bluuebunny/crossref_metadata_2025_split huggingface dataset:
Putative Terminase Subunits of Herpes Simplex Virus 1 Form a Complex in the Cytoplasm and Interact with Portal Protein in the Nucleus
Authors: Yang Kui , Homa Fred , Baines Joel D. 
Published: March 2007

ABSTRACT

Herpes simplex virus (HSV) terminase is an essential component of the molecular motor that translocates DNA through the portal vertex in the capsid during DNA packaging. The HSV terminase is believed to consist of the U
L
15, U
L
28, and U
L
33 gene products (pU
L
15, pU
L
28, and pU
L
33, respectively), whereas the HSV type 1 portal vertex is encoded by U
L
6. Immunoprecipitation reactions revealed that pU
L
15, pU
L
28, and pU
L
33 interact in cytoplasmic and nuclear lysates. Deletion of a canonical nuclear localization signal (NLS) from pU
L
15 generated a dominant-negative protein that, when expressed in an engineered cell line, decreased the replication of wild-type virus up to 80-fold. When engineered into the genome of recombinant HSV, this mutation did not interfere with the coimmunoprecipitation of pU
L
15, pU
L
28, and pU
L
33 from cytoplasmic lysates of infected cells but prevented viral replication, most nuclear import of both pU
L
15 and pU
L
28, and coimmunoprecipitation of pU
L
15, pU
L
28, and pU
L
33 from nuclear lysates. When the pU
L
15/pU
L
28 interaction was reduced in infected cells by the truncation of the C terminus of pU
L
28, pU
L
28 remained in the cytoplasm. Whether putative terminase components localized in the nucleus or cytoplasm, pU
L
6 localized in infected cell nuclei, as viewed by indirect immunofluorescence. The finding that the portal and terminase do eventually interact was supported by the observation that pU
L
6 coimmunoprecipitated strongly with pU
L
15 and weakly with pU
L
28 from extracts of infected cells in 1.0 M NaCl. These data are consistent with the hypothesis that the pU
L
15/pU
L
28/pU
L
33 complex forms in the cytoplasm and that an NLS in pU
L
15 is used to import the complex into the nucleus where at least pU
L
15 and pU
L
28 interact with the portal to mediate DNA packaging.
Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway
Authors: Carroll-Anzinger Deborah , Kumar Anvita , Adarichev Vyacheslav , Kashanchi Fatah , Al-Harthi Lena 
Published: March 2007

ABSTRACTAstrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-γ), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-γ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-γ-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HIV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-γ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-γ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HIV replication within and outside of the brain.
Proteolytic Processing and Deubiquitinating Activity of Papain-Like Proteases of Human Coronavirus NL63
Authors: Chen Zhongbin , Wang Yanhua , Ratia Kiira , Mesecar Andrew D. , Wilkinson Keith D. , Baker Susan C. 
Published: March 2007

ABSTRACTHuman coronavirus NL63 (HCoV-NL63), a common human respiratory pathogen, is associated with both upper and lower respiratory tract disease in children and adults. Currently, no antiviral drugs are available to treat CoV infections; thus, potential drug targets need to be identified and characterized. Here, we identify HCoV-NL63 replicase gene products and characterize two viral papain-like proteases (PLPs), PLP1 and PLP2, which process the viral replicase polyprotein. We generated polyclonal antisera directed against two of the predicted replicase nonstructural proteins (nsp3 and nsp4) and detected replicase proteins from HCoV-NL63-infected LLC-MK2 cells by immunofluorescence, immunoprecipitation, and Western blot assays. We found that HCoV-NL63 replicase products can be detected at 24 h postinfection and that these proteins accumulate in perinuclear sites, consistent with membrane-associated replication complexes. To determine which viral proteases are responsible for processing these products, we generated constructs representing the amino-terminal end of the HCoV-NL63 replicase gene and established proteasecis-cleavage assays. We found that PLP1 processes cleavage site 1 to release nsp1, whereas PLP2 is responsible for processing both cleavage sites 2 and 3 to release nsp2 and nsp3. We expressed and purified PLP2 and used a peptide-based assay to identify the cleavage sites recognized by this enzyme. Furthermore, by using K48-linked hexa-ubiquitin substrate and ubiquitin-vinylsulfone inhibitor specific for deubiquitinating enzymes (DUBs), we confirmed that, like severe acute respiratory syndrome (SARS) CoV PLpro, HCoV-NL63 PLP2 has DUB activity. The identification of the replicase products and characterization of HCoV-NL63 PLP DUB activity will facilitate comparative studies of CoV proteases and aid in the development of novel antiviral reagents directed against human pathogens such as HCoV-NL63 and SARS-CoV.
Electrostatic Interactions Drive Membrane Association of the Human Immunodeficiency Virus Type 1 Gag MA Domain
Authors: Dalton Amanda K. , Ako-Adjei Danso , Murray Paul S. , Murray Diana , Vogt Volker M. 
Published: March 2007

ABSTRACT
The assembly of most retroviruses occurs at the plasma membrane. Membrane association is directed by MA, the N-terminal domain of the Gag structural protein. For human immunodeficiency virus type 1 (HIV-1), this association is mediated in part by a myristate fatty acid modification. Conflicting evidence has been presented on the relative importance of myristoylation, of ionic interactions between protein and membrane, and of Gag multimerization in membrane association in vivo. We addressed these questions biochemically by determining the affinity of purified myristoylated HIV-1 MA for liposomes of defined composition, both for monomeric and for dimeric forms of the protein. Myristoylation increases the barely detectable intrinsic affinity of the apo-protein for liposomes by only 10-fold, and the resulting affinity is still weak, similar to that of the naturally nonmyristoylated MA of Rous sarcoma virus. Membrane binding of HIV-1 MA is absolutely dependent on the presence of negatively charged lipid and is abrogated at high ionic strength. Forced dimerization of MA increases its membrane affinity by several orders of magnitude. When green fluorescent protein fusions of monomeric or dimeric MA are expressed in cells, the dimeric but not the monomeric protein becomes strongly membrane associated. Computational modeling supports these results and suggests a molecular mechanism for the modest effect of myristoylation on binding, wherein the membrane provides a hydrophobic environment for the myristate that is energetically similar to that provided by the protein. Overall, the results imply that the driving force for membrane association stems largely from ionic interactions between multimerized Gag and negatively charged phospholipids.
Offending Heaven and Earth: Sin and Expiation in Islamic Homicide Law
Authors: Powers Paul 
Published: March 2007

AbstractThe Qur'ān clearly condemns homicide and assigns the freeing of a slave to any who kill accidentally. Classical fiqh manuals, however, display a remarkable range of responses to and disagreements about this dictate. Many jurists hold that freeing a slave here is an instance of kaffāra (expiation), understood as an antidote to sin. Yet accidental homicide is widely deemed non-sinful, so kaffāra is assigned for a non-sin. Further, many say the sin of intentional homicide cannot be expiated. Hanafīs often add the idiosyncratic assertion that freeing a slave is not kaffāra but rather an instance of "thanking the benefactor," an altogether different kind of act. I conclude that freeing a slave in response to homicide is not consistently treated as the expiation of sin. Further, the jurists' treatment of kaffāra forces a reconsideration of the commonplace assertion that Islamic law treats murder as more tort than crime.
Critical Rigor vs. Juridical Pragmatism: How Legal Theorists and Hadīth Scholars Approached the Backgrowth of Isnāds in the Genre of 'Ilal al-Hadīth
Authors: Brown Jonathan 
Published: March 2007

AbstractModern scholarship has accepted the 'backgrowth of isnāds' in the early hadīth tradition, but this phenomenon did not occur without controversy among classical Muslim scholars. Hadīth critics were aware that material was being pushed back to the Prophet, a phenomenon they approached through the lens of ziyāda (addition). By examining works devoted to criticizing hadīth narrations ('ilal) from the 3rd/9th to the 8th/14th centuries, we will see that the original non-Prophetic versions of many hadīths survived alongside their Prophetic counterparts well into the 5th/11th century. More importantly, certain hadīth scholars from the 3rd/9th to the 7th/13th centuries believed that Prophetic reports in the canonical hadīth collections were actually statements of other early Muslims. The position of these critics, however, was marginalized in the 5th/11th century, when mainstream Sunni jurists chose to accept the Prophetic versions categorically. Although the jurists' position became dominant in Sunni Islam, criticism of the backgrowth of isnāds has continued in the work of select hadīth scholars until today.
The Book of the Young Master of Accountancy: An Ancient Chinese Economics Text
Authors: Milburn Olivia 
Published: March 2007

AbstractIn ancient China, economic theory developed from the Warring States period onwards. Many philosophers included economic ideas in their works. A number of important theories were first articulated in an extremely obscure text, the Jinizi, a book was associated with the preunification state of Yue. The Jinizi is the earliest known text to include the concept of economic cycles, and it stresses the role of investment and savings in economic development, and price stabilisation. These ideas subsequently formed the cornerstone of ancient Chinese economic theory. This paper includes the first translation of the Jinizi into English. En Chine ancienne, la théorie économique se développa à partir de la période des Royaumes Combattants. Plusieurs philosophes inclurent des concepts économiques dans leurs travaux. Un nombre de théories importantes furent articulées dans un texte extrêmement obscure, le Jinizi, un livre associé avec l'état de Yue avant l'unification de la Chine. Le Jinizi est le premier texte à avoir inclu le concept des cycles économiques, et il appuie le rôle de l'investissement et de l'épargne dans le développement économique, et de la stabilisation des prix. Ces idées formèrent par la suite le point clé de la théorie économique en Chine ancienne. Cet article comprend la première traduction du Jinizi en Anglais.
Descartes on Time and Duration
Authors: Gorham Geoffrey 
Published: March 2007

AbstractDescartes' account of the material world relies heavily on time. Most importantly, time is a component of speed, which figures in his fundamental conservation principle and laws. However, in his most systematic discussion of the concept, time is treated as some-how reducible both to thought and to motion. Such reductionistic views, while common among Descartes' late scholastic contemporaries, are very ill-suited to Cartesian physics. I show that, in spite of the apparent identifications with thought and motion, Cartesian time retains—in the form of what I will call 'successive duration'—precisely the intrinsic structure necessary to serve as an independent parameter of quantitative physics. As is often the case with Descartes, he gives the impression of embracing traditional doctrines while in fact radically transforming the underlying concepts to serve his scientific agenda. His theory of time, though formulated in Aristotelian terms, anticipates Newton in important respects.
Scotus as the Father of Modernity. The Natural Philosophy of the English Franciscan Christopher Davenport in 1652
Authors: Davenport Anne 
Published: March 2007

AbstractThis article examines the philosophical teaching of a colorful Oxford alumnus and Roman Catholic convert, Christopher Davenport, also known as Franciscus à Sancta Clara or Francis Coventry. At the peak of Puritan power during the English Interregnum and after five of his Franciscan confrères had perished for their missionary work, our author tried boldly to claim modern cosmology and atomism as the unrecognized fruits of medieval Scotism. His hope was to revive English pride in the golden age of medieval Oxford and to defend English Franciscans as more legitimately patriotic and scientifically progressive than Puritan millenarians.
Does Priming Improve Performance?—An Evaluation Based on a Simulation Game
Authors: Chlosta Simone , Johann Tobias , Klandt Heinz 
Published: March 2007

This study focuses on the priming effect on performance in a simulation game. It took place during the regular course programme at the European Business School (Germany). Two groups of students were chosen randomly to play a business game (Szyperski & Klandt, 1988) that simulated the start-up and early development phase of a software company including a large variety of decisions. By means of the study design the amount of cognitive involvement before the game was varied. Thus, one of the groups received a strategy questionnaire while the other did not. It contained questions about production, supply, personnel, advertising, etc. The intention was to prime the students towards the use of strategies. According to former experiments by Higgins, Rholes and Jones (1977) priming influences cognition and memory and leads to a faster retrieval of information. This should be transferred to the performance in a simulation game.
A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature
Authors: Cooley Sarah , Xiao Feng , Pitt Michelle , Gleason Michelle , McCullar Valarie , Bergemann Tracy L. , McQueen Karina L. , Guethlein Lisbeth A. , Parham Peter , Miller Jeffrey S. 
Published: March 2007

AbstractHow receptor acquisition correlates with the functional maturation of natural killer (NK) cells is poorly understood. We used quantitative real-time polymerase chain reaction (PCR) assays to compare NKG2 and killer immunoglobulin-like receptor (KIR) gene expression in NK cells from allogeneic transplant recipients and their donors. Marked differences were observed in the NK subsets of recipients who had 8-fold more CD56bright cells, diminished KIR expression (except 2DL4), and increased NKG2A. In normal blood not all CD56dim cells express KIR, and a novel subpopulation of cells committed to the NK-cell lineage was defined. These cells, which comprise 19.4% ± 2.8% of the CD56dim NK population in healthy donors, express the activating NKG2D and NKG2E receptors but no KIR or NKG2A. Although the CD56dim NKG2A− KIR− NK cells lack “at least one” inhibitory receptor for autologous MHC class I, they are not fully responsive, but rather functionally immature cells with poor cytotoxicity and IFN-γ production. Upon culture with IL-15 and a stromal cell line, CD56dim and CD56bright KIR− NK cells proliferate, express KIR, and develop cytotoxicity and cytokine-producing potential. These findings have implications for the function of NK cells reconstituting after transplantation and support a model for in vivo development in which CD56bright cells precede CD56dim cells.
Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I–induced leukemia and suppresses leukemic stem cells
Authors: Peng Cong , Brain Julia , Hu Yiguo , Goodrich Ami , Kong Linghong , Grayzel David , Pak Roger , Read Margaret , Li Shaoguang 
Published: March 2007

Abstract
Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome–positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL–induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.
Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK–positive anaplastic large-cell lymphoma
Authors: Damm-Welk Christine , Busch Kerstin , Burkhardt Birgit , Schieferstein Jutta , Viehmann Susanne , Oschlies Ilske , Klapper Wolfram , Zimmermann Martin , Harbott Jochen , Reiter Alfred , Woessmann Willi 
Published: March 2007

AbstractClinical and histopathological characteristics have limited prognostic value for children with anaplastic large-cell lymphoma (ALCL). We evaluated the presence, extent, and prognostic impact of circulating tumor cells in bone marrow (BM) and peripheral blood (PB) of children and adolescents with NPM-ALK–positive ALCL at diagnosis using qualitative and quantitative polymerase chain reaction (PCR) for NPM-ALK. Numbers of NPM-ALK transcripts were normalized to 104 copies ABL (NCNs). BM was analyzed from 80 patients and PB from 52. BM was positive for NPM-ALK in 47.5% of patients, and positivity was significantly correlated with clinical stage, mediastinal or visceral involvement, microscopic BM involvement, and histologic subtype. Qualitative and quantitative PCR results in BM and PB strongly correlated. BM PCR was associated with the cumulative incidence of relapses (CI-Rs): CI-R was 50% ± 10% for 38 PCR-positive and 15% ± 7% for 42 PCR-negative patients (P < .001). Sixteen patients with more than 10 NCNs NPM-ALK in BM had a CI-R of 71% ± 14% compared with a CI-R of 18% ± 6% for 59 patients with 10 or fewer NCNs (P < .001). PB PCR results led to a similar grouping. Thus, quantitative PCR in BM or PB allows identification of 20% of patients experiencing 60% of all relapses with an event-free survival of 20%.
Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats
Authors: Tillie-Leblond I. , Gosset P. , Le Berre R. , Janin A. , Prangère T. , Tonnel A. B. , Guery B. P. H. 
Published: March 2007

Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma.KGF (1 mg·kg−1) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed.Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins β-catenin and zonula occludens protein-1.In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.
Genetic association studies of interleukin-13 receptor α1 subunit gene polymorphisms in asthma and atopy
Authors: Konstantinidis A. K. , Barton S. J. , Sayers I. , Yang I. A. , Lordan J. L. , Rorke S. , Clough J. B. , Holgate S. T. , Holloway J. W. 
Published: March 2007

Interleukin (IL)-13 plays a central role in asthma pathogenesis by binding to the IL-13 receptor, which is a heterodimer composed of the IL-13 receptor α1 subunit (IL-13Rα1) and IL-4Rα. The genetic diversity at the IL-13Rα1 gene (IL13RA1) locus on chromosome Xq24 was characterised and the association of identified polymorphisms with asthma and atopy phenotypes examined.The promoter and coding region ofIL13RA1were screened for common genetic variants, and polymorphisms found were genotyped in a large cohort of 341 asthmatic Caucasian families (each containing at least two asthmatic siblings) and 182 nonasthmatic control subjects. Genetic association was determined using case–control and transmission disequilibrium test analyses.Two common polymorphisms were identified, a newly found thymidine (T) to guanine (G) transition of nucleotide -281 (-281T>G) single nucleotide polymorphism in theIL13RA1promoter and the previously described 1365A>G variant in theIL13RA1proximal 3′ untranslated region. No significant association of either -281T>G or 1365A>G with risk of asthma or atopy phenotypes was found, apart from a suggestive association between theIL13RA1-281T/1365A haplotype and raised total serum immunoglobulin E levels in adult female asthmatics.These findings indicate that the interleukin-13 receptor α1 subunit gene -281T>G and 1365A>G polymorphisms do not contribute to asthma susceptibility or severity, although the interleukin-13 receptor α1 subunit gene locus might be involved in the control of immunoglobulin E production.