bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presenilin function and γ‐secretase activity
Authors: Brunkan A. L. , Goate A. M. 
Published: April 2005

AbstractAlzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by the accumulation of β‐amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Genetic studies of AD first highlighted the importance of the presenilins (PS). Subsequent functional studies have demonstrated that PS form the catalytic subunit of the γ‐secretase complex that produces the Aβ peptide, confirming the central role of PS in AD biology. Here, we review the studies that have characterized PS function in the γ‐secretase complex in Caenorhabditis elegans, mice and in in vitro cell culture systems, including studies of PS structure, PS interactions with substrates and other γ‐secretase complex members, and the evidence supporting the hypothesis that PS are aspartyl proteases that are active in intramembranous proteolysis. A thorough knowledge of the mechanism of PS cleavage in the context of the γ‐secretase complex will further our understanding of the molecular mechanisms that cause AD, and may allow the development of therapeutics that can alter Aβ production and modify the risk for AD.
SOCIAL MATRICES AND INDICATORS IN THE TRADITIONAL AFRICAN ECONOMY
Authors: O'Loughlin Carleen , Ewusi Kodwo 
Published: April 2005

This paper discusses the relevance of the conventional national accounts systems to the traditional African economy and concludes that they contribute little because they omit certain economic activities and fail to recognise the reciprocity between social and economic activities. Social accounting is thus more relevant. Lack of statistical data may make it necessary to conduct special surveys and in some cases a tribe or village or economic region may be a more useful accounting unit than a nation. A modified system of accounts is suggested, based on the frame work of the four consolidated accounts of the SNA. It provides linkages to many more nonmonetised activities. Other linkages would be provided through supporting tables emphasising social activities and transfers. A system of transactor accounts in matrix form is also suggested. In the case of communities smaller than the nation several external transactor sectors could be included. It is recognised that the problem of evaluation of social activities and a number of economic activities remains to be solved and it is concluded that “time spent” may be the only common unit or value to equate such activities.The final section deals with investment in human resources and proposes a balance sheet approach to indicative planning. This exercise would be related to demographic projections in several variants. Other factors to be analysed dynamically would be education and health status, public finance and, ultimately, distribution of income and wealth since it is noted that the process of monetisation is having an impact which may have important welfare implications.
Intracranial EEG Substrates of Scalp EEG Interictal Spikes
Authors: Tao James X. , Ray Amit , Hawes‐Ebersole Susan , Ebersole John S. 
Published: April 2005

Summary:  Purpose: To determine the area of cortical generators of scalp EEG interictal spikes, such as those in the temporal lobe epilepsy. Methods: We recorded simultaneously 26 channels of scalp EEG with subtemporal supplementary electrodes and 46 to 98 channels of intracranial EEG in 16 surgery candidates with temporal lobe epilepsy. Cerebral discharges with and without scalp EEG correlates were identified, and the area of cortical sources was estimated from the number of electrode contacts demonstrating concurrent depolarization. Results: We reviewed ∼600 interictal spikes recorded with intracranial EEG. Only a very few of these cortical spikes were associated with scalp recognizable potentials; 90% of cortical spikes with a source area of >10 cm2 produced scalp EEG spikes, whereas only 10% of cortical spikes having <10 cm2 of source area produced scalp potentials. Intracranial spikes with <6 cm2 of area were never associated with scalp EEG spikes. Conclusions: Cerebral sources of scalp EEG spikes are larger than commonly thought. Synchronous or at least temporally overlapping activation of 10–20 cm2 of gyral cortex is common. The attenuating property of the skull may actually serve a useful role in filtering out all but the most significant interictal discharges that can recruit substantial surrounding cortex.
Occipital Lobe Epilepsy: Clinical Characteristics, Surgical Outcome, and Role of Diagnostic Modalities
Authors: Kun Lee Sang , Young Lee Seo , Kim Dong‐Wuk , Soo Lee Dong , Chung Chun‐Kee 
Published: April 2005

Summary:  Purpose: To assess the role of various diagnostic modalities, to identify surgical prognostic factors and concordances with presurgical evaluations, and to characterize the clinical features of occipital lobe epilepsy (OLE), we studied 26 patients who were diagnosed as having OLE and underwent epilepsy surgery. Methods: Diagnoses were established by standard presurgical evaluations, which included magnetic resonance imaging (MRI), fluorodeoxyglucose–positron emission tomography (FDG‐PET), ictal single‐photon emission computed tomography (SPECT), scalp video‐EEG monitoring, and intracranial EEG monitoring. After epilepsy surgery, patients were followed up for >2 years. Results: Sixteen (61.5%) of the 26 became seizure free after surgery, and another eight patients had a favorable outcome. Sixteen of the 26 patients experienced a type of visual aura (i.e., visual hallucination, visual illusion, blindness, or a field defect). Nine patients had both automotor seizures and secondary generalized tonic–clonic seizures at different times. Interictal EEG showed correctly localizing spikes in 10 of the 16 patients who became seizure free, and in three of the 10 non–seizure‐free patients. MRI correctly localized the lesion in seven of these 16 seizure‐free patients, and in three of the 10 non–seizure‐free patients. FDG‐PET correctly localized the lesion in eight of the 16 seizure‐free patients, and in three of nine non–seizure‐free patients. Ictal SPECT was performed in 19 patients and correctly localized the lesion in only three of 12 seizure‐free patients, and in four of seven non–seizure‐free patients. Ictal EEG correctly localized the lesion in 13 of the 16 seizure‐free patients, and in five of the 10 non–seizure‐free patients. No significant relation was found between the diagnostic accuracy of any modality and surgical outcome. The localizations of epileptogenic zones by these different diagnostic methods were complementary. The concordance of three or more modalities was significantly observed in seizure‐free patients (p = 0.042). However, no definite relation was observed between the presence of lateralizing clinical seizure manifestation and surgical outcome (p = 0.108). Conclusions
: Some specific auras indicated an occipital epilepsy onset. Various diagnostic methods can be useful to diagnose OLE, and a greater concordance between presurgical evaluation modalities indicates a better surgical outcome.
High-Level Expression of Marek's Disease Virus Glycoprotein C Is Detrimental to Virus Growth In Vitro
Authors: Tischer B. Karsten , Schumacher Daniel , Chabanne-Vautherot Danièlle , Zelnik Vladimir , Vautherot Jean-François , Osterrieder Nikolaus 
Published: April 2005

ABSTRACT

Expression levels of Marek's disease virus (MDV) glycoprotein C (gC) are significantly reduced after serial virus passage in cell culture. Reduced gC expression coincides with enhanced MDV growth in vitro and attenuation. To analyze this phenomenon in detail, a full-length infectious MDV clone was modified by Red-based and shuttle mutagenesis in
Escherichia coli
. Besides a gC-negative deletion mutant harboring a kanamycin resistance gene, a markerless mutant with the

U
L

44
gene deleted was constructed. On the basis of this deletion mutant, the original or a modified

U
L

44
gene with a mutated start codon (AUG→ACG) was reinserted into the authentic locus. Similarly, mutants expressing authentic gC or the start codon mutation under the control of a strong constitutive promoter were generated. In vitro studies demonstrated that gC deletion mutants induced twofold-larger plaques than the parental virus did, whereas constitutive overexpression of the glycoprotein resulted in a more than twofold reduction in plaque size. In addition, plaque sizes of the gC deletion mutant were reduced when virus was grown using supernatants from cells infected with parental virus, but supernatants obtained from cells infected with the gC deletion mutant had no measurable effect on plaque size. The results indicated that (i) expression of MDV gC, albeit at low levels in a highly passaged virus, had a significant negative impact on the cell-to-cell spread capabilities of the virus, which was alleviated in its absence and exacerbated by its overexpression, and that (ii) this activity was mediated by the secreted form of MDV gC.
Evaluation of Human Monoclonal Antibody 80R for Immunoprophylaxis of Severe Acute Respiratory Syndrome by an Animal Study, Epitope Mapping, and Analysis of Spike Variants
Authors: Sui Jianhua , Li Wenhui , Roberts Anjeanette , Matthews Leslie J. , Murakami Akikazu , Vogel Leatrice , Wong Swee Kee , Subbarao Kanta , Farzan Michael , Marasco Wayne A. 
Published: April 2005

ABSTRACT
In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a human monoclonal antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.
Amino Acid 36 in the Human Immunodeficiency Virus Type 1 gp41 Ectodomain Controls Fusogenic Activity: Implications for the Molecular Mechanism of Viral Escape from a Fusion Inhibitor
Authors: Kinomoto Masanobu , Yokoyama Masaru , Sato Hironori , Kojima Asato , Kurata Takeshi , Ikuta Kazuyoshi , Sata Tetsutaro , Tokunaga Kenzo 
Published: April 2005

ABSTRACT
We have previously described a human immunodeficiency virus type 1 (HIV-1) proviral clone, pL2, derived from defective viral particles with higher fusogenicity than the prototypic NL4-3 virus. In this study, we attempted to determine the region that confers the enhanced fusion activity by creating envelope recombinants between pL2 and pNL4-3, as well as point mutants based on pNL4-3. The results indicate that amino acid 36 of gp41 is key for the fusogenic activity and infectivity enhancement and that glycine 36 (36G) of gp41 in pL2 is conserved in nearly all HIV-1 isolates except for pNL4-3. The mutation 36G→D in a primary-isolate-derived Env decreased syncytium-forming activity and infectivity. The assays for cell-cell fusion and viral binding suggested that the enhanced fusion mediated by the 36D→G mutation is not due to increased binding efficiency but is directly due to actual enhancement of viral fusion activity. Interestingly, this amino acid position is exactly equivalent to that at which the mutation of HIV-1 isolates that have escaped from a fusion inhibitor, enfuvirtide (T-20), has been frequently observed. The correlation between these previous findings and our findings was suggested by structural analysis. Our finding, therefore, has implications for a molecular basis of the viral escape from this drug.
Functional Mimicry of a Human Immunodeficiency Virus Type 1 Coreceptor by a Neutralizing Monoclonal Antibody
Authors: Xiang Shi-Hua , Farzan Michael , Si Zhihai , Madani Navid , Wang Liping , Rosenberg Eric , Robinson James , Sodroski Joseph 
Published: April 2005

ABSTRACT
Interaction of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein with the primary receptor, CD4, promotes binding to a chemokine receptor, either CCR5 or CXCR4. The chemokine receptor-binding site on gp120 elicits CD4-induced (CD4i) antibodies in some HIV-1-infected individuals. Like CCR5 itself, the CD4i antibody 412d exhibits a preference for CCR5-using HIV-1 strains and utilizes sulfated tyrosines to achieve binding to gp120. Here, we show that 412d binding requires the gp120 β19 strand and the base of the V3 loop, elements that are important for the binding of the CCR5 N terminus. Two gp120 residues in the V3 loop base determined 412d preference for CCR5-using HIV-1 strains. A chimeric molecule in which the 412d heavy-chain third complementarity-determining loop sequence replaces the CCR5 N terminus functioned as an efficient second receptor, selectively supporting the entry of CCR5-using HIV-1 strains. Sulfation of N-terminal tyrosines contributed to the function of this chimeric receptor. These results emphasize the close mimicry of the CCR5 N terminus by the gp120-interactive region of a naturally elicited CD4i antibody.
Nuclear Localization of the Nipah Virus W Protein Allows for Inhibition of both Virus- and Toll-Like Receptor 3-Triggered Signaling Pathways
Authors: Shaw Megan L. , Cardenas Washington B. , Zamarin Dmitriy , Palese Peter , Basler Christopher F. 
Published: April 2005

ABSTRACT
The Nipah virus V and W proteins, which are encoded by the P gene via RNA editing, have a common N-terminal domain but unique C-terminal domains. They localize to the cytoplasm and nucleus, respectively, and have both been shown to function as inhibitors of JAK/STAT signaling. Here we report that V and W proteins also block virus activation of the beta interferon (IFN-β) promoter and the IFN regulatory factor 3 (IRF3)-responsive IFN-stimulated gene 54 promoter. Surprisingly, only W protein shows strong inhibition of promoter activation in response to stimulation of Toll-like receptor 3 (TLR3) by extracellular double-stranded RNA. This activity is dependent on the nuclear localization of W protein. Within the unique C-terminal domain of W protein, we have identified a nuclear localization signal (NLS) that requires basic residues at positions 439, 440, and 442. This NLS is responsible for mediating the preferential interaction of W protein with karyopherin-α 3 and karyopherin-α 4. Nuclear localization of W protein therefore enables it to target both virus and TLR3 pathways, whereas the cytoplasmic V protein is restricted to inhibiting the virus pathway. We propose that this discrepancy is in part due to the V protein being less able to block signaling in response to the kinase, TBK-1, whereas both V and W can prevent promoter activation in response to IKKε. We demonstrate that, when the TLR3 pathway is stimulated, the levels of phosphorylated IRF3 are reduced in the presence of W protein but not V protein, confirming the differential effects of these proteins and illustrating that W protein-mediated inhibition is due to a loss of active IRF3.
Comparative Host Gene Transcription by Microarray Analysis Early after Infection of the Huh7 Cell Line by Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus 229E
Authors: Tang Bone S. F. , Chan Kwok-hung , Cheng Vincent C. C. , Woo Patrick C. Y. , Lau Susanna K. P. , Lam Clarence C. K. , Chan Tsun-leung , Wu Alan K. L. , Hung Ivan F. N. , Leung Suet-yi , Yuen Kwok-yung 
Published: April 2005

ABSTRACT
The pathogenesis of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) at the cellular level is unclear. No human cell line was previously known to be susceptible to both SARS-CoV and other human coronaviruses. Huh7 cells were found to be susceptible to both SARS-CoV, associated with SARS, and human coronavirus 229E (HCoV-229E), usually associated with the common cold. Highly lytic and productive rates of infections within 48 h of inoculation were reproducible with both viruses. The early transcriptional profiles of host cell response to both types of infection at 2 and 4 h postinoculation were determined by using the Affymetrix HG-U133A microarray (about 22,000 genes). Much more perturbation of cellular gene transcription was observed after infection by SARS-CoV than after infection by HCoV-229E. Besides the upregulation of genes associated with apoptosis, which was exactly opposite to the previously reported effect of SARS-CoV in a colonic carcinoma cell line, genes related to inflammation, stress response, and procoagulation were also upregulated. These findings were confirmed by semiquantitative reverse transcription-PCR, reverse transcription-quantitative PCR for mRNA of genes, and immunoassays for some encoded proteins. These transcriptomal changes are compatible with the histological changes of pulmonary vasculitis and microvascular thrombosis in addition to the diffuse alveolar damage involving the pneumocytes.
Unusual Topological Arrangement of Structural Motifs in the Baboon Reovirus Fusion-Associated Small Transmembrane Protein
Authors: Dawe Sandra , Corcoran Jennifer A. , Clancy Eileen K. , Salsman Jayme , Duncan Roy 
Published: April 2005

ABSTRACT

Select members of the
Reoviridae
are the only nonenveloped viruses known to induce syncytium formation. The fusogenic orthoreoviruses accomplish cell-cell fusion through a distinct class of membrane fusion-inducing proteins referred to as the fusion-associated small transmembrane (FAST) proteins. The p15 membrane fusion protein of baboon reovirus is unique among the FAST proteins in that it contains two hydrophobic regions (H1 and H2) recognized as potential transmembrane (TM) domains, suggesting a polytopic topology. However, detailed topological analysis of p15 indicated only the H1 domain is membrane spanning. In the absence of an N-terminal signal peptide, the H1 TM domain serves as a reverse signal-anchor to direct p15 membrane insertion and a bitopic N
exoplasmic
/C
cytoplasmic
topology. This topology results in the translocation of the smallest ectodomain (∼20 residues) of any known viral fusion protein, with the majority of p15 positioned on the cytosolic side of the membrane. Mutagenic analysis indicated the unusual presence of an N-terminal myristic acid on the small p15 ectodomain is essential to the fusion process. Furthermore, the only other hydrophobic region (H2) present in p15, aside from the TM domain, is located within the endodomain. Consequently, the p15 ectodomain is devoid of a fusion peptide motif, a hallmark feature of membrane fusion proteins. The exceedingly small, myristoylated ectodomain and the unusual topological distribution of structural motifs in this nonenveloped virus membrane fusion protein necessitate alternate models of protein-mediated membrane fusion.
Biochemical Characterization of Rous Sarcoma Virus MA Protein Interaction with Membranes
Authors: Dalton Amanda K. , Murray Paul S. , Murray Diana , Vogt Volker M. 
Published: April 2005

ABSTRACTThe MA domain of retroviral Gag proteins mediates association with the host cell membrane during assembly. The biochemical nature of this interaction is not well understood. We have used an in vitro flotation assay to directly measure Rous sarcoma virus (RSV) MA-membrane interaction in the absence of host cell factors. The association of purified MA and MA-containing proteins with liposomes of defined composition was electrostatic in nature and depended upon the presence of a biologically relevant concentration of negatively charged lipids. A mutant MA protein known to be unable to promote Gag membrane association and budding in vivo failed to bind to liposomes. These results were supported by computational modeling. The intrinsic affinity of RSV MA for negatively charged membranes appears insufficient to promote efficient plasma membrane binding during assembly. However, an artificially dimerized form of MA bound to liposomes by at least an order of magnitude more tightly than monomeric MA. This result suggests that the clustering of MA domains, via Gag-Gag interactions during virus assembly, drives membrane association in vivo.
Impact of Viral Factors on Very Early In Vivo Replication Profiles in Simian Immunodeficiency Virus SIVagm-Infected African Green Monkeys
Authors: Pandrea Ivona , Kornfeld Christopher , Ploquin Mickael J.-Y. , Apetrei Cristian , Faye Abdourahmane , Rouquet Pierre , Roques Pierre , Simon François , Barré-Sinoussi Françoise , Müller-Trutwin Michaela C. , Diop Ousmane M. 
Published: April 2005

ABSTRACTTo better understand which factors govern the levels of viral loads in early lentiviral infections of primates, we developed a model that allows distinguishing between the influences of host and viral factors on viremia. Herein we report that two species of African green monkeys (Chlorocebus sabaeusandC. pygerythrus) infected with their respective wild-type simian immunodeficiency virus SIVagm viruses (SIVagm.sab92018 and SIVagm.ver644) consistently showed reproducible differences in viremia during primary infection but not at later stages of infection. Cross-infections of SIVagm.sab92018 and SIVagm.ver644 into, respectively,C. pygerythrusandC. sabaeusrevealed that the dynamics of viral replication during primary infection were dependent on the viral strain used for the infection but not on the host. Hence, the kinetics of SIVagm.sab92018 and SIVagm.ver644 were similar in both sabaeus and vervet animals, indicating that the difference in viremia levels between the two groups during the early phase of infection was not associated with the host. Coreceptor usage for these two strains showed a larger coreceptor repertoire for SIVagm.sab92018, which is able to efficiently use CXCR4 in addition to CCR5, than for SIVagm.ver644, which showed a classical CCR5 coreceptor usage pattern. These differences could not be explained by different charges of the V3 loop for SIVagm.sab92018 and for SIVagm.ver644. In conclusion, our study showed that the extent of virus replication during the primary infection is primarily dependent on viral determinants.