bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Papillomavirus Types 16, 18, and 31 Share Similar Endocytic Requirements for Entry
Authors: Spoden Gilles , Kühling Lena , Cordes Nicole , Frenzel Bettina , Sapp Martin , Boller Klaus , Florin Luise , Schelhaas Mario 
Published: April 2013

ABSTRACT
Human papillomavirus type 18 (HPV18), one of the HPVs with malignant potential, enters cells by an unknown endocytic mechanism. The key cellular requirements for HPV18 endocytosis were tested in comparison to those for HPV16 and -31 endocytoses. HPV18 (like HPV16 and -31) entry was independent of clathrin, caveolin, dynamin, and lipid rafts but required actin polymerization and tetraspanin CD151, and the viruses were routed to the same LAMP-1-positive compartment. Hence, the viruses shared similar cellular requirements for endocytic entry.
Modulation of GB Virus B RNA Abundance by MicroRNA-122: Dependence on and Escape from MicroRNA-122 Restriction
Authors: Sagan Selena M. , Sarnow Peter , Wilson Joyce A. 
Published: April 2013

ABSTRACT
Hepatitis C virus (HCV) RNA forms an unusual interaction with human microRNA-122 (miR-122) that promotes viral RNA accumulation in cultured human liver cells and in the livers of infected chimpanzees. GB virus B (GBV-B) is a hepatotropic virus and close relative of HCV. Thus, GBV-B has been used as a surrogate system to study HCV amplification in cultured cells and in infected tamarins. It was discovered that the 5′-terminal sequences of GBV-B RNA, like HCV RNA, forms an Argonaute 2-mediated complex with two miR-122 molecules that are essential for accumulation of GBV-B subgenomic replicon RNA. However, sequences in miR-122 that anneal to each viral RNA genome were different, suggesting distinct overall structural features in HCV:miR-122 and GBV-B:miR-122 complexes. Surprisingly, a deletion that removed both miR-122 binding sites from the subgenomic GBV-B RNAs rendered viral RNA amplification independent from miR-122 and Argonaute 2. This finding suggests that structural features at the end of the viral genome dictate whether miR-122 is required to aid in maintaining viral RNA abundance.
Toll-Like Receptor 7 Inhibits Early Acute Retroviral Infection through Rapid Lymphocyte Responses
Authors: Browne Edward P. 
Published: April 2013

ABSTRACTEarly events during retroviral infection play a critical role in determining the course of infection and pathogenesis, but the mechanisms that regulate this phase of infection are poorly understood. Toll-like receptor 7 (TLR7) is required for promoting germinal center reactions and virus-specific neutralizing antibodies at later time points postinfection, but TLR7's role in early acute infection has not been determined. By infecting TLR7-deficient mice with a retroviral pathogen, Friend virus (FV), I determined that TLR7 potently inhibits retroviral replication during the first 5 days of infection and is required for rapid secretion of virus-specific IgM and interleukin-10 (IL-10) in response to infection. Although the IgM response was nonneutralizing, plasmas from wild-type mice but not TLR7-deficient mice inhibited FV replication when passively transferred to infected mice, suggesting an indirect mechanism of antibody function. Interestingly, IL-10 was secreted primarily by CD4 T cells, and IL-10-deficient mice also exhibited accelerated early virus spread, demonstrating that this response inhibits acute infection. Surprisingly, TLR7-deficient mice exhibited normal or elevated secretion of proinflammatory cytokines during acute infection, revealing the existence of a TLR7-independent retrovirus-sensing pathway that drives inflammatory cytokine secretion. Together, these results establish a previously unappreciated role for lymphocytes in mediating rapid TLR7-dependent inhibition of early retroviral infection through nonneutralizing IgM and IL-10.
Foamy Virus Gag p71-p68 Cleavage Is Required for Template Switch of the Reverse Transcriptase
Authors: Spannaus Ralf , Schneider Anna , Hartl Maximilian J. , Wöhrl Birgitta M. , Bodem Jochen 
Published: April 2013

ABSTRACT
In contrast to orthoretroviruses, processing of foamy viral p71 Gag is limited to a single cleavage site. Nevertheless, Gag maturation is essential for infectivity, but deletion of p3 results in a modest drop in infectivity. Here, we show that Gag processing of p71 to p68 and p3 is essential for full-length cDNA synthesis, while inactivation of Gag cleavage results in cDNAs containing only the RU5 region; cDNAs encompassing the U3 region were almost undetectable.
Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8
+
T-Cell Antiviral Activity and Correlates with Preservation of the CD4
+
T-Cell Compartment
Authors: Turk Gabriela , Ghiglione Yanina , Falivene Juliana , Socias María Eugenia , Laufer Natalia , Coloccini Romina Soledad , Rodriguez Ana María , Ruiz María Julia , Pando María Ángeles , Giavedoni Luis David , Cahn Pedro , Sued Omar , Salomon Horacio , Gherardi María Magdalena 
Published: April 2013

ABSTRACT

The important role of the CD8
+
T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity,
ex vivo
viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8
+
T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8
+
T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4
+
T-cell set points were observed in PHI subjects with higher HIV-specific CD8
+
T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8
+
T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection.
A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages
Authors: Mounce Bryan C. , Mboko Wadzanai P. , Bigley Tarin M. , Terhune Scott S. , Tarakanova Vera L. 
Published: April 2013

ABSTRACT

Gammaherpesviruses are ubiquitious pathogens that establish lifelong infection and are associated with several malignancies. All gammaherpesviruses encode a conserved protein kinase that facilitates viral replication and chronic infection and thus represents an attractive therapeutic target. In this study, we identify a novel function of gammaherpesvirus protein kinase as a regulator of class I histone deacetylases (HDAC). Mouse gammaherpesvirus 68 (MHV68)-encoded protein kinase orf36 interacted with HDAC1 and 2 and prevented association of these HDACs with the viral promoter driving expression of RTA, a critical immediate early transcriptional activator. Furthermore, the ability to interact with HDAC1 and 2 was not limited to the MHV68 orf36, as BGLF4, a related viral protein kinase encoded by Epstein-Barr virus, interacted with HDAC1
in vitro
. Importantly, targeting of HDAC1 and 2 by orf36 was independent of the kinase's enzymatic activity. Additionally, orf36 expression, but not its enzymatic activity, induced changes in the global deacetylase activity observed in infected primary macrophages. Combined deficiency of HDAC1 and 2 rescued attenuated replication and viral DNA synthesis of the orf36 null MHV68 mutant, indicating that the regulation of HDAC1 and 2 by orf36 was relevant for viral replication. Understanding the mechanism by which orf36 facilitates viral replication, including through HDAC targeting, will facilitate the development of improved therapeutics against gammaherpesvirus kinases.
Conformational Plasticity of the 2A Proteinase from Enterovirus 71
Authors: Cai Qixu , Yameen Muhammad , Liu Weihua , Gao Zhenting , Li Yaozong , Peng Xuanjia , Cai Yaxian , Wu Caiming , Zheng Qian , Li Jian , Lin Tianwei 
Published: April 2013

ABSTRACT

The 2A proteinase (2A
pro
) is an enterovirally encoded cysteine protease that plays essential roles in both the processing of viral precursor polyprotein and the hijacking of host cell translation and other processes in the virus life cycle. Crystallographic studies of 2A
pro
from enterovirus 71 (EV71) and its interaction with the substrate are reported here. EV71 2A
pro
was comprised of an N-terminal domain of a four-stranded antiparallel β sheet and a C-terminal domain of a six-stranded antiparallel β barrel with a tightly bound zinc atom. Unlike in other 2A
pro
structures, there is an open cleft across the surface of the protein in an open conformation. As demonstrated by the crystallographic studies and modeling of the complex structure, the open cleft could be fitted with the substrate. On comparison 2A
pro
of EV71 to those of the human rhinovirus 2 and coxsackievirus B4, the open conformation could be closed with a hinge motion in the bII2 and cII β strands. This was supported by molecular dynamic simulation. The structural variation among different 2A
pro
structures indicates a conformational flexibility in the substrate-binding cleft. The open structure provides an accessible framework for the design and development of therapeutics against the viral target.
Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design
Authors: Ping Li-Hua , Joseph Sarah B. , Anderson Jeffrey A. , Abrahams Melissa-Rose , Salazar-Gonzalez Jesus F. , Kincer Laura P. , Treurnicht Florette K. , Arney Leslie , Ojeda Suany , Zhang Ming , Keys Jessica , Potter E. Lake , Chu Haitao , Moore Penny , Salazar Maria G. , Iyer Shilpa , Jabara Cassandra , Kirchherr Jennifer , Mapanje Clement , Ngandu Nobubelo , Seoighe Cathal , Hoffman Irving , Gao Feng , Tang Yuyang , Labranche Celia , Lee Benhur , Saville Andrew , Vermeulen Marion , Fiscus Susan , Morris Lynn , Karim Salim Abdool , Haynes Barton F. , Shaw George M. , Korber Bette T. , Hahn Beatrice H. , Cohen Myron S. , Montefiori David , Williamson Carolyn , Swanstrom Ronald 
Published: April 2013

ABSTRACT

Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine. We compared phenotypic and genetic variation in HIV-1
env
genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission. We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell. We confirmed an earlier observation that the transmitted viruses were, on average, modestly underglycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event. We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies. We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of
env
, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.
The value of the difference between ED and prehospital vital signs in predicting outcome in trauma
Authors: Bruijns Stevan R , Guly Henry R , Bouamra Omar , Lecky Fiona , Wallis Lee A 
Published: April 2013

IntroductionTraditional vital signs are seen as an important part of trauma assessment, despite their poor predictive value in this regard.ObjectiveThis study evaluated whether the difference between systolic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and shock index (SI) taken in the emergency department (ED) and prehospital can predict 48 h mortality postadmission following trauma.MethodsRetrospective cohort was obtained from the Trauma Audit and Research Network. Subjects were excluded if head or spinal injuries, prehospital intubation or CPR were present. Main outcome was 48 h mortality. The difference (delta, Δ) between ED and prehospital values were used as study variables (ie, ΔSI=SI-ED minus SI-prehospital). Accuracy was assessed using area under receiver operator characteristic curve (AUROC). AUROC coordinates were used to identify 95% specificity cut points and described further using sensitivity and likelihood ratios (LRs).ResultsSignificant AUROC statistics were revealed for ΔSBP (0.57) and ΔRR (0.56) for the full sample, ΔSBP (0.62) and ΔSI (0.65) for moderate, and ΔRR (0.6) for severe injury. Best LRs were 3.4 and 2.4 for ΔRR and ΔSI, respectively, but sensitivities were low (<=26%). Cut point values for ΔSBP, ΔRR and ΔSI were 37 mm Hg, 8 breaths/min and 0.2, respectively.DiscussionΔSBP and ΔRR performed best overall, but ΔSI performed best in the moderate injury group, suggesting earlier identification with ΔSI. Use of Δ values result in good rule-in of 48 h mortality and may supplement trauma treatment decisions.
Rare earth element and gold exploration in glaciated terrain: example from the Mäkärä area, northern Finland
Authors: Sarapää Olli , Sarala Pertti 
Published: April 2013

The Mäkärä Au-rare earth element (REE) prospect area is located in the Tana Belt, south of the 1.9 Ga Lapland Granulite Belt, in northern Finland. The Belt has prominent lanthanum (La) and yttrium (Y) anomalies in regional till and bedrock geochemical data. High Y indicates enrichment of heavy REE in the bedrock. At Mäkärä, promising narrow Au-hematite-quartz veins occur in connection with tensional fractures in the great shear zone.
Under the latest ice divide of the last glaciation, subglacial erosion was weak and glacial transport distance short. High Au contents in saprolite and till together with deep weathering have a strong positive correlation with the positive electromagnetic anomalies caused by the sulphidic gneisses. The highest La and Y contents in till correlate well with the Th maxima of airborne-radiometric datasets. Locally, the <0.06 mm till size fraction contains up to 0.4% REE. A recent exploration project in Mäkärä revealed a 13 m wide Au-hematite-quartz vein with a mean of 3 ppm Au and 0.04–0.1% REE in kaolinitic saprolite derived from arkosic gneiss. The elevated REE content resembles that of ionic adsorption clays in China. Typical REE-rich minerals are monazite, rhabdophane, xenotime and kaolinite. Till geochemistry proved useful in REE exploration.
IL-17–Mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws
Authors: Zhang Qunzhou , Atsuta Ikiru , Liu Shiyu , Chen Chider , Shi Shihong , Shi Songtao , Le Anh D. 
Published: April 2013

AbstractPurpose: Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of interleukin (IL)-17–mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ).Experimental Design: The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease.Results: Increased T-helper (TH)17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-γ–induced M1 polarization through augmenting STAT-1 phosphorylation while suppressing IL-4–mediated M2 conversion via inhibiting STAT-6 activation.Conclusions: These findings have established a compelling linkage between activated IL-17–mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models. Clin Cancer Res; 19(12); 3176–88. ©2013 AACR.
CRM1 and BRAF Inhibition Synergize and Induce Tumor Regression in BRAF-Mutant Melanoma
Authors: Salas Fragomeni Roberto A. , Chung Hye Won , Landesman Yosef , Senapedis William , Saint-Martin Jean-Richard , Tsao Hensin , Flaherty Keith T. , Shacham Sharon , Kauffman Michael , Cusack James C. 
Published: April 2013

Abstract
Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival, and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor antitumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276, and KPT-330 were used to induce CRM1 inhibition. Analogs PLX-4720 and PLX-4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell-cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization and retinoblastoma protein (pRb) and survivin modulation. Furthermore, we found that BRAF inhibition abrogates extracellular signal–regulated kinase phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF-mutant and wild-type melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF-mutant melanoma. Mol Cancer Ther; 12(7); 1171–9. ©2013 AACR.
Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary
Authors: Hisamatsu Takeshi , Mabuchi Seiji , Matsumoto Yuri , Kawano Mahiru , Sasano Tomoyuki , Takahashi Ryoko , Sawada Kenjiro , Ito Kimihiko , Kurachi Hirohisa , Schilder Russell J. , Testa Joseph R. , Kimura Tadashi 
Published: April 2013

Abstract
The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2–AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment. Mol Cancer Ther; 12(7); 1367–77. ©2013 AACR.
Bioactive Lipids S1P and C1P Are Prometastatic Factors in Human Rhabdomyosarcoma, and Their Tissue Levels Increase in Response to Radio/Chemotherapy
Authors: Schneider Gabriela , Bryndza Ewa , Abdel-Latif Ahmed , Ratajczak Janina , Maj Magdalena , Tarnowski Maciej , Klyachkin Yuri M. , Houghton Peter , Morris Andrew J. , Vater Axel , Klussmann Sven , Kucia Magdalena , Ratajczak Mariusz Z. 
Published: April 2013

Abstract
Evidence suggests that bioactive lipids may regulate pathophysiologic functions such as cancer cell metastasis. Therefore, we determined that the bioactive lipid chemoattractants sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) strongly enhanced the in vitro motility and adhesion of human rhabdomyosarcoma (RMS) cells. Importantly, this effect was observed at physiologic concentrations for both bioactive lipids, which are present in biologic fluids, and were much stronger than the effects observed in response to known RMS prometastatic factors such as stromal derived factors-1 (SDF-1/CXCL12) or hepatocyte growth factor/scatter factor (HGF/SF). We also present novel evidence that the levels of S1P and C1P were increased in several organs after γ-irradiation or chemotherapy, which indicates an unwanted prometastatic environment related to treatment. Critically, we found that the metastasis of RMS cells in response to S1P can be effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high-affinity Spiegelmer. These data indicate that bioactive lipids play a vital role in dissemination of RMS and contribute to the unwanted side effects of radio/chemotherapy by creating a prometastatic microenvironment. Mol Cancer Res; 11(7); 793–807. ©2013 AACR.