bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against
Candida
spp.: Results from a Global Antifungal Surveillance Program
Authors: Pfaller M. A. , Messer S. A. , Boyken L. , Tendolkar S. , Hollis R. J. , Diekema D. J. 
Published: December 2007

ABSTRACT

There are currently no FDA-approved broth microdilution antifungal susceptibility testing products or interpretive breakpoints for susceptibility testing of the new triazole posaconazole. Fluconazole and voriconazole are in the same triazole class as posaconazole, have CLSI-approved interpretive MIC breakpoints, and are available on some commercially available MIC panels. We investigated whether one or both of these agents may be useful as a surrogate marker for posaconazole susceptibility. Fluconazole, voriconazole, and posaconazole MIC results for 10,807 isolates of
Candida
spp. were analyzed to validate a potential surrogate marker for posaconazole activity against indicated species. For illustrative purposes, we applied the voriconazole MIC breakpoints to posaconazole (susceptible, ≤1 μg/ml; susceptible dose dependent, 2 μg/ml; resistant, ≥4 μg/ml) and compared these MIC results and categorical interpretations with those of fluconazole and voriconazole by using regression statistics and categorical agreement. For all 10,807 isolates, the absolute categorical agreement was 91.1% (0.1% very major errors [VME], 1.2% major errors [ME], and 7.6% minor errors [M]) using fluconazole as the surrogate marker and 97.7% (0.3% VME 0.1% ME, and 1.9% M) using voriconazole as the surrogate. The results with fluconazole improved to a categorical agreement of 93.7% (0.1% VME, 0.2% ME, and 6.0% M) when results for
Candida krusei
(not indicated for fluconazole testing) were omitted. Either fluconazole or voriconazole MIC results may serve as surrogate markers to predict the susceptibility of
Candida
spp. to posaconazole.
Definition of the Minimal
cis
-Acting Sequences Necessary for Genome Maturation of the Herpesvirus Murine Cytomegalovirus
Authors: Wang Jian Ben , Nixon Daniel E. , McVoy Michael A. 
Published: December 2007

ABSTRACT

Herpesvirus DNA replication proceeds via concatemeric replicative intermediates that are comprised of head-to-tail-linked genomes. Genome maturation is carried out by the terminase, a protein complex that mediates both insertion of concatemer DNA into capsids and its subsequent cleavage to release genomes within these capsids. This cleavage is sequence specific, but the governing
cis
-acting DNA sequences are only partially characterized. Two highly conserved motifs called
pac1
and
pac2
lie near the ends of herpesvirus genomes and are known to be critical for genome maturation. However, the potential importance of other sequences has not been fully investigated. We have undertaken to define all of the sequences necessary for efficient genome maturation for a herpesvirus by inserting ectopic cleavage sites into the murine cytomegalovirus genome and assessing their ability to mediate genome maturation. A combination of deletion and substitution mutations revealed that the minimal cleavage site is large (∼180 bp) and complex. Sequences distal of
pac1
(relative to the point of cleavage) were dispensable, suggesting that
pac1
may be the sole
cis
-acting element on this side of the cleavage site. In contrast, a region distal to
pac2
up to 150 bp from the point of cleavage was essential. Scanning substitutions revealed that the
pac2
side of the cleavage site is complex and may contain multiple
cis
-acting sequence elements in addition to
pac2
. These results should facilitate the identification of
trans
-acting factors that bind to these elements and the elucidation of their functions. Such information will be critical for understanding the molecular basis of this complex process.
Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus
Authors: Castilow Elaine M. , Olson Matthew R. , Meyerholz David K. , Varga Steven M. 
Published: December 2007

ABSTRACTSecondary exposure to respiratory syncytial virus (RSV) can lead to immunopathology and enhanced disease in vaccinated individuals. Vaccination with individual RSV proteins influences the type of secondary RSV-specific immune response that develops upon challenge RSV infection, as well as the extent of immunopathology. RSV-specific memory CD4 T cells can directly contribute to immunopathology through their cytokine production. Immunization of BALB/c mice with a recombinant vaccinia virus (vv) expressing the attachment (G) protein of RSV results in pulmonary eosinophilia upon RSV challenge, whereas immunization of mice with a vv expressing the fusion (F) protein does not. We analyzed the CD4 T-cell response to an I-Ed-restricted CD4 T-cell epitope within the F protein of RSV corresponding to amino acids 51 to 66 in an effort to better understand the similarities and differences in the immune response elicited by the G versus the F protein. Vaccination with the G protein induces a mixture of RSV G-specific Th1 and Th2 cells with a restricted T-cell receptor repertoire. In contrast, we demonstrate here that immunization with the F protein elicits a broad repertoire of RSV F-specific CD4 T cells that predominantly exhibit a Th1 phenotype. However, in the absence of gamma interferon (IFN-γ), RSV F51-66-specific CD4 T cells secreted interleukin-5, and mice developed pulmonary eosinophilia after RSV challenge. IFN-γ-deficient mice exhibited decreased weight loss compared to wild-type controls, suggesting that IFN-γ exacerbates systemic disease. These data demonstrate that IFN-γ can have both beneficial and detrimental effects during a secondary RSV infection.
Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction
Authors: Kitayama Hiroko , Miura Yoshiharu , Ando Yoshinori , Hoshino Shigeki , Ishizaka Yukihito , Koyanagi Yoshio 
Published: December 2007

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.
Human Immunodeficiency Virus Type 1 Nef Recruits the Guanine Exchange Factor Vav1 via an Unexpected Interface into Plasma Membrane Microdomains for Association with p21-Activated Kinase 2 Activity
Authors: Rauch Susanne , Pulkkinen Kati , Saksela Kalle , Fackler Oliver T. 
Published: December 2007

ABSTRACT
Alterations of T-cell receptor signaling by human immunodeficiency virus type 1 (HIV-1) Nef involve its association with a highly active subpopulation of p21-activated kinase 2 (PAK2) within a dynamic signalosome assembled in detergent-insoluble membrane microdomains. Nef-PAK2 complexes contain the GTPases Rac and Cdc42 as well as a factor providing guanine nucleotide exchange factor (GEF) activity for Rac/Cdc42. However, the identity of this GEF has remained controversial. Previous studies suggested the association of Nef with at least three independent GEFs, Vav, DOCK2/ELMO1, and βPix. Here we used a broad panel of approaches to address which of these GEFs is involved in the functional interaction of Nef with PAK2 activity. Biochemical fractionation and confocal microscopy revealed that Nef recruits Vav1, but not DOCK2/ELMO1 or βPix, to membrane microdomains. Transient RNAi knockdown, analysis of cell lines defective for expression of Vav1 or DOCK2 as well as use of a βPix binding-deficient PAK2 variant confirmed a role for Vav1 but not DOCK2 or βPix in Nef's association with PAK2 activity. Nef-mediated microdomain recruitment of Vav1 occurred independently of the Src homology 3 domain binding PxxP motif, which is known to connect Nef to many cellular signaling processes. Instead, a recently described protein interaction surface surrounding Nef residue F195 was identified as critical for Nef-mediated raft recruitment of Vav1. These results identify Vav1 as a relevant component of the Nef-PAK2 signalosome and provide a molecular basis for the role of F195 in formation of a catalytically active Nef-PAK2 complex.
Structure of Antibody-Neutralized Murine Norovirus and Unexpected Differences from Viruslike Particles
Authors: Katpally Umesh , Wobus Christiane E. , Dryden Kelly , Virgin Herbert W. , Smith Thomas J. 
Published: December 2007

ABSTRACT

Noroviruses (family
Caliciviridae
) are the major cause of epidemic nonbacterial gastroenteritis in humans, but the mechanism of antibody neutralization is unknown and no structure of an infectious virion has been reported. Murine norovirus (MNV) is the only norovirus that can be grown in tissue culture, studied in an animal model, and reverse engineered via an infectious clone and to which neutralizing antibodies have been isolated. Presented here are the cryoelectron microscopy structures of an MNV virion and the virion in complex with neutralizing Fab fragments. The most striking differences between MNV and previous calicivirus structures are that the protruding domain is lifted off the shell domain by ∼16Å and rotated ∼40° in a clockwise fashion and forms new interactions at the P1 base that create a cagelike structure engulfing the shell domains. Neutralizing Fab fragments cover the outer surface of each copy of the capsid protein P2 domains without causing any apparent conformational changes. These unique features of MNV suggest that at least some caliciviruses undergo a capsid maturation process akin to that observed with other plant and bacterial viruses.
The Glycoprotein and the Matrix Protein of Rabies Virus Affect Pathogenicity by Regulating Viral Replication and Facilitating Cell-to-Cell Spread
Authors: Pulmanausahakul Rojjanaporn , Li Jianwei , Schnell Matthias J. , Dietzschold Bernhard 
Published: December 2007

ABSTRACT
While the glycoprotein (G) of rabies virus (RV) is known to play a predominant role in the pathogenesis of rabies, the function of the RV matrix protein (M) in RV pathogenicity is not completely clear. To further investigate the roles of these proteins in viral pathogenicity, we constructed chimeric recombinant viruses by exchanging the G and M genes of the attenuated SN strain with those of the highly pathogenic SB strain. Infection of mice with these chimeric viruses revealed a significant increase in the pathogenicity of the SN strain bearing the RV G from the pathogenic SB strain. Moreover, the pathogenicity was further increased when both G and M from SB were introduced into SN. Interestingly, the replacement of the G or M gene or both in SN by the corresponding genes of SB was associated with a significant decrease in the rate of viral replication and viral RNA synthesis. In addition, a chimeric SN virus bearing both the M and G genes from SB exhibited more efficient cell-to-cell spread than a chimeric SN virus in which only the G gene was replaced. Together, these data indicate that both G and M play an important role in RV pathogenesis by regulating virus replication and facilitating cell-to-cell spread.
Single Intranasal Immunization with Recombinant Adenovirus-Based Vaccine Induces Protective Immunity against Respiratory Syncytial Virus Infection
Authors: Yu Jae-Rang , Kim Sol , Lee Jee-Boong , Chang Jun 
Published: December 2007

ABSTRACTRespiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The G glycoprotein of RSV, a major attachment protein, is a potentially important target for protective antiviral immune responses. Here, a recombinant replication-deficient adenovirus-based vaccine, rAd/3xG, expressing the soluble core domain of G glycoprotein (amino acids 130 to 230) engineered by codon optimization and tandem repetition for higher-level expression, was constructed and evaluated for its potential as an RSV vaccine in a murine model. A single intranasal immunization with rAd/3xG provided potent protection against RSV challenge which lasted for more than 10 weeks. Strong mucosal immunoglobulin A responses were also induced by a single intranasal immunization but not by intramuscular or oral administration of rAd/3xG. Interestingly, neither gamma interferon- nor interleukin-4-producing CD4 T cells directed to I-Ed-restricted epitope were detected in the lungs of rAd/3xG-immune mice upon challenge, whereas priming with vaccinia virus expressing RSV G (vvG) elicited strong Th1/Th2 mixed CD4 T-cell responses. Lung eosinophilia and vaccine-induced weight loss were significantly lower in the rAd/3xG-immune group than in the vvG-primed group. Together, our data demonstrate that a single intranasal administration of rAd/3xG elicits beneficial protective immunity and represents a promising vaccine regimen against RSV infection.
Petroleum and progress in geology
Authors: HEDBERG HOLLIS DOW 
Published: December 2007

If W
illiam
S
mith
had lived in the 20th century, he might well have been a great petroleum geologist. Even in his time, at the turn of the 18th century, it was needs, similar to those of the present for heat, power and transportation that led him, through the surveying of coal mines and canals, into a geological career, and that made him one of the great contributors to the fundamentals of the petroleum geology which was to come only long after his time. Let us consider then, in what manner petroleum may have repaid, in part, the debt which it owes to William Smith and to other early pioneers in stratigraphy and related fields of geology.

In the midst of our aggressive search for new geological facts and our enthusiastic attempts at new geological hypotheses, it is perhaps well to step aside for a moment to appraise and evaluate some of the factors and influences which have helped to bring us to where we are in geology today. I am, therefore, pleased that the Council of the Geological Society has seen fit to encourage me in presenting, not the usual story of new research results, but rather an appreciation of the contributions to geology which have grown out of the quest for a particular and unique mineral resource.
We are living today in a brief and fleeting period of world history which may well be known as the Petroleum Age. We have had the Stone Age, the Bronze Age, the
Systematics in palaeontology
Authors: GEORGE THOMAS NEVILLE 
Published: December 2007

A ‘natural’ taxonomic system, inherent in organisms that themselves demonstrate their ‘affinity’, is to be recognized perhaps only in the biospecies. The concept of the biospecies as a comprehensive taxon is, however, only notional amongst the vast majority of living organisms, and it is not directly applicable to fossils. ‘Natural’ systems of Linnaean kind rest on assumptions made
a priori
and are imposed by the systematist. The graded time-sequence of the lineage and the clade introduces factors into a systematics that cannot well be accommodated under pre-Darwinian assumptions or be formulated by a Linnaean nomenclatural method.

The fossil evidence of ‘affinity’ is best served by a system of classes defining intrinsic relationships that are phylogenetic. Multiple demic variants, clinal bioseries, variable rates of evolutionary change, pulses of biased selection pressure in expanded and restricted palaeodemes, and permutations of character-expression in the evolutionary plexus impose a need for a palaeontologically-orientated systematics under which (in evolutionary descent) could be subsumed the taxa of the neontological moment.
Environmentally controlled morphs, biofacies variants, migrating variation fields, and typological segregants are sources of ambiguity in a distinction between phenetic and genetic fossil grades. Trends in variants are not to be confused with trends in transients; and sequential demes may (in time and space) show trend reversals as a sign of nongenetic (phenetic) selection. The morphospecies of the local palaeodeme is then to be distinguished from the holomorphospecies of the lineage segment, both in kind and in taxonym; and the association of variant morphotypes in a unitary deme is no justification for a splitting of the deme into several morphospecies.
Criteria of cladal disjunction are multiple. They may rest in one or a few ‘differential’ characters, or (in a ‘numerical’ taxonomy) on an Adansonian equal-weighting of ‘all’ characters. A consequence is to impose on an inferred phylogeny taxonomic incompatibilities deriving from contrasted interpretations of homology and homoeomorphy. Clinal disjunction as an incipient sign of cladal branching presents other problems in nomenclature and in the definition of taxon-range. Accelerated and retarded rates of bioserial change in sub-parallel lineages further complicate systematics notably in mosaic evolution. A basic distinction between Linnaean (morphotypic) and evolutionary systematics rests in the relevance of the question that asks whether the class determines the characters or the characters the class.
THE SILURIAN-DEVONIAN BOUNDARY—
Authors: Westoll T. S. , Shirley J. , Dineley D. L. , Ball H. W. 
Published: December 2007

For over a century the position of the Silurian-Devonian Boundary has excited controversy and the problem continues to exercise the Committee on the Silurian-Devonian Boundary instituted by the International Commission on Stratigraphy. There has been vigorous activity to examine and adopt a new horizon at which to draw this boundary. Little enough has been said to maintain the value, usefulness and claims of the boundary that has served so long. While we do not wish to stand in the way of an innovation that may, insofar as recognised graptolite zones are used, be better than that which we have used so far, we question whether British geologists have assessed adequately what is involved in the recommendation of the British Silurian Subcommittee. The matter was indeed raised in a letter to the Editor of the Geological Magazine (March–April, 1969, pp. 215–216) by P. T. Warren on behalf of the Institute of Geological Sciences. Warren said ‘. . . we shall, as a matter of policy, in the immediate future at least, continue to use the Ludlovian-Downtonian boundary as the Siluro-Devonian boundary.’ We offer the following points for serious consideration and we stress that it is more important for British geologists to deliberate fully a recommendation before endorsing it, than to give unqualified assent when indeed there are important grounds for hesitation.
Despite the Silurian Committee’s conclusion that the Downtonian stage be included within the Silurian system, there appear to the undersigned to be good reasons for retaining the base
Geology and society in Britain—the need for a comprehensive appraisal
Authors: BASSETT DOUGLAS 
Published: December 2007

One hundred and fiftyyears ago, when the major qualitative changes initiated during the so-called 'Heroic Age of Geology' were beginning to be appreciated and to take effect, it was possible for one man to have a reasonably comprehensive grasp of the state of geology in this country. Nowadays, however, individual geologists are unable to keep abreast of the developments in their own field let alone keep track of the rapidly changing structure of geology in general, and of its relations with other sciences and with society.Considerable effort is, of course, being made by various individuals, institutions and societies to keep abreast of the exponential growth of geological literature by providing bibliographies, abstracts and reviews. And although it is becoming increasingly difficult 'to keep up with keeping up,' there is definite evidence of co-operative effort between scientists and librarians in tackling the problem.Similarly, statistical and other surveys are being carried out regarding the distribution of geological manpower as part of the triennial manpower surveys of persons in employment with qualifications in engineering, science and technology and also of the place of geology in education, in industry and in other sections of society. These assessments are, however, being carried out by a diversity of bodies and the results commonly appear in publications which either have restricted distribution, or are little known to practising geologists. Any one individual geologist has, therefore, little chance of appreciating the overall picture. Because of this, I wish to make three inter-related suggestions :–– that
Processes of geological evolution
Authors: SYLVESTER-BRADLEY PETER 
Published: December 2007

T
he heart
of geology has always been represented by a synthesis of diverse disciplines. In the early days of our science, it was from this synthesis that the great historical pageant of the last four thousand million years was built up. A hundred years ago, the generalisations of geology culminated in the contribution they made to the history of the Earth. It seemed then that the goal of every geologist, whatever his discipline, was to add a page, a chapter or an appendix to a record of events that embraced everything from the origin of the Earth to the dominance of man.

But this is no longer the case. Now it is not a record of events that lies at the heart of our science. Our curiosity is busy with another question. It is a question set by the history itself. We can see that we are not dealing with an arbitrary repetition of cycles. There is an overall, inexorable, dynamic change relentlessly driving forward. The Earth is changing in nature, and the synthesis that we are looking for now is one that explains that change. What processes are at work? How far is geological evolution a part of a more general process, affecting all planets? Can geological processes be grouped together as a special case of planetary evolution?
The concept of planetary evolution is opposed to that of a 'steady state'; it is not opposed to the more sacred principle of uniformitarianism. If the Earth, in not opposed to