on at least one of these steps. Polyanionic HIV-1 inhibitors comprise a family of compounds that are generally considered entry inhibitors. The main mechanism of anti-HIV-1 activity associated with these compounds involves electrostatic interactions with HIV-1 glycoprotein 120 that ultimately prevent binding of the virus to target cells. A number of these compounds have been considered for systemic use and for use as microbicides, which are products designed to prevent sexual HIV-1 transmission. These compounds have been studied extensively using in vitro assays of activity, cytotoxicity, and mechanism of action, ex vivo models of HIV-1 transmission, and animal models of in vivo efficacy and toxicity. Three of these polyanionic compounds - cellulose sulfate, carrageenan, and PRO 2000 - were advanced into clinical trials of microbicide safety and efficacy. Although phase I and phase II clinical trials showed these compounds to be safe and well tolerated, none of the phase III trials provided any evidence that these compounds were effective against heterosexual HIV-1 transmission. Furthermore, clinical and in vitro results suggest enhancement of HIV-1 infection in the presence of polyanionic compounds. We discuss the preclinical development of polyanionic HIV-1 inhibitors, the clinical trials of polyanionic compounds used systemically and as topical vaginal microbicides, and the prospects for the future development of these compounds as inhibitors of HIV-1 infection. © 2011 Elsevier B.V.
Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse modelAbhay P S Rathore | Prasad N. Paradkar | Satoru Watanabe | Kah Hin Tan | Cynthia Sung | John E. Connolly | Jenny Low | Eng Eong Ooi | Subhash G. Vasudevan
Volume 92, Issue 3, December 2011, Pages 453-460
Dengue virus (DENV) infections continue to spread aggressively around the world. Here we demonstrate that celgosivir (6-O-butanoyl castanospermine), strongly inhibits all four DENV serotypes. We show by fluorescence microscopy that the antiviral mechanism of celgosivir, is in part, due to misfolding and accumulation of DENV non-structural protein 1 (NS1) in the endoplasmic reticulum. Moreover, celgosivir modulates the host's unfolded protein response (UPR) for its antiviral action. Significantly, celgosivir is effective in lethal challenge mouse models that recapitulate primary or secondary antibody-dependent enhanced DENV infection. Celgosivir treated mice showed enhanced survival, reduced viremia and robust immune response, as reflected by serum cytokine analysis. Importantly, survival increased even after treatment was delayed till 2. days post-infection. Together the present study suggests that celgosivir, which has been clinically determined to be safe in humans, may be a valuable candidate for clinical testing in dengue patients. © 2011 Elsevier B.V.
Schmallenberg virus: A new Shamonda/Sathuperi-like virus on the rise in EuropeMutien Marie Garigliany | Calixte Bayrou | Déborah Kleijnen | Dominique Cassart | Sandra Jolly | Annick Linden | Daniel Desmecht
Volume 95, Issue 2, August 2012, Pages 82-87
In the summer-fall of 2011, a nonspecific febrile syndrome characterized by hyperthermia, drop in milk production and watery diarrhea was reported in adult dairy cows from a series of farms located in North-West Europe. Further, in November 2011, an enzootic outbreak of abortion, stillbirth and birth at term of lambs, kids and calves with neurologic signs and/or head, spine or limb malformations emerged throughout several European countries. Both syndromes were associated with the presence in the blood (adults) or in the central nervous system (newborns) of the genome of a new Shamonda-Sathuperi reassortant orthobunyavirus provisionally named Schmallenberg virus after the place where the first positive samples were collected. The clinical, pathological, virological and epidemiological facts that were made publicly available during the first 6. months after the emergence are presented here. Current knowledge of the epidemiology of the phylogenetically closest relatives of the newcomer (Shamonda, Sathuperi, Aino and Akabane viruses) is not exhaustive enough to predict whether the current outbreak of Schmallenberg virus is the prelude to endemicity or to a 2. years long outbreak before the infection burns out when serologically naïve animals are no longer available. In the future, cyclic epizootic reemergences are a possibility too, either synchronized with a global decrease of herd immunity or due to antigenic variants escaping the immunity acquired against their predecessors. The latter hypothesis seems unlikely because of the wide array of biologic constraints acting on the genome of viruses whose life cycle requires transmission by a vector, which represses genetic drift. The remarkable stability of the Shamonda virus genome over the last forty years is reassuring in this regard. © 2012 Elsevier B.V..
Myxomatosis in Australia and Europe: A model for emerging infectious diseasesPeter J. Kerr
Volume 93, Issue 3, March 2012, Pages 387-415
Myxoma virus is a poxvirus naturally found in two American leporid (rabbit) species (Sylvilagus brasiliensis and Sylvilagus bachmani) in which it causes an innocuous localised cutaneous fibroma. However, in European rabbits (Oryctolagus cuniculus) the same virus causes the lethal disseminated disease myxomatosis. The introduction of myxoma virus into the European rabbit population in Australia in 1950 initiated the best known example of what happens when a novel pathogen jumps into a completely naïve new mammalian host species. The short generation time of the rabbit and their vast numbers in Australia meant evolution could be studied in real time. The carefully documented emergence of attenuated strains of virus that were more effectively transmitted by the mosquito vector and the subsequent selection of rabbits with genetic resistance to myxomatosis is the paradigm for pathogen virulence and host-pathogen coevolution. This natural experiment was repeated with the release of a separate strain of myxoma virus in France in 1952. The subsequent spread of the virus throughout Europe and its coevolution with the rabbit essentially paralleled what occurred in Australia. Detailed molecular studies on myxoma virus have dissected the role of virulence genes in the pathogenesis of myxomatosis and when combined with genomic data and reverse genetics should in future enable the understanding of the molecular evolution of the virus as it adapted to its new host. This review describes the natural history and evolution of myxoma virus together with the molecular biology and experimental pathogenesis studies that are informing our understanding of evolution of emerging diseases. © 2012.
In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutantIlenia Delogu | Boris Pastorino | Cécile Baronti | Antoine Nougairède | Emilie Bonnet | Xavier de Lamballerie
Volume 90, Issue 3, June 2011, Pages 99-107
Arbidol (ARB) is an antiviral drug originally licensed in Russia for use against influenza and other respiratory viral infections. Although a broad-spectrum antiviral activity has been reported for this drug, there is until now no data regarding its effects against alphavirus infection. Here, the in vitro antiviral effect of ARB on Chikungunya virus (CHIKV) replication was investigated and this compound was found to present potent inhibitory activity against the virus propagated onto immortalized Vero cells or primary human fibroblasts (MRC-5 lung cells) (IC50<10μg/ml). A CHIKV resistant mutant was then selected and adapted to growth in the presence of 30μg/ml ARB in MRC5 cells; its complete sequence analysis revealed a single amino acid substitution (G407R) localized in the E2 envelope protein. To confirm the G407R role in the molecular mechanism of ARB resistance, a CHIKV infectious clone harboring the same substitution was engineered, tested, and was found to display a similar level of resistance. Finally, our results demonstrated the effective in vitro antiviral activity of ARB against CHIKV and gave some tracks to understand the molecular basis of ARB activity. © 2011 Elsevier B.V.
Virostatic potential of micro-nano filopodia-like ZnO structures against herpes simplex virus-1Yogendra Kumar Mishra | Rainer Adelung | Claudia Röhl | Deepak Shukla | Frank Spors | Vaibhav Tiwari
Volume 92, Issue 2, November 2011, Pages 305-312
Herpes simplex virus type-1 (HSV-1) entry into target cell is initiated by the ionic interactions between positively charged viral envelop glycoproteins and a negatively charged cell surface heparan sulfate (HS). This first step involves the induction of HS-rich filopodia-like structures on the cell surface that facilitate viral transport during cell entry. Targeting this initial first step in HSV-1 pathogenesis, we generated different zinc oxide (ZnO) micro-nano structures (MNSs) that were capped with multiple nanoscopic spikes mimicking cell induced filopodia. These MNSs were predicted to target the virus to compete for its binding to cellular HS through their partially negatively charged oxygen vacancies on their nanoscopic spikes, to affect viral entry and subsequent spread. Our results demonstrate that the partially negatively charged ZnO-MNSs efficiently trap the virions via a novel virostatic mechanism rendering them unable to enter into human corneal fibroblasts - a natural target cell for HSV-1 infection. The anti-HSV-1 activity of ZnO MNSs was drastically enhanced after creating additional oxygen vacancies under UV-light illumination. Our results provide a novel insight into the significance of ZnO MNSs as the potent HSV-1 inhibitor and rationalize their development as a novel topical agent for the prevention of HSV-1 infection. © 2011 Elsevier B.V.
Prophylactic, therapeutic and neutralizing effects of zinc oxide tetrapod structures against herpes simplex virus type-2 infectionThessicar E. Antoine | Yogendra K. Mishra | James Trigilio | Vaibhav Tiwari | Rainer Adelung | Deepak Shukla
Volume 96, Issue 3, December 2012, Pages 363-375
The attachment of Herpes simplex virus type-2 (HSV-2) to a target cell requires ionic interactions between negatively charged cell surface co-receptor heparan sulfate (HS) and positively charged residues on viral envelop glycoproteins, gB and gC. Effective blocking of this first step of HSV-2 pathogenesis demonstrates significant prophylactic effects against the viral disease; any in vitro therapeutic effects of blocking this interaction, however, are not clear. Here, we provide new evidence that zinc oxide tetrapod micro-nanostructures synthesized by flame transport approach significantly block HSV-2 entry into target cells and, in addition, demonstrate the potential to stop the spread of the virus among already infected cells. The zinc oxide tetrapods (ZnOTs) also exhibit the ability to neutralize HSV-2 virions. Natural target cells such as human vaginal epithelial and HeLa cells showed highly reduced infectivity when infected with HSV-2 virions that were pre-incubated with the ZnOTs. The mechanism behind the ability of ZnOTs to prevent, neutralize or reduce HSV-2 infection relies on their ability to bind the HSV-2 virions. We used fluorescently labeled ZnOTs and GFP-expressing HSV-2 virions to demonstrate the binding of the ZnOTs with HSV-2. We also show that the binding and hence, the antiviral effects of ZnOTs can be enhanced by illuminating the ZnOTs with UV light. Our results provide new insights into the anti-HSV-2 effects of ZnOT and rationalize their development as a HSV-2 trapping agent for the prevention and/or treatment of infection. The observed results also demonstrate that blocking HSV-2 attachment can have prophylactic as well as therapeutic applications. © 2012 Elsevier B.V.
Current and future applications of dried blood spots in viral disease managementIngrid J M Snijdewind | Jeroen J A Van Kampen | Pieter L A Fraaij | Marchina E. Van der Ende | Albert D M E Osterhaus | Rob A. Gruters
Volume 93, Issue 3, March 2012, Pages 309-321
Almost five decades after their first application in diagnostics, dried blood spot (DBS) cards remain to be of key interest in many research areas and clinical applications. The advantages of sample stability during transport and storage, can now be combined with the high sensitivity of novel diagnostic techniques for the measurement and analysis of nucleic acids, proteins and small molecules which may overcome the limitations of the small samples sizes in DBS cards. Here we present a survey of the literature on the use of DBS cards for diagnosis, monitoring and epidemiological studies of virus infections other than HIV, including CMV, HBV, HCV, HAV, HEV, HTLV, EBV, HSV, measles-, rubella- and dengue-virus. The minimal invasiveness of sampling and the relative ease of handling and storing DBS cards is expected to offer additional opportunities to measure and analyze biomarkers of viral disease in resource poor settings or when limited amount of blood can be obtained. Large retrospective studies of virus infections in newborns using stored DBS cards have already been undertaken for screening of congenital infections. In addition, DBS cards have been used prospectively for prevalence studies, outbreak surveillance, mass screening for viral infections, follow-up of chronic infection and its treatment in resource-limited areas. We do not expect that current wet sampling techniques of plasma or serum will be replaced by DBS sampling but it allows extension of sampling in persons and settings that are currently difficult to access or that lack suitable storage facilities. In conclusion, DBS card sampling and storage will aid adequate outbreak management of existing and emerging viral diseases. © 2012 Elsevier B.V.
Identification of an antioxidant small-molecule with broad-spectrum antiviral activityRekha G. Panchal | St Patrick Reid | Julie P. Tran | Alison A. Bergeron | Jay Wells | Krishna P. Kota | Javad Aman | Sina Bavari
Volume 93, Issue 1, January 2012, Pages 23-29
The highly lethal filoviruses, Ebola and Marburg cause severe hemorrhagic fever in humans and non-human primates. To date there are no licensed vaccines or therapeutics to counter these infections. Identifying novel pathways and host targets that play an essential role during infection will provide potential targets to develop therapeutics. Small molecule chemical screening for Ebola virus inhibitors resulted in identification of a compound NSC 62914. The compound was found to exhibit anti-filovirus activity in cell-based assays and in vivo protected mice following challenge with Ebola or Marburg viruses. Additionally, the compound was found to inhibit Rift Valley fever virus, Lassa virus and Venezuelan equine encephalitis virus in cell-based assays. Investigation of the mechanism of action of the compound revealed that it had antioxidant properties. Specifically, compound NSC 62914 was found to act as a scavenger of reactive oxygen species, and to up-regulate oxidative stress-induced genes. However, four known antioxidant compounds failed to inhibit filovirus infection, thus suggesting that the mechanistic basis of the antiviral function of the antioxidant NSC 62914 may involve modulation of multiple signaling pathways/targets. © 2011.
Entry inhibitors and their use in the treatment of HIV-1 infectionAiman A. Haqqani | John C. Tilton
Volume 98, Issue 2, April 2013, Pages 158-170
Entry of HIV into target cells is a complex, multi-stage process involving sequential attachment and CD4 binding, coreceptor binding, and membrane fusion. HIV entry inhibitors are a complex group of drugs with multiple mechanisms of action depending on the stage of the viral entry process they target. Two entry inhibitors are currently approved for the treatment of HIV-infected patients. Maraviroc, a CCR5 antagonist, blocks interactions between the viral envelope proteins and the CCR5 coreceptor. Enfuvirtide, a fusion inhibitor, disrupts conformational changes in gp41 that drive membrane fusion. A wide array of additional agents are in various stages of development. This review covers the entry inhibitors and their use in the treatment of HIV-infected patients. © 2013 Elsevier B.V.
Antiviral drug discovery for the treatment of enterovirus 71 infectionsLuqing Shang | Mengying Xu | Zheng Yin
Volume 97, Issue 2, February 2013, Pages 183-194
Enterovirus 71 (EV71) is a small, positive-sense, single-stranded RNA virus in the genus Enterovirus, family Picornavirus. It causes hand, foot and mouth disease in infants and children, which in a small percentage of cases progresses to central nervous system infection, ranging from aseptic meningitis to fatal encephalitis. Sporadic cases of EV71 infection occur throughout the world, but large epidemics have occurred recently in Southeast Asia and China. There are currently no approved vaccines or antiviral therapies for the prevention or treatment of EV71 infection. This paper reviews efforts to develop antiviral therapies against EV71. © 2012 Elsevier B.V.
New opportunities in anti-hepatitis C virus drug discovery: Targeting NS4BRoopa Rai | Jerome Deval
Volume 90, Issue 2, May 2011, Pages 93-101
Current therapy for chronic hepatitis C virus (HCV) infection constitutes a combination of pegylated interferon alfa-2a or alpha-2b and ribavirin. Although successful for many patient populations, this regimen has numerous limitations, including non-response, relapse, poor tolerability and long duration of treatment. To address these shortcomings, new small molecule agents are advancing in clinical development. Most of the current clinical candidates act by directly inhibiting key enzymes in the viral life-cycle: the NS5B polymerase, or the NS3/4A protease. Less well-studied, the non-structural 4B (NS4B) protein has recently emerged as an alternative target for Direct-acting Antiviral Agents (DAAs). NS4B is a 27-kDa membrane protein that is primarily involved in the formation of membrane vesicles - also named membranous web - used as scaffold for the assembly of the HCV replication complex. In addition, NS4B contains NTPase and RNA binding activities, as well as anti-apoptotic properties. This review summarizes the current understanding of the structure and functions of NS4B, an essential component of the replication machinery of HCV. In this literature and patent review, we report the recent developments in anti-NS4B drug discovery. These advances open the possibility for future combination therapies with other DAAs. © 2011 Elsevier B.V.
From SARS to MERS: 10 years of research on highly pathogenic human coronavirusesRolf Hilgenfeld | Malik Peiris
Volume 100, Issue 1, September 2013, Pages 286-295
This article introduces a series of invited papers in Antiviral Research marking the 10th anniversary of the outbreak of severe acute respiratory syndrome (SARS), caused by a novel coronavirus that emerged in southern China in late 2002. Until that time, coronaviruses had not been recognized as agents causing severe disease in humans, hence, the emergence of the SARS-CoV came as a complete surprise. Research during the past ten years has revealed the existence of a diverse pool of coronaviruses circulating among various bat species and other animals, suggesting that further introductions of highly pathogenic coronaviruses into the human population are not merely probable, but inevitable. The recent emergence of another coronavirus causing severe disease, Middle East respiratory syndrome (MERS), in humans, has made it clear that coronaviruses pose a major threat to human health, and that more research is urgently needed to elucidate their replication mechanisms, identify potential drug targets, and develop effective countermeasures. In this series, experts in many different aspects of coronavirus replication and disease will provide authoritative, up-to-date reviews of the following topics: - clinical management and infection control of SARS; - reservoir hosts of coronaviruses; - receptor recognition and cross-species transmission of SARS-CoV; - SARS-CoV evasion of innate immune responses; - structures and functions of individual coronaviral proteins; - anti-coronavirus drug discovery and development; and - the public health legacy of the SARS outbreak. Each article will be identified in the last line of its abstract as belonging to the series "From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.". © 2013 Elsevier B.V. All rights reserved.
Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trialSatoru Watanabe | Abhay P S Rathore | Cynthia Sung | Fan Lu | Yok Moi Khoo | John Connolly | Jenny Low | Eng Eong Ooi | How Sung Lee | Subhash G. Vasudevan
Volume 96, Issue 1, October 2012, Pages 32-35
Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compound fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50. mg/kg twice daily (BID) for 5. days and was effective even after 48. h delayed treatment. Here we show that the protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10. mg/kg is more protective than a single daily dose of 100. mg/kg. Treatment with 50. mg/kg BID castanospermine had comparable efficacy as 25. mg/kg BID celgosivir, suggesting that celgosivir is approximately twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of celgosivir tested suggests that the steady-state minimum concentration is a critical parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clinical trial of celgosivir as a treatment against dengue fever. © 2012 Elsevier B.V.


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"I do know this - and we've got to address it - we have to protect [Michael Vick] better. We've got times where he is at the top of his drop and he is sticking his foot into the ground and there's pressure on him. That's not on Mike."
- Chip Kelly, after Eagles' 52-20 loss to the Broncos
THE EAGLES' offensive line was supposed to be one of the team's greatest strengths this season.
With the return to health of All-Pro left tackle Jason Peters (ruptured Achilles'), center Jason Kelce (torn ACL) and right guard Todd Herremans (broken foot), the emergence of left guard Evan Mathis as a Pro Bowl-level blocker, and the addition of a right tackle - Lane Johnson - who was the fourth overall pick in the April draft, both Vick and running back LeSean McCoy appeared to be in very good hands.

subset: commoncrawl


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Countries served by TAP Portugal
Cities served by TAP Portugal
Home » Airlines » TAP Portugal
TAP Portugal AirlinesTAP Portugal, commonly known as TAP, is the national airline of Portugal and a member of the Star Alliance. TAP's hub in Lisbon is a key European gateway at the crossroads of Africa, South America and North America. TAP's route network comprises 69 destinations in 31 countries worldwide. TAP operates over 1,600 weekly flights with a fleet of 58 Airbus aircraft, and 16 further aircraft servicing regional subsidiary carrier Portugalia.
Number of Airplanes :
Average Age of Fleet :
9 Years
Home City :
Hub :
Portela Arpt.
Porto Arpt.
Awards Information:
Awards Information not avaliable for this Airline
Frequent Flyer Program :
TAP Frequent Flyer Program
Frequent Flyer Partners :
Air Canada (AC)
bmi (BD)
Continental Airlines (CO)
Spanair (JK)
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Uploaded for a second time due to display issues on the site, I may have uploaded this as the system was being reactivated. A slightly cropped 360 degree pano of the ruins of Coventry's old Cathedral. I had hoped to be finished before the Sun appeared around the column but 390 images took a little long and just c...
This pan is an homage to www.gigapan.org/viewGigapan.php?id=15344 which is what a tidy office should look like, and can be seen on two of the screens in the pan if you look closely.
A view of Lichfield Cathedral on a frosty January Day. A little dark due to the general white haze around.
A view of Lichfield Cathedral on a frosty January day. First GigaPan taken using the Imager.
A view from Oliver's Mount of Scarborough, towards the harbour and castle. Testing out my lovely new Manfrotto Modo 785B I was greatfully bought for Christmas. Slightly rushed due to the cold wind and impending rain.
I made this panorama with my Canon Rebel XTi on my visit to England over the summer. I've never made a panorama before but I decided to try my hand at stitching. I shot all of these images handheld and then stitched them together in Photoshop CS3. I've just purchased a Gigapan Imager and a Canon G10 for the expres...


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DONUT 1: It's so cliché. "Halftime adjustments.'' And I don't much buy the chestnut. (I know for a fact that "halftime adjustments'' in the NFL mostly means changing out of sweaty undershirts and not listening to the linebackers coach yell at people.)
But …
*Think of the changes Dallas made against the Spurs on Friday, when Manu scored about half his 31 points in the first quarter but was contained from there.
*Think of what Carlisle said on Saturday night about coming out of halftime against Miami: "We made a point to get out of the locker room and get loose, show (the Heat) that we would be warm and we wanted to pick up the pace. We felt that by pushing the ball, it wasn't necessarily their game. ...''
*And think of what a different game Monday night's was, from first half to second. Consider especially what Dallas did once it was determined that Houston was going to run things to and through Luis Scola …
And Dallas doubled-down on Scola when he received the ball inside.
I'm sure at halftime, sweaty shirts and angry words are exchanged. But I think Carlisle and staff are in there with a clipboard, too.
DONUT 2: The Texas Legends' roster is loaded.
It already featured five former NBA first-round picks: Joe Alexander, Rashad McCants, Antonio Daniels, Sean Williams and Reece Gaines. … and now down goes DoJo.
He's disappointed, of course. (Think about it; as of the preseason trip to Palm Springs, he was being discussed openly by the club as a contender to start at the 2.) He was dragging a bit at Monday's shootaround, and he performed poorly once he did get into the Mavs-Rockets game, part of the Hamburger Helper portion of the contest.
But he'll be back. The Mavs' first-rounder (one of six first-round Legends!) is expected to spend the week in Frisco, maybe play three games there. And then he should boomerang back to the big club.
"It's a chance to play,'' Carlisle said. "It's a chance to work on his game. I'm sure (coach Nancy Lieberman) will kick his ass, which is great. It's an opportunity. Not many teams have a D-League team this close in proximity, so it's an opportunity for us and for him."
So it's a temporary thing. I know Nancy loves DoJo, so that will be good. But temporary love, OK? A short-term affair.
P.S.: I've got an NBA talent guy who says Joe Alexander isn't long for the D-League, either.
DONUT 3: Do I sense some reluctance from the Mavs fan base as it regards believing in Tuff Juice?
I get that. His success against Miami and Houston (23 and 19 points, respectively) was largely about effective jumpshooting. And you still want to see him go to the rim.
Maybe it's a process. Have a nice quarter against Detroit, OKC and San Antonio. Then have huge quarters against Miami (12 in the third) and against Houston (6-of-7 shooting for 13 points). And then, with the confidence flowing, all shots will flow.
DONUT 4: Speaking of confidence, here's the point when you knew Dallas knew that Dallas was going to win:
Mavs up nine, midway through the third. Other guys are clicking … hell, everybody is clicking. … but the fifth option on the floor – and traditionally for the Mavs during his life in Dallas, the 13th offensive option on the team – is DeShawn Stevenson.
Yet he receives the ball on the right baseline. And instead of immediately swinging it back outside, he backs in, spins, and launches an off-balance fade-away. It's Dirkesque (or, if you hated it, J-Hoish) … but it goes, and at 6:49 of the third, the Mavs are up 66-53.
DeShawn usually has permission to take his early-game 3's. But when he knows he has permission to take midway-through-the-third iso fadeaways?
You know Dallas is going to win.
DONUT 5: Three great ways to stay in touch with what the heck is going on around here: DB.com Boards, DB.com Mavs coverage on Twitter, and Friending Fish on Facebook. Come say hi. I seem nice.
DONUT 6: I had Dallas down for a 30-9 run that spilled into the third quarter.
Now let's check the archives.
Against OKC, it was a 24-3 run.
Against San Antonio, it was a 12-2 run.
And now this.
"That's what Dallas has been known for," Rockets center Brad Miller observed. "They have been able to go on big runs for many, many years."
DONUT 7: Oh, and make sure you note what's happening on both ends during these runs. That means a long stretch of Durant and Westbrook and Manu and Parker and Martin not scoring. And that's how you accumulate the NBA's fewest games allowing 100 points, which Dallas has done, with just three allowed.
DONUT 8: There are now Mavs upper-deck tickets to the post-Christmas game with the Raptors and for one ticket, the price is as high as $22.
And that's where I come in.
It's DB.com Night at the Mavs! We'll get together at the AAC on Tuesday, Dec. 28 … It's Raptors at Mavs, and when you visit The newly re-opened DB.com Store to order …
We'll get you:
*Your TWO upper-deck tickets
*Your special-edition DB.com Night at the Mavs t-shirt
*And your pre-game meet-and-greet with a special guest or two
For a grand total of 22 bucks! (Or just $29 if you want two shirts!)
Yes, this is a very affordable way for you to do this. ... a DB.com Get-Together at a very low price! ... It's time for us to get together, time for us to get in the game, time for us to get suited up!
The shirts (DB.com originals designed by the brilliant Beau Shoulders) are limited-edition, and there is a limit to the ticket availability, too, though Ryan at MavCowTickets is pulling all the strings he can. …
So let's get in the game! DB.com Night at the Mavs! And other DB.com Mavs gear from The DB.com Store! C'mon along!
DONUT 9: The cut-down NBA.com video feeds your eyes:
DONUT 10: I enjoyed Carlisle's pregame pep talk concerning pep talks.
"Those guys have heard every speech there is to hear about 'focus' and 'staying hungry,'" he said. "We've worked hard to get ourselves on a bit of a roll here, and we'll see how we respond.''
The roll continued. No pep talk needed.
And what is it Uncle Nellie used to say about explosive locker-room speeches? That a coach only has about six bullets a year?
You certainly didn't want to use one of the bullets at home, in November, against a Rockets team playing tired.
DONUT 11: I sat down for a lengthy and pretty-damn-cool one-on-one with Tyson Chandler this week … Everything You Ever Wanted To Know About Tyson Chandler (Or, At Least The Stuff I Could Think Of) … coming up Wednesday morning.
DONUT 12: Perspective: This was the Mavericks' sixth consecutive victory. That is one more than the Rockets have all season.


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Birds may be chirping and flowers may be blooming outside, but your home's interior may still feel a bit like a wintry dungeon. Break your home free of its winter woes with a few quick tips that makes it feel like spring has arrived in all its glory.
Let in the light.
Letting in the light can be as simple as opening those heavy curtains you used all winter to keep out the cold. Go one better and trade your heavy curtains for a lightweight, gauzy set or dangle colorful sun catchers in front of the glass. Go all out by giving your most prominent windows a quick cleaning so the sun can really shine its way in.
Stow away your winter wares.
Haul away the hefty comforters and dark throw rugs and replace them with lighter, brighter substitutes. Spruce up the area in front of your kitchen or bathroom sink with a rug showcasing a sweet floral design for instant springtime impact.
Organize your clutter.
Your home will instantly feel fresher and lighter with a bit of creative organization. Spring is the perfect time to dust and organize your bookshelves and pack up your winter boots, coats, hats and scarves.
Delight in fresh flowers.
A dazzling bouquet of daffodil, daisies or lilies adds an instant burst of spring fragrance and color to your kitchen. Pick up a bouquet of cut flowers at your supermarket, or swing by your nearest nursery for potted flowers you can keep inside until the weather turns warmer.
Get cheery with spring decor.
Spring decor is cheery decor, and even a little cheer goes a long way for transforming your home into a seasonal sensation. Invest in a few key pieces that can brighten your home year after year, such as a vibrant flower or butterfly wreath, a dashing new welcome mat or a bright canvas print to perk up the entrance or hallway. Check out the cheery spring decor at Lillian Vernon to brighten your home today.


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During our short stay at Bury St Edmunds we had a tour of the Abbey gardens along with a very informative history lesson on the surrounding ruins of the old Abbey. The gardens are... read more
A special offer for TripAdvisor travelers! You'll get a $25 Amazon.com Gift Card when you book a hotel on TripAdvisor and review your stay.* It's perfect for books, music, travel bags, or millions of other items at Amazon.com.
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Woods' caddie opens mouth, inserts Foot-Joy
Suddenly, Tiger Woods has more to rehabilitate than his surgical left knee.
He's got to deal with his caddie's big mouth.
The golf world is abuzz over Steve Williams' comments at a charity dinner Friday night in New Plymouth, New Zealand. Woods' caddie, close friend and unofficial bodyguard was quoted in the Taranaki Daily News as saying he wouldn't call Phil Mickelson a great player "because I think he's a (expletive)." Williams also apparently poked fun at Mickelson's weight and upper-body physique.
It's no secret that Woods, the top-ranked player in the world, and Mickelson, ranked No. 3, have had a tense professional relationship. They've insisted publicly that they felt no real animosity toward each other and especially in recent years have gone out of their way to lob compliments at each other. But Williams' comments were revealing. He wasn't speaking for Woods, but it's hard to believe he's never said similar things to his boss in private moments.
Private conversations are one thing. Williams' comments were made in public, though he later said he did not think they'd appear in print. But in an interview the next day with another New Zealand newspaper, the Sunday Star Times, Williams said he was simply being honest.
"I don't particularly like (Mickelson)," Williams said in the Star Times. "He pays me no respect at all and hence, I don't pay him any respect. It's no secret we don't get along, either."
Contacted by The Associated Press at his home in New Zealand, Williams said, "I shouldn't have said it, but no harm was meant. I was just having some fun."
Some fun? Woods needs this like he needs another knee operation. Williams' blatant disrespect for Woods' biggest rival was unprofessional and embarrassing. Woods doesn't take kindly to members of his camp speaking out of turn.
"I was disappointed to read the comments attributed to Steve Williams about Phil Mickelson, a player that I respect," Woods said in a statement. "It was inappropriate. The matter has been discussed and dealt with."
Mickelson's management company issued a statement that included a comment by Mickelson: "After seeing Steve Williams' comments, all I could think of was how lucky I am to have a class act like 'Bones' (Jim Mackay) on my bag and representing me."
In a telephone news conference Tuesday for the ADT Skills Challenge, caddie Mike "Fluff" Cowan and Peter Jacobsen weighed in on the controversy. Cowan was Woods' first professional caddie and also worked for Jacobsen for several years.
"When you caddie for a high-profile player, things that you say are going to reach the public if you're not careful about it," Cowan said. "You need to know who you're talking to. I think there are times no matter what your opinion might be, no matter who you are talking to, you just keep it to yourself.
"I certainly feel badly this has reached the public. Obviously, Steve is not a big Phil Mickelson fan, but that's not for me to judge one way or the other."
Said Jacobsen, "We've all said and done things we regret. We've all said things in a joking manner that have backfired. I don't know if he said it in a joking manner. He very possibly could have. He also might have made a comment off the cuff that didn't have the desired impact that it was meant to have. So I feel badly for what happened."
Though I have never interviewed Williams, I've observed him in action at more than 25 major championships and for what it's worth my opinion of him is that he's a self-important jerk and a bully. At the U.S. Open in 2004, he wrestled a camera away from a fan -- an off-duty police officer, no less -- and he once threw a corporate photographer's camera into a pond at the Skins Game.
Williams carries golf clubs on his shoulder for a living. He's not the show, though sometimes he acts the part. As for Williams' contention that Mickelson "pays me no respect," is Mickelson supposed to bow to Williams on the first tee? The guy is a caddie. His job is to show up, shut up and keep up. His primary focus should be to keep Woods' clubs clean, give yardages and rake bunkers.
Woods probably won't fire Williams over this transgression. But, surely, we haven't heard the last of Caddie-gate.
- Kaddy Korner: Ready for the stretch drive with Cody
- Midwest Cup has become top-tier amateur tournament
- Kaddy Korner: Things are looking up as Cody finishes 20th
- Stricker inserts himself into Ryder Cup conversation
- Meyer's July 4 by the numbers: 162 holes played, $66,000 raised
- Kaddy Korner: Getting some much-needed rest before the final push
- Meyer set for ninth annual '100 Holes for our Heroes' at Chenequa
- Hallberg, Terasa qualify for U.S. Senior Open
- Kaddy Korner: Another weekend off, more frustration
- Ryan Helminen qualifies for PGA Championship
PGA Tour
LPGA Tour
European Tour
Champions Tour


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A Johns Island man is accused of stabbing a Summerville man on Sunday, according to Charleston County Sheriff's officials.
Jason Ammons, 35, was charged with attempted murder and is currently detained Al Cannon Detention Center.
A judge is expected to consider setting bail Monday afternoon.
Ammons and Phillip Kinard, 21, got into an argument inside a car on Chisolm Road at around 11:11 p.m., according to an incident report.
They were with another man and were traveling from Folly Beach, authorities said.
Ammons reached into his pocket, pulled out a knife and stabbed Kinard in the stomach, according to the report.
His friend, who was also in the car, drove Kinard to a gas station for help, authorities said.
Kinard was transported to Medical University Hospital. A deputy had to accompany Kinard in the ambulance due to his "extremely aggressive behavior" towards the EMS crew and everyone he spoke to, the report stated.
See news happening in your neighborhood? Send us your news tips, photos and videos by email to email@example.com or call (843) 937-5581.


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New film 'Role Play' with all Milwaukee cast & soundtrack premiering this weekend at Art Museum
This Saturday, the feature film "Role Play", directed by nationally known Milwaukee-native Rubin Whitmore opens at the Art Museum. This comedy features an all-Milwaukee cast lead by comedians Terrence "T-Dot" Kingsby, Kelly "Kellz" Sunnett Davis, Adrian "Da Jester" Patrick, Ruth "MsCutnup" Troop, and also Gig Jackson. T-Dot and Kellz play a struggling married couple and after visiting a relationship counselor, they have an out of body experience that will test the value of their marriage. I can't give you all the details but know it's funny and Milwaukee hasn't seen so much talent come together like this in a long time. »Read Full Blog Post
The five most memorable moments at the Grammys
In revisiting the most memorable moments of the 55th Grammy Awards, there are several places we can start. Shall we begin with the surprise album of the year victory by Mumford & Sons? Or with the hearty superstar tribute to Levon Helm? Or perhaps with Katy Perry's provocative dress, the most revealing outfit since J. Lo's chest-plunging ensemble (or lack thereof)?
For this Grammy post-mortem I'll be keeping my eyes on the music (although you should really check out this pic of Ellen DeGeneres with Perry). Photos below courtesy of Reuters. »Read Full Blog Post
Mumford & Sons wins album of the year at Grammys
British folk band Mumford & Sons pulled off a surprise victory at the 55th annual Grammy Awards on Sunday night, winning album of the year away from fellow nominees the Black Keys, and fun., who were dominating the night.
Before the nominations were announced last year, Mumford was an early favorite to win music's biggest prize. Its sophomore album, "Babel," had the second-highest week of sales last year according to Billboard, and the band's sweeping, banjo-strumming style paved the way for a lucrative folk renaissance, inspiring other acts like the Lumineers and Phillip Phillips, who've also had big sales successes. »Read Full Article(2)
Despite memo, Grammy red carpet features plenty of skin
Los Angeles - A warning not to show too much skin didn't seem to deter the stars out Sunday for the Grammy Awards.
Jennifer Lopez was among those showing off thigh-high - or higher - openings in their dresses, and she joked about it as she took the stage to present an award. Katy Perry showed down-to-there cleavage in a seafoam gown. »Read Full Article
Classical producer Alspaugh wins Grammy for Florentine/MSO recording
A project with ties to Milwaukee won a Grammy Award early Sunday night in the hours before the start of the 55th annual awards show in Los Angeles.
Blanton Alspaugh won the Grammy for classical producer of the year, in part for his work on the Florentine Opera and the Milwaukee Symphony Orchestra's recording of "Davis: Rio De Sangre," an original opera from Don Davis. »Read Full Article
Mayfair celebrating Chinese Lunar New Year on Feb. 16
Shoppers at Mayfair this weekend may find the place looking more festive than usual. To celebrate the end of winter and the arrival of Chinese New Year, the mall will host its second Chinese Lunar New Year celebration from 11 a.m. until 2 p.m. on Saturday.
Which explains the food samples, dancers and tai chi demonstrations. »Read Full Article
Kaplan's revue a musical tribute to friendship
The enduring theme in the many collaborations between James Kaplan and the late Fred Alley was friendship, through which others pull us out of ourselves and challenge us to grow.
It's therefore only fitting that Kaplan's latest - a moving show that honors Alley, the creative force behind American Folklore Theatre, in so many ways - is titled "Jimmy Kaplan and Friends." It opened over the weekend in the Sunset Playhouse's Studio Theatre in Elm Grove. »Read Full Article


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I wanted to play Rise of the Tomb Raider [official site] more than I realised I did. It's nice to not have yet another BrawnMan in the middle of my screen, sure, but for me it's the idea of vaguely puzzley, vaguely sandboxy adventures in a not-too-fantastical wilderness which appeals.
Enthused by Adam's review, I picked up the PC version, but it wasn't long before I was hissing through my teeth at the bad balance of impossible escapes from death, relentlessly dour and earnest tone, mechanically-delivered dialogue and preposterous animal-massacre-based-crafting (because, once again, Lara had gone on an incredibly dangerous adventure without packing anything more than a glowstick and the first option you get if you type 'bow and arrow' into Amazon then sort by Price: Low To High). Fortunately, the Endurance Mode DLC turned out to be game I wanted.
Read the rest of this entry »


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Circus, auto show, RV show this week
Come one, come all
For four days only, take part in a form of entertainment beloved by children of all ages, going back generations. See the Tripoli Shrine Circus on Thursday through next Sunday at the U.S. Cellular Arena, 400 W. Kilbourn Ave. Nine performances of athletic skills with aerialists and acrobats. Watch elephants and big cats perform in one of the three rings of action all lead by Ringmistress Michelle Audrey. Tickets range from $9 to $35; there are also free tickets available for adults bringing a child along. See www.milwaukeecircus.com for information and to purchase tickets. »Read Full Article
Five singers declared winners in local Met Opera auditions
Five singers were selected by judges to advance to the next round at Saturday's Wisconsin District Metropolitan Opera National Council Auditions.
Countertenor Kangmin Justin Kim, mezzo-soprano Corrie Stallings, soprano Caitlin Ruby Miller, tenor Ian D. Koziar and tenor Joe Shadday will compete at the Upper Midwest Regional in St. Paul, Minn. The five vocalists also won $2,000 each. »Read Full Article
'Belle of Amherst' best when profiling Dickinson's poetry
Walt Whitman may have rightly claimed that his poetry contains multitudes, but Emily Dickinson can stake an equally valid claim to being America's greatest poet.
She is also the hardest one to know. Harold Bloom once wrote that no poet "seems so separate from us as Dickinson," adding that "we have no accurate approaches to her." »Read Full Article


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Can trading pursuant to an algorithmic program properly be found to constitute "spoofing" in violation of CEA Section 4c(a)(5)(C): What constitutes "the intent to cancel the bid or offer before execution"? ...more
The Committee on Capital Markets Regulation—a nonprofit that represents execs from many of the US's largest banks—will release a paper today arguing that the Fed illegally sidestepped the APA by adopting "central parts of its...more
US regulators are "ramping up oversight" of Swift—the financial messaging system used throughout global finance that's been a key conduit for hackers in recent attacks of Bangladeshi and Ecuadorian banks....more
The last several years have seen law enforcement and regulatory bodies sharpen their focus on trading activity in the securities and derivatives markets. This focus has coincided with the advent of new and expanded reporting,...more
Broker-Dealer Sanctioned US $415 Million by SEC for Violating Customer Protection Requirements:
Two Merrill Lynch entities agreed to pay sanctions of US $415 million to resolve charges brought by the Securities and...more
On June 10, 2016, Staff for the Commodity Futures Trading Commission ("CFTC") held a public roundtable to discuss its proposed Regulation Automated Trading ("Regulation AT"). The CFTC proposed Regulation AT in an attempt to...more
SEC Adopts Amendment to Form 10-K Permitting the Summary of Business and Financial Information -
On June 1, the Securities and Exchange Commission adopted an interim final rule (Rule), as mandated...more
Hedge fund managers—not that long ago the titans of Wall Street, thanks in part to their "2 and 20 model" that saw them receiving fees of 2% of assets under management and 20% of any gain in any year—are reeling from the loss...more
CFTC Hosts Regulation AT Roundtable; Chairman Implies Risk Rules Sufficient for 2016:
Staff of the Commodity Futures Trading Commission sponsored a roundtable on proposed Regulation Automated Trading last Friday. The...more
The Commodity Futures Trading Commission announced last week that staff will host a public roundtable to discuss five aspects of Regulation Automated Trading, initially proposed in November 2015....more
A Commission Delegated Regulation, outlining the Regulatory Technical Standards on ratios of unexecuted orders to transactions, was adopted by the European Commission. The adopted RTS will supplement the requirements set out...more
On April 7, 2016, the Securities and Exchange Commission ("SEC") approved the Financial Industry Regulatory Authority's ("FINRA") proposal to amend NASD Rule 1032 (Categories of Representative Registration) to require...more
On April 7, the Securities and Exchange Commission (SEC) approved amendments to NASD Rule 1032(f) which will require registration as Securities Traders of associated persons who are primarily responsible for the design,...more
Alleged Spoofer, Blamed for Partly Causing Flash Crash, Loses UK Extradition Hearing -
Navinder Sarao, the London-based futures trader who in April 2015 was sued by the Commodity Futures Trading Commission and criminally...more
Industry Comments to Regulation AT Argue CFTC Proposed Rules Too Prescriptive; Registration and Source Code Requirements Particularly Objectionable -
After declining multiple requests to extend the comment period that...more
On February 11, 2016, the Financial Industry Regulatory Authority ("FINRA") filed a proposed rule with the Securities and Exchange Commission ("SEC") that would require individuals who "design, develop or significantly modify...more
It's a whole new ballgame for Wall Street traders—and one suspects it's involving a lot fewer actual ballgames and a lot more algorithms, as the advanced-degree coders and their ETF firms take on the old guard – NYTimes...more
The Financial Industry Regulatory Authority (FINRA) has filed with the Securities and Exchange Commission (SEC) a proposed rule change that would require the registration of associated persons of FINRA member firms who are...more
2015 was not exactly the year of the hedge fund, and 2016's starting off with its worst start for the industry since 2008. But if you think that's keeping managers from starting new portfolios with an eye toward hitting it...more
On Wednesday, the Securities and Exchange Commission (SEC) adopted rules that will affect firms operating in the global security-based swap market. Specifically, the SEC is requiring non-US firms that arrange, negotiate, or...more
Regulators were busy at the end of 2015, especially in the United States, perhaps being motivated to push forward new rule proposals in anticipation of a change in administration after the presidential elections later this...more
The Commodity Futures Trading Commission (CFTC) has proposed new rules — Regulation Automated Trading (Regulation AT) — that would impose new and potentially burdensome risk and compliance controls on any person engaged in...more
On November 24, 2015, the Commodity Futures Trading Commission ("CFTC") approved the issuance of proposed rules to implement a framework of registration, reporting, recordkeeping and other compliance requirements for market...more
On November 18, 2015, the Securities and Exchange Commission ("SEC" or "Commission") proposed significant changes to the regulatory requirements applicable to dark pools and other alternative trading systems ("ATSs") that...more
On November 24, 2015, the Commodity Futures Trading Commission ("CFTC") held an open meeting at which it unanimously approved its long-anticipated notice of proposed rules referred to as Regulation Automated Trading...more
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Your little one is guaranteed a great night's sleep, every time, with the assistance of Safetots and our handy collection of bed rails.
A well-designed bed guard is the perfect solution to avoiding your child from falling out of their bed as they roll over and waking up from a nice dream with a startle. Take a look at our extensive selection of bed rails and you will see that we stock nifty accessories ideal for wooden and mesh beds alike. Even when you are heading on holiday, you can enhance safety in the hotel room for your tiny treasure with one of our handy inflatable rail tubes. Browse all of our bed guards and complete a purchase online without delay. We price match all of our products, so you are guaranteed the best deal on the market.


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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Newegg.com - Computer Parts, Laptops, Electronics, HDTVs, Digital Cameras and More!
Showing Results: Most Recent
This review is from: Samsung 48" Smart 1080p Clear Motion Rate 240 LED HDTV
Pros: Great picture. Setup was super easy. Interface is pretty intuitive.
Cons: Poor technology execution, and poor support. On my first call to support, the tech tried throwing the retailer under the bus, blaming them for selling the TV before it was ready for release (then why was it ever shipped from your factory?). That was in very poor form. There are many bad reviews on another site, with problems varying from apps not working to wireless not working, and no picture.
I first called Samsung about wireless problems a week and a half ago, and have endured 6 calls, most of which with people for whom English is not their first language so there was some difficulty communicating. After my patience ran out, I was escalated to what they called "Executive Support" (someone that sounded professional and US based) and have now got a day for a technician to come out. Hoping for the best. At least the picture looks good!
To describe my issue: The wireless adapter has problems seeing wireless networks. When you go to network setup and select wireless, it searches then eventually gives up without an error message. I question whether the latest firmware update rendered it completely inoperable, because it did detect wireless networks on a couple random occasions and then since the firmware version 1110 update this weekend, it went completely kaput, regardless of resetting the tv.
This review is from: MSI Radeon HD 7850 DirectX 11 R7850 Twin Frozr 2GD5/OC 2GB 256-Bit GDDR5 PCI Express 3.0 x16 HDCP Ready CrossFireX Support Video Card
Pros: Pretty decent little card. Good performer and very quiet.
Got awesome deal at ~$100 after rebate during Black Friday sales. Looks like my rebate has processed and is on its way with no problems, but it's not without painstaking effort with extreme attention to detail.
Cons: While monitor is asleep, fans intermittently spin up. I've submitted a support ticket. We'll see what they come back with. However, I really don't want to go through a stupid RMA process. I'll probably throw away this card and replace it with an Intel if MSI tells me to ship it back.
As usual, I'm experiencing errors with CCC install which is truly annoying, but outside of MSI's control. Of all the times I've installed or upgraded CCC over the past several years, only twice has it gone smoothly. This is beyond annoying so I'll likely go with Intel cards in all future builds.
This review is from: BYTECC ME350V4-ISA-BK Aluminum 3.5" Black IDE / SATA USB 2.0 External Enclosure
Pros: It says that it supports both SATA and IDE.
Cons: I have no way of knowing whether the manufacturer's claims are true because I CANNOT OPEN THE CASE.
1. There are no instructions, but I found another person's review helpful to open via screws in the back.
2. I've been trying to unscrew the screws for the past 20 minutes, with every bit of force I have in my body, and the screws simply WON'T BUDGE.
3. I bought from a local retailer, so I will have to drive the 12 miles back there to return this junk.
Other Thoughts: I should have looked up reviews while I was in the store before I purchased. I won't make the same mistake again. I also will never buy anything by Bytecc again. They're going to get this back with the screws stripped, by the time I'm done with it.READ FULL REVIEW


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Stockton is the best Fox can present. WR could be the number one or #
2 pick next draft, you have to have reliable playmakers; also a Tackle
, ILB and OLB. Jared Bush had a remarkable game and maybe earned
the dime spot--the best he's ever played. The CB position seems less
of a concern. Pass rush is always a priority. Tough call on Jenkins....In
a Super Bowl there are no excuses for the lack of concentration, guts ,
whatever, and the subsequent drops by these receivers. They are not


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To the Editor.—The data presented by
Dr Halm and colleagues1 indicate that, from
the respondents' perspective, gatekeeping had a negative effect on almost
every aspect of care that was measured, including the patient-physician relationship,
time with the patient, freedom in clinical decision making, and the ability
to use resources appropriately (eg, the use of hospitalization, the use of
specialists, and the choice of medication). In contrast, the only positive
effects on clinical care that were reported were in the use of preventive
services and the coordination of care. How, then, do the authors conclude
that "nearly three quarters of physicians thought gatekeeping was better than
or comparable to traditional care overall"?
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The Sherwood Inn offers a range of business meeting space options to groups planning meetings, corporate conferences, or other events. Meeting and banquet facilities at the Sherwood Inn include nearly 3,400 square feet of function space comprised of five rooms, three of which may be opened into one large business meeting space (totalling 2,060 sq. ft.) or two large business meeting spaces. In addition, the enclosed Front and West Porches offer comfortable seating for either meetings or dining with breathtaking scenic lake views.
With its unmatched lake views and tastefully appointed antique décor, the Sherwood Inn's Front Porch and West Porch may also be rented for private dinners or special functions, lending a unique environment to delight your guests.
Whether hosting a large or small meeting, the Sherwood Inn staff is ready to provide the ultimate in service.
*The Sherwood Inn's business meeting space and dining facilities are wheelchair accessible.
"The New York Onsite Wastewater Treatment Training Network, an educational not-for-profit organization, has been holding our annual Alternative and Innovative Onsite Wastewater Treatment System Training and Tour at Sherwood Inn for close to 10 years. We enjoy the central location since we do field work around the Lake on the second day of our event. The first day is all-day classroom training at the Inn. Sherwood Inn staff are always accomodating and professional, and the training room and porch allow us to have space to have demonstration booths simultaneous with the professional presentations. The setting is beautiful and the hotel provides historic and comfortable accomodations. The restaurant and the catering is always pleasing and the rooms at the Inn are individual and charming." -CB
"Our event last night was awesome. I have heard great feedback from our associates; the food was delicious, the room set-up was beautiful, and the hors d'oeuvres were just right. Thanks so much to you and your team for making our appreciation dinner so special." CH, August 2016


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Prof. Ott, Prof. Yorke & Alumnus Grebogi Named 2016 Thomson Reuters Citation Laureates
UMD Center for Disaster Resilience Leads Hill Discussion on D.C. Flood Risk
John S. Baras to be inducted into Clark School Innovation Hall of Fame
UMD Bioengineers Work to Reprogram Lymph Node Function to Fight Multiple Sclerosis
Siemens, Koffel Gifts Help Fire Protection Engineering Reach $2.5M Milestone in Legacy Campaign
Chellappa to Receive Distinguished Alumnus Award from Indian Institute of Science
UMD Physicists Discover "Smoke Rings" Made of Laser Light
University of Maryland Hosts 2016 Leidos Intern Symposium
Timothy Koeth, Associate Research Professor, Profiled in The Washington Post
University of Maryland Achieves First Successful Solar-Powered Helicopter Flight
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Ethan Schaler
Ethan Schaler, a Clark School senior majoring in mechanical engineering, has won one of only fourteen 2011-12 Churchill Scholarships to the University of Cambridge, in the United Kingdom.
The Churchill Scholarship covers tuition and all fees at the University of Cambridge, as well as a living and travel allowance from $16,500-$20,000.
Schaler will complete a one-year Master of Philosophy in micro and nanotechnology enterprise before continuing doctoral studies in the U.S. He plans to pursue engineering studies through graduate school and focus his research on developing mobile and networked micro-robots.
Schaler is active in the campus chapter of Engineers Without Borders, serving as project manager for five projects in Brazil, Burkina Faso, Ethiopia, Peru and the U.S., while developing a new project in Thailand. He is proficient in Japanese, and has studied abroad and conducted research in Japan on several occasions while at UM. A 4.0 student with numerous publication and presentation credits, Schaler has worked for several years in Prof. Sarah Bergbreiter's lab. Prof. Santiago Solares also served as a UM recommender for Ethan's Churchill Scholarship application.
Schaler has previously won the Goldwater Scholarship and a Bridging Scholarship for study in Japan.
The Churchill Scholarship is one of the most prestigious and academically competitive opportunities of its kind, and is the only major scholarship to the UK devoted exclusively to outstanding students in the sciences, mathematics and engineering.
Related Articles:
Rebois Awarded Prestigious Marshall Scholarship
EWB Team Implements Chlorinator in Peru
Record Breaking Year for Women in Engineering
Engineers Without Borders Chapter Receives Grants
Clark School Leads Nation in NASA Aeronautics Scholarships
Watch Stephens UMD Commencement Speech Online
Abutaleb and Ruppel Named Stamps Banneker/Key Scholars
Olatunji Godo, B.S. '11, Establishes Biomedical Research Scholarship
Casarez Wins Goldwater Scholarship
Clark School Student Wins Udall Scholarship
January 19, 2011
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Bloom Room 35" Decorative Beaded Floral Spray-White
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BUY ONLINE PICK-UP IN-STORE now available in a store near you.
Pick-up in one of our locations near you.
Additional Information
Elegant Glitter Ting Ting with pearl accents, a beautiful addition to Wedding, Home Decor and Holiday arrangements.
- 35" White Beaded Ting.
- Color: White
- Indoor use only.
- Handling Code:
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May I extend a very warm welcome to our website.
For prospective parents we trust the information you will find on the subsequent pages is both useful and informative as an introduction to our learning community.
For our parents who are already partners with us we aim for the site to be an additional way of keeping informed about what is going on in school on a day to day basis and the learning your children are experiencing. We are very proud to have been rated as an'Outstanding Primary School' in our latest Ofsted evaluation.
For our pupils it is a celebration of their achievements and an exciting learning resource to further individual progress and development.
Lee White
Head of Teaching and Learning