bluuebunny/crossref_metadata_2025_split huggingface dataset:
Underwater Options and the Dynamics of Executive Pay‐to‐Performance Sensitivities
Authors: HALL BRIAN J. , KNOX THOMAS A. 
Published: April 2004

ABSTRACTWe empirically analyze the dynamics of executives' pay‐to‐performance sensitivities. Option pay‐to‐performance sensitivities become weaker as options fall underwater, often leading to pressures to reprice options or restore pay‐to‐performance sensitivity in other ways. Building a detailed data set on executives' portfolios of stock and options, we find that the responsiveness of pay‐to‐performance sensitivities (created by all executive holdings of stock and options) to changes in stock price is large. The elasticity of pay‐to‐performance sensitivities with respect to stock price decreases is about 0.7 and is larger for high‐option executives and for executives with high percentages of options already underwater. The dominant mechanism through which companies offset declines in option pay‐to‐performance sensitivities is larger option grants following stock price declines; on average, these larger grants restore approximately 40% of the stock‐price‐induced pay‐to‐performance sensitivity declines. Option repricings are inconsequential in this regard, despite the attention they have attracted. In looking at positive returns, we find the reverse: higher returns both directly increase pay‐to‐performance sensitivities and lead to larger option grants, which raise pay‐to‐performance sensitivities further. Thus, option grants to executives tend to be largest following large stock price increases or large stock price decreases.
Redox Potential Regulates Binding of Universal Minicircle Sequence Binding Protein at the Kinetoplast DNA Replication Origin
Authors: Onn Itay , Milman-Shtepel Neta , Shlomai Joseph 
Published: April 2004

ABSTRACTKinetoplast DNA, the mitochondrial DNA of the trypanosomatidCrithidia fasciculata, is a remarkable structure containing 5,000 topologically linked DNA minicircles. Their replication is initiated at two conserved sequences, a dodecamer, known as the universal minicircle sequence (UMS), and a hexamer, which are located at the replication origins of the minicircle L- and H-strands, respectively. A UMS-binding protein (UMSBP), binds specifically the conserved origin sequences in their single stranded conformation. The five CCHC-type zinc knuckle motifs, predicted in UMSBP, fold into zinc-dependent structures capable of binding a single-stranded nucleic acid ligand. Zinc knuckles that are involved in the binding of DNA differ from those mediating protein-protein interactions that lead to the dimerization of UMSBP. Both UMSBP DNA binding and its dimerization are sensitive to redox potential. Oxidation of UMSBP results in the protein dimerization, mediated through its N-terminal domain, with a concomitant inhibition of its DNA-binding activity. UMSBP reduction yields monomers that are active in the binding of DNA through the protein C-terminal region.C. fasciculatatrypanothione-dependent tryparedoxin activates the binding of UMSBP to UMS DNA in vitro. The possibility that UMSBP binding at the minicircle replication origin is regulated in vivo by a redox potential-based mechanism is discussed.
Role of Micronucleus-Limited DNA in Programmed Deletion of mse2.9 during Macronuclear Development of
Tetrahymena thermophila
Authors: Fillingham Jeffrey S. , Pearlman Ronald E. 
Published: April 2004

ABSTRACT

Extensive programmed DNA rearrangements occur during the development of the somatic macronucleus from the germ line micronucleus in the sexual cycle of the ciliated protozoan
Tetrahymena thermophila
. Using an in vivo processing assay, we analyzed the role of micronucleus-limited DNA during the programmed deletion of mse2.9, an internal eliminated sequence (IES). We identified a 200-bp region within mse2.9 that contains an important
cis
-acting element which is required for the targeting of efficient programmed deletion. Our results, obtained with a series of mse2.9-based chimeric IESs, led us to suggest that the
cis
-acting elements in both micronucleus-limited and macronucleus-retained flanking DNAs stimulate programmed deletion to different degrees depending on the particular eliminated sequence. The mse2.9 IES is situated within the second intron of the micronuclear locus of the
ARP1
gene. We show that the expression of
ARP1
is not essential for the growth of
Tetrahymena
. Our results also suggest that mse2.9 is not subject to epigenetic regulation of DNA deletion, placing possible constraints on the scan RNA model of IES excision.
pdf1
, a Palmitoyl Protein Thioesterase 1 Ortholog in
Schizosaccharomyces pombe
: a Yeast Model of Infantile Batten Disease
Authors: Cho Steve K. , Hofmann Sandra L. 
Published: April 2004

ABSTRACT

Infantile Batten disease is a severe neurodegenerative storage disorder caused by mutations in the human
PPT1
(palmitoyl protein thioesterase 1) gene, which encodes a lysosomal hydrolase that removes fatty acids from lipid-modified proteins.
PPT1
has orthologs in many species, including lower organisms and plants, but not in
Saccharomyces cerevisiae.
The fission yeast
Schizosaccharomyces pombe
contains a previously uncharacterized open reading frame (SPBC530.12c) that encodes the
S. pombe
Ppt1p ortholog fused in frame to a second enzyme that is highly similar to a previously cloned mouse dolichol pyrophosphatase (Dolpp1p). In the present study, we characterized this interesting gene (designated here as
pdf1
, for palmitoyl protein thioesterase-dolichol pyrophosphate phosphatase fusion 1) through deletion of the open reading frame and complementation by plasmids bearing mutations in various regions of the
pdf1
sequence. Strains bearing a deletion of the entire
pdf1
open reading frame are nonviable and are rescued by a
pdf1
expression plasmid. Inactivating mutations in the Dolpp1p domain do not rescue the lethality, whereas mutations in the Ppt1p domain result in cells that are viable but abnormally sensitive to sodium orthovanadate and elevated extracellular pH. The latter phenotypes have been previously associated with class C and class D vacuolar protein sorting (
vps
) mutants and vacuolar membrane H
+
-ATPase (
vma
) mutants in
S. cerevisiae
. Importantly, the Ppt1p-deficient phenotype is complemented by the human
PPT1
gene. These results indicate that the function of
PPT1
has been widely conserved throughout evolution and that
S. pombe
may serve as a genetically tractable model for the study of human infantile Batten disease.
Nrg1 and Nrg2 Transcriptional Repressors Are Differently Regulated in Response to Carbon Source
Authors: Berkey Cristin D. , Vyas Valmik K. , Carlson Marian 
Published: April 2004

ABSTRACT

The Nrg1 and Nrg2 repressors of
Saccharomyces cerevisiae
have highly similar zinc fingers and closely related functions in the regulation of glucose-repressed genes. We show that
NRG1
and
NRG2
are differently regulated in response to carbon source at both the RNA and protein levels. Expression of
NRG1
RNA is glucose repressed, whereas
NRG2
RNA levels are nearly constant. Nrg1 protein levels are elevated in response to glucose limitation or growth in nonfermentable carbon sources, whereas Nrg2 levels are diminished. Chromatin immunoprecipitation assays showed that Nrg1 and Nrg2 bind DNA both in the presence and absence of glucose. In mutant cells lacking the corepressor Ssn6(Cyc8)-Tup1, promoter-bound Nrg1, but not Nrg2, functions as an activator in a reporter assay, providing evidence that the two Nrg proteins have distinct properties. We suggest that the differences in expression and function of these two repressors, in combination with their similar DNA-binding domains, contribute to the complex regulation of the large set of glucose-repressed genes.
Translational Accuracy during Exponential, Postdiauxic, and Stationary Growth Phases in
Saccharomyces cerevisiae
Authors: Stahl Guillaume , Salem Samia N. Ben , Chen Lifeng , Zhao Bing , Farabaugh Philip J. 
Published: April 2004

ABSTRACT

When the yeast
Saccharomyces cerevisiae
shifts from rapid growth on glucose to slow growth on ethanol, it undergoes profound changes in cellular metabolism, including the destruction of most of the translational machinery. We have examined the effect of this metabolic change, termed the diauxic shift, on the frequency of translational errors. Recoding sites are mRNA sequences that increase the frequency of translational errors, providing a convenient reporter of translational accuracy. We found that the diauxic shift causes no overall change in translational accuracy but does cause a strong reduction in the frequency of one type of programmed error: Ty +1 frameshifting. Genetic data suggest that this effect may be due to changes in the relative amounts of tRNA participating in translation elongation. We discuss possible implications for expression strategies that use recoding.
Role of a Mitogen-Activated Protein Kinase Pathway during Conidial Germination and Hyphal Fusion in
Neurospora crassa
Authors: Pandey Amita , Roca M. Gabriela , Read Nick D. , Glass N. Louise 
Published: April 2004

ABSTRACT

Mitogen-activated protein (MAP) kinase signaling pathways are ubiquitous and evolutionarily conserved in eukaryotic organisms. MAP kinase pathways are composed of a MAP kinase, a MAP kinase kinase, and a MAP kinase kinase kinase; activation is regulated by sequential phosphorylation. Components of three MAP kinase pathways have been identified by genome sequence analysis in the filamentous fungus
Neurospora crassa
. One of the predicted MAP kinases in
N. crassa
, MAK-2, shows similarity to Fus3p and Kss1p of
Saccharomyces cerevisiae
, which are involved in sexual reproduction and filamentation, respectively. In this study, we show that an
N. crassa
mutant disrupted in
mak
-
2
exhibits a pleiotropic phenotype: derepressed conidiation, shortened aerial hyphae, lack of vegetative hyphal fusion, female sterility, and autonomous ascospore lethality. We assessed the phosphorylation of MAK-2 during conidial germination and early colony development. Peak levels of MAK-2 phosphorylation were most closely associated with germ tube elongation, branching, and hyphal fusion events between conidial germlings. A MAP kinase kinase kinase (NRC-1) is the predicted product of
N. crassa nrc
-
1
locus and is a homologue of
STE11
in
S. cerevisiae.
An
nrc
-
1
mutant shares many of the same phenotypic traits as the
mak
-
2
mutant and, in particular, is a hyphal fusion mutant. We show that MAK-2 phosphorylation during early colony development is dependent upon the presence of NRC-1 and postulate that phosphorylation of MAK-2 is required for hyphal fusion events that occur during conidial germination.
Genetic Dissection of the
Kluyveromyces lactis
Telomere and Evidence for Telomere Capping Defects in
TER1
Mutants with Long Telomeres
Authors: Underwood Dana H. , Carroll Coleen , McEachern Michael J. 
Published: April 2004

ABSTRACT

In the yeast
Kluyveromyces lactis
, the telomeres are composed of perfect 25-bp repeats copied from a 30-nucleotide RNA template defined by 5-nucleotide terminal repeats. A genetic dissection of the
K. lactis
telomere was performed by using mutant telomerase RNA (
TER1
) alleles to incorporate mutated telomeric repeats. This analysis has shown that each telomeric repeat contains several functional regions, some of which may physically overlap. Mutations in the terminal repeats of the template RNA typically lead to telomere shortening, as do mutations in the right side of the Rap1p binding site. Mutations in the left half of the Rap1p binding site, however, lead to the immediate formation of long telomeres. When mutated, the region immediately 3′ of the Rap1p binding site on the TG-rich strand of the telomere leads to telomeres that are initially short but eventually undergo extreme telomere elongation. Mutations between this region and the 3′ terminal repeat cause elevated recombination despite the presence of telomeres of nearly wild-type length. Mutants with highly elongated telomeres were further characterized and exhibit signs of telomere capping defects, including elevated levels of subtelomeric recombination and the formation of extrachromosomal and single-stranded telomeric DNA. Lengthening caused by some Rap1 binding site mutations can be suppressed by high-copy-number
RAP1
. Mutated telomeric repeats from a delayed elongation mutant are shown to be defective at regulating telomere length in cells with wild-type telomerase, indicating that the telomeric repeats are defective at telomere length regulation.
Polarized Hyphal Growth in
Candida albicans
Requires the Wiskott-Aldrich Syndrome Protein Homolog Wal1p
Authors: Walther A. , Wendland J. 
Published: April 2004

ABSTRACT

The yeast-to-hypha transition is a key feature in the cell biology of the dimorphic human fungal pathogen
Candida albicans
. Reorganization of the actin cytoskeleton is required for this dimorphic switch in
Candida
. We show that
C. albicans WAL1
mutants with both copies of the Wiskott-Aldrich syndrome protein (WASP) homolog deleted do not form hyphae under all inducing conditions tested. Growth of the wild-type and
wal1
mutant strains was monitored by in vivo time-lapse microscopy both during yeast-like growth and under hypha-inducing conditions. Isotropic bud growth produced round
wal1
cells and unusual mother cell growth. Defects in the organization of the actin cytoskeleton resulted in the random localization of actin patches. Furthermore,
wal1
cells exhibited defects in the endocytosis of the lipophilic dye FM4-64, contained increased numbers of vacuoles compared to the wild type, and showed defects in bud site selection. Under hypha-inducing conditions
wal1
cells were able to initiate polarized morphogenesis, which, however, resulted in the formation of pseudohyphal cells. Green fluorescent protein (GFP)-tagged Wal1p showed patch-like localization in emerging daughter cells during the yeast growth phase and at the hyphal tips under hypha-inducing conditions. Wal1p-GFP localization largely overlapped with that of actin. Our results demonstrate that Wal1p is required for the organization of the actin cytoskeleton and hyphal morphogenesis in
C. albicans
as well as for endocytosis and vacuole morphology.
Cryptosporidium parvum
Mitochondrial-Type HSP70 Targets Homologous and Heterologous Mitochondria
Authors: Šlapeta Jan , Keithly Janet S. 
Published: April 2004

ABSTRACT

A mitochondrial HSP70 gene (
Cp-mtHSP70
) is described for the apicomplexan
Cryptosporidium parvum
, an agent of diarrhea in humans and animals. Mitochondrial HSP70 is known to have been acquired from the proto-mitochondrial endosymbiont. The amino acid sequence of Cp-mtHSP70 shares common domains with mitochondrial and proteobacterial homologues, including 34 amino acids of an NH
2
-terminal mitochondrion-like targeting presequence. Phylogenetic reconstruction places Cp-mtHSP70 within the mitochondrial clade of HSP70 homologues. Using reverse transcription-PCR,
Cp-mtHSP70
mRNA was observed in
C. parvum
intracellular stages cultured in HCT-8 cells. Polyclonal antibodies to Cp-mtHSP70 recognize a ∼70-kDa protein in Western blot analysis of sporozoite extracts. Both fluorescein- and immunogold-labeled anti-Cp-mtHSP70 localize to a single mitochondrial compartment in close apposition to the nucleus. Furthermore, the NH
2
-terminal presequence of Cp-mtHSP70 can correctly target green fluorescent protein to the single mitochondrion of the apicomplexan
Toxoplasma gondii
and the mitochondrial network of the yeast
Saccharomyces cerevisiae
. When this presequence was truncated, the predicted amphiphilic α-helix was shown to be essential for import into the yeast mitochondrion. These data further support the presence of a secondarily reduced relict mitochondrion in
C. parvum
.
A
Theileria annulata
DNA Binding Protein Localized to the Host Cell Nucleus Alters the Phenotype of a Bovine Macrophage Cell Line
Authors: Shiels Brian R. , McKellar Sue , Katzer Frank , Lyons Kim , Kinnaird Jane , Ward Chris , Wastling Jonathan M. , Swan David 
Published: April 2004

ABSTRACT

The apicomplexan parasite
Theileria annulata
is the only intracellular eukaryote that is known to induce the proliferation of mammalian cells. However, as the parasite undergoes stage differentiation, host cell proliferation is inhibited, and the leukocyte is eventually destroyed. We have isolated a parasite gene (
SuAT1
) encoding an AT hook DNA binding polypeptide that has a predicted signal peptide, PEST motifs, nuclear localization signals, and domains which indicate interaction with regulatory components of the higher eukaryotic cell cycle. The polypeptide is localized to the nuclei of macroschizont-infected cells and was detected at significant levels in cells that were undergoing parasite stage differentiation. Transfection of an uninfected transformed bovine macrophage cell line, BoMac, demonstrated that SuAT1 can modulate cellular morphology and alter the expression pattern of a cytoskeletal polypeptide in a manner similar to that found during the infection of leukocytes by the parasite. Our findings indicate that
Theileria
parasite molecules that are transported to the leukocyte nucleus have the potential to modulate the phenotype of infected cells.
LaeA, a Regulator of Secondary Metabolism inAspergillusspp
Authors: Bok Jin Woo , Keller Nancy P. 
Published: April 2004

ABSTRACTSecondary metabolites, or biochemical indicators of fungal development, are of intense interest to humankind due to their pharmaceutical and/or toxic properties. We present here a novelAspergillusnuclear protein, LaeA, as a global regulator of secondary metabolism in this genus. Deletion oflaeA (ΔlaeA) blocks the expression of metabolic gene clusters, including the sterigmatocystin (carcinogen), penicillin (antibiotic), and lovastatin (antihypercholesterolemic agent) gene clusters. Conversely, overexpression oflaeAtriggers increased penicillin and lovastatin gene transcription and subsequent product formation.laeAexpression is negatively regulated by AflR, a sterigmatocystin Zn2Cys6transcription factor, in a unique feedback loop, as well as by two signal transduction elements, protein kinase A and RasA. Although these last two proteins also negatively regulate sporulation, ΔlaeAstrains show little difference in spore production compared to the wild type, indicating that the primary role of LaeA is to regulate metabolic gene clusters.
Inactivation of Transcription Factor Gene
ACE2
in the Fungal Pathogen
Candida glabrata
Results in Hypervirulence
Authors: Kamran Mohammed , Calcagno Ana-Maria , Findon Helen , Bignell Elaine , Jones Michael D. , Warn Peter , Hopkins Philip , Denning David W. , Butler Geraldine , Rogers Thomas , Mühlschlegel Fritz A. , Haynes Ken 
Published: April 2004

ABSTRACT

During an infection, the coordinated orchestration of many factors by the invading organism is required for disease to be initiated and to progress. The elucidation of the processes involved is critical to the development of a clear understanding of host-pathogen interactions. For
Candida
species, the inactivation of many fungal attributes has been shown to result in attenuation. Here we demonstrate that the
Candida glabrata
homolog of the
Saccharomyces cerevisiae
transcription factor gene
ACE2
encodes a function that mediates virulence in a novel way. Inactivation of
C. glabrata ACE2
does not result in attenuation but, conversely, in a strain that is hypervirulent in a murine model of invasive candidiasis.
C. glabrata ace2
null mutants cause systemic infections characterized by fungal escape from the vasculature, tissue penetration, proliferation in vivo, and considerable overstimulation of the proinflammatory arm of the innate immune response. Compared to the case with wild-type fungi, mortality occurs much earlier in mice infected with
C. glabrata ace2
cells, and furthermore, 200-fold lower doses are required to induce uniformly fatal infections. These data demonstrate that
C. glabrata ACE2
encodes a function that plays a critical role in mediating the host-
Candida
interaction. It is the first virulence-moderating gene to be described for a
Candida
species.
Strand-Specific RNA Synthesis Determinants in the RNA-Dependent RNA Polymerase of Poliovirus
Authors: Cornell Christopher T. , Perera Rushika , Brunner Jo Ellen , Semler Bert L. 
Published: April 2004

ABSTRACT

The viral RNA-dependent RNA polymerase (3D
pol
) is highly conserved between the closely related enteroviruses poliovirus type 1 (PV1) and coxsackievirus B3 (CVB3). In this study, we generated PV1/CVB3 chimeric polymerase sequences in the context of full-length poliovirus transcripts to determine the role of different subdomains within the RNA-dependent RNA polymerase of PV1 that are required for functions critical for RNA replication in vitro and in cell culture. The substitution of CVB3 sequences in the carboxy-terminal portion (thumb subdomain) of the polymerase resulted in transcripts incapable of RNA replication. In contrast, three of the seven chimeras were capable of synthesizing RNA, albeit to reduced levels compared to that of wild-type PV1 RNA. Interestingly, one of the replication-competent chimeras (CPP) displayed an inability to generate positive strands, indicating the presence of amino-terminal sequences within the 3D polymerase and/or the 3D domain of the 3CD precursor polypeptide that are necessary for the assembly of strand-specific RNA synthesis complexes. In some constructs, the partial reestablishment of PV1 amino acid sequences in this region was capable of rescuing RNA replication in vitro and in cell culture.
Human Immunodeficiency Virus (HIV) Type 1 Vpu Induces the Expression of CD40 in Endothelial Cells and Regulates HIV-Induced Adhesion of B-Lymphoma Cells
Authors: Henderson Winnie W. , Ruhl Rebecca , Lewis Paul , Bentley Matthew , Nelson Jay A. , Moses Ashlee V. 
Published: April 2004

ABSTRACTAIDS-related B-cell non-Hodgkin's lymphoma (AIDS-NHL) is a significant cause of morbidity and mortality among individuals infected with human immunodeficiency virus type 1 (HIV-1). AIDS-NHL is clinically and histologically heterogeneous, but common features include an aggressive clinical course and frequent extranodal presentation. HIV-1 infection of nonimmune cells that interact with malignant B cells at extranodal sites may influence both the development and the clinical presentation of disease. Our previous studies have shown that coculture of B-lymphoma (BL) cells with HIV-1-infected endothelial cells (EC) leads to contact activation of EC and firm BL-cell adhesion. The key event promoting EC-BL-cell adhesion was HIV-1 upregulation of endothelial CD40, which allowed induction of vascular cell adhesion molecule 1 (VCAM-1) in a CD40-dependent manner. The present study was designed to identify the HIV-1 protein(s) that influence EC-BL-cell adhesion. When HIV-1 proteins were individually expressed in EC by using recombinant adenoviruses, cultured BL cells adhered exclusively to Vpu-transduced EC. As with HIV-infected EC, adhesive properties were linked to the capacity of Vpu to upregulate CD40, which in turn allowed efficient expression of VCAM-1. When EC were infected with an HIV-1 pseudotype lacking the Vpu gene, CD40 upregulation and BL-cell adhesive properties were lost, indicating an essential role for Vpu in EC-BL-cell interactions. Thus, these data reveal a novel function for HIV-1 Vpu and further suggest a role for Vpu in the development of AIDS-NHL at EC-rich extranodal sites.