bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteome-Wide Overexpression of Host Proteins for Identification of Factors Affecting Tombusvirus RNA Replication: an Inhibitory Role of Protein Kinase C
Authors: Shah Nawaz-ul-Rehman Muhammad , Martinez-Ochoa Natalia , Pascal Helene , Sasvari Zsuzsanna , Herbst Christin , Xu Kai , Baker Jannine , Sharma Monika , Herbst Alan , Nagy Peter D. 
Published: June 2012

ABSTRACT

To identify host genes affecting replication of
Tomato bushy stunt virus
(TBSV), a small model positive-stranded RNA virus, we overexpressed 5,500 yeast proteins individually in
Saccharomyces cerevisiae
, which supports TBSV replication. In total, we identified 141 host proteins, and overexpression of 40 of those increased and the remainder decreased the accumulation of a TBSV replicon RNA. Interestingly, 36 yeast proteins were identified previously by various screens, greatly strengthening the relevance of these host proteins in TBSV replication. To validate the results from the screen, we studied the effect of protein kinase C1 (Pkc1), a conserved host kinase involved in many cellular processes, which inhibited TBSV replication when overexpressed. Using a temperature-sensitive mutant of Pkc1p revealed a high level of TBSV replication at a semipermissive temperature, further supporting the idea that Pkc1p is an inhibitor of TBSV RNA replication. A direct inhibitory effect of Pkc1p was shown in a cell-free yeast extract-based TBSV replication assay, in which Pkc1p likely phosphorylates viral replication proteins, decreasing their abilities to bind to the viral RNA. We also show that cercosporamide, a specific inhibitor of Pkc-like kinases, leads to increased TBSV replication in yeast, in plant single cells, and in whole plants, suggesting that Pkc-related pathways are potent inhibitors of TBSV in several hosts.
Mammalian Innate Resistance to Highly Pathogenic Avian Influenza H5N1 Virus Infection Is Mediated through Reduced Proinflammation and Infectious Virus Release
Authors: Nelli Rahul K. , Dunham Stephen P. , Kuchipudi Suresh V. , White Gavin A. , Baquero-Perez Belinda , Chang Pengxiang , Ghaemmaghami Amir , Brookes Sharon M. , Brown Ian H. , Chang Kin-Chow 
Published: June 2012

ABSTRACT
Respiratory epithelial cells and macrophages are the key innate immune cells that play an important role in the pathogenesis of influenza A virus infection. We found that these two cell types from both human and pig showed comparable susceptibilities to initial infection with a highly pathogenic avian influenza (HPAI) H5N1 virus (A/turkey/Turkey/1/05) and a moderately pathogenic human influenza H1N1 virus (A/USSR/77), but there were contrasting differences in host innate immune responses. Human cells mounted vigorous cytokine (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokine (CXCL9, CXCL10, and CXCL11) responses to H5N1 virus infection. However, pig epithelial cells and macrophages showed weak or no TNF-α and chemokine induction with the same infections. The apparent lack of a strong proinflammatory response, corroborated by the absence of TNF-α induction in H5N1 virus-challenged pigs, coincided with greater cell death and the reduced release of infectious virus from infected pig epithelial cells. Suppressor of cytokine signaling 3 (SOCS3), a protein suppressor of the JAK-STAT pathway, was constitutively highly expressed and transcriptionally upregulated in H5N1 virus-infected pig epithelial cells and macrophages, in contrast to the corresponding human cells. The overexpression of SOCS3 in infected human macrophages dampened TNF-α induction. In summary, we found that the reported low susceptibility of pigs to contemporary Eurasian HPAI H5N1 virus infections coincides at the level of innate immunity of respiratory epithelial cells and macrophages with a reduced output of viable virus and an attenuated proinflammatory response, possibly mediated in part by SOCS3, which could serve as a target in the treatment or prevention of virus-induced hypercytokinemia, as observed for humans.
Hepatitis B Virus Nucleocapsid but Not Free Core Antigen Controls Viral Clearance in Mice
Authors: Lin Yi-Jiun , Wu Hui-Lin , Chen Ding-Shinn , Chen Pei-Jer 
Published: June 2012

ABSTRACT
We have recently shown that hepatitis B virus (HBV) core antigen (HBcAg) is the major viral factor for HBV clearance using a hydrodynamics-based mouse model. Knockout of HBcAg hampers the development of antiviral immune responses and thus promotes HBV persistence. Here, we further demonstrated that only in the capsid form, but not the free or dimer form, can HBcAg exert its contributory role in HBV clearance. HBcAg is the main structural protein of HBV icosahedral nucleocapsid. A mutant HBV DNA which expresses an assembly-defective HBcAg, HBcAgY132A, surprisingly prolonged HBV surface antigenemia in both C57BL/6 and BALB/c mice without affecting viral transcription and translation. This result was not due to a loss of the possible immune epitope caused by the single-amino-acid substitution of HBcAg. Moreover, the particular HBV mutant failed to induce robust humoral and cellular immunity against HBV. These data revealed the requirement of capsid structure for inducing adequate immunity that leads to HBV clearance in mice.
Functional Balance of the Hemagglutinin and Neuraminidase Activities Accompanies the Emergence of the 2009 H1N1 Influenza Pandemic
Authors: Xu Rui , Zhu Xueyong , McBride Ryan , Nycholat Corwin M. , Yu Wenli , Paulson James C. , Wilson Ian A. 
Published: June 2012

ABSTRACTThe 2009 H1N1 influenza pandemic is the first human pandemic in decades and was of swine origin. Although swine are believed to be an intermediate host in the emergence of new human influenza viruses, there is still little known about the host barriers that keep swine influenza viruses from entering the human population. We surveyed swine progenitors and human viruses from the 2009 pandemic and measured the activities of the hemagglutinin (HA) and neuraminidase (NA), which are the two viral surface proteins that interact with host glycan receptors. A functional balance of these two activities (HA binding and NA cleavage) is found in human viruses but not in the swine progenitors. The human 2009 H1N1 pandemic virus exhibited both low HA avidity for glycan receptors as a result of mutations near the receptor binding site and weak NA enzymatic activity. Thus, a functional match between the hemagglutinin and neuraminidase appears to be necessary for efficient transmission between humans and may be an indicator of the pandemic potential of zoonotic viruses.
Analysis by Single-Gene Reassortment Demonstrates that the 1918 Influenza Virus Is Functionally Compatible with a Low-Pathogenicity Avian Influenza Virus in Mice
Authors: Qi Li , Davis A. Sally , Jagger Brett W. , Schwartzman Louis M. , Dunham Eleca J. , Kash John C. , Taubenberger Jeffery K. 
Published: June 2012

ABSTRACTThe 1918-1919 “Spanish” influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight “7:1” chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus.
Glycosylation of Simian Immunodeficiency Virus Influences Immune-Tissue Targeting during Primary Infection, Leading to Immunodeficiency or Viral Control
Authors: Sugimoto Chie , Nakamura Shinichiro , Hagen Shoko I. , Tsunetsugu-Yokota Yasuko , Villinger Francois , Ansari Aftab A. , Suzuki Yasuo , Yamamoto Naoki , Nagai Yoshiyuki , Picker Louis J. , Mori Kazuyasu 
Published: June 2012

ABSTRACT

Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Δ5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4
+
T cells reside. The results showed that Δ5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Δ5G-infected animals deplete CXCR3
+
CCR5
+
transitional memory (TrM) CD4
+
T cells. An early robust Δ5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6
+
CXCR3
−
CCR5
+
effector memory CD4
+
T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4
+
T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively.
The PDZ1 and PDZ3 Domains of MAGI-1 Regulate the Eight-Exon Isoform of the Coxsackievirus and Adenovirus Receptor
Authors: Kolawole Abimbola Olayinka , Sharma Priyanka , Yan Ran , Lewis Kyle Joseph Edward , Xu Zhigang , Hostetler Heather Ann , Ashbourne Excoffon Katherine Julie Diane 
Published: June 2012

ABSTRACT

Epithelial integrity is essential for homeostasis and poses a formidable barrier to pathogen entry. Major factors for viral entry into epithelial cells are the localization and abundance of the primary receptor. The coxsackievirus and adenovirus receptor (CAR) is a primary receptor for these two pathogenic groups of viruses. In polarized epithelia, a low-abundance, alternatively spliced eight-exon isoform of CAR, CAR
Ex8
, is localized apically where it can support viral infection from the air-exposed surface. Using biochemical, cell biology, genetic, and spectroscopic approaches, we show that the levels of apical CAR
Ex8
are negatively regulated by the PDZ domain-containing protein MAGI-1 (membrane-associated guanylate kinase with inverted orientation protein-1) and that two MAGI-1 PDZ domains, PDZ1 and PDZ3, regulate CAR
Ex8
levels in opposing ways. Similar to full-length MAGI-1, expression of the isolated PDZ3 domain significantly reduces cell surface CAR
Ex8
abundance and adenovirus infection. In contrast, the PDZ1 domain is able to rescue CAR
Ex8
and adenovirus infection from MAGI-1-mediated suppression. These data suggest a novel cell-based strategy to either suppress viral infection or augment adenovirus-based gene therapy.
Geology and geochronology of Tlaloc, Telapón, Iztaccíhuatl, and Popocatépetl volcanoes, Sierra Nevada, central Mexico
Authors: Macías J.L. , Arce J.L. , García-Tenorio F. , Layer P.W. , Rueda H. , Reyes-Agustin G. , López-Pizaña F. , Avellán D. 
Published: June 2012

Abstract
The Sierra Nevada Volcanic Range includes, from south to north, the active Popocatépetl (5452 m), Iztaccíhuatl (5272 m) with several volcanic edifices, Telapón (4000 m), and Tlaloc (4150 m) volcanoes. It has been generally assumed that volcanic activity has migrated from Tlaloc (north) to Popocatépetl (south) over time. New evidence obtained from previous studies, field reconnaissance, and radiometric dating indicate that magmatism at the Sierra Nevada Volcanic Range likely started at 1.8–1.4 Ma with the construction of Paleo-Tlaloc volcano, which is today buried by younger deposits. The activity continued between 1.07 and 0.89 Ma with the emplacement of dacitic domes (Puico, Yahualica, Yeloxochitl, Tearco, and Torrecillas), lavas and associated pyroclastic flows as the San Francisco (1 Ma), and Chicoloapan (0.9 Ma). Afterwards, the main edifice of modern Tlaloc was built up through the emission of dacitic lava flows (0.94–0.84 Ma). Iztaccíhuatl began its activity ca. 1.1 Ma with the formation of several volcanic edifices up to 0.45 Ma, time during which a Mount St. Helens—type event destroyed the southeastern flank of Los Pies Recientes cone, producing a debris avalanche and pyroclastic deposits. Telapón volcano formed approximately between 0.38 Ma and 0.34 Ma ago with the emplacement of lava flows and a dome that become quiescent afterwards. Apparently, ca. 0.32 Ma, Popocatépetl began its eruptive activity that continues today. Strikingly, Tlaloc reawakened with the emission of rhyolitic magma at 0.129 Ma followed by the emplacement of the El Papayo dacite (118 ka) to the south and Téyotl summit lavas (80 ka). Activity continued at Tlaloc with the generation of five explosive eruptions at 44, 38, 33, 31, and 25 ka and the growth of the summit dome. Coevally, Popocatépetl, at the southern end of the range, had collapsed twice to the south and had intense volcanic activity up until today. Holocene activity has taken place at Iztaccíhuatl with the 9 ka Buenavista dacitic lava flow and repetitive Plinian eruptions of Popocaté-petl including some historic events and the 1994—present eruption. Popocatépetl's reawakening reminded authorities, scientists, media, and the public of its potential risk. In fact, on 22 January 2001, the rapid collapse of an eruptive column generated scoria-rich pyroclastic flows that partly melted the glacier producing lahars. From the above considerations it is obvious that magmatism of the Sierra Nevada Volcanic Range did not keep a continuous north to south migrating path, but it rather shifted back and forth chaotically throughout its evolution. It is worth mentioning that major gaps presented in the eruptive sequence are most likely due to poor radiometric coverage of the area that may improve in the future.
IntestinalStaphylococcus spp.and virulent features associated with coeliac disease
Authors: Sánchez Ester , Ribes-Koninckx Carmen , Calabuig Miguel , Sanz Yolanda 
Published: June 2012

AimTo determine whether intestinalStaphylococcus spp.and their pathogenic features differed between coeliac disease (CD) patients and healthy controls.Methods60 children, including active CD (n=20) and non-active CD (n=20) patients and healthy controls (n=20), were studied. Staphylococci were isolated from faeces and identified by PCR and DNA sequencing. The carriage of virulent genes, including adhesion (atlEandfbe), cell aggregation (icaD), global regulatory (agrandsar) and methicillin-resistant (mecA) genes, was analysed by PCR.ResultsStaphylococcusepidermidiswas more abundant in the microbiota of active and non-active CD patients than in controls.Staphylococcushaemolyticuswas more abundant in active CD patients than in control subjects.Staphylococcusaureuswas less abundant in active CD patients than in the other child groups.Staphylococcus spp.diversity was higher in active CD patients than in non-active CD patients and controls. The presence of themecAgene and the simultaneous presence of both themecAandatlEgenes were higher inS. epidermidisclones isolated from CD patients, with active and non-active disease, than in those from control subjects. The individual presence of the other virulent genes was lower inS. epidermidisfrom active CD patients than in those from the other -child- groups.ConclusionsIncreased abundance ofS. epidermidiscarrying themecAgene, in active and non-active CD patients, most likely reflects increased exposure of these subjects to opportunistic pathogens and antimicrobials.
Mucosal large cell neuroendocrine carcinoma of the head and neck regions in Japanese patients: a distinct clinicopathological entity
Authors: Kusafuka Kimihide , Abe Masato , Iida Yoshiyuki , Onitsuka Tetsuro , Fuke Tomohito , Asano Rei , Kamijo Tomoyuki , Nakajima Takashi 
Published: June 2012

BackgroundsLarge cell neuroendocrine carcinoma (LCNEC) is well-known as a lung cancer subtype. This study assessed the prevalence of head and neck mucosal LCNEC (M-LCNEC).MethodsM-LCNEC was studied clinically, histologically and immunohistochemically.ResultsOf 814 surgically resected cases of mucosal head and neck carcinoma, only eight cases (0.98%; all men, mean age 64.6 years) were rediagnosed as M-LCNEC. They occurred in the oropharynx (n=3), larynx (n=4) and hypopharynx (n=1). Seven of the cases had regional lymph node metastases and four resulted in death. Histologically, M-LCNEC had a sheet-like trabacular organoid growth pattern of relatively large basaloid cells in which central necrosis, rosette formation, peripheral palisading and high mitotic figures were evident. M-LCNEC was immunopositive for two or three neuroendocrine markers (CD56, chromogranin-A and synaptophysin). All cases showed high proliferative activity.ConclusionM-LCNEC in the head and neck regions is a distinct histopathological entity whose positivity for neuroendocrine markers makes its diagnosis important. As about half of the patients died of the disease, M-LCNEC has a relatively poor prognosis.
Transient cranial neuropathies as sequelae of Onyx embolization of arteriovenous shunt lesions near the skull base: possible axonotmetic traction injuries
Authors: Nyberg Eric MacKenzie , Chaudry M Imran , Turk Aquilla S , Turner Raymond D 
Published: June 2012

IntroductionTransarterial embolization with Onyx is a relatively safe and increasingly common method of treating cranial dural arteriovenous fistulas (DAVF) and arteriovenous malformations (AVM). Cranial neuropathy resulting from this procedure has been reported.Case reportsThree case histories are presented in two patients treated for a DAVF and an AVM near the skull base with heavily parasitized supply from external carotid artery branches. Transarterial embolization resulted in transient cranial neuropathies including two cases of lower facial nerve palsy and one case of trigeminal nerve mandibular segment (V3) neuralgia which resolved spontaneously over a few months. Treatment of the DAVF and AVM was otherwise successful.DiscussionThe most common cranial neuropathies following transarterial Onyx embolization procedures are facial nerve palsy and V3 neuralgia. The middle meningeal and internal maxillary arteries are common conduits used in dural-based and facial arteriovenous shunt lesions and are in proximity to the facial nerve and maxillary segment of the trigeminal nerve as they exit the skull base. Based on their relative frequency and anatomic proximity, it is surmised that these facial neuropathies are traction-type injuries related to microcatheter extraction from the Onyx cast.ConclusionsCranial neuropathies, specifically facial nerve palsy and V3 neuralgia, following transarterial Onyx embolizations are probably axonotmetic traction injuries related to microcatheter extraction. These appear to be self-limiting and resolve over a few months.
Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not
Authors: Scaltriti Maurizio , Dawood Shaheenah , Cortes Javier 
Published: June 2012

AbstractMany kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance. Clin Cancer Res; 18(17); 4508–13. ©2012 AACR.
Regulatory Polymorphisms in β-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy
Authors: Leandro-García Luis J. , Leskelä Susanna , Jara Carlos , Gréen Henrik , Åvall-Lundqvist Elisabeth , Wheeler Heather E. , Dolan M. Eileen , Inglada-Perez Lucia , Maliszewska Agnieszka , de Cubas Aguirre A. , Comino-Méndez Iñaki , Mancikova Veronika , Cascón Alberto , Robledo Mercedes , Rodríguez-Antona Cristina 
Published: June 2012

Abstract
Purpose: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through β-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in β-tubulin genes.
Experimental Design: We measured variation in gene expression of three β-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with β-tubulin expression as measured by Affymetrix exon array.
Results: We found a 63-fold variation in β-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at −101, −112, and −157 in TUBB2A promoter correlated with increased mRNA levels. The −101 and −112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42–0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity.
Conclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a β-tubulin gene. Clin Cancer Res; 18(16); 4441–8. ©2012 AACR.