bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simian Virus 40 Activates ATR-Δp53 Signaling To Override Cell Cycle and DNA Replication Control
Authors: Rohaly Gabor , Korf Katharina , Dehde Silke , Dornreiter Irena 
Published: August 2010

ABSTRACT
During infection, simian virus 40 (SV40) attempts to take hold of the cell, while the host responds with various defense systems, including the ataxia-telangiectasia mutated/ATM-Rad3 related (ATM/ATR)-mediated DNA damage response pathways. Here we show that upon viral infection, ATR directly activates the p53 isoform Δp53, leading to upregulation of the Cdk inhibitor p21 and downregulation of cyclin A-Cdk2/1 (AK) activity, which force the host to stay in the replicative S phase. Moreover, downregulation of AK activity is a prerequisite for the generation of hypophosphorylated, origin-competent DNA polymerase α-primase (hypo-Polα), which is, unlike AK-phosphorylated Polα (P-Polα), recruited by SV40 large T antigen (T-Ag) to initiate viral DNA replication. Prevention of the downregulation of AK activity by inactivation of ATR-Δp53-p21 signaling significantly reduced the T-Ag-interacting hypo-Polα population and, accordingly, SV40 replication efficiency. Moreover, the ATR-Δp53 pathway facilitates the proteasomal degradation of the 180-kDa catalytic subunit of the non-T-Ag-interacting P-Polα, giving rise to T-Ag-interacting hypo-Polα. Thus, the purpose of activating the ATR-Δp53-p21-mediated intra-S checkpoint is to maintain the host in S phase, an optimal environment for SV40 replication, and to modulate the host DNA replicase, which is indispensable for viral amplification.
Variable Loop Glycan Dependency of the Broad and Potent HIV-1-Neutralizing Antibodies PG9 and PG16
Authors: Doores Katie J. , Burton Dennis R. 
Published: August 2010

ABSTRACT

The HIV-1-specific antibodies PG9 and PG16 show marked cross-isolate neutralization breadth and potency. Antibody neutralization has been shown to be dependent on the presence of N-linked glycosylation at position 160 in gp120. We show here that (i) the loss of several key glycosylation sites in the V1, V2, and V3 loops; (ii) the generation of pseudoviruses in the presence of various glycosidase inhibitors; and (iii) the growth of pseudoviruses in a mutant cell line (GnT1
−/−
) that alters envelope glycosylation patterns all have significant effects on the sensitivity of virus to neutralization by PG9 and PG16. However, the interaction of antibody is not inhibited by sugar monosaccharides corresponding to those found in glycans on the HIV surface. We show that some of the glycosylation effects described are isolate dependent and others are universal and can be used as diagnostic for the presence of PG9 and PG16-like antibodies in the sera of HIV-1-infected patients. The results suggest that PG9 and PG16 recognize a conformational epitope that is dependent on glycosylation at specific variable loop N-linked sites. This information may be valuable for the design of immunogens to elicit PG9 and PG16-like antibodies, as well as constructs for cocrystallization studies.
Long-Term Restriction by APOBEC3F Selects Human Immunodeficiency Virus Type 1 Variants with Restored Vif Function
Authors: Albin John S. , Haché Guylaine , Hultquist Judd F. , Brown William L. , Harris Reuben S. 
Published: August 2010

ABSTRACT

Tandem stop mutations K26X and H27X in human immunodeficiency virus type 1 (HIV-1)
vif
compromise virus replication in human T-cell lines that stably express APOBEC3F (A3F) or APOBEC3G (A3G). We previously reported that partial resistance to A3G could develop in these Vif-deficient viruses through a nucleotide A200-to-T/C transversion and a
vpr
null mutation, but these isolates were still susceptible to restriction by A3F. Here, long-term selection experiments were done to determine how these A3G-selected isolates might evolve to spread in the presence of A3F. We found that A3F, like A3G, is capable of potent, long-term restriction that eventually selects for heritable resistance. In all 7 instances, the selected isolates had restored Vif function to cope with A3F activity. In two isolates, Vif Q26-Q27 and Y26-Q27, the resistance phenotype recapitulated in molecular clones, but when the selected
vif
alleles were analyzed in the context of an otherwise wild-type viral background, a different outcome emerged. Although HIV-1 clones with Vif Q26-Q27 or Y26-Q27 were fully capable of overcoming A3F, they were now susceptible to restriction by A3G. Concordant with prior studies, a lysine at position 26 proved essential for A3G neutralization. These data combine to indicate that A3F and A3G exert at least partly distinct selective pressures and that Vif function may be essential for the virus to replicate in the presence of A3F.
Chromosomal Integration of Adenoviral Vector DNA
In Vivo
Authors: Stephen Sam Laurel , Montini Eugenio , Sivanandam Vijayshankar Ganesh , Al-Dhalimy Muhseen , Kestler Hans A. , Finegold Milton , Grompe Markus , Kochanek Stefan 
Published: August 2010

ABSTRACT

So far there has been no report of any clinical or preclinical evidence for chromosomal vector integration following adenovirus (Ad) vector-mediated gene transfer
in vivo
. We used liver gene transfer with high-capacity Ad vectors in the FAH
Δexon5
mouse model to analyze homologous and heterologous recombination events between vector and chromosomal DNA. Intravenous injection of Ad vectors either expressing a fumarylacetoacetate hydrolase (FAH) cDNA or carrying part of the FAH genomic locus resulted in liver nodules of FAH-expressing hepatocytes, demonstrating chromosomal vector integration. Analysis of junctions between vector and chromosomal DNA following heterologous recombination indicated integration of the vector genome through its termini. Heterologous recombination occurred with a median frequency of 6.72 × 10
−5
per transduced hepatocyte, while homologous recombination occurred more rarely with a median frequency of 3.88 × 10
−7
. This study has established quantitative and qualitative data on recombination of adenoviral vector DNA with genomic DNA
in vivo
, contributing to a risk-benefit assessment of the biosafety of Ad vector-mediated gene transfer.
Convergence of Kaposi's Sarcoma-Associated Herpesvirus Reactivation with Epstein-Barr Virus Latency and Cellular Growth Mediated by the Notch Signaling Pathway in Coinfected Cells
Authors: Spadavecchia Sophia , Gonzalez-Lopez Olga , Carroll Kyla Driscoll , Palmeri Diana , Lukac David M. 
Published: August 2010

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL). All PEL cell lines are infected with KSHV, and 70% are coinfected with Epstein-Barr virus (EBV). KSHV reactivation from latency requires promoter-specific transactivation by the KSHV Rta protein through interactions with RBP-Jk (CSL), the cellular DNA-binding component of the Notch signal transduction pathway. EBV transformation of primary B cells requires EBV nuclear antigen 2 (EBNA-2) to interact with RBP-Jk to direct the latent viral and cellular gene expression program. Although KSHV Rta and EBV EBNA-2 both require RBP-Jk for transactivation, previous studies have suggested that RBP-Jk-dependent transactivators do not function identically. We have found that the EBV latent protein LMP-1 is expressed in less than 5% of KSHV
+
/EBV
+
PEL cells but is induced in an Rta-dependent fashion when KSHV reactivates. KSHV Rta transactivates the EBV latency promoters in an RBP-Jk-dependent fashion and forms a ternary complex with RBP-Jk on the promoters. In B cells that are conditionally transformed by EBV alone, we show that KSHV Rta complements a short-term EBNA-2 growth deficiency in an autocrine/paracrine manner. Complementation of EBNA-2 deficiency by Rta depends on RBP-Jk and LMP-1, and Rta transactivation is required for optimal growth of KSHV
+
/EBV
+
PEL lines. Our data suggest that Rta can contribute to EBV-driven cellular growth by transactivating RBP-Jk-dependent EBV latency genes. However, our data also suggest that EBNA-2 and Rta induce distinct alterations in the cellular proteomes that contribute to the growth of infected cells.
Basic Residues within the Ebolavirus VP35 Protein Are Required for Its Viral Polymerase Cofactor Function
Authors: Prins Kathleen C. , Binning Jennifer M. , Shabman Reed S. , Leung Daisy W. , Amarasinghe Gaya K. , Basler Christopher F. 
Published: August 2010

ABSTRACT
The ebolavirus (EBOV) VP35 protein binds to double-stranded RNA (dsRNA), inhibits host alpha/beta interferon (IFN-α/β) production, and is an essential component of the viral polymerase complex. Structural studies of the VP35 C-terminal IFN inhibitory domain (IID) identified specific structural features, including a central basic patch and a hydrophobic pocket, that are important for dsRNA binding and IFN inhibition. Several other conserved basic residues bordering the central basic patch and a separate cluster of basic residues, called the first basic patch, were also identified. Functional analysis of alanine substitution mutants indicates that basic residues outside the central basic patch are not required for dsRNA binding or for IFN inhibition. However, minigenome assays, which assess viral RNA polymerase complex function, identified these other basic residues to be critical for viral RNA synthesis. Of these, a subset located within the first basic patch is important for VP35-nucleoprotein (NP) interaction, as evidenced by the inability of alanine substitution mutants to coimmunoprecipitate with NP. Therefore, first basic patch residues are likely critical for replication complex formation through interactions with NP. Coimmunoprecipitation studies further demonstrate that the VP35 IID is sufficient to interact with NP and that dsRNA can modulate VP35 IID interactions with NP. Other basic residue mutations that disrupt the VP35 polymerase cofactor function do not affect interaction with NP or with the amino terminus of the viral polymerase. Collectively, these results highlight the importance of conserved basic residues from the EBOV VP35 C-terminal IID and validate the VP35 IID as a potential therapeutic target.
Chikungunya Virus Nonstructural Protein 2 Inhibits Type I/II Interferon-Stimulated JAK-STAT Signaling
Authors: Fros Jelke J. , Liu Wen Jun , Prow Natalie A. , Geertsema Corinne , Ligtenberg Maarten , Vanlandingham Dana L. , Schnettler Esther , Vlak Just M. , Suhrbier Andreas , Khromykh Alexander A. , Pijlman Gorben P. 
Published: August 2010

ABSTRACT
Chikungunya virus (CHIKV) is an emerging human pathogen transmitted by mosquitoes. Like that of other alphaviruses, CHIKV replication causes general host shutoff, leading to severe cytopathicity in mammalian cells, and inhibits the ability of infected cells to respond to interferon (IFN). Recent research, however, suggests that alphaviruses may have additional mechanisms to circumvent the host's antiviral IFN response. Here we show that CHIKV replication is resistant to inhibition by interferon once RNA replication has been established and that CHIKV actively suppresses the antiviral IFN response by preventing IFN-induced gene expression. Both CHIKV infection and CHIKV replicon RNA replication efficiently blocked STAT1 phosphorylation and/or nuclear translocation in mammalian cells induced by either type I or type II IFN. Expression of individual CHIKV nonstructural proteins (nsPs) showed that nsP2 was a potent inhibitor of IFN-induced JAK-STAT signaling. In addition, mutations in CHIKV-nsP2 (P718S) and Sindbis virus (SINV)-nsP2 (P726S) that render alphavirus replicons noncytopathic significantly reduced JAK-STAT inhibition. This host shutoff-independent inhibition of IFN signaling by CHIKV is likely to have an important role in viral pathogenesis.
Mucosal Trafficking of Vector-Specific CD4
+
T Lymphocytes following Vaccination of Rhesus Monkeys with Adenovirus Serotype 5
Authors: Masek-Hammerman Katherine , Li Hualin , Liu Jinyan , Abbink Peter , La Porte Annalena , O'Brien Kara L. , Whitney James B. , Carville Angela , Mansfield Keith G. , Barouch Dan H. 
Published: August 2010

ABSTRACT

Post hoc analysis of the phase 2b Step study evaluating a recombinant adenovirus serotype 5 (rAd5)-based HIV-1 vaccine candidate suggested a potential increased risk of HIV-1 acquisition in subjects who were baseline Ad5 seropositive and uncircumcised. These concerns had a profound impact on the HIV-1 vaccine development field, although the mechanism underlying this observation remains unknown. It has been hypothesized that rAd5 vaccination of baseline Ad5-seropositive individuals may have resulted in anamnestic, vector-specific CD4
+
T lymphocytes that could have trafficked to mucosal sites and served as increased targets for HIV-1 infection. Here we show that Ad5-specific CD4
+
T lymphocyte responses at mucosal sites following rAd5-Gag/Pol/Nef vaccination were comparable in rhesus monkeys with and without baseline Ad5 immunity. Moreover, the total cellular inflammatory infiltrates and the CD3
+
, CD4
+
, HLA-DR
+
, Ki67
+
, and langerin
+
cellular subpopulations in colorectal and foreskin mucosa were similar in both groups. Thus, no greater trafficking of Ad5-specific CD4
+
T lymphocytes to mucosal target sites was observed following rAd5 vaccination of rhesus monkeys with baseline Ad5 immunity. These findings from this nonhuman primate model provide evidence against the hypothesis that recruitment of vector-specific target cells to mucosal sites led to increased HIV-1 acquisition in Ad5-seropositive, uncircumcised vaccinees in the Step study.
A Single-Amino-Acid Substitution in Herpes Simplex Virus 1 Envelope Glycoprotein B at a Site Required for Binding to the Paired Immunoglobulin-Like Type 2 Receptor α (PILRα) Abrogates PILRα-Dependent Viral Entry and Reduces Pathogenesis
Authors: Arii Jun , Wang Jing , Morimoto Tomomi , Suenaga Tadahiro , Akashi Hiroomi , Arase Hisashi , Kawaguchi Yasushi 
Published: August 2010

ABSTRACTPaired immunoglobulin-like type 2 receptor α (PILRα) is a herpes simplex virus 1 (HSV-1) entry receptor that associates with O-glycans on HSV-1 envelope glycoprotein B (gB). Two threonine residues (Thr-53 and Thr-480) in gB, which are required for the addition of the principal gB O-glycans, are essential for binding to soluble PILRα. However, the role of the two threonines in PILRα-dependent viral entry remains to be elucidated. Therefore, we constructed a recombinant HSV-1 carrying an alanine replacement of gB Thr-53 alone (gB-T53A) or of both gB Thr-53 and Thr-480 (gB-T53/480A) and demonstrated that these mutations abrogated viral entry in CHO cells expressing PILRα. In contrast, the mutations had no effect on viral entry in CHO cells expressing known host cell receptors for HSV-1 gD, viral entry in HL60 cells expressing myelin-associated glycoprotein (MAG) (another HSV-1 gB receptor), viral attachment to heparan sulfate, and viral replication in PILRα-negative cells. These results support the hypothesis that gB Thr-53 and Thr-480 as well as gB O-glycosylation, probably at these sites, are critical for PILRα-dependent viral entry. Interestingly, following corneal inoculation in mice, the gB-T53A and gB-T53/480A mutations significantly reduced viral replication in the cornea, the development of herpes stroma keratitis, and neuroinvasiveness. The abilities of HSV-1 to enter cells in a PILRα-dependent manner and to acquire specific carbohydrates on gB are therefore linked to an increase in viral replication and virulence in the experimental murine model.
Pulsed radiofrequency versus conventional transcutaneous electrical nerve stimulation in painful shoulder: a prospective, randomized study
Authors: Korkmaz Onur Kιvιlcιm , Capaci Kazιm , Eyigor Can , Eyigor Sibel 
Published: August 2010

Objective: To compare the efficacy of pulse radiofrequency applied to the suprascapular nerve with the efficacy of conventional transcutaneous electrical nerve stimulation treatment in patients with shoulder pain. Design: A randomized, controlled trial. Setting: An outpatient physical therapy and rehabilitation clinic. Subjects: Forty patients with shoulder pain lasting at least three months were included in the study. Subjects were randomly allocated into either a pulsed radiofrequency treatment or a conventional transcutaneous electrical nerve stimulation treatment. All patients received exercise therapy. Main measurements: Outcome measurements were performed using the visual analogue scale for pain and range of motion; the Shoulder Pain and Disability Index was used for disability; and the Short Form-36 was used to establish quality of life. All of the measurements were assessed at four points in time (before the intervention, and for 1, 4 and 12 weeks afterwards). Results: When the groups were compared, no significant difference was found between the groups in terms of visual analogue scale, range of motion, the Shoulder Pain and Disability Index (except for the Shoulder Pain and Disability Index total score), Short Form-36 subscores, and paracetamol consumption for all weeks (P >0.05). Conclusion: Our results showed that there is no difference in effect between transcutaneous electrical nerve stimulation and pulsed radiofrequency treatment for shoulder pain.
Recovery after spinal cord relapse in multiple sclerosis is predicted by radial diffusivity
Authors: Freund Patrick , Wheeler-Kingshott Claudia , Jackson Jonathan , Miller David , Thompson Alan , Ciccarelli Olga 
Published: August 2010

Background: The aim of this study was to determine whether the diffusion tensor-derived radial diffusivity and axial diffusivity, measured in the cortico-spinal tract in the cervical cord, predict clinical recovery after a cord relapse in patients with multiple sclerosis, and change over time. Methods: Fourteen patients were clinically assessed at the onset of a cervical cord relapse and after 1, 3 and 6 months. Patients and 13 age-matched healthy controls underwent spinal cord diffusion tensor imaging at each time point. The directional diffusivities from diffusion tensor imaging, termed radial diffusivity and axial diffusivity, were calculated in regions of interest placed in the lateral columns, where the cortico-spinal tract is located, and in the anterior and posterior columns. Regression analyses identified predictors of clinical outcome, adjusting for age, gender, cord cross-sectional area and baseline clinical score, and estimated the differences in the rate of change in diffusion tensor imaging measures between groups over time, adjusting for changes in cord cross-sectional area. Results: Lower radial diffusivity of the cortico-spinal tract at baseline was associated with better clinical outcome. As patients improved clinically during the follow-up, they showed greater decrease in radial diffusivity of the cortico-spinal tract than controls. Conclusions: The predictive role of radial diffusivity and its dynamic changes over time suggest that this index reflects spinal cord pathological processes, including resolution of inflammation and remyelination, that contribute to clinical recovery in multiple sclerosis. This suggests that radial diffusivity may be useful in trials that promote recovery after spinal cord injury and could be applied to other neurological diseases affecting the spinal cord.
Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood
Authors: Brunstein Claudio G. , Gutman Jonathan A. , Weisdorf Daniel J. , Woolfrey Ann E. , DeFor Todd E. , Gooley Theodore A. , Verneris Michael R. , Appelbaum Frederick R. , Wagner John E. , Delaney Colleen 
Published: August 2010

AbstractEffectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)–matched related donor (MRD, n = 204), HLA allele–matched unrelated donor (MUD, n = 152) or 1-antigen–mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% [95% confidence interval (CI), 41%-59%]; MRD 33% [95% CI, 26%-41%]; MUD 48% [40%-56%]; MMUD 38% [95% CI, 25%-51%]). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative.
Bilateral somatosensory evoked potentials following intermittent theta-burst repetitive transcranial magnetic stimulation
Authors: Premji Azra , Ziluk Angela , Nelson Aimee J 
Published: August 2010

Abstract

Background
Intermittent theta-burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that may alter cortical excitability in the primary somatosensory cortex (SI). The present study investigated the effects of iTBS on subcortical and early cortical somatosensory evoked potentials (SEPs) recorded over left, iTBS stimulated SI and the right-hemisphere non-stimulated SI. SEPs were recorded before and at 5, 15, and 25 minutes following iTBS.

Results
Compared to pre-iTBS, the amplitude of cortical potential N20/P25 was significantly increased for 5 minutes from non-stimulated SI and for 15 to 25 minutes from stimulated SI. Subcortical potentials recorded bilaterally remained unaltered following iTBS.

Conclusion
We conclude that iTBS increases the cortical excitability of SI bilaterally and does not alter thalamocortical afferent input to SI. ITBS may provide one avenue to induce cortical plasticity in the somatosensory cortex.
Spread of a highly mucoid Streptococcus pyogenes emm3/ST15 clone
Authors: Tamayo Esther , Montes Milagrosa , García-Medina Guadalupe , García-Arenzana José M , Pérez-Trallero Emilio 
Published: August 2010

Abstract

Background
Hyaluronic acid capsule plays a key role in Streptococcus pyogenes virulence. Circulation of mucoid or highly encapsulated strains has been related to rheumatic fever epidemics and invasive disease in several countries. In 2009, an outbreak of mucoid S. pyogenes isolates was detected in northern Spain. The aim of the study was to describe clinical and molecular characteristics of mucoid strains causing this outbreak and to compare them with a sample of non-mucoid S. pyogenes isolates obtained during the same period of time.

Methods
All S. pyogenes isolates with a mucoid colony morphology (n = 132), 10% of non-mucoid (n = 144) and all invasive S. pyogenes isolates (n = 7) obtained in 2009 were included. Characterization was performed by T-agglutination, emm typing, pulsed field gel electrophoresis and multilocus sequence typing.

Results
One clone characterized as emm3.1/ST15 comprised 98.5% (n = 130) of all mucoid isolates. Subjects of all ages were affected. Main clinical manifestations were pharyngitis and scarlet fever, but this clone also caused invasive disease: two cases of streptococcal toxic shock syndrome, one arthritis, and one celullitis with a fatal outcome. Mucoid isolates were more prone to cause invasive disease than non-mucoid isolates (p = 0.001).

Conclusions
Although no acute rheumatic fever cases were detected, the most worrisome characteristics of this clone were the success for causing invasive disease and the merge of two virulent features: the serotype, emm3, and capsule hyper-production, expressed as a mucoid morphology.