bluuebunny/crossref_metadata_2025 huggingface dataset:
Remarkable compartmentalization of transposable elements and pseudogenes in the heterochromatin of the
Tetraodon nigroviridis
genome
Authors: Dasilva Corinne , Hadji Hajer , Ozouf-Costaz Catherine , Nicaud Sophie , Jaillon Olivier , Weissenbach Jean , Crollius Hugues Roest
Published: October 2002

Tetraodon nigroviridis
is among the smallest known vertebrate genomes and as such represents an interesting model for studying genome architecture and evolution. Previous studies have shown that
Tetraodon
contains several types of tandem and dispersed repeats, but that their overall contribution is >10% of the genome. Using genomic library hybridization, fluorescent
in situ
hybridization, and whole genome shotgun and directed sequencing, we have investigated the global and local organization of repeat sequences in
Tetraodon
. We show that both tandem and dispersed repeat elements are compartmentalized in specific regions that correspond to the short arms of small subtelocentric chromosomes. The concentration of repeats in these heterochromatic regions is in sharp contrast to their paucity in euchromatin. In addition, we have identified a number of pseudogenes that have arisen through either duplication of genes or the retro-transcription of mRNAs. These pseudogenes are amplified to high numbers, some with more than 200 copies, and remain almost exclusively located in the same heterochromatic regions as transposable elements. The sequencing of one such heterochromatic region reveals a complex pattern of duplications and inversions, reminiscent of active and frequent rearrangements that can result in the truncation and hence inactivation of transposable elements. This tight compartmentalization of repeats and pseudogenes is absent in large vertebrate genomes such as mammals and is reminiscent of genomes that remain compact during evolution such as
Drosophila
and
Arabidopsis
.
Members of the synaptobrevin/vesicle-associated membrane protein (VAMP) family in
Drosophila
are functionally interchangeable
in vivo
for neurotransmitter release and cell viability
Authors: Bhattacharya Sharmila , Stewart Bryan A. , Niemeyer Barbara A. , Burgess Robert W. , McCabe Brian D. , Lin Peter , Boulianne Gabrielle , O'Kane Cahir J. , Schwarz Thomas L.
Published: October 2002

Synaptobrevins or VAMPs are vesicle-associated membrane proteins, often called v-SNARES, that are important for vesicle transport and fusion at the plasma membrane.
Drosophila
has two characterized members of this gene family: synaptobrevin (
syb
) and neuronal synaptobrevin (
n
-
syb
). Mutant phenotypes and gene-expression patterns indicate that n-Syb is exclusively neuronal and required only for synaptic vesicle secretion, whereas Syb is ubiquitous and, as shown here, essential for cell viability. When the eye precursor cells were made homozygous for
syb
−
, the eye failed to develop. In contrast,
n
-
syb
−
eye clones developed appropriately but failed to activate downstream neurons. To determine whether the two proteins are structurally specialized to accomplish these distinct
in vivo
functions, we have driven the expression of each gene in the absence of the other to look for phenotypic rescue. We find that expression of
n
-
syb
during eye development can rescue the cell lethality of the
syb
mutations, as can rat VAMP2 and cellubrevin. Expression of
syb
can restore synaptic transmission to
n
-
syb
mutants as assayed both by electroretinogram and recordings of excitatory junctional currents at the neuromuscular junction. Therefore, we find that Syb, which usually is not involved in synaptic function, can mediate Ca
2+
-triggered synaptic activity and that no particular specialization of the v-SNARE is required to differentiate synaptic exocytosis from other forms.
Virulence control in group AStreptococcusby a two-component gene regulatory system: Global expression profiling andin vivoinfection modeling
Authors: Graham Morag R. , Smoot Laura M. , Migliaccio Cristi A. Lux , Virtaneva Kimmo , Sturdevant Daniel E. , Porcella Stephen F. , Federle Michael J. , Adams Gerald J. , Scott June R. , Musser James M.
Published: October 2002

Two-component gene regulatory systems composed of a membrane-bound sensor and cytoplasmic response regulator are important mechanisms used by bacteria to sense and respond to environmental stimuli. Group AStreptococcus, the causative agent of mild infections and life-threatening invasive diseases, produces many virulence factors that promote survival in humans. A two-component regulatory system, designatedcovRS(cov, control of virulence; csrRS), negatively controls expression of five proven or putative virulence factors (capsule, cysteine protease, streptokinase, streptolysin S, and streptodornase). Inactivation ofcovRSresults in enhanced virulence in mouse models of invasive disease. Using DNA microarrays and quantitative RT-PCR, we found that CovR influences transcription of 15% (n= 271) of all chromosomal genes, including many that encode surface and secreted proteins mediating host–pathogen interactions. CovR also plays a central role in gene regulatory networks by influencing expression of genes encoding transcriptional regulators, including other two-component systems. Differential transcription of genes influenced bycovRalso was identified in mouse soft-tissue infection. This analysis provides a genome-scale overview of a virulence gene network in an important human pathogen and adds insight into the molecular mechanisms used by group AStreptococcusto interact with the host, promote survival, and cause disease.
Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection
Authors: Oxenius Annette , Price David A. , Günthard Huldrych F. , Dawson Sara J. , Fagard Catherine , Perrin Luc , Fischer Marek , Weber Rainer , Plana Montserrat , García Felipe , Hirschel Bernard , McLean Angela , Phillips Rodney E.
Published: October 2002

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (
i
) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (
ii
) the magnitude and the breadth of the HIV-specific CD8
+
T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (
iii
) individuals with strong and broad HIV-specific CD8
+
T lymphocyte responses at baseline retained these characteristics during and after STI; (
iv
) the increase in HIV-specific CD8
+
T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (
v
) HIV-specific CD4
+
T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8
+
T cell responses in patients with established infection.
A potent analog of 1α,25-dihydroxyvitamin D
3
selectively induces bone formation
Authors: Shevde Nirupama K. , Plum Lori A. , Clagett-Dame Margaret , Yamamoto Hironori , Pike J. Wesley , DeLuca Hector F.
Published: October 2002

1,25-Dihydroxyvitamin D
3
[1,25(OH)
2
D
3
] is a principal regulator of calcium and phosphorus homeostasis through actions on intestine, kidney, and bone. 1,25(OH)
2
D
3
is not considered to play a significant role in bone formation, except for its role in supporting mineralization. We report here on the properties of 2-methylene-19-nor
-
(20S)-1α,25(OH)
2
D
3
(2MD), a highly potent analog of 1,25(OH)
2
D
3
that induces bone formation both
in vitro
and
in vivo
. Selectivity for bone was first demonstrated through the observation that 2MD is at least 30-fold more effective than 1,25(OH)
2
D
3
in stimulating osteoblast-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium transport. 2MD is also highly potent in promoting osteoblast-mediated osteoclast formation
in vitro
, a process essential to both bone resorption and formation. Most significantly, 2MD at concentrations as low as 10
−12
M causes primary cultures of osteoblasts to produce bone
in vitro
. This effect is not found with 1,25(OH)
2
D
3
even at 10
−8
M, suggesting that 2MD might be osteogenic
in vivo
. Indeed, 2MD (7 pmol/day) causes a substantial increase (9%) in total body bone mass in ovariectomized rats over a 23-week period. 1,25(OH)
2
D
3
(500 pmol three times a week) only prevented the bone loss associated with ovariectomy and did not increase bone mass. These results indicate that 2MD is a potent bone-selective analog of 1,25(OH)
2
D
3
potentially effective in treating bone loss diseases.
Recognition of the DNA sequence by an inorganic crystal surface
Authors: Sampaolese Beatrice , Bergia Anna , Scipioni Anita , Zuccheri Giampaolo , Savino Maria , Samorì Bruno , De Santis Pasquale
Published: October 2002

The sequence-dependent curvature is generally recognized as an important and biologically relevant property of DNA because it is involved in the formation and stability of association complexes with proteins. When a DNA tract, intrinsically curved for the periodical recurrence on the same strand of A-tracts phased with the B-DNA periodicity, is deposited on a flat surface, it exposes to that surface either a T- or an A-rich face. The surface of a freshly cleaved mica crystal recognizes those two faces and preferentially interacts with the former one. Statistical analysis of scanning force microscopy (SFM) images provides evidence of this recognition between an inorganic crystal surface and nanoscale structures of double-stranded DNA. This finding could open the way toward the use of the sequence-dependent adhesion to specific crystal faces for nanotechnological purposes.
Innate recognition of bacteria by a macrophage cytosolic surveillance pathway
Authors: O'Riordan Mary , Yi Caroline H. , Gonzales Ramona , Lee Kyung-Dall , Portnoy Daniel A.
Published: October 2002

Host recognition of bacterial pathogens is a critical component of the immune response. Intracellular bacterial pathogens are able to evade the humoral immune system by residing within the host cell. Here we show the existence of an innate host surveillance mechanism in macrophages that specifically distinguishes bacteria in the cytosol from bacteria in the vacuole. Recognition of Gram-positive and Gram-negative bacterial products by this surveillance system results in transcription of the
ifnb
gene. The activation of cytosol-specific signaling is associated with translocation of NF-κB into the nucleus and phosphorylation of the p38 mitogen-activated protein (MAP) kinase. Activation of the p38 kinase is required for the induction of gene expression by the cytosolic surveillance pathway. Our studies suggest that infection by intracellular bacterial pathogens results in an immune response distinct from that of infection by extracellular bacterial pathogens.
Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
Authors: Tee Andrew R. , Fingar Diane C. , Manning Brendan D. , Kwiatkowski David J. , Cantley Lewis C. , Blenis John
Published: October 2002

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the
TSC1
or
TSC2
genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of
TSC2
derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.
Folding free energy function selects native-like protein sequences in the core but not on the surface
Authors: Jaramillo Alfonso , Wernisch Lorenz , Héry Stéphanie , Wodak Shoshana J.
Published: October 2002

An automatic protein design procedure is used to select amino acid sequences that optimize the folding free energy function for a given protein. The only information used in designing the sequences is a set of known backbone structures for each protein, a rotamer library, and a well established classical empirical force field, which relies on basic physical chemical principles that underlie molecular interactions and protein stability, and has not been adjusted to yield native-like sequences. Applying the procedure to 7 different known protein folds, representing a total of 45 different native protein structures, yields ensembles of designed sequences displaying remarkable similarity to their natural counterparts in the protein core, but which are distinctly non-native on the protein surface. We show that natural and designed sequences for a given fold score significantly higher than random sequences against profiles derived from both, designed and natural sequence ensembles. Furthermore, we find that designed sequence profiles can be used to retrieve the native sequences for many of the analyzed proteins using standard PSI-BLAST searches in sequence databases. These findings may have important implications for our understanding the selection pressures operating on natural protein sequences and hold promise for improving fold recognition.
IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytes
Authors: Xue Hai-Hui , Kovanen Panu E. , Pise-Masison Cynthia A. , Berg Maria , Radovich Michael F. , Brady John N. , Leonard Warren J.
Published: October 2002

Interleukin (IL)-2 is a type I four-α-helical bundle cytokine that plays vital roles in antigen-mediated proliferation of peripheral blood T cells and also is critical for activation-induced cell death. We now demonstrate that IL-2 potently decreases expression of IL-7 receptor α chain (IL-7Rα) mRNA and protein. The fact that IL-7Rα is a component of the receptors for both IL-7 and thymic stromal lymphopoietin (TSLP) suggests that IL-2 can negatively regulate signals by each of these cytokines. Previously it was known that the IL-2 and IL-7 receptors shared the common cytokine receptor γ chain, γc, which suggested a possible competition between these cytokines for a receptor component. Our findings now suggest a previously unknown type of cross-talk between IL-2 and IL-7 signaling by showing that IL-2 signaling can diminish IL-7Rα expression via a phosphatidylinositol 3-kinase/Akt-dependent mechanism.
S
-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: Further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase
Authors: Leiper James , Murray-Rust Judith , McDonald Neil , Vallance Patrick
Published: October 2002

The enzyme dimethylarginine dimethylaminohydrolase (DDAH) hydrolyses asymmetrically methylated arginine residues that are endogenously produced inhibitors of nitric oxide synthases (NOS). We and others have proposed that DDAH activity is a key determinant of intracellular methylarginine concentrations and that factors that regulate the activity of DDAH may modulate nitric oxide (NO) production
in vivo
. We recently solved the crystal structure of a bacterial DDAH and identified a Cys-His-Glu catalytic triad [Murray-Rust, J., Leiper, J. M., McAlister, M., Phelan, J., Tilley, S., Santa Maria, J., Vallance, P. & McDonald, N. (2001)
Nat. Struct. Biol.
8, 679–683]. The presence of a reactive cysteine residue (Cys-249) in the active site of DDAH raised the possibility that DDAH activity might be directly regulated by
S
-nitrosylation of this residue by NO. In the present study, we demonstrate that recombinant DDAH is reversibly inhibited after incubation with NO donors
in vitro
. Similarly mammalian DDAH in cytosolic extracts is also reversibly inhibited by NO donors. In cultured endothelial cells, heterologously expressed human DDAH II was
S
-nitrosylated after cytokine induced expression of the inducible NOS isoforms. The implication of these findings is that under certain conditions when NO generation increases,
S
-nitrosylation diminishes DDAH activity and this would be expected to lead to accumulation of asymmetric dimethylarginine and inhibition of NOS. This observation may help explain why expression of iNOS often leads to inhibition of activity of constitutively expressed NOS isozymes. We also identify Cys-His-Glu as a nitrosylation motif that is conserved in a family of arginine handling enzymes.
Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1
in vitro
Authors: Kemkemer Ralf , Schrank Stephanie , Vogel Walther , Gruler Hans , Kaufmann Dieter
Published: October 2002

In human diseases related to tumor-suppressor genes, it is suggested that only the complete loss of the protein results in specific symptoms such as tumor formation, whereas simple reduction of protein quantity to 50%, called haploinsufficiency, essentially does not affect cellular behavior. Using a model of gene expression, it was presumed that haploinsufficiency is related to an increased noise in gene expression also
in vivo
[Cook, D. L., Gerber, A. N. & Tapscott, S. J. (1998)
Proc. Natl. Acad. Sci. USA
95, 15641–15646]. Here, we demonstrate that haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 (
NF1
) results in an increased variation of dendrite formation in cultured NF1 melanocytes. These morphological differences between NF1 and control melanocytes can be described by a mathematical model in which the cell is considered to be a self-organized automaton. The model describes the adjustment of the cells to a set point and includes a noise term that allows for stochastic processes. It describes the experimental data of control and NF1 melanocytes. In the cells haploinsufficient for
NF1
we found an altered signal-to-noise ratio detectable as increased variation in dendrite formation in two of three investigated morphological parameters. We also suggest that
in vivo
NF1 haploinsufficiency results in an increased noise in cellular regulation and that this effect of haploinsufficiency may be found also in other tumor suppressors.
A dominant block to HIV-1 replication at reverse transcription in simian cells
Authors: Münk Carsten , Brandt Stephanie M. , Lucero Ginger , Landau Nathaniel R.
Published: October 2002

Although nonhuman primates are genetically close to humans, their T cells do not support productive replication of HIV-1. In contrast, HIV-1 replicates in activated human CD4
+
T cells, monocytes, and metabolically active human cells of a variety of cell types become permissive for HIV-1 replication when transduced to express CD4 and CCR5 or CXCR4. The molecular basis of this species restriction to HIV-1 replication was investigated by using African green monkey and rhesus macaque cell lines that were stably transduced to express human CD4 and CCR5. The cells supported replication of cognate viruses [simian immunodeficiency virus from African green monkeys (SIV-AGM) and macaques (SIVmac239)] but did not support replication of an R5-tropic cytopathic HIV-1. A β-lactamase-based HIV-1 entry assay was used to show that the virus efficiently entered the nonhuman primate cells. Provirus formation was reduced 50-fold compared with similarly infected human cells. Real-time PCR quantitation demonstrated that reverse transcription failed to initiate efficiently in the simian cells. The block to reverse transcription was overridden at multiplicity of infection >1 or by preincubation of the nonhuman primate cells with virus, a feature reminiscent of the Friend virus resistance gene-1 (FV-1), restriction to murine leukemia virus replication in mouse cells. Heterokaryon analysis in which human and simian cells were fused demonstrated that the block was dominant. These findings suggested that the primate cells contain a dominant inhibitor that prevents HIV-1 reverse transcription.
The tomato
fer
gene encoding a bHLH protein controls iron-uptake responses in roots
Authors: Ling Hong-Qing , Bauer Petra , Bereczky Zsolt , Keller Beat , Ganal Martin
Published: October 2002

Iron deficiency is among the most common nutritional disorders in plants. To cope with low iron supply, plants with the exception of the Gramineae increase the solubility and uptake of iron by inducing physiological and developmental alterations including iron reduction, soil acidification, Fe(II) transport and root-hair proliferation (strategy I). The chlorotic tomato
fer
mutant fails to activate the strategy I. It was shown previously that the
fer
gene is required in the root. Here, we show that
fer
plants exhibit root developmental phenotypes after low and sufficient iron nutrition indicating that FER acts irrespective of iron supply. Mutant
fer
roots displayed lower
Leirt1
expression than wild-type roots. We isolated the
fer
gene by map-based cloning and demonstrate that it encodes a protein containing a basic helix–loop–helix domain.
fer
is expressed in a cell-specific pattern at the root tip independently from iron supply. Our results suggest that FER may control root physiology and development at a transcriptional level in response to iron supply and thus may be the first identified regulator for iron nutrition in plants.
The function of bursts of spikes during visual fixation in the awake primate lateral geniculate nucleus and primary visual cortex
Authors: Martinez-Conde Susana , Macknik Stephen L. , Hubel David H.
Published: October 2002

When images are stabilized on the retina, visual perception fades. During voluntary visual fixation, however, constantly occurring small eye movements, including microsaccades, prevent this fading. We previously showed that microsaccades generated bursty firing in the primary visual cortex (area V-1) in the presence of stationary stimuli. Here we examine the neural activity generated by microsaccades in the lateral geniculate nucleus (LGN), and in the area V-1 of the awake monkey, for various functionally relevant stimulus parameters. During visual fixation, microsaccades drove LGN neurons by moving their receptive fields across a stationary stimulus, offering a likely explanation of how microsaccades block fading during normal fixation. Bursts of spikes in the LGN and area V-1 were associated more closely than lone spikes with preceding microsaccades, suggesting that bursts are more reliable than are lone spikes as neural signals for visibility. In area V-1, microsaccade-generated activity, and the number of spikes per burst, was maximal when the bar stimulus centered over a receptive field matched the cell's optimal orientation. This suggested burst size as a neural code for stimuli optimality (and not solely stimuli visibility). As expected, burst size did not vary with stimulus orientation in the LGN. To address the effectiveness of microsaccades in generating neural activity, we compared activity correlated with microsaccades to activity correlated with flashing bars. Onset responses to flashes were about 7 times larger than the responses to the same stimulus moved across the cells' receptive fields by microsaccades, perhaps because of the relative abruptness of flashes.
Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin
Authors: Jin Lei , Harrison Stephen C.
Published: October 2002

Calcineurin (Cn), a Ca
2+
/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug–protein complexes in turn inhibit Cn. We report the crystal structure of a Cyp/CsA/Cn ternary complex, determined to a resolution of 3.1 Å. Residues 3–9 of CsA, particularly
N
-methyl leucines 4 and 6, and Trp-121 of Cyp form a composite surface for interaction with Cn. The hydrophobic interface buries two hydrogen bonds. The structure accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity.
Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation
Authors: Roozendaal Benno , Brunson Kristen L. , Holloway Brian L. , McGaugh James L. , Baram Tallie Z.
Published: October 2002

It is well established that adrenal stress hormone-induced activation of the basolateral complex of the amygdala (BLA) influences memory consolidation. The present experiments investigated the involvement of corticotropin-releasing hormone (CRH) in the BLA in modulating memory consolidation. Bilateral infusions of the CRH receptor antagonist [9–41]-α-helical CRH (0.3, 1.0, or 3.0 μg in 0.2 μl) administered into the BLA of male Sprague–Dawley rats immediately after aversively motivated inhibitory avoidance training produced dose-dependent impairment of 48-h retention performance. Because the CRH receptor antagonist infusions did not impair retention when administered into the BLA 3 h after training, the retention impairment selectively was due to time-dependent influences on memory consolidation. Furthermore, because immediate posttraining infusions of [9–41]-α-helical CRH into the adjacent central nucleus of the amygdala (CEA) were ineffective, the effect selectively involved the BLA. Immunocytochemistry showed that the aversive training stimulus of a single, brief footshock increased CRH levels in the CEA. These findings indicate that activation of CRH receptors in the BLA, likely by training-induced release of endogenous peptide originating from the CEA, participates in mediating stress effects on memory consolidation.
Adaptation to famine: A family of stationary-phase genes revealed by microarray analysis
Authors: Tani Travis H. , Khodursky Arkady , Blumenthal Robert M. , Brown Patrick O. , Matthews Rowena G.
Published: October 2002

Bacterial adaptation to nutrient limitation and increased population densities is central to survival and virulence. Surprisingly, <3% of
Escherichia coli
genes are known to play roles specific to the stationary phase. There is evidence that the leucine-responsive regulatory protein (Lrp) may play an important role in stationary phase, so this study used microarrays representing >98% of
E. coli
genes to more comprehensively identify those controlled by Lrp. The primary analysis compared isogenic Lrp
+
and Lrp
−
strains in cells growing in steady state in glucose minimal medium, either in the presence or absence of leucine. More than 400 genes were significantly Lrp-responsive under the conditions used. Transcription of 147 genes was lower in Lrp
+
than in Lrp
−
cells whether or not leucine was present; most of these genes were tightly coregulated under several conditions, including a burst of synthesis on transition to stationary phase. This cluster includes 56 of 115 genes already known to play roles in stationary phase. Our results suggest that the actual number of genes induced on entrance into stationary phase is closer to 200 and that Lrp affects nearly three-quarters of them, including genes involved in response to nutrient limitation, high concentrations of organic acids, and osmotic stress.
Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus
Authors: Tumpey Terrence M. , García-Sastre Adolfo , Mikulasova Andrea , Taubenberger Jeffery K. , Swayne David E. , Palese Peter , Basler Christopher F.
Published: October 2002

The 1918 influenza pandemic caused more than 20 million deaths worldwide. Thus, the potential impact of a re-emergent 1918 or 1918-like influenza virus, whether through natural means or as a result of bioterrorism, is of significant concern. The genetic determinants of the virulence of the 1918 virus have not been defined yet, nor have specific clinical prophylaxis and/or treatment interventions that would be effective against a re-emergent 1918 or 1918-like virus been identified. Based on the reported nucleotide sequences, we have reconstructed the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes of the 1918 virus. Under biosafety level 3 (agricultural) conditions, we have generated recombinant influenza viruses bearing the 1918 HA, NA, or M segments. Strikingly, recombinant viruses possessing both the 1918 HA and 1918 NA were virulent in mice. In contrast, a control virus with the HA and NA from a more recent human isolate was unable to kill mice at any dose tested. The recombinant viruses were also tested for their sensitivity to U.S. Food and Drug Administration-approved antiinfluenza virus drugs
in vitro
and
in vivo
. Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was inhibited effectively both in tissue culture and
in vivo
by the M2 ion-channel inhibitors amantadine and rimantadine. These data suggest that current antiviral strategies would be effective in curbing the dangers of a re-emergent 1918 or 1918-like virus.
Combinatorial mutagenesis to restrict amino acid usage in an enzyme to a reduced set
Authors: Akanuma Satoshi , Kigawa Takanori , Yokoyama Shigeyuki
Published: October 2002

We developed an effective strategy to restrict the amino acid usage in a relatively large protein to a reduced set with conservation of its
in vivo
function. The 213-residue
Escherichia coli
orotate phosphoribosyltransferase was subjected to 22 cycles of segment-wise combinatorial mutagenesis followed by 6 cycles of site-directed random mutagenesis, both coupled with a growth-related phenotype selection. The enzyme eventually tolerated 73 amino acid substitutions: In the final variant, 9 amino acid types (A, D, G, L, P, R, T, V, and Y) occupied 188 positions (88%), and none of 7 amino acid types (C, H, I, M, N, Q, and W) appeared. Therefore, the catalytic function associated with a relatively large protein may be achieved with a subset of the 20 amino acid. The converged sequence also implies simpler constituents for proteins in the early stage of evolution.
Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis
Authors: Ruhrberg Christiana , Gerhardt Holger , Golding Matthew , Watson Rose , Ioannidou Sofia , Fujisawa Hajime , Betsholtz Christer , Shima David T.
Published: October 2002

Branching morphogenesis in the mammalian lung andDrosophila trachea relies on the precise localization of secreted modulators of epithelial growth to select branch sites and direct branch elongation, but the intercellular signals that control blood vessel branching have not been previously identified. We found that VEGF120/120 mouse embryos, engineered to express solely an isoform of VEGF-A that lacks heparin-binding, and therefore extracellular matrix interaction domains, exhibited a specific decrease in capillary branch formation. This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor. Rather, changes in the extracellular localization of VEGF-A in heparin-binding mutant embryos resulted in an altered distribution of endothelial cells within the growing vasculature. Instead of being recruited into additional branches, nascent endothelial cells were preferentially integrated within existing vessels to increase lumen caliber. The disruption of the normal VEGF-A concentration gradient also impaired the directed extension of endothelial cell filopodia, suggesting that heparin-binding VEGF-A isoforms normally provide spatially restricted stimulatory cues that polarize and thereby guide sprouting endothelial cells to initiate vascular branch formation. Consistent with this idea, we found opposing defects in embryos harboring only a heparin-binding isoform of VEGF-A, including excess endothelial filopodia and abnormally thin vessel branches in ectopic sites. We conclude that differential VEGF-A isoform localization in the extracellular space provides a control point for regulating vascular branching pattern.
The MSc management development: a programme in management or a management development process? A study focusing on the MSc in management development at Edge Hill
Authors: Choueke Richard , West Penny
Published: October 2002

Focuses on the MSc in management development at Edge Hill. Describes the environment in which the programme was developed and takes particular account of some of the different strands of management learning discussed in the literature and how these issues have informed the development of the programme. Provides a sample of course members’ views of the programme matched against their personal objectives for their participation in the programme and the impact on their careers as a consequence of their participation. Evidence from both the literature and from the empirical study will contribute to a view as to whether the MSc in Management Development at Edge Hill is merely a programme in management or whether indeed it is a management development process.
Effectiveness of bank audit in Bangladesh
Authors: Siddiqui Javed , Podder Jyotirmoy
Published: October 2002

The study examines the effectiveness of financial audit of banking companies operating within Bangladesh. The scope of bank audit has also been examined. The audited financial statements of 14 sample banking companies have been considered. The study identifies seven sample companies that have actually overstated their profits. In spite of that, the firms auditing those financial statements have failed to issue qualified audit reports. Therefore, the study questions the level of independence, objectivity and competence of the auditors assigned for auditing banking companies.
The NHS Performance Assessment Framework
Authors: Chang Li‐cheng , Lin Stephen W. , Northcott Deryl N.
Published: October 2002

The NHS in the UK has recently adopted a new Performance Assessment Framework (PAF), aiming to provide a broader view of performance within the NHS. The PAF is not only a multi‐stakeholder approach reflecting various stakeholders’ interests across six dimensions, but is also used by the Government as a strategic management tool to link national strategies with local operation activities. The Government claims that the PAF is a “balanced scorecard” approach. This study discusses the concepts of the BSC underlying the NHS PAF.
Guest editorial
Authors: Gray Brendan J. , Hooley Graham J.
Published: October 2002

The service sector is an increasingly important source of job creation and economic wealth, and accounts for more than 75 per cent of the GDP of many developed economies. Yet there has been surprisingly little research into the relationship between market orientation and service firm performance. This editorial reviews the major research themes relating to market orientation and service firm performance and suggests an agenda for future research to improve understanding of this important marketing and management issue.
Market orientation and social services in private non‐profit organisations
Authors: Vázquez Rodolfo , Álvarez Luis Ignacio , Leticia Santos María
Published: October 2002

Very little attention has been devoted so far to the study of the market orientation concept in private non‐profit organisations. However, there is a general agreement concerning the positive effects that this concept’s adoption has on the non‐profit services implementation as well as on these organisations’ long‐term success. Thus this paper aims at obtaining further empirical evidence on this field of research using a private foundations sample. Nevertheless, it is considered that the distinctive and specific nature of private non‐profit organisations’ activities deserves the development of a special instrument to evaluate their degree of market orientation. In this sense, one of this study’s main contributions is the development of a market orientation measurement scale which accounts for the peculiarities of private non‐profit organisations’ operations. Additionally, the study proves the positive effect of market orientation on the non‐profit outcomes and on the fulfilment of these organisations’ missions.
Culture and leadership in market‐oriented service organisations
Authors: Kasper Hans
Published: October 2002

The fields of market orientation and services marketing are still rather new domains of scientific research. It appears that they have quite a few challenging topics in common. This paper combines some of those topics. It focuses on the culture of market‐oriented services organisations and the leadership styles that may belong to such a culture. An open culture which is reflected in clarity in marketing goals and a strong drive to be the best (deliver superior value or quality) are the essential features of such a culture. This calls for achievement‐oriented leaders who care about people.
An overview of plant diversity, land use and degradation in the Mediterranean region of Turkey
Authors: Ozturk M. , Celik A. , Yarci C. , Aksoy A. , Feoli E.
Published: October 2002

The Turkish Mediterranean region covers an area of 198.165km2, including ten states and a coastline of about 4,389km. The area has served as a womb for several civilisations. However, its rich plant diversity has been victimized through anthropomorphic pressures. Southwestern shores of Turkey are the main centre of coastal endemism in the Mediterranean basin. The flora in the region on the whole includes more than 700 endemics, out of which about 600 are East‐Mediterranean elements. Out of the endemic taxa distributed in the region more than 40 are facing a threat of extirpation. The region embodies tertiary endemics as well, like Liquidamber orientalis, Eryngium thorifolium and Flueggea anatolica. High mountain zones abound in neoendemics. Although several protected areas have been created lately, demographic pressure, urbanisation, grazing, fires and erosion, are still posing a great threat to the plant diversity. This paper enlightens the impact of the aforementioned land degradation processes on the plant cover of this phytogeographical region in Turkey.
A public health problem?
Authors: Pyatt F.B. , Pyatt A.J. , Grattan J.P.
Published: October 2002

Large metalliferous spoil and smelting tip sites, generated during the Nabatean, Roman and Byzantine periods, continue to exist in southern Jordan and still exert important effects on both plants and animals (including humans) inhabiting the area. Humans are exposed to both copper and lead pollution as a consequence of the inhalation and ingestion of heavy metals, which often involves significant bio‐accumulation through trophic levels. This paper explores aspects of an important source of severe dietary contamination which has potential public health implications in terms of effects on the health of exposed individuals.
Joint forest management in India and its ecological impacts
Authors: Murali K.S. , Murthy Indu K. , Ravindranath N.H.
Published: October 2002

Ecological impact of joint forest management (JFM) in India was assessed using the studies undertaken at national, state and forest division levels. It was found that there are very few studies that have specifically addressed the ecological aspects under JFM. The study noted that there are significant strides made in promoting JFM, but the program still needs to address a lot of inadequacies. Though it is estimated that little over 14 million ha of forests are brought under JFM, covering nearly 50 per cent of the open forests in India, how much of it has developed into good forests is not really known. It also needs to be noted that there are many lacunae in implementation of the program and there are also gaps in policies to promote JFM. The study noted that in four states, i.e. Andhra Pradesh, Madhya Pradesh, Orissa and West Bengal, the recruitment was significant, amounting to 17 per cent of the regenerating individuals. In Karnataka, over 10 per cent of open forest has been brought under JFM, while a lot of wasteland could still be brought under JFM. The JFM plantations are dominated with exotic firewood species and low in timber and non‐timber species, resulting in lower biodiversity. Biomass growth rate was comparatively higher in JFM forests as compared to the national average. Other support activities to JFM indicated that various biomass conservation programs were initiated, installing a substantial number of energy saving and alternate energy devices. However, the study also notes that effectiveness of such support programs is not clearly known in terms of its functioning and biomass saved.
Maximization, partial regulation, and system dominance
Authors: Munoz Lucio
Published: October 2002

Three of the fundamental aspects under which current development programs operate are self‐interest‐based plans, compartmentalized regulatory environments, and unbalanced competition. These forces are important components of traditional sustainable development frameworks as they allow for processes based on maximization, partial regulation, and system dominance. It is pointed out in this paper, using qualitative comparative means, that these forces are drivers of sustained development, but not of true sustainability. And the reason is that under true sustainability, there is no maximization; there is no partial regulation; and there are no dominated systems.
Executive and management attitudes towards corporate social responsibility in Malaysia
Authors: Abdul Zabid , Ibrahim Saadiatul
Published: October 2002

Examines the attitudes of Malaysian managers and executives towards social responsibility and also the extent of socially responsible activities involved, corporate disclosure, and the factors determining the attitudes towards social responsibility. A structured questionnaire was developed based on studies by Ford and McLaughin, Teoh and Gregory Thong, Gill and Leinbach and Jones. A total of 198 responses were used for analysis in this study. The results showed that only five statements (of the 14 statements) have scores of more than 50 per cent agreement or endorsement of socially responsible activities. About 69 per cent of the respondents believed that involvement by a business in improving its community’s quality of life will also improve long run profitability. Nearly 65 per cent agreed that socially responsible activities provide a favourable public image. The analysis of variance showed that there were significant differences in the attitudes of managers working in banking, telecommunication, manufacturing and construction towards social responsibility. Nearly all of the respondents agreed that their companies were involved in socially responsible activities, that they were responsive to consumers’ complaints (83 per cent), and that they were maintaining product/service quality (77 per cent). Of the respondents nearly 54 per cent mentioned that their companies informed the general public of their socially responsible activities. The results also showed that the most influential factor determining the attitude towards social responsibility was family upbringing. The other important factors were traditional beliefs and customs, and common practices in the industry. Discusses the implications of the findings.
Examining gender on corporate boards: a regional study
Authors: McCormick Hyland MaryAnne , Marcellino Patricia Ann
Published: October 2002

The representation of women in organizations has become an increasingly important topic for academics and practitioners. Despite the growing presence of women in the workforce, representation of women in corporate governance is relatively low. The present study examined the gender composition of corporate boards as a function of organization size and industry. Data from government filings were collected for the top 100 public companies in a suburban region of the USA. Results indicated a positive relationship between organization size and women on boards. Partial support was found for hypotheses related to industry. Practical implications and areas for future study are discussed.
The role of helix stabilizing residues in GCN4 basic region folding and DNA binding
Authors: Hollenbeck Jessica J. , McClain Diana L. , Oakley Martha G.
Published: October 2002

Basic region leucine zipper (bZip) proteins contain a bipartite DNA‐binding motif consisting of a coiled‐coil leucine zipper dimerization domain and a highly charged basic region that directly contacts DNA. The basic region is largely unfolded in the absence of DNA, but adopts a helical conformation upon DNA binding. Although a coil → helix transition is entropically unfavorable, this conformational change positions the DNA‐binding residues appropriately for sequence‐specific interactions with DNA. The N‐terminal residues of the GCN4 DNA‐binding domain, DPAAL, make no DNA contacts and are not part of the conserved basic region, but are nonetheless important for DNA binding. Asp and Pro are often found at the N‐termini of α‐helices, and such N‐capping motifs can stabilize α‐helical structure. In the present study, we investigate whether these two residues serve to stabilize a helical conformation in the GCN4 basic region, lowering the energetic cost for DNA binding. Our results suggest that the presence of these residues contributes significantly to helical structure and to the DNA‐binding ability of the basic region in the absence of the leucine zipper. Similar helix‐capping motifs are found in approximately half of all bZip domains, and the implications of these findings for in vivo protein function are discussed.