bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sox proteins in melanocyte development and melanoma
Authors: Harris Melissa L. , Baxter Laura L. , Loftus Stacie K. , Pavan William J. 
Published: April 2010

SummaryOver 10 years have passed since the first Sox gene was implicated in melanocyte development. Since then, we have discovered that SOX5, SOX9, SOX10 and SOX18 all participate as transcription factors that affect key melanocytic genes in both regulatory and modulatory fashions. Both SOX9 and SOX10 play major roles in the establishment and normal function of the melanocyte; SOX10 has been shown to heavily influence melanocyte development and SOX9 has been implicated in melanogenesis in the adult. Despite these advances, the precise cellular and molecular details of how these SOX proteins are regulated and interact during all stages of the melanocyte life cycle remain unknown. Improper regulation of SOX9 or SOX10 is also associated with cancerous transformation, and thus understanding the normal function of SOX proteins in the melanocyte will be key to revealing how these proteins contribute to melanoma.
A lower bound for Garsia’s entropy for certain Bernoulli convolutions
Authors: Hare Kevin G. , Sidorov Nikita 
Published: April 2010

AbstractLet β∈(1,2) be a Pisot number and let Hβ denote Garsia’s entropy for the Bernoulli convolution associated with β. Garsia, in 1963, showed that Hβ<1 for any Pisot β. For the Pisot numbers which satisfy xm=xm−1+xm−2+⋯+x+1 (with m≥2), Garsia’s entropy has been evaluated with high precision by Alexander and Zagier for m=2 and later by Grabner, Kirschenhofer and Tichy for m≥3, and it proves to be close to 1. No other numerical values for Hβ are known. In the present paper we show that Hβ>0.81 for all Pisot β, and improve this lower bound for certain ranges of β. Our method is computational in nature.
Utility of a Commercial Nonstructural Protein 1 Antigen Capture Kit as a Dengue Virus Diagnostic Tool
Authors: Bessoff Kovi , Phoutrides Elena , Delorey Mark , Acosta Luz N. , Hunsperger Elizabeth 
Published: April 2010

ABSTRACT
Annually, over 2.5 billion people are at risk for infection with dengue virus (DENV), while between 50 and 100 million people contract the infection. There is an urgent need for alternative diagnostic tools that can detect DENV during acute infection. Recent studies have shown that DENV nonstructural protein 1 (NS1) is detectable in the blood as early as the onset of symptoms and persists well into the convalescent phase of the infection. We evaluated the utility of the Bio-Rad Platelia DENV NS1 antigen capture kit in combination with real-time reverse transcriptase PCR (RT-PCR) and an IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) for refining a new algorithm for the diagnosis of acute- or convalescent-phase DENV infection with a single clinical sample. We tested the Bio-Rad kit with three panels of sera. These panels were designed to evaluate the sensitivities of the NS1 kit for (i) early-convalescent-phase samples, (ii) acute-phase samples with false-negative PCR results, and (iii) IgM-negative convalescent-phase samples from patients with confirmed secondary DENV infections. Results show that NS1 can be detected in 22% of serum samples collected more than 10 days after the onset of illness and in 22% of samples that did not elicit an IgM response. Additionally, NS1 was detected in 37% of the tested acute-phase samples with false-negative PCR results, suggesting that NS1 detection may be valuable in increasing the sensitivity of current acute-phase diagnostics. These results will improve diagnosis with a single acute-phase or early-convalescent-phase sample for disease surveillance and clinical diagnosis.
Impact of
Pseudomonas aeruginosa
Genomic Instability on the Application of Typing Methods for Chronic Cystic Fibrosis Infections
Authors: Fothergill Joanne L. , White Judith , Foweraker Juliet E. , Walshaw Martin J. , Ledson Martin J. , Mahenthiralingam Eshwar , Winstanley Craig 
Published: April 2010

ABSTRACT

The Liverpool epidemic strain (LES) of
Pseudomonas aeruginosa
is widespread among cystic fibrosis (CF) patients in the United Kingdom and has emerged recently in North America. In this study, we report the analysis of 24 “anomalous” CF isolates of
P. aeruginosa
that produced inconsistent results with regard to either pulsed-field gel electrophoresis (PFGE) or PCR tests for the LES. We used a new typing method, the ArrayTube genotyping system, to determine that of the 24 anomalous isolates tested, 13 were confirmed as the LES. LES isolates could not be clearly distinguished from non-LES isolates by two other commonly used genetic fingerprinting tests, randomly amplified polymorphic DNA (RAPD) analysis and BOX-PCR, and varied considerably in their carriage of LES genomic islands and prophages. The genomic instability of the LES suggests that identification of this emerging transmissible strain could be a challenging task, and it questions whether discrimination is always a desirable feature of bacterial typing methods in the context of chronic CF infections.
Evidence for a Second Genomic Island Conferring Multidrug Resistance in a Clonal Group of Strains of
Salmonella
enterica
Serovar Typhimurium and its Monophasic Variant Circulating in Italy, Denmark, and the United Kingdom
Authors: Lucarelli Claudia , Dionisi Anna Maria , Torpdahl Mia , Villa Laura , Graziani Caterina , Hopkins Katie , Threlfall John , Caprioli Alfredo , Luzzi Ida 
Published: April 2010

ABSTRACT

During the 2000s, a new clonal group with resistances to ampicillin, streptomycin, sulfonamides, and tetracycline (ASSuT) emerged in Italy among strains of
Salmonella enterica
serovar Typhimurium and its monophasic variant,
Salmonella enterica
subspecies
enterica
serovar 4,[5],12:i:−. The PulseNet Europe database allowed us to identify ASSuT strains of both
S
. Typhimurium and its monophasic variant, isolated in Denmark and the United Kingdom, with the same or very closely related pulsed-field gel electrophoresis (PFGE) patterns as the Italian strains, suggesting that the ASSuT clonal group is circulating in different European countries. With the aim of analyzing the molecular basis of antibiotic resistance, resistance genes were identified and their localization was investigated in 66 ASSuT strains and, as controls, in 11 strains with different resistance patterns and PFGE profiles, belonging both to
S
. Typhimurium and to its monophasic variant, isolated from humans in Italy, Denmark, and the United Kingdom. All the ASSuT strains were positive for the following resistance genes:
bla
TEM-1
,
strA
-
strB
,
sul
2, and
tet
(B). A localization experiment demonstrated that the ASSuT resistance genes are chromosomally located. This study confirms that a multidrug-resistant clonal group, ASSuT, of
S
. Typhimurium and its monophasic variant has emerged and is circulating in Italy, Denmark, and the United Kingdom. Moreover, the results of this work demonstrate that the multidrug resistance in this clonal group of
Salmonella
strains is conferred by a new genomic island.
Respiratory Syncytial Virus-Mediated NF-κB p65 Phosphorylation at Serine 536 Is Dependent on RIG-I, TRAF6, and IKKβ
Authors: Yoboua Fabrice , Martel Alexis , Duval Annick , Mukawera Espérance , Grandvaux Nathalie 
Published: April 2010

ABSTRACT
Respiratory syncytial virus (RSV) is the etiological agent of acute respiratory diseases, such as bronchiolitis and pneumonia. The exacerbated production of proinflammatory cytokines and chemokines in the airways in response to RSV is an important pillar in the development of these pathologies. As such, a keen understanding of the mechanisms that modulate the inflammatory response during RSV infection is of pivotal importance to developing effective treatment. The NF-κB transcription factor is a major regulator of proinflammatory cytokine and chemokine genes. However, RSV-mediated activation of NF-κB is far from characterized. We recently demonstrated that aside from the well-characterized IκBα phosphorylation and degradation, the phosphorylation of p65 at Ser536 is an essential event regulating the RSV-mediated NF-κB-dependent promoter transactivation. In the present study, using small interfering RNA and pharmacological inhibitors, we now demonstrate that RSV sensing by the RIG-I cytoplasmic receptor triggers a signaling cascade involving the MAVS and TRAF6 adaptors that ultimately leads to p65ser536 phosphorylation by the IKKβ kinase. In a previous study, we highlighted a critical role of the NOX2-containing NADPH oxidase enzyme as an upstream regulator of both the IκBαSer32 and p65Ser536 in human airway epithelial cells. Here, we demonstrate that inhibition of NOX2 significantly decreases IKKβ activation. Taken together, our data identify a new RIG-I/MAVS/TRAF6/IKKβ/p65Ser536 pathway placed under the control of NOX2, thus characterizing a novel regulatory pathway involved in NF-κB-driven proinflammatory response in the context of RSV infection.
TRIM5α Disrupts the Structure of Assembled HIV-1 Capsid Complexes
In Vitro
Authors: Black Lesa R. , Aiken Christopher 
Published: April 2010

ABSTRACT

The host restriction factor TRIM5α provides intrinsic defense against retroviral infections in mammalian cells. TRIM5α blocks infection by targeting the viral capsid after entry but prior to completion of reverse transcription, but whether this interaction directly alters the structure of the viral capsid is unknown. A previous study reported that rhesus macaque TRIM5α protein stably associates with cylindrical complexes formed by assembly of recombinant HIV-1 CA-NC protein
in vitro
and that restriction leads to accelerated HIV-1 uncoating in target cells. To gain further insight into the mechanism of TRIM5α-dependent restriction, we examined the structural effects of TRIM5 proteins on preassembled CA-NC complexes by electron microscopy. Incubation of assembled complexes with lysate of cells expressing the restrictive rhesus TRIM5α protein resulted in marked disruption of the normal cylindrical structure of the complexes. In contrast, incubation with lysate of control cells or cells expressing comparable levels of the nonrestrictive human TRIM5α protein had little effect on the complexes. Incubation with lysate of cells expressing the TRIMCyp restriction factor also disrupted the cylinders. The effect of TRIMCyp was prevented by the addition of cyclosporine, which inhibits binding of TRIMCyp to the HIV-1 capsid. Thus, disruption of CA-NC cylinders by TRIM5α and TRIMCyp was correlated with the specificity of restriction. Collectively, these results suggest that TRIM5α-dependent restriction of HIV-1 infection results from structural perturbation of the viral capsid leading to aberrant HIV-1 uncoating in target cells.
Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs
Authors: Li Jianhua , Lin Shanshan , Chen Qiying , Peng Lu , Zhai Jianwei , Liu Yinghui , Yuan Zhenghong 
Published: April 2010

ABSTRACT
Myeloid differentiation primary response protein 88 (MyD88), which can be induced by alpha interferon (IFN-α), has an antiviral activity against the hepatitis B virus (HBV). The mechanism of this antiviral activity remains poorly understood. Here, we report that MyD88 inhibited HBV replication in HepG2.2.15 cells and in a mouse model. The knockdown of MyD88 expression weakened the IFN-α-induced inhibition of HBV replication. Furthermore, MyD88 posttranscriptionally reduced the levels of viral RNA. Remarkably, MyD88 accelerated the decay of viral pregenomic RNA in the cytoplasm. Mapping analysis showed that the RNA sequence located in the 5′-proximal region of the pregenomic RNA was critical for the decay. In addition, MyD88 inhibited the nuclear export of pre-S/S RNAs via the posttranscriptional regulatory element (PRE). The retained pre-S/S RNAs were shown to degrade in the nucleus. Finally, we found that MyD88 inhibited the expression of polypyrimidine tract-binding protein (PTB), a key nuclear export factor for PRE-containing RNA. Taken together, our results define a novel antiviral mechanism against HBV mediated by MyD88.
Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus
Authors: Miao Hongyu , Hollenbaugh Joseph A. , Zand Martin S. , Holden-Wiltse Jeanne , Mosmann Tim R. , Perelson Alan S. , Wu Hulin , Topham David J. 
Published: April 2010

ABSTRACTSeasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ∼1.2 days, and the half-life of free infectious IAV is ∼4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ∼0.5 days, and the average half-life of free infectious virus is ∼1.8 min. During the adaptive phase, model fitting confirms that CD8+CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.
Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease
Authors: Lin Ying-Chuan , Torbett Bruce E. , Elder John H. 
Published: April 2010

ABSTRACT

Feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteases (PRs) share only 23% amino acid identity and exhibit distinct specificities yet have very similar 3-dimensional structures. Chimeric PRs in which HIV residues were substituted in structurally equivalent positions in FIV PR were prepared in order to study the molecular basis of PR specificity. Previous
in vitro
analyses showed that such substitutions dramatically altered the inhibitor specificity of mutant PRs but changed the rate and specificity of Gag cleavage so that chimeric FIVs were not infectious. Chimeric PRs encoding combinations of the I37V, N55M, M56I, V59I, L97T, I98P, Q99V, and P100N mutations were cloned into FIV Gag-Pol, and those constructs that best approximated the temporal cleavage pattern generated by wild-type FIV PR, while maintaining HIV-like inhibitor specificity, were selected. Two mutations, M56I and L97T, were intolerant to change and caused inefficient cleavage at NC-p2. However, a mutant PR with six substitutions (I37V, N55M, V59I, I98P, Q99V, and P100N) was selected and placed in the context of full-length FIV-34TF10. This virus, termed YCL6, had low-level infectivity
ex vivo
, and after passage, progeny that exhibited a higher growth rate emerged. The residue at the position of one of the six mutations, I98P, further mutated on passage to either P98H or P98S. Both PRs were sensitive to the HIV-1 PR inhibitors lopinavir (LPV) and darunavir (DRV), as well as to the broad-based inhibitor TL-3, with 50% inhibitory concentrations (IC
50
) of 30 to 40 nM, consistent with
ex vivo
results obtained using mutant FIVs. The chimeras offer an infectivity system with which to screen compounds for potential as broad-based PR inhibitors, define structural parameters that dictate specificity, and investigate pathways for drug resistance development.
Productive Infection and bICP0 Early Promoter Activity of Bovine Herpesvirus 1 Are Stimulated by E2F1
Authors: Workman Aspen , Jones Clinton 
Published: April 2010

ABSTRACT

Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen of cattle. Like other members of the subfamily
Alphaherpesvirinae
, BoHV-1 establishes latency in sensory neurons and has the potential to reactivate from latency. Dexamethasone (DEX) treatment of latently infected calves or rabbits consistently leads to reactivation from latency. The BoHV-1 transcript encoding the infected cell protein 0 (bICP0) is consistently detected during reactivation from latency, in part because the bICP0 early promoter is activated by DEX. During DEX-induced reactivation from latency, cyclin expression is stimulated in infected sensory neurons. Cyclin-dependent kinase activity phosphorylates Rb (retinoblastoma tumor suppressor gene product) family proteins and consequently releases the E2F family of transcription factors, suggesting that E2F family members stimulate productive infection and/or reactivation from latency. In this study, we provide evidence that repression of E2F1 by a specific small interfering RNA (siRNA) reduced productive infection approximately 5-fold. E2F1 or E2F2 stimulated bICP0 early promoter activity at least 100-fold in transient transfection assays. Two E2F-responsive regions (ERR) were identified within the early promoter, with one adjacent to the TATA box (ERR1) and one approximately 600 bp upstream from the TATA box (ERR2). Mobility shift assays suggested that E2F interacts with ERR1 and ERR2. E2F1 protein levels were increased at late times after infection, which correlated with enhanced binding to a consensus E2F binding site, ERR1, or ERR2. Collectively, these studies suggest that E2F1 stimulates productive infection and bICP0 early promoter activity, in part because E2F family members interact with ERR1 and ERR2.
Epstein-Barr Virus Latent Membrane Protein 1 Modulates Distinctive NF-κB Pathways through C-Terminus-Activating Region 1 To Regulate Epidermal Growth Factor Receptor Expression
Authors: Kung Che-Pei , Raab-Traub Nancy 
Published: April 2010

ABSTRACT

Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1) is required for EBV B-lymphocyte transformation, transforms rodent fibroblasts, and can induce lymphoma and epithelial hyperplasia in transgenic mice. Two domains have been identified within the intracellular carboxy terminus that can activate NF-κB, C-terminus-activating region 1 (CTAR1) and CTAR2, through interactions with tumor necrosis receptor-associated factors (TRAFs). CTAR1 can activate both the canonical and noncanonical NF-κB pathways and has unique effects on cellular gene expression. The epidermal growth factor receptor (EGFR) is highly induced by LMP1-CTAR1 in epithelial cells through activation of a novel NF-κB form containing p50 homodimers and Bcl-3. To further understand the regulation of NF-κB in CTAR1-induced EGFR expression, we evaluated the ability of CTAR1 to induce EGFR in mouse embryonic fibroblasts (MEFs) defective for different NF-κB effectors. CTAR1-mediated EGFR induction required the

N

F-κB-

i

nducing

k

inase (NIK) but not the IκB kinase (IKK) complex components that regulate canonical or noncanonical NF-κB pathways. CTAR1-mediated induction of nuclear p50 occurred in IKKβ-, IKKγ-, and NIK-defective MEFs, indicating that this induction is not dependent on the canonical or noncanonical NF-κB pathways. EGFR and nuclear p50 were expressed at high levels in TRAF2
−/−
fibroblasts and were not induced by CTAR1. In TRAF3
−/−
MEFs, CTAR1 induced nuclear p50 but did not affect basal levels of STAT3 serine phosphorylation or induce EGFR expression. EGFR was induced by LMP1 in TRAF6
−/−
MEFs. These findings suggest that this novel NF-κB pathway is differentially regulated by TRAF2 and TRAF3, and that distinct interactions of LMP1 and its effectors regulate LMP1-mediated gene expression.
Three Arginine Residues within the RGG Box Are Crucial for ICP27 Binding to Herpes Simplex Virus 1 GC-Rich Sequences and for Efficient Viral RNA Export
Authors: Corbin-Lickfett Kara A. , Souki Stuart K. , Cocco Melanie J. , Sandri-Goldin Rozanne M. 
Published: April 2010

ABSTRACT

ICP27 is a multifunctional protein that is required for herpes simplex virus 1 mRNA export. ICP27 interacts with the mRNA export receptor TAP/NXF1 and binds RNA through an RGG box motif. Unlike other RGG box proteins, ICP27 does not bind G-quartet structures but instead binds GC-rich sequences that are flexible in structure. To determine the contribution of arginines within the RGG box, we performed
in vitro
binding assays with N-terminal proteins encoding amino acids 1 to 160 of wild-type ICP27 or arginine-to-lysine substitution mutants. The R138,148,150K triple mutant bound weakly to sequences that were bound by the wild-type protein and single and double mutants. Furthermore, during infection with the R138,148,150K mutant, poly(A)
+
RNA and newly transcribed RNA accumulated in the nucleus, indicating that viral RNA export was impaired. To determine if structural changes had occurred, nuclear magnetic resonance (NMR) analysis was performed on N-terminal proteins consisting of amino acids 1 to 160 from wild-type ICP27 and the R138,148,150K mutant. This region of ICP27 was found to be highly flexible, and there were no apparent differences in the spectra seen with wild-type ICP27 and the R138,148,150K mutant. Furthermore, NMR analysis with the wild-type protein bound to GC-rich sequences did not show any discernible folding. We conclude that arginines at positions 138, 148, and 150 within the RGG box of ICP27 are required for binding to GC-rich sequences and that the N-terminal portion of ICP27 is highly flexible in structure, which may account for its preference for binding flexible sequences.
Cytotoxic T Lymphocytes Established by Seasonal Human Influenza Cross-React against 2009 Pandemic H1N1 Influenza Virus
Authors: Tu Wenwei , Mao Huawei , Zheng Jian , Liu Yinping , Chiu Susan S. , Qin Gang , Chan Ping-Lung , Lam Kwok-Tai , Guan Jing , Zhang Lijuan , Guan Yi , Yuen Kwok-Yung , Peiris J. S. Malik , Lau Yu-Lung 
Published: April 2010

ABSTRACTWhile few children and young adults have cross-protective antibodies to the pandemic H1N1 2009 (pdmH1N1) virus, the illness remains mild. The biological reasons for these epidemiological observations are unclear. In this study, we demonstrate that the bulk memory cytotoxic T lymphocytes (CTLs) established by seasonal influenza viruses from healthy individuals who have not been exposed to pdmH1N1 can directly lyse pdmH1N1-infected target cells and produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Using influenza A virus matrix protein 1 (M158-66) epitope-specific CTLs isolated from healthy HLA-A2+individuals, we further found that M158-66epitope-specific CTLs efficiently killed both M158-66peptide-pulsed and pdmH1N1-infected target cells ex vivo. These M158-66-specific CTLs showed an effector memory phenotype and expressed CXCR3 and CCR5 chemokine receptors. Of 94 influenza A virus CD8 T-cell epitopes obtained from the Immune Epitope Database (IEDB), 17 epitopes are conserved in pdmH1N1, and more than half of these conserved epitopes are derived from M1 protein. In addition, 65% (11/17) of these epitopes were 100% conserved in seasonal influenza vaccine H1N1 strains during the last 20 years. Importantly, seasonal influenza vaccination could expand the functional M158-66epitope-specific CTLs in 20% (4/20) of HLA-A2+individuals. Our results indicated that memory CTLs established by seasonal influenza A viruses or vaccines had cross-reactivity against pdmH1N1. These might explain, at least in part, the unexpected mild pdmH1N1 illness in the community and also might provide some valuable insights for the future design of broadly protective vaccines to prevent influenza, especially pandemic influenza.