bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Characterization and Target Validation of Alternative Complex I of
Plasmodium falciparum
Mitochondria
Authors: Biagini Giancarlo A. , Viriyavejakul Parnpen , O'Neill Paul M. , Bray Patrick G. , Ward Stephen A. 
Published: April 2006

ABSTRACT

This study reports on the first characterization of the alternative NADH:dehydrogenase (also known as alternative complex I or type II NADH:dehydrogenase) of the human malaria parasite
Plasmodium falciparum
, known as PfNDH2. PfNDH2 was shown to actively oxidize NADH in the presence of quinone electron acceptors CoQ
1
and decylubiquinone with an apparent

K
m

for NADH of approximately 17 and 5 μM, respectively. The inhibitory profile of PfNDH2 revealed that the enzyme activity was insensitive to rotenone, consistent with recent genomic data indicating the absence of the canonical NADH:dehydrogenase enzyme. PfNDH2 activity was sensitive to diphenylene iodonium chloride and diphenyl iodonium chloride, known inhibitors of alternative NADH:dehydrogenases. Spatiotemporal confocal imaging of parasite mitochondria revealed that loss of PfNDH2 function provoked a collapse of mitochondrial transmembrane potential (Ψ
m
), leading to parasite death. As with other alternative NADH:dehydrogenases, PfNDH2 lacks transmembrane domains in its protein structure, and therefore, it is proposed that this enzyme is not directly involved in mitochondrial transmembrane proton pumping. Rather, the enzyme provides reducing equivalents for downstream proton-pumping enzyme complexes. As inhibition of PfNDH2 leads to a depolarization of mitochondrial Ψ
m
, this enzyme is likely to be a critical component of the electron transport chain (ETC). This notion is further supported by proof-of-concept experiments revealing that targeting the ETC's Q-cycle by inhibition of both PfNDH2 and the
bc
1
complex is highly synergistic. The potential of targeting PfNDH2 as a chemotherapeutic strategy for drug development is discussed.
Curcumin-Artemisinin Combination Therapy for Malaria
Authors: Nandakumar Dalavaikodihalli Nanjaiah , Nagaraj Viswanathan Arun , Vathsala Palakkod Govindan , Rangarajan Pundi , Padmanaban Govindarajan 
Published: April 2006

ABSTRACT

Artemisinin and curcumin show an additive interaction in killing
Plasmodium falciparum
in culture. In vivo, 3 oral doses of curcumin following a single injection of α,β-arteether to
Plasmodium berghei
-infected mice are able to prevent recrudescence due to α,β-arteether monotherapy and ensure almost 100% survival of the animals.
Antimicrobial Susceptibility Pattern of
Clostridium difficile
and Its Relation to PCR Ribotypes in a Swedish University Hospital
Authors: Aspevall Olle , Lundberg Annika , Burman Lars G. , Åkerlund Thomas , Svenungsson Bo 
Published: April 2006

ABSTRACT

All 238
Clostridium difficile
isolates were susceptible to metronidazole and vancomycin, whereas 84% and 1% were resistant to clindamycin and fusidic acid. Etest MICs for metronidazole were lower than agar dilution MICs (
P
< 0.01) but without difference in susceptible-intermediate-resistant categorization. No particular PCR ribotype was associated with clindamycin or fusidic acid resistance.
Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8+T-Cell Epitopes
Authors: Goonetilleke Nilu , Moore Stephen , Dally Len , Winstone Nicola , Cebere Inese , Mahmoud Abdul , Pinheiro Susana , Gillespie Geraldine , Brown Denise , Loach Vanessa , Roberts Joanna , Guimaraes-Walker Ana , Hayes Peter , Loughran Kelley , Smith Carole , De Bont Jan , Verlinde Carl , Vooijs Danii , Schmidt Claudia , Boaz Mark , Gilmour Jill , Fast Pat , Dorrell Lucy , Hanke Tomas , McMichael Andrew J. 
Published: April 2006

ABSTRACTA double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8+T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2× MVA.HIVA) (n= 8) or two doses of placebo (2× placebo) (n= 4). The second group received 2× pTHr.HIVA followed by one dose of MVA.HIVA (n= 8) or 3× placebo (n= 4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-γ) ELISPOT (group mean, 210 spot-forming cells/106cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2× MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-γ ELISPOT assay, positive responses mainly mediated by CD4+T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2× MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4+T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8+T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1β. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.
NS1 Interaction with CKIIα: Novel Protein Complex Mediating Parvovirus-Induced Cytotoxicity
Authors: Nüesch Jürg P. F. , Rommelaere Jean 
Published: April 2006

ABSTRACT

During a productive infection, the prototype strain of the parvovirus minute virus of mice (MVMp) induces dramatic morphological alterations in permissive A9 fibroblasts, culminating in cell lysis at the end of infection. These cytopathic effects (CPE) result from rearrangements and destruction of the cytoskeletal micro- and intermediate filaments, while other structures such as the nuclear lamina and particularly the microtubule network remain protected throughout the infection (J. P. F. Nüesch et al., Virology
331:
159-174, 2005). In order to unravel the mechanism(s) by which parvoviruses trigger CPE, we searched for NS1 interaction partners by differential affinity chromatography, using distinct NS1 mutants debilitated specifically for this function. Thereby, we isolated an NS1 partner polypeptide, whose interaction with NS1 correlated with the competence of the viral product for CPE induction, and further identified it by tandem mass spectrometry and Western blotting analyses to consist of the catalytic subunit of casein kinase II, CKIIα. This interaction of NS1 with CKIIα suggested interference by the viral protein with intracellular signaling. Using permanent cell lines expressing dominant-negative CKIIα mutants, we were able to show that this kinase activity was indeed specifically involved in parvoviral CPE and progeny particle release. Furthermore, the NS1/CKIIα complex proved to be able to specifically phosphorylate viral capsids, indicating a mediator function of NS1 for CKII activity and specificity, at least in vitro. Altogether our data suggest that parvovirus-induced CPE is mediated by NS1 interference with intracellular CKII signaling.
Neutralizing Antibodies Do Not Mediate Suppression of Human Immunodeficiency Virus Type 1 in Elite Suppressors or Selection of Plasma Virus Variants in Patients on Highly Active Antiretroviral Therapy
Authors: Bailey Justin R. , Lassen Kara G. , Yang Hung-Chih , Quinn Thomas C. , Ray Stuart C. , Blankson Joel N. , Siliciano Robert F. 
Published: April 2006

ABSTRACT

Neutralizing antibodies (NAb) against autologous virus can reach high titers in human immunodeficiency virus type 1 (HIV-1)-infected patients with progressive disease. Less is known about the role of NAb in HIV-1-infected patients with viral loads of <50 copies/ml of plasma, including patients on effective highly active antiretroviral therapy (HAART) and elite suppressors, who control HIV-1 replication without antiretroviral therapy. In this study, we analyzed full-length
env
sequences from plasma viruses and proviruses in resting CD4
+
T cells of HAART-treated patients, elite suppressors, and untreated HIV-1-infected patients with progressive disease. For each patient group, we assessed plasma virus neutralization by autologous, contemporaneous plasma. The degree of
env
diversity, the number of N-linked glycosylation sites, and the lengths of variable loops were all lower in elite suppressors than in HAART-treated and untreated viremic patients. Both elite suppressors and HAART-treated patients had lower titers of NAb against HIV-1 lab strains than those of untreated viremic patients. Surprisingly, titers of NAb against autologous, contemporaneous plasma viruses were similarly low in chronic progressors, elite suppressors, and HAART-treated patients. In elite suppressors and HAART-treated patients, titers of NAb against autologous plasma viruses also did not differ significantly from titers against autologous proviruses from resting CD4
+
T cells. These results suggest that high-titer NAb are not required for maintenance of viral suppression in elite suppressors and that NAb do not select plasma virus variants in most HAART-treated patients. Both drug-mediated and natural suppression of HIV-1 replication to levels below 50 copies/ml may limit the stimulation and maintenance of effective NAb responses.
Long-Term-Infected Telomerase-Immortalized Endothelial Cells: a Model for Kaposi's Sarcoma-Associated Herpesvirus Latency In Vitro and In Vivo
Authors: An Feng-Qi , Folarin Hope Merlene , Compitello Nicole , Roth Justin , Gerson Stanton L. , McCrae Keith R. , Fakhari Farnaz D. , Dittmer Dirk P. , Renne Rolf 
Published: April 2006

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. Most KS tumor cells are latently infected with KSHV and are of endothelial origin. While PEL-derived cell lines maintain KSHV indefinitely, all KS tumor-derived cells to date have lost viral genomes upon ex vivo cultivation. To study KSHV latency and tumorigenesis in endothelial cells, we generated
t
elomerase-
i
mmortalized human umbilical
v
ein
e
ndothelial (TIVE) cells. TIVE cells express all KSHV latent genes 48 h postinfection, and productive lytic replication could be induced by RTA/Orf50. Similar to prior models, infected cultures gradually lost viral episomes. However, we also obtained, for the first time, two endothelial cell lines in which KSHV episomes were maintained indefinitely in the absence of selection. Long-term KSHV maintenance correlated with loss of reactivation in response to RTA/Orf50 and complete oncogenic transformation. Long-term-infected TIVE cells (LTC) grew in soft agar and proliferated under reduced-serum conditions. LTC, but not parental TIVE cells, formed tumors in nude mice. These tumors expressed high levels of the latency-associated nuclear antigen (LANA) and expressed lymphatic endothelial specific antigens as found in KS (LYVE-1). Furthermore, host genes, like those encoding interleukin 6, vascular endothelial growth factor, and basic fibroblast growth factor, known to be highly expressed in KS lesions were also induced in LTC-derived tumors. KSHV-infected LTCs represent the first xenograft model for KS and should be of use to study KS pathogenesis and for the validation of anti-KS drug candidates.
N-Glycans on Nipah Virus Fusion Protein Protect against Neutralization but Reduce Membrane Fusion and Viral Entry
Authors: Aguilar Hector C. , Matreyek Kenneth A. , Filone Claire Marie , Hashimi Sara T. , Levroney Ernest L. , Negrete Oscar A. , Bertolotti-Ciarlet Andrea , Choi Daniel Y. , McHardy Ian , Fulcher Jennifer A. , Su Stephen V. , Wolf Mike C. , Kohatsu Luciana , Baum Linda G. , Lee Benhur 
Published: April 2006

ABSTRACTNipah virus (NiV) is a deadly emerging paramyxovirus. The NiV attachment (NiV-G) and fusion (NiV-F) envelope glycoproteins mediate both syncytium formation and viral entry. Specific N-glycans on paramyxovirus fusion proteins are generally required for proper conformational integrity and biological function. However, removal of individual N-glycans on NiV-F had little negative effect on processing or fusogenicity and has even resulted in slightly increased fusogenicity. Here, we report that in both syncytium formation and viral entry assays, removal of multiple N-glycans on NiV-F resulted in marked increases in fusogenicity (>5-fold) but also resulted in increased sensitivity to neutralization by NiV-F-specific antisera. The mechanism underlying the hyperfusogenicity of these NiV-F N-glycan mutants is likely due to more-robust six-helix bundle formation, as these mutants showed increased fusion kinetics and were more resistant to neutralization by a fusion-inhibitory reagent based on the C-terminal heptad repeat region of NiV-F. Finally, we demonstrate that the fusogenicities of the NiV-F N-glycan mutants were inversely correlated with the relative avidities of NiV-F's interactions with NiV-G, providing support for the attachment protein “displacement” model of paramyxovirus fusion. Our results indicate that N-glycans on NiV-F protect NiV from antibody neutralization, suggest that this “shielding” role comes together with limiting cell-cell fusion and viral entry efficiencies, and point to the mechanisms underlying the hyperfusogenicity of these N-glycan mutants. These features underscore the varied roles that N-glycans on NiV-F play in the pathobiology of NiV entry but also shed light on the general mechanisms of paramyxovirus fusion with host cells.
Human Rhinovirus Attenuates the Type I Interferon Response by Disrupting Activation of Interferon Regulatory Factor 3
Authors: Peng Tao , Kotla Swathi , Bumgarner Roger E. , Gustin Kurt E. 
Published: April 2006

ABSTRACTThe type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-κB, interferon regulatory factor 3 (IRF-3), and ATF-2, which in turn activate transcription from the IFN-β promoter. Synthesis and subsequent secretion of IFN-β activate the Jak/STAT signaling pathway, resulting in the transcriptional induction of the full spectrum of antiviral gene products. We utilized high-density microarrays to examine the transcriptional response to rhinovirus type 14 (RV14) infection in HeLa cells, with particular emphasis on the type I interferon response and production of IFN-β. We found that, although RV14 infection results in altered levels of a wide variety of host mRNAs, induction of IFN-β mRNA or activation of the Jak/STAT pathway is not seen. Prior work has shown, and our results have confirmed, that NF-κB and ATF-2 are activated following infection. Since many viruses are known to target IRF-3 to inhibit the induction of IFN-β mRNA, we analyzed the status of IRF-3 in infected cells. IRF-3 was translocated to the nucleus and phosphorylated in RV14-infected cells. Despite this apparent activation, very little homodimerization of IRF-3 was evident following infection. Similar results in A549 lung alveolar epithelial cells demonstrated the biological relevance of these findings to RV14 pathogenesis. In addition, prior infection of cells with RV14 prevented the induction of IFN-β mRNA following treatment with double-stranded RNA, indicating that RV14 encodes an activity that specifically inhibits this innate host defense pathway. Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.
Alpha and Lambda Interferon Together Mediate Suppression of CD4 T Cells Induced by Respiratory Syncytial Virus
Authors: Chi Bo , Dickensheets Harold L. , Spann Kirsten M. , Alston Marc A. , Luongo Cindy , Dumoutier Laure , Huang Jiaying , Renauld Jean-Christophe , Kotenko Sergei V. , Roederer Mario , Beeler Judy A. , Donnelly Raymond P. , Collins Peter L. , Rabin Ronald L. 
Published: April 2006

ABSTRACTThe mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [3H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus orStaphylococcusenterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-α; median, 43 pg/ml) and IFN-λ (approximately 1 to 20 ng/ml). Neutralization of IFN-α with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-λ with MAb against either of its receptor chains, IFN-λR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.
Isolation and Genetic Characterization of New Reassortant H3N1 Swine Influenza Virus from Pigs in the Midwestern United States
Authors: Ma Wenjun , Gramer Marie , Rossow Kurt , Yoon Kyoung-Jin 
Published: April 2006

ABSTRACT
Since the introduction of H3N2 swine influenza viruses (SIVs) into U.S. swine in 1998, H1N2 and H1N1 reassortant viruses have emerged from reassortment between classical H1N1 and H3N2 viruses. In 2004, a new reassortant H3N1 virus (A/Swine/Minnesota/00395/2004) was identified from coughing pigs. Phylogenetic analyses revealed a hemagglutinin segment similar to those of contemporary cluster III H3N2 SIVs and a neuraminidase sequence of contemporary H1N1 origin. The internal genes were of swine, human, and avian influenza virus origin, similar to those of contemporary U.S. cluster III H3N2 SIVs. The recovery of H3N1 is further evidence of reassortment among SIVs and justifies continuous surveillance.
Immunoglobulin GM and KM Allotypes and Prevalence of Anti-LKM1 Autoantibodies in Patients with Hepatitis C Virus Infection
Authors: Muratori Paolo , Sutherland Susan E. , Muratori Luigi , Granito Alessandro , Guidi Marcello , Pappas Georges , Lenzi Marco , Bianchi Francesco B. , Pandey Janardan P. 
Published: April 2006

ABSTRACTGM and KM allotypes—genetic markers of immunoglobulin (Ig) γ and κ chains, respectively—are associated with humoral immunity to several infection- and autoimmunity-related epitopes. We hypothesized that GM and KM allotypes contribute to the generation of autoantibodies to liver/kidney microsomal antigen 1 (LKM1) in hepatitis C virus (HCV)-infected persons. To test this hypothesis, we characterized 129 persons with persistent HCV infection for several GM and KM markers and for anti-LKM1 antibodies. The heterozygous GM 1,3,17 23 5,13,21 phenotype was significantly associated with the prevalence of anti-LKM1 antibodies (odds ratio, 5.13;P= 0.002), suggesting its involvement in this autoimmune phenomenon in HCV infection.
Are “Great Salinity Anomalies” Advective?
Authors: Wadley Martin R. , Bigg Grant R. 
Published: April 2006

Abstract
“Great Salinity Anomalies” (GSAs) have been observed to propagate around the North Atlantic subpolar gyre. Similar anomalies occur in the Third Hadley Centre Coupled Atmosphere–Ocean GCM (HadCM3) of preindustrial climate. It has been hypothesized that these salinity anomalies result from the advection of anomalously low salinity waters around the subpolar gyre. Here, the consequences of using passive tracers in the HadCM3 climate model to tag the anomalously low salinity water associated with a GSA in the Greenland and Labrador Seas are reported. Rather than predominantly advecting around the modeled subpolar gyre in accordance with the upper-ocean salinity anomaly, the tracers mix to intermediate depths, before becoming incorporated into the model's North Atlantic Deep Water. Horizontal advection of the tracer in the upper ocean is limited to around 1000 km, compared with the gyre-scale propagation of the salinity anomalies. It is concluded that GSAs are unlikely to be caused by the advection of salinity anomalies; rather anomalous oceanic currents or surface fluxes are responsible.
Twenty-First-Century Climate Impacts from a Declining Arctic Sea Ice Cover
Authors: Singarayer Joy S. , Bamber Jonathan L. , Valdes Paul J. 
Published: April 2006

Abstract
A steady decline in Arctic sea ice has been observed over recent decades. General circulation models predict further decreases under increasing greenhouse gas scenarios. Sea ice plays an important role in the climate system in that it influences ocean-to-atmosphere fluxes, surface albedo, and ocean buoyancy. The aim of this study is to isolate the climate impacts of a declining Arctic sea ice cover during the current century. The Hadley Centre Atmospheric Model (HadAM3) is forced with observed sea ice from 1980 to 2000 (obtained from satellite passive microwave radiometer data derived with the Bootstrap algorithm) and predicted sea ice reductions until 2100 under one moderate scenario and one severe scenario of ice decline, with a climatological SST field and increasing SSTs. Significant warming of the Arctic occurs during the twenty-first century (mean increase of between 1.6° and 3.9°C), with positive anomalies of up to 22°C locally. The majority of this is over ocean and limited to high latitudes, in contrast to recent observations of Northern Hemisphere warming. When a climatological SST field is used, statistically significant impacts on climate are only seen in winter, despite prescribing sea ice reductions in all months. When correspondingly increasing SSTs are incorporated, changes in climate are seen in both winter and summer, although the impacts in summer are much smaller. Alterations in atmospheric circulation and precipitation patterns are more widespread than temperature, extending down to midlatitude storm tracks. Results suggest that areas of Arctic land ice may even undergo net accumulation due to increased precipitation that results from loss of sea ice. Intensification of storm tracks implies that parts of Europe may experience higher precipitation rates.