bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gödelian time‐travel and anthropic cosmology
Authors: Richmond Alasdair M. 
Published: May 2004

AbstractThis paper looks at Kurt Gödel's causally‐pathological cosmological models (derived from general relativity), in the light of anthropic explanations. If a Gödelian world is a possible world, could anthropic reasoning shed any light on whether or not our world is Gödelian? This paper argues that while there are some good anthropic reasons why our world ought to be Gödelian, too many observations suggest that our world can’t possibly be Gödelian in fact. If Gödel's world is a possible one, anthropic teleology alone cannot explain why it isn’t the world we inhabit. Furthermore, if our world were Gödelian, anthropic arguments against the existence of extraterrestrial intelligences would imply a bleak human future. En route, some general objections to relativistic causal pathologies are addressed and some anthropic arguments to the effect that Gödelian worlds couldn’t sustain life are also addressed and dismissed.
An objection to gareth evans’ account of self‐identity
Authors: Roos Andrew 
Published: May 2004

AbstractIn chapter seven ‘Self Identification’ of his challenging book The Varieties of Reference, Gareth Evans attempts to give an account of how it is that one is able to think about oneself self‐consciously. On Evans’ view, when one attempts to think of oneself self‐consciously that person is having what he calls an ‘I’ thought. Since these ‘I’ thoughts are a case of reference, more specifically self‐reference, Evans thinks that these thoughts can be explained by employing the same theoretical framework that he uses to explain other kinds of reference.Evans thinks all thoughts are essentially structured, and this means that they must fall under his ‘generality constraint’. Since ‘I’ thoughts are also ‘thoughts’ they are essentially structured as well, and they too must be subject to the generality constraint. The radical implication of this is that Evans thinks that if ‘I’ thoughts are subject to the generality constraint, then he can show that self‐reference must be reference to a thing which we can locate on a spatio‐temporal map.In this article I hope to accomplish three things. First, I will spell out in detail the argument Evans uses to arrive at his claim that self‐reference must be reference to something located on a spatio‐temporal map. Second, I will raise an objection, which states that Evans’ conclusion that self‐reference must involve spatio‐temporal location is not a consequence of the generality constraint. Finally I will argue that Evans’ conclusion that self‐reference must involve spatio‐temporal location is in fact in tension with the generality constraint, rather than being an implication of it.
In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum
Authors: Hernández‐Viadel Mariluz , Castoldi Anna F. , Coccini Teresa , Manzo Luigi , Erceg Slaven , Felipo Vicente 
Published: May 2004

AbstractCarbon monoxide induces delayed neurological and neuropathological alterations, including memory loss and cognitive impairment. The bases for the delay remain unknown. Activation of soluble guanylate cyclase by nitric oxide modulates some forms of learning and memory. Carbon monoxide binds to soluble guanylate cyclase, activating it but interfering with its activation by nitric oxide. The aim of this work was to assess whether exposure of rats to carbon monoxide alters the activity of soluble guanylate cyclase or its modulation by nitric oxide in cerebellum or cerebral cortex. Rats exposed chronically or acutely to carbon monoxide were killed 24 h or 7 days later. Acute carbon monoxide exposure decreased cyclic guanosine monophosphate (cGMP) content and reduced activation of soluble guanylate cyclase by nitric oxide. Cortex was more sensitive than cerebellum to chronic exposure, which reduced activation of soluble guanylate cyclase by nitric oxide in cortex. In cerebellum, chronic exposure induced delayed impairment of soluble guanylate cyclase activation by nitric oxide. Acute exposure effects were also stronger at 7 days than at 24 h after exposure. This delayed impaired modulation of soluble guanylate cyclase by nitric oxide may contribute to delayed memory loss and cognitive impairment in humans exposed to carbon monoxide.
Enhanced G‐protein activation by a mixture of Aβ(25–35), Aβ(1–40/42) and zinc
Authors: Molnár Zs. , Kovács P. , Laczkó I. , Soós K. , Fülöp L. , Penke B. , Lengyel I. 
Published: May 2004

Abstractβ‐Amyloid peptides (Aβs) bind to several G‐protein coupled receptor proteins and stimulate GTPase activity in neurons. In this study we determined the effects of Aβ(1–42), Aβ(1–40), Aβ(25–35) and their mixtures on [35S]GTP binding in rat brain cortical membranes in the absence and presence of zinc. We found that the Aβs alone induced a concentration‐dependent activation of G‐proteins (IC50∼ 10−6 m), while aggregated Aβ fibrils only affected GTP binding at concentrations above 10−5 m. Mixing Aβ(25–35) with Aβ(1–42) or Aβ(1–40) induced a several‐fold increase in GTP‐binding. This potentiation followed a bell shaped curve with a maximum at 50 : 50 ratios. No potentiating effect could be seen by mixing Aβ(1–40) and Aβ(1–42) or highly aggregated Aβs. Zinc had no effect on Aβ(1–40/42) but strongly potentiated the Aβ(25–35) or the mixed peptides‐induced GTP‐binding. Changes in secondary structure accompanied the mixed peptides or the peptide/zinc complexes induced potentiation, revealing that structural alterations are behind the increased biological action. These concentration dependent potentiating effects of zinc and the peptide mixtures could be physiologically important at brain regions where peptide fragments and/or zinc are present at elevated concentrations.
The International Interdisciplinary Wound Care Course at the University of Toronto: a 4‐year evolution
Authors: Sibbald R Gary , Orsted Heather 
Published: May 2004

AbstractThe International Interdisciplinary Wound Care Course at the University of Toronto was designed to emphasise interdisciplinary collaboration, examine the evidence base and develop wound care opinion leaders across Canada and internationally. There is a need to translate the new wound care evidence base for diagnosis and treatment into patient care and ultimately improve patient outcomes.
Fournier's gangrene exposed
Authors: Harper Dl , Banwell Pe 
Published: May 2004

AbstractNecrotising fasciitis is a condition associated with significant morbidity and mortality. Fournier‘s gangrene is a variant of the condition affecting the perineum. Although presentation is usually acute, it may also present in an insidious manner. Following radical surgical debridement, meticulous attention to wound management is required.
Development of an experimental model of infected skin ulcer
Authors: Tachi Masahiro , Hirabayashi Shinichi , Yonehara Yoshiyuki , Suzuki Yasutoshi , Bowler Philip 
Published: May 2004

AbstractA model of infected skin ulceration could prove useful in assessing the clinical effectiveness of antimicrobial ointments and dressings. However, no such models have been previously established. Three types of wound were induced in rats: full‐thickness wounds covered with gauze, burn wounds and wounds resulting from mechanical trauma. Wounds were inoculated with S. aureus or P. aeruginosa. Persistent infected wounds were observed only in full‐thickness wounds covered with gauze. In a second experiment, colonies of P. aeruginosa or S. aureus were counted within 15 × 15 mm full‐thickness wounds covered with gauze. Wounds were inoculated with 1·0 × 106 colony‐forming units (CFU) of P. aeruginosa or S. aureus and then sealed to ensure an enclosed environment. Tissue bacterial counts exceeded 106 CFU/g from the next day until day 9 after infection. Bacterial counts exceeded 108 CFU/ml in wound exudate collected between days 1 and 7. We have developed a model of wound infection in which persistence of infection can be achieved for 9 days following ulceration due to the application of gauze to the base of a full‐thickness wound.
Nuclear Translocation of Papillomavirus Minor Capsid Protein L2 Requires Hsc70
Authors: Florin Luise , Becker Katrin A. , Sapp Cornelia , Lambert Carsten , Sirma Hüseyin , Müller Martin , Streeck Rolf E. , Sapp Martin 
Published: May 2004

ABSTRACT
Minor capsid protein L2 of papillomaviruses plays an essential role in virus assembly by recruiting viral components to PML bodies, the proposed sites of virus morphogenesis. We demonstrate here that the function of L2 in virus assembly requires the chaperone Hsc70. Hsc70 was found dispersed in naturally infected keratinocytes and cultured cells. A dramatic relocation of Hsc70 from the cytoplasm to PML bodies was induced in these cells by L2 expression. Hsc70-L2 complex formation was confirmed by coimmunoprecipitation. The complex was modulated by the cochaperones Hip and Bag-1, which stabilize and destabilize Hsc70-substrate complexes, respectively. Cytoplasmic depletion of Hsc70 caused retention of wild-type and N-terminally truncated L2, but not of C-terminally truncated L2, in the cytoplasm. This retention was partially reversed by overexpression of Hsc70 fused to green fluorescent protein but not by ATPase-negative Hsc70. Hsc70 associated with L1-L2 virus-like particles (VLPs) but not with VLPs composed either of L1 alone or of L1 and C-terminally truncated L2. Moreover, displacement of Hsc70 from L1-L2 VLPs by encapsidation of DNA, generating pseudovirions, was found. These data indicate that Hsc70 transiently associates with viral capsids during the integration of L2, possibly via the L2 C terminus. Completion of virus assembly results in displacement of Hsc70 from virions.
Conformational Changes in the Nuclear Lamina Induced by Herpes Simplex Virus Type 1 Require Genes U
L
31 and U
L
34
Authors: Reynolds Ashley E. , Liang Li , Baines Joel D. 
Published: May 2004

ABSTRACT

The herpes simplex virus type 1 (HSV-1) U
L
31 and U
L
34 proteins are dependent on each other for proper targeting to the nuclear membrane and are required for efficient envelopment of nucleocapsids at the inner nuclear membrane. In this work, we show that whereas the solubility of lamins A and C (lamin A/C) was not markedly increased, HSV induced conformational changes in the nuclear lamina of infected cells, as viewed after staining with three different lamin A/C-specific antibodies. In one case, reactivity with a monoclonal antibody that recognizes an epitope in the lamin tail domain was greatly reduced in HSV-infected cells. This apparent HSV-induced epitope masking required both U
L
31 and U
L
34, but these proteins were not sufficient to mask the epitope in uninfected cells, indicating that other HSV proteins are also required. In the second case, staining with a rabbit polyclonal antibody that primarily recognizes epitopes in the lamin A/C rod domain revealed that U
L
34 is required for HSV-induced decreased availability of epitopes for reaction with the antibody, whereas U
L
31 protein was dispensable for this effect. Still another polyclonal antibody indicated virtually no difference in lamin A/C staining in infected versus uninfected cells, indicating that the HSV-induced changes are more conformational than the result of lamin depletion at the nuclear rim. Further evidence supporting an interaction between the nuclear lamina and the U
L
31/U
L
34 protein complex includes the observations that (i) overexpression of the U
L
31 protein in uninfected cells was sufficient to relocalize lamin A/C from the nuclear rim into nucleoplasmic aggregates, (ii) overexpression of U
L
34 was sufficient to relocalize some lamin A/C into the cytoplasm, and (iii) both U
L
31 and U
L
34 could directly bind lamin A/C in vitro. These studies suggest that the U
L
31 and U
L
34 proteins modify the conformation of the nuclear lamina in infected cells, possibly by direct interaction with lamin A/C, and that other proteins are also likely involved. Given that the nuclear lamina potentially excludes nucleocapsids from envelopment sites at the inner nuclear membrane, the lamina alteration may reflect a role of the U
L
31/U
L
34 protein complex in perturbing the lamina to promote nucleocapsid egress from the nucleus. Alternatively, the data are compatible with a role of the lamina in targeting the U
L
31/U
L
34 protein complex to the nuclear membrane.
T-Cell Epitopes in Severe Acute Respiratory Syndrome (SARS) Coronavirus Spike Protein Elicit a Specific T-Cell Immune Response in Patients Who Recover from SARS
Authors: Wang Yue-Dan , Sin Wan-Yee Fion , Xu Guo-Bing , Yang Huang-Hua , Wong Tin-yau , Pang Xue-Wen , He Xiao-Yan , Zhang Hua-Gang , Ng Joice Na Lee , Cheng Chak-Sum Samuel , Yu Jing , Meng Li , Yang Rui-Feng , Lai Sik-To , Guo Zhi-Hong , Xie Yong , Chen Wei-Feng 
Published: May 2004

ABSTRACTThe immunogenicity of HLA-A2-restricted T-cell epitopes in the S protein of the Severe acute respiratory syndrome coronavirus (SARS-CoV) and of human coronavirus strain 229e (HCoV-229e) was analyzed for the elicitation of a T-cell immune response in donors who had fully recovered from SARS-CoV infection. We employed online database analysis to compare the differences in the amino acid sequences of the homologous T epitopes of HCoV-229e and SARS-CoV. The identified T-cell epitope peptides were synthesized, and their binding affinities for HLA-A2 were validated and compared in the T2 cell system. The immunogenicity of all these peptides was assessed by using T cells obtained from donors who had fully recovered from SARS-CoV infection and from healthy donors with no history of SARS-CoV infection. HLA-A2 typing by indirect immunofluorescent antibody staining showed that 51.6% of SARS-CoV-infected patients were HLA-A2 positive. Online database analysis and the T2 cell binding test disclosed that the number of HLA-A2-restricted immunogenic epitopes of the S protein of SARS-CoV was decreased or even lost in comparison with the homologous sequences of the S protein of HCoV-229e. Among the peptides used in the study, the affinity of peptides from HCoV-229e (H77 and H881) and peptides from SARS-CoV (S978 and S1203) for binding to HLA-A2 was higher than that of other sequences. The gamma interferon (IFN-γ) release Elispot assay revealed that only SARS-CoV-specific peptides S1203 and S978 induced a high frequency of IFN-γ-secreting T-cell response in HLA-A2+donors who had fully recovered from SARS-CoV infection; such a T-cell epitope-specific response was not observed in HLA-A2+healthy donors or in HLA-A2−donors who had been infected with SARS-CoV after full recovery. Thus, T-cell epitopes S1203 and S978 are immunogenic and elicit an overt specific T-cell response in HLA-A2+SARS-CoV-infected patients.
Multiple Enzymatic Activities Associated with Severe Acute Respiratory Syndrome Coronavirus Helicase
Authors: Ivanov Konstantin A. , Thiel Volker , Dobbe Jessika C. , van der Meer Yvonne , Snijder Eric J. , Ziebuhr John 
Published: May 2004

ABSTRACT
Severe acute respiratory syndrome coronavirus (SARS-CoV), a newly identified group 2 coronavirus, is the causative agent of severe acute respiratory syndrome, a life-threatening form of pneumonia in humans. Coronavirus replication and transcription are highly specialized processes of cytoplasmic RNA synthesis that localize to virus-induced membrane structures and were recently proposed to involve a complex enzymatic machinery that, besides RNA-dependent RNA polymerase, helicase, and protease activities, also involves a series of RNA-processing enzymes that are not found in most other RNA virus families. Here, we characterized the enzymatic activities of a recombinant form of the SARS-CoV helicase (nonstructural protein [nsp] 13), a superfamily 1 helicase with an N-terminal zinc-binding domain. We report that nsp13 has both RNA and DNA duplex-unwinding activities. SARS-CoV nsp13 unwinds its substrates in a 5′-to-3′ direction and features a remarkable processivity, allowing efficient strand separation of extended regions of double-stranded RNA and DNA. Characterization of the nsp13-associated (deoxy)nucleoside triphosphatase ([dNTPase) activities revealed that all natural nucleotides and deoxynucleotides are substrates of nsp13, with ATP, dATP, and GTP being hydrolyzed slightly more efficiently than other nucleotides. Furthermore, we established an RNA 5′-triphosphatase activity for the SARS-CoV nsp13 helicase which may be involved in the formation of the 5′ cap structure of viral RNAs. The data suggest that the (d)NTPase and RNA 5′-triphosphatase activities of nsp13 have a common active site. Finally, we established that, in SARS-CoV-infected Vero E6 cells, nsp13 localizes to membranes that appear to be derived from the endoplasmic reticulum and are the likely site of SARS-CoV RNA synthesis.
Increased Sensitivity to CD4 Binding Site-Directed Neutralization following In Vitro Propagation on Primary Lymphocytes of a Neutralization-Resistant Human Immunodeficiency Virus IIIB Strain Isolated from an Accidentally Infected Laboratory Worker
Authors: Beaumont Tim , Quakkelaar Esther , van Nuenen Ad , Pantophlet Ralph , Schuitemaker Hanneke 
Published: May 2004

ABSTRACTWe previously described the adaptation of the neutralization-sensitive human immunodeficiency virus type 1 (HIV-1) strain IIIB to a neutralization-resistant phenotype in an accidentally infected laboratory worker. During long-term propagation of this resistant isolate, designated FF3346, on primary peripheral blood leukocytes in vitro, an HIV-1 variant appeared that had regained sensitivity to neutralization by soluble CD4 (sCD4) and the broadly neutralizing monoclonal antibody b12. When an early passage of FF3346 was subjected to limiting-dilution culture in peripheral blood mononuclear cells, eight virus variants with various degrees of neutralization resistance were isolated. Two of them, the sCD4 neutralization-resistant variant LW_H8resand the sCD4 neutralization-sensitive variant LW_G9sens, were selected for further study. Interestingly, these two viruses were equally resistant to neutralization by agents that recognize domains other than the CD4 binding site. Site-directed mutagenesis revealed that the increased neutralization sensitivity of variant LW_G9sensresulted from only two changes, an Asn-to-Ser substitution at position 164 in the V2 loop and an Ala-to-Glu substitution at position 370 in the C3 domain of gp120. In agreement with this notion, the affinity of b12 for monomeric gp120 containing the N164S and A370E substitutions in the background of the molecular clone LW_H8reswas higher than its affinity for the parental gp120. Surprisingly, no correlation was observed between CD4 binding affinity for monomeric gp120 and the level of neutralization resistance, suggesting that differences in sCD4 neutralization sensitivity between these viruses are only manifested in the context of the tertiary or quaternary structure of gp120 on the viral surface. The results obtained here indicate that the neutralization-sensitive strain IIIB can become neutralization resistant in vivo under selective pressure by neutralizing antibodies but that this resistance may be easily reversed in the absence of immunological pressure.
Capsid Is a Dominant Determinant of Retrovirus Infectivity in Nondividing Cells
Authors: Yamashita Masahiro , Emerman Michael 
Published: May 2004

ABSTRACT
A major difference between lentiviruses such as human immunodeficiency virus (HIV) and most other retroviruses is their ability to productively infect nondividing cells. We present here genetic evidence for involvement of the capsid protein (CA) in the infectious phenotype in nondividing cells. A chimeric HIV type 1 (HIV-1) in which the MA and CA of HIV-1 are replaced with the MA, p12, and CA encoding sequences from murine leukemia virus (MLV) loses the ability to efficiently infect nondividing cells. Analysis of the accumulation of two-long-terminal-repeat circles implies that the impairment of nuclear transport of preintegration complexes is responsible for the restricted infection of this chimeric virus in nondividing cells. Incorporation of MLV MA and MLV p12 into HIV virions alone does not exert any adverse effects on viral infection in interphase cells. These results suggest that CA is the dominant determinant for the difference between HIV and MLV in the ability to transduce nondividing cells.
Passive and Active Inclusion of Host Proteins in Human Immunodeficiency Virus Type 1 Gag Particles during Budding at the Plasma Membrane
Authors: Hammarstedt Maria , Garoff Henrik 
Published: May 2004

ABSTRACT

Human immunodeficiency virus type 1 particles form by budding at the surface of most cell types. In this process, a piece of the plasma membrane is modified into an enveloped virus particle. The process is driven by the internal viral protein Pr55

gag

. We have studied how host proteins in the membrane are dealt with by Pr55

gag

during budding. Are they included in or excluded from the particle? The question was approached by measuring the relative concentrations of host and viral proteins in the envelope of Pr55

gag

particles and in their donor membranes in the cell. We observed that the bulk of the host proteins, including actin and clathrin, were passively included into the virus-like Gag particles. This result suggests that budding by Pr55

gag

proceeds without significant alteration of the original host protein composition at the cell membrane. Nevertheless, some proteins were concentrated in the particles, and a few were excluded. The concentrated proteins included cyclophilin A and Tsg-101. These were recruited to the plasma membrane by Pr55

gag

. The membrane-bound cyclophilin A was concentrated into particles as efficiently as Pr55

gag

, whereas Tsg-101 was concentrated more efficiently. The latter finding is consistent with a role for Tsg-101 in Gag particle release.
Degradation of p53, Not Telomerase Activation, by E6 Is Required for Bypass of Crisis and Immortalization by Human Papillomavirus Type 16 E6/E7
Authors: McMurray H. R. , McCance D. J. 
Published: May 2004

ABSTRACT
Bypass of two arrest points is essential in the process of cellular immortalization, one of the components of the transformation process. Expression of human papillomavirus type 16 E6 and E7 together can escape both senescence and crisis, processes which normally limit the proliferative capacity of primary human keratinocytes. Crisis is thought to be mediated by telomere shortening. Because E6 stimulates telomerase activity and exogenous expression of the TERT gene with E7 can immortalize keratinocytes, this function is thought to be important for E6 to cooperate with E7 to bypass crisis. However, it has also been reported that E6 dissociates increased telomerase activity from maintenance of telomere length and that a dominant-negative p53 molecule can substitute for E6 in cooperative immortalization of keratinocytes with E7. Thus, to determine which functions of E6 are required to allow bypass of crisis and immortalization of keratinocytes with E7, immortalization assays were performed using specific mutants of E6, in tandem with E7. In these experiments, every clone expressing an E6 mutant capable of degrading p53 was able to bypass crisis and immortalize, regardless of telomerase induction. All clones containing E6 mutants incapable of degrading p53 died at crisis. These results suggest that the ability of E6 to induce degradation of p53 compensates for continued telomere shortening in E6/E7 cells and demonstrate that degradation of p53 is required for immortalization by E6/E7, while increased telomerase activity is dispensable.