bluuebunny/crossref_metadata_2025 huggingface dataset:
Balancing Act
Authors: Foley John F.
Published: June 2008

The tumor suppressor protein p53 responds to such cell stress-inducing stimuli as DNA damage and hypoxia. The resulting nuclear accumulation of p53 triggers the repression or activation of the appropriate genes to lead to apoptosis or cell-cycle arrest, thus halting cell proliferation. In a search for new p53 target genes, Basak
et al
. exposed various primary cell types from wild-type or
p53
-deficient mice to DNA-damaging stimuli such as Doxorubicin or γ irradiation. Microarray analyses showed that expression of the gene
Prl-3
was induced by these stimuli in a p53-dependent manner, and Western blotting showed that Prl-3 protein increased in abundance accordingly. This was unexpected because Prl-3, a protein phosphatase, is known to promote tumor metastasis. Chromatin immunoprecipitation assays demonstrated that p53 bound to
Prl-3
, and reporter assays in wild-type and p53-deficient mouse embryo fibroblasts (MEFs) showed that Prl-3 was a transcriptional target of p53. Proliferation assays showed that Prl-3, when overexpressed in MEFs, triggered cell-cycle arrest but not apoptosis. Western blotting analysis demonstrated that overexpression of Prl-3 in human fibrosarcoma cells initially led to activation of the kinase Akt, which is known to enhance cell proliferation. However, as Prl-3 abundance increased with time, it inhibited Akt activity through a negative-feedback mechanism, leading to cell-cycle arrest. Indeed, Prl-3 could not induce cell-cycle arrest in Akt-deficient MEFs. To add even more complexity, knockdown of Prl-3 in MEFs also led to cell-cycle arrest, in a p53-dependent manner. Together, these data suggest that the abundance of Prl-3, a new target of p53 (see commentary by Hinds), must be tightly controlled for normal cell-cycle progression.

S. Basak, S. B. R. Jacobs, A. J. Krieg, N. Pathak, Q. Zeng, P. Kaldis, A. J. Giaccia, L. D. Attardi, The metastasis-associated gene
Prl-3
is a p53 target involved in cell-cycle regulation.
Mol
.
Cell
30
, 303-314 (2008).
[PubMed]

P. W. Hinds, Too much of a good thing: The
Prl-3
in p53’s oyster.
Mol
.
Cell
30
, 260-261 (2008).
[PubMed]
ACEing Lipid Metabolism
Authors: VanHook Annalisa M.
Published: June 2008

The renin-angiotensin system (RAS) regulates blood volume and pressure through the peptide hormones angiotensin II and bradykinin, which have opposing functions as a vasoconstrictor and vasodilator, respectively. Increased production of angiotensin 2 has also been linked to increased fat accumulation in both humans and rodents. Jayasooriya
et al.
report phenotypic analyses of mice that lack angiotensin-converting enzyme (ACE), which both degrades bradykinin and produces angiotensin II from its biologically inactive precursor angiotensin I.
ACE
knockout (

ACE
–/–

) mice weighed less and had less abdominal fat than their wild-type control littermates, yet they were not more physically active, did not eat any less food, and did not secrete more fat in their waste.

ACE
–/–

animals cleared glucose from their blood faster than controls, and respiration measurements indicated that they also expended more energy regardless of their activity level or food consumption. Quantitative PCR analysis revealed that genes required for lipid metabolism were more highly expressed in the livers of

ACE
–/–

animals, so it appeared that

ACE
–/–

mice metabolized fat faster than normal mice. The authors hypothesized that the increased fat metabolism was mediated by the decrease in angiotensin II activity, because mice that produce lower-than-normal amounts of angiotensin II have similar phenotypes. The glucose clearance phenotype, however, could not be readily explained, but the authors speculated that vasodilation induced by the increase in circulating bradykinin in

ACE
–/–

mice may have increased the rate at which glucose is cleared from the blood by delivering it to tissues faster. The authors conclude that the previously recognized role of RAS in regulating body fat accumulation is mediated by controlling the rate of metabolism rather than that of adipose tissue formation.

A. P. Jayasooriya, M. L. Mathai, L. L. Walker, D. P. Begg, D. A. Denton, D. Cameron-Smith, G. F. Egan, M. J. McKinley, P. D. Rodger, A. J. Sinclair, J. D. Wark, H. S. Weisinger, M. Jois, R. S. Weisinger, Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.
Proc. Natl. Acad. Sci. U.S.A.
105
, 6531-6536 (2008).
[Abstract]
[Full Text]
Identifying Receptor-Ligand Pairs
Authors: Ray L. Bryan
Published: June 2008

Secreted proteins that interact with receptors on the cell surface control all sorts of biological processes and provide targets for therapeutic intervention. Lin
et al
. used a systematic approach to search for previously unknown ligand-receptor pairs. They produced recombinant proteins from genes that appeared to encode secreted proteins and then tested the proteins individually for effects in a range of in vitro assays. Having identified a new cytokine, interleukin 34 (IL-34), the authors then looked for binding to recombinant extracellular domains of about 1600 transmembrane proteins, which led to the detection of IL-34 binding to the colony-stimulating factor 1 (CSF-1) receptor. Biological effects of IL-34 mediated through the CSF-1 receptor were confirmed in further studies. Thus, the authors' approach can identify important regulatory proteins and their receptors.

H. Lin, E. Lee, K. Hestir, C. Leo, M. Huang, E. Bosch, R. Halenbeck, G. Wu, A. Zhou, D. Behrens, D. Hollenbaugh, T. Linnemann, M. Qin, J. Wong, K. Chu, S. K. Doberstein, L. T. Williams, Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.
Science
320
, 807-811 (2008).
[Abstract]
[Full Text]
Shaping Signals
Authors: Ray L. Bryan
Published: June 2008

Although keeping up with them can present difficulty for some human brains, it is evident that there are not enough distinct signaling mechanisms to account for the elaborate range of regulatory events that are controlled in a living organism. Neves
et al.
show one way in which fine-tuning of the same signaling pathway can allow distinct patterns of control. They examined the way in which cell shape impacts a classical signaling pathway from the β-adrenergic receptor through the second messenger adenosine 3′,5′-monophosphate (cAMP) to activation of mitogen-activated protein kinases (MAPKs) in neurons. Neves
et al.
used a combination of mathematical modeling of the system with measurements of temporal and spatial dynamics of signaling in isolated mouse hippocampal neurons with fluorescence resonance energy transfer imaging techniques. Their results show that the presence of adenylate cyclase activated by β-adrenergic receptors at the cell surface, with phosphodiesterase activity (which degrades cAMP) in the cytosol, along with other properties of the system, led to activation of gradients of signaling through cAMP to MAPKs. Furthermore, in part because the surface-to-volume ratio is very different in the narrow dendrites of a neuron compared with that in the neuronal cell body, there was a distinctly stronger signal in the dendrites than in the cell body, even though receptors are evenly distributed on the surface of the cell. Modeling indicated that the negative regulators would be key factors in controlling the size of microdomains of activation and propagation of spatially distinct signals through the pathway, and experimental manipulations verified this, with pharmacological inhibition of phosphodiesterase 4 allowing MAP kinase activation in the cell body as well as the dendrites. Kholodenko and Kolch provide commentary.

S. R. Neves, P. Tsokas, A. Sarkar, E. A. Grace, P. Rangamani, S. M. Taubenfeld, C. M. Alberini, J. C. Schaff, R. D. Blitzer, I. I. Moraru, R. Iyengar, Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks.
Cell
133
, 666-680 (2008).
[PubMed]

B. N. Kholodenko, W. Kolch, Giving space to cell signaling.
Cell
133
, 566-567 (2008).
[PubMed]
Cadherins and Guidepost Neurons
Authors: Hines Pamela J.
Published: June 2008

The
Celsr3
gene, which encodes a cell-surface cadherin molecule, is widely expressed in neurons of the developing brain after they have migrated when they are refining their connections. Zhou
et al
. prevented
Celsr3
expression in a variety of specific regions of the developing mouse brain.
Celsr3
expression was critical to the function of guidepost neurons--cells that developing axons use as flags to find their way. In particular, the axon tracts that connect thalamus and cortex depend upon Celsr3 interactions as they develop.

L. Zhou, I. Bar, Y. Achouri, K. Campbell, O. De Backer, J. M. Hebert, K. Jones, N. Kessaris, C. L. de Rouvroit, D. O'Leary, W. D. Richardson, A. M. Goffinet, F. Tissir, Early forebrain wiring: Genetic dissection using conditional
Celsr3
mutant mice.
Science
320
, 946-949 (2008).
[Abstract]
[Full Text]
A Polarized Viewpoint?
Authors: Adler Elizabeth M.
Published: June 2008

Invertebrates, like vertebrates, use the light-activated heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) rhodopsin as a photoreceptor in visual signal transduction. Unlike vertebrate rhodopsin, which signals through transducin, invertebrate rhodopsin signals through G
q
-type G proteins to stimulate an inositol 1,4,5-trisphosphate-based signaling pathway (see Schertler). Murakami and Kouyama determined the 2.5 Å resolution crystal structure of squid rhodopsin, shedding new light on mechanisms of signaling involving this GPCR family. Crystallization of truncated squid rhodopsin (lacking a C-terminal extension that is not involved in signal transduction) revealed two cytoplasmic helices as well as the seven transmembrane helices characteristic of GPCRs. Transmembrane helices V and VI projected 25 Å into the cytoplasm to form, together with cytoplasmic helices VIII and IX, a structure that is not present in bovine rhodopsin, which the authors propose is involved in interactions with G
q
. Rhodopsin consists of the protein opsin and the covalently bound chromatophore retinal; the amino acid residues in contact with retinal in squid rhodopsin differ from those in bovine rhodopsin, and retinal assumes a less distorted configuration in the former. Intriguingly, the arrangement of chromatophores in crystallized squid rhodopsin may provide insight into the ability of invertebrates to detect the polarization plane of light.

M. Murakami, T. Kouyama, Crystal structure of squid rhodopsin.
Nature
453
, 363-367 (2008).
[PubMed]

G. F. X. Schertler, The rhodopsin story continued.
Nature
453
, 292-293 (2008).
[PubMed]
Patterned by Smell
Authors: VanHook Annalisa M.
Published: June 2008

Olfactory and visual signals are transduced through nonmotile cilia, some of which have elaborate structural modifications. Mukhopadhyay
et al.
report that the architecture of one such sensory neuron’s cilia are shaped by the sensory input the cell receives. The AWB neuron in the nematode
Caenorhabditis elegans
is a chemosensory neuron that detects repulsive cues from bacteria through long, branched cilia. The AWB of worms raised without bacteria in the culture medium had cilia with short, wide branches with increased membrane surface area. This phenotype was also observed in worms that lacked any one of several proteins required in AWB for sensory signaling, including two cyclic nucleotide-gated channel subunits, a guanylyl cyclase, and a G protein-coupled receptor kinase. Cilium remodeling also required the second messengers Ca
2+
and guanosine 3',5'-monophosphate (cGMP), as well as proteins required for ciliary biogenesis such as Kinesin-II and RAB8. The signaling requirement for proper morphology was cell-autonomous, because transgenically providing these proteins to only the AWB neuron restored wild-type morphology. TAX-2, a subunit of cyclic nucleotide-gated ion channel predicted to be permeable to Ca
2+
, was specifically required during late larval development to maintain wild-type ciliary structure, because inactivation of
tax-2
during this time period using temperature-sensitive alleles produced cilia with altered morphology. Therefore, the ciliary architecture of the AWB neuron was affected by sensory input only during a defined developmental window. These findings identify a cell-autonomous requirement for sensory input in shaping the structure of the sensory cilia and suggest that plasticity in ciliary architecture could provide a means for increasing the sensory surface area (and therefore increasing sensitivity) to olfactory signals as an adaptation to sensory deprivation experienced during a critical developmental time period.

S. Mukhopadhyay, Y. Lu, S. Shaham, P. Sengupta, Sensory signaling-dependent remodeling of olfactory cilia architecture in
C. elegans
.
Dev
.
Cell
14
, 762-774 (2008).
[PubMed]

J. F. Reiter, A cilium is not a cilium is not a cilium: Signaling contributes to ciliary morphological diversity.
Dev
.
Cell
14
, 635-636 (2008).
[PubMed]
Notch Presents a Challenge
Authors: Foley John F.
Published: June 2008

In patients with asthma, inflammation and airway hyperresponsiveness (AHR) are associated with the accumulation of CD8
+
T cells in the lungs. Mouse models of asthma involve administering an allergen to the airway (sensitization), followed by a second exposure to allergen (challenge), which triggers AHR. Okamoto
et al
. previously showed that AHR was less severe in
CD8
–/–
mice than in wild-type mice and could be restored by the transfer of CD8
+
effector (T
EFF
), but not CD8
+
central memory (T
CM
), T cells to the
CD8
–/–
mice. In the current study, microarray analyses showed that Notch1 mRNA was more abundant in T
EFF
than in T
CM
cells. Notch receptors determine cell fate in developmental processes, including during T cell lineage commitment. Activation of Notch receptors by their ligands, members of the Delta-like and Jagged families, results in γ-secretase-dependent cleavage of the Notch intracellular domain (NICD), which translocates to the nucleus to activate target gene transcription. Stimulation of the T cell receptors of T
EFF
cells in vitro increased the abundance of NICD compared with that in untreated cells, as determined by Western blotting. When T
EFF
cells were treated in vitro with a γ-secretase inhibitor (GSI) before transfer to allergen-challenged
CD8
–/–
mice, AHR was less severe than that in mice that received vehicle-treated T
EFF
cells. Finally, when allergen-sensitized wild-type mice were treated with an antibody against the Notch ligand Delta1 before allergen challenge, their AHR was less severe than that of control antibody-treated mice. Together, these data indicate a role for Notch signaling in the development of CD8
+
T cell-mediated AHR and suggest Delta1 as a potential therapeutic target in the treatment of allergen-induced AHR.

M. Okamoto, K. Takeda, A. Joetham, H. Ohnishi, H. Matsuda, C. H. Swasey, B. J. Swanson, K. Yasutomo, A. Dakhama, E. W. Gelfand, Essential role of Notch signaling in effector memory CD8
+
T cell-mediated airway hyperresponsiveness and inflammation.
J
.
Exp
.
Med
.
205
, 1087-1097 (2008).
[Abstract]
[Full Text]
Signaling Clock Timing
Authors: Ray L. Bryan
Published: June 2008

Transcriptional feedback loops are at the heart of circadian clocks of mammals and other organisms, but evidence is emerging that suggests that other signaling mechanisms also have important roles in basic functions of the clock. O’Neill
et al.
(see the Perspective by Harrisingh and Nitabach) show that cytosolic signaling through adenosine 3′,5′-monophosphate (cAMP) integrates with the transcriptional timing mechanism, sustains it, and determines the fundamental properties (amplitude, phase, and period) of the transcriptional feedback loops of the mammalian circadian pacemaker. This expands the paradigm of cellular circadian oscillation control by transcriptional feedback loops to include small-molecule cytoplasmic signals that differ between species--cAMP in mammals, Ca
2+
in mammals and insects, and cyclic ADP ribose in plants.

J. S. O'Neill, E. S. Maywood, J. E. Chesham, J. S. Takahashi, M. H. Hastings, cAMP-dependent signaling as a core component of the mammalian circadian pacemaker.
Science
320
, 949-953 (2008).
[Abstract]
[Full Text]

M. C. Harrisingh, M. N. Nitabach, Integrating circadian timekeeping with cellular physiology.
Science
320
, 879-880 (2008).
[Summary]
[Full Text]
Plant Responses to Salt Stress
Authors: Hines Pamela J.
Published: June 2008

Detrimental levels of salt can result when agriculture is extended to marginal lands or relies on irrigation. Using the
Arabidopsis
root tip, Dinneny
et al
. (see the Perspective by Voesenek and Pierik) examined how different cells within a tissue respond to the physiological stresses due to salinity. Different layers of cells, whether at the surface of the root or more internal, responded differently to the environmental stress of too much salt. Furthermore, stressed cells could influence their neighbors, and gene expression patterns changed over the duration of the stress.

J. R. Dinneny, T. A. Long, J. Y. Wang, J. W. Jung, D. Mace, S. Pointer, C. Barron, S. M. Brady, J. Schiefelbein, P. N. Benfey, Cell identity mediates the response of
Arabidopsis
roots to abiotic stress.
Science
320
, 942- 945 (2008).
[Abstract]
[Full Text]

L. A. C. J. Voesenek, R. Pierik, Plant stress profiles.
Science
320
, 880-881 (2008).
[Summary]
[Full Text]
Determining Pathway Bandwidth
Authors: Gough Nancy R.
Published: June 2008

Signaling pathways allow cells and organisms to respond to changes in the environment. But how quickly a signaling pathway can be activated and deactivated dictates the pathway’s bandwidth--the maximum frequency with which a cell can faithfully reproduce changes in the stimulus. Hersen
et al
. developed a microfluidic device to trigger periodic changes in culture medium and then used it to rapidly and periodically increase osmolarity while monitoring, using fluorescent reporters, the activation of the high-osmolarity glycerol (HOG) pathway in
Saccharomyces cerevisiae
. The HOG pathway consists of a mitogen-activated protein kinase (MAPK) cascade, which can be activated by either a two-component phosphorelay (the Sln1 pathway from Sln1 to Ssk1 to the MAPKKKs Ssk2 and Ssk22 to the MAPK Pbs2 to the MAPK Hog1) or an enzymatic sensor system (the Sho1 pathway from Sho1 to the MAPKKK Ste11 to Pbs2 to Hog1). The authors monitored nuclear translocation of a green fluorescent protein (GFP)-tagged Hog1 or production of Gpd1-GFP (encoded by a Hog1 target gene) and calculated a pathway bandwidth of 0.0046 Hz. When the osmolarity was changed at a frequency less than the pathway bandwidth, Hog1-GFP translocation and Gpd1-GFP production increased and decreased in sync with the input stimulus. When the osmolarity was changed more rapidly than the pathway bandwidth, the pathway integrated the input and Hog1-GFP accumulated in the nucleus without oscillating and then reached a plateau. Gpd1-GFP also accumulated, reaching a plateau, without oscillating when the frequency of the change in osmolarity exceeded the pathway bandwidth. This behavior is consistent with the pathway serving as a low-pass filter. The bandwidth calculated for cell swelling was lower than the pathway bandwidth, which suggests that the mechanical change in cell shape was not the limiting factor. Instead, pathway bandwidth was limited by the activation and deactivation rates of the biochemical reactions that mediate the HOG response. Only mutants of the Sln1 pathway, but not the Sho1 pathway, had a bandwidth less than the bandwidth of the pathway in wild-type cells; thus, this input into the HOG MAPK cascade sets the frequency with which the pathway can respond. Furthermore, only the Sln1 pathway was required for integration of high-frequency stimulation that exceeded the pathway bandwidth. The calculated rate of deactivation of the pathway (0.0041 Hz) derived by monitoring Hog1 translocation in wild-type cells or cells that contained mutations that deactivated either the Sho1 arm or the Sln1 arm matched the pathway bandwidth, which suggests that deactivation of HOG signaling, that is, dephosphorylation, at or downstream of Pbs2 set the pathway bandwidth.

P. Hersen, M. N. McClean, L. Mahadevan, S. Ramanathan, Signal processing by the HOG MAP kinase pathway.
Proc. Natl. Acad. Sci. U.S.A.
105
, 7165-7170 (2008).
[Abstract]
[Full Text]
Reorganizing Dendrites
Authors: Adler Elizabeth M.
Published: June 2008

Newborn female rat pups have only about half the number of dendritic spines on their hypothalamic neurons as newborn male rat pups, a difference that disappears when the newborn females are treated with testosterone (which is aromatized to estradiol in the brain). Schwarz
et al
. found that estradiol treatment increased dendritic length and number of spines on neurons in the medial basal hypothalamus of newborn females to levels comparable to those in male pups and increased the abundance of the protein spinophilin. The glutamate agonist
N
-methyl-D-aspartate (NMDA) mimicked these effects, whereas NMDA- and AMPA-type glutamate receptor antagonists blocked the increase in spinophilin. Estradiol did not affect the abundance or the function of hypothalamic NMDA- and AMPA-type glutamate receptors. Rather, analysis of the ratio of the amplitudes of paired excitatory postsynaptic currents indicated that estradiol increased glutamate release from presynaptic neurons, as did experiments assessing depolarization- or electrical stimulation-dependent loss of the fluorescent dye FM4-54. Moreover, in vitro experiments indicated that stimulating glutamate release with α-latrotoxin also induced an increase in spinophilin. Estradiol’s stimulation of glutamate release did not depend on protein synthesis. Estradiol stimulated phosphorylation of the phosphatidylinositol 3-kinase (PI3K) substrate Akt and of extracellular signal-regulated kinase 1 and 2 [ERK 1/2, a target of MEK 1/2 (mitogen-activated or extracellular signal-regulated protein kinase kinase)]; timing and pharmacological analysis implicated PI3 kinase in the estradiol-dependent increase in glutamate release and indicated that ERK was phosphorylated downstream of glutamate receptor activation but upstream of the increase in spinophilin. In vitro experiments also implicated c-Jun N-terminal kinase (JNK) in the postsynaptic response. The authors conclude that the effects of estradiol on hypothalamic dendritic morphology are nongenomic and depend on PI3K activation and the consequent enhancement of presynaptic glutamate release.

J. M. Schwarz, S.-L. Liang, S. M. Thompson, M. M. McCarthy, Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: A mechanism for organizational sex differences.
Neuron
58
, 584-598 (2008).
[PubMed]
Regulating
S
-Nitrosylation
Authors: Ray L. Bryan
Published: June 2008

Covalent modification of proteins by
S
-nitrosylation is an important mechanism for regulation of biochemical activity in cells. However, mechanisms of protein denitrosylation have not been well characterized. The protease caspase-3, which promotes apoptosis, is inhibited by
S
-nitrosylation and is denitrosylated in cells in which the cell death-promoting receptor Fas is activated. Benhar
et al
. (see the Perspective by Holmgren) purified a protein fraction that catalyzed denitrosylation of caspase-3 and identified thioredoxin-1 (Trx1) as the protein most likely to be responsible for the denitrosylation activity. Depletion of Trx1 caused accumulation of
S
-nitrosylated caspase-3 and other
S
-nitrosylated proteins in cultured cells, and Fas-induced denitrosylation of caspase-3 was inhibited by depleting thioredoxin reductase 2. Thus, regulated denitrosylation of target proteins by Trx1 appears to provide a key component of enzymatic regulation of caspase-3 and possibly other proteins by
S-
nitrosylation.

M. Benhar, M. T. Forrester, D. T. Hess, J. S. Stamler, Regulated protein denitrosylation by cytosolic and mitochondrial thioredoxins.
Science
320
, 1050-1054 (2008).
[Abstract]
[Full Text]

A. Holmgren, SNO Removal.
Science
320
, 1019-1020 (2008).
[Summary]
[Full Text]
Diversification of the Function of Cell-to-Cell Signaling in Regulation of Virulence Within Plant Pathogenic Xanthomonads
Authors: Dow Max
Published: June 2008

The virulence of plant pathogenic bacteria belonging to the genera
Xanthomonas
and
Xylella
depends upon cell-to-cell signaling mediated by the diffusible signal molecule DSF (Diffusible Signaling Factor). Synthesis and perception of the DSF signal require products of the
rpf
gene cluster. The synthesis of DSF depends on RpfF, whereas the RpfC/RpfG two-component system is implicated in DSF perception and signal transduction. The sensor RpfC acts to negatively regulate synthesis of DSF. In
Xanthomonas campestris
, mutation of
rpfF
or
rpfC
leads to a coordinate down-regulation in synthesis of virulence factors and a reduction in virulence. In contrast, in
Xylella fastidiosa
, the causal agent of Pierce’s disease of grape, mutation of
rpfF
and
rpfC
have opposite effects on virulence, with
rpfF
mutants exhibiting a hypervirulent phenotype. The findings suggest that different xanthomonads have adapted the perception and function of similar types of signaling molecule to fit the specific needs for colonization of different hosts.
Extended-Spectrum β-Lactamase Production Is Associated with an Increase in Cell Invasion and Expression of Fimbrial Adhesins in
Klebsiella pneumoniae
Authors: Sahly H. , Navon-Venezia S. , Roesler L. , Hay A. , Carmeli Y. , Podschun R. , Hennequin C. , Forestier C. , Ofek I.
Published: June 2008

Extended-spectrum β-lactamase (ESBL)-producing
Klebsiella pneumoniae
strains are suggested to possess higher pathogenic potential than non-ESBL producers. Microbial adherence to and invasion of host cells are critical steps in the infection process, so we examined the expression of type 1 and 3 fimbrial adhesins by 58 ESBL-producing and 152 nonproducing isolates of
K. pneumoniae
and their abilities to invade ileocecal and bladder epithelial cells. Mannose-sensitive hemagglutination of guinea pig erythrocytes and mannose-resistant hemagglutination of ox erythrocytes were evaluated to determine the strains’ abilities to express type 1 and type 3 fimbriae, respectively. Bacterial adhesion to and invasion of epithelial cells were tested by enzyme-linked immunosorbent assay and imipenem killing assay, respectively. The adherence of ESBL- and non-ESBL-producing strains to epithelial cells did not differ significantly (
P
> 0.05). In contrast, the proportion of strains capable of invading (>5% relative invasion) ileocecal and bladder epithelial cells was significantly higher among ESBL producers (81%,
n
= 47/58, and 27.6%,
n
= 16/58, respectively) than among non-ESBL producers (61%,
n
= 93/152, and 10%,
n
= 15/152, respectively) (
P
= 0.0084, odds ratio [OR] = 2.711, 95% confidence interval [CI] = 1.302 to 5.643 and
P
= 0.0021, OR = 4.79, 95% CI = 1.587 to 7.627). The mean invasion by ESBL producers (5.5% ± 2.8% and 3.3% ± 2.7%, respectively) was significantly higher than that by non-ESBL producers (2.9% ± 2.6% and 1.8% ± 2%, respectively) (
P
< 0.0001). Likewise, the proportion of ESBL producers coexpressing both fimbrial adhesins was significantly higher (79.3%;
n
= 46/58) than that of non-ESBL producers (61.8%;
n
= 94/152) (
P
= 0.0214; OR = 2,365; 95% CI = 1.157 to 4.834). Upon acquisition of SHV-12-encoding plasmids, two transconjugants switched on to produce type 3 fimbriae while expression of type 1 fimbriae was not affected. The acquisition of an ESBL plasmid appeared to upregulate the phenotypic expression of one or more genes, resulting in greater invasion ability.
Clostridium difficileInfections in a Canadian Tertiary Care Hospital before and during a Regional Epidemic Associated with the BI/NAP1/027 Strain
Authors: Labbé Annie-Claude , Poirier Louise , MacCannell Duncan , Louie Thomas , Savoie Michel , Béliveau Claire , Laverdière Michel , Pépin Jacques
Published: June 2008

Since 2002, an epidemic ofClostridium difficileinfections has occurred in southern Quebec, Canada. At Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada, the incidence ofC. difficileinfections increased from 11/1,000 admissions (1999 to 2002) to 27/1,000 admissions (2003 to 2005). We compared the exposures and outcomes for patients infected with strains with different ribopatterns isolated before (n= 55) and during (n= 175) the epidemic, as well as the in vitro activities of antibiotics against those isolates. During the preepidemic period, 46 isolates (84%) were of ribotype 001, 1 was of ribotype 027, and 8 were of other ribopattern types. During the epidemic period, ribotype 027 strains accounted for 140 (80%) isolates; 26 (15%) were of ribotype 001, and 7 were of other ribopattern types. Ribotype 027 strains were highly resistant to fluoroquinolones (FQs) but were susceptible to clindamycin. A pattern of prior specific antibiotic exposure that selected for antibiotic-resistant ribotypeC. difficileinfections was observed for FQs (ribotype 027) and clindamycin (ribotype 001). The rate of mortality was higher among older patients, those with a high Charlson comorbidity index, and those with longer previous hospitalizations. By multivariate analysis, patients infected with ribotype 027 were twice as likely to die within 30 days of diagnosis than patients infected with other ribotypes (adjusted odds ratio, 2.06; 95% confidence interval, 1.00 to 4.22). The observations from this study support the notion that continued selective antibiotic pressure resulted in the superimposition of the hypertoxigenic ribotype 027 clone on top of the prior dominant ribotype 001 clone in a setting of preexisting high endemicity, thus leading to the high rates of morbidity and mortality seen in the Quebec outbreak. Stringent antibiotic stewardship measures, combined with aggressive infection control, are required to curtail the epidemic ofC. difficileinfections.
Antimicrobial Activity of DC-159a, a New Fluoroquinolone, against 1,149 Recently Collected Clinical Isolates
Authors: Jones Ronald N. , Fritsche Thomas R. , Sader Helio S.
Published: June 2008

The activity of DC-159a, a novel orally administered fluorinated quinolone, was evaluated by reference broth microdilution or agar dilution methods against 1,149 recently collected clinical isolates from five continents. Against pathogens associated with community-acquired respiratory tract infections (CA-RTIs), the MIC
90
s were 0.12 μg/ml for
Streptococcus pneumoniae
, 0.015 to 0.03 μg/ml for
Haemophilus influenzae
, 0.03 μg/ml for
Moraxella catarrhalis
, and 0.12 μg/ml for beta-hemolytic streptococci. Similarly, DC-159a was potent against various types of staphylococci (MIC
90
range, 0.03 to 2 μg/ml),
Enterococcus faecalis
(MIC
90
, 4 μg/ml), wild-type isolates of the family
Enterobacteriaceae
(MIC
90
range, 0.06 to 2 μg/ml), wild-type
Pseudomonas aeruginosa
(MIC
90
, 2 μg/ml), and
Acinetobacter
spp. (MIC
90
, 0.12 μg/ml). Fluoroquinolone-nonsusceptible organism subsets usually had elevated DC-159a MICs, but the MICs were often two- to fourfold lower than those of levofloxacin and moxifloxacin. In conclusion, DC-159a appears to possess a balanced broad spectrum of activity that exceeds the activities of the currently marketed fluoroquinolones, especially against pathogens that cause CA-RTIs.
The KQ Element, a Complex Genetic Region Conferring Transferable Resistance to Carbapenems, Aminoglycosides, and Fluoroquinolones in
Klebsiella pneumoniae
Authors: Rice Louis B. , Carias Lenore L. , Hutton Rebecca A. , Rudin Susan D. , Endimiani Andrea , Bonomo Robert A.
Published: June 2008

The
bla
KPC-3
and
qnrB19
determinants of transferable
Klebsiella pneumoniae
plasmid pLRM24 reside within a complex region consisting of a Tn
1331
backbone into which a Tn
4401
-like element and
qnrB19
mobilized by an adjacent IS
Ecp1
insertion sequence have been inserted. This novel element represents a coalescence of genes conferring multidrug resistance in
K. pneumoniae
.
Genome of
Mycoplasma arthritidis
Authors: Dybvig Kevin , Zuhua Cao , Lao Ping , Jordan David S. , French C. Todd , Tu Anh-Hue T. , Loraine Ann E.
Published: June 2008

The genomes of several species of mycoplasma have been sequenced. Most of these species rely on the glycolytic pathway for energy production, with the one exception of
Ureaplasma
, a species that breaks down urea as its principle source of acquiring energy. Several species, including as
Mycoplasma arthritidis
, are nonglycolytic and can use arginine as their source of energy. Described here are the genome sequence and a transposon library of
M. arthritidis
. The genome of 820,453 bp is typical in size for a mycoplasma and contains two large families of genes that are predicted to code for phase-variable proteins. The transposon library was constructed using a minitransposon that inserts stably into the mycoplasma genome. Of the 635 predicted coding regions, 218 were disrupted in a library of 1,100 members. Dispensable genes included the gene coding for the MAM superantigen and genes coding for ribosomal proteins S15, S18, and L15.
Decreased Susceptibility of Mice to Infection withListeria monocytogenesin the Absence of Interleukin-18
Authors: Lochner Matthias , Kastenmüller Kathrin , Neuenhahn Michael , Weighardt Heike , Busch Dirk H. , Reindl Wolfgang , Förster Irmgard
Published: June 2008

The induction of proinflammatory cytokines such as gamma interferon (IFN-γ) and tumor necrosis factor alpha is crucial for the early control of bacterial infections. Since interleukin-18 (IL-18) acts as a potent inducer of IFN-γ, it might play an important role in the induction of a protective immune response in listeriosis. We used a murine model of systemicListeria monocytogenesinfection to study the immune response to these intracellular bacteria in the absence of IL-18. For this purpose, IL-18-deficient mice and mice treated with anti-IL-18 neutralizing antibody were infected withL. monocytogenes, and their innate and adaptive immune responses were compared to those of control mice. Unexpectedly, we found that mice deficient in IL-18 were partially resistant to primary infection withL. monocytogenes. At day 3 after infection, the numbers oflisteriaein the livers and spleens of control mice were up to 500 times higher than those in IL-18-deficient or anti-IL-18 antibody-treated mice. In addition, the level of proinflammatory cytokines was markedly reduced in IL-18-deficient mice. Enhanced resistance toL. monocytogenesinfection in IL-18-deficient mice was accompanied by increased numbers of leukocytes and reduced apoptosis in the spleen 48 to 72 h after infection. In contrast, control and IL-18-deficient mice showed no significant differences in their abilities to mount a protectiveL. monocytogenes-specific T-cell response.
Bias and Error Propagation in Logistic Production Models
Authors: Mohn Robert K.
Published: June 2008

Maximum sustainable yield (MSY) and the effort at MSY (EMSY) are estimated from simulated catch and effort data to determine the biasing and susceptibility to error propagation of three commonly used techniques. The effects of smoothing, distribution of error between catch and effort, and delays in the density-dependent growth are investigated with respect to forming such estimates. It is found that MSY and EMSY levels derived from these methods suffer in varying degrees to bias (sometimes greater than a factor of 2) and variability (sometimes a coefficient of variation greater than 1). These results are dependent upon the method used and the parameters used to produce the data, especially how dynamic the modeled stock is. Therefore, information about the biological nature of the stock, especially the intrinsic growth rate, is important to correct the biasing of an estimation method. It is concluded that Gulland's and Schnute's methods should both be used keeping in mind the expected biases from this study.Key words: production model, management, maximum sustainable yield, error propagation
The Valuation of Recreational Fisheries
Authors: Cauvin D.
Published: June 2008

Contemporary valuation of recreational fisheries resources proceeds from the proposition that fisheries resources are nonpriced resources. There is a fundamental need to challenge this proposition. Present valuation techniques for recreational fisheries serve neither the requirements for economic efficiency nor the distributional objectives of government. A price system, which is widely accepted in much of Canadian life, is presented as an alternative.Key words: nonpriced resources, valuation, public goods, proxy values, consumer surplus, price system
Environmental Factors Influencing the Production of an Antibacterial Metabolite from a Marine Dinoflagellate,Prorocentrum minimum
Authors: Trick Charles G. , Andersen Raymond J. , Harrison Paul J.
Published: June 2008

Prorocentrum minimum, an ubiquitous marine dinoflagellate that does not form toxic red tides, produces biologically active extracellular metabolites, one of which is 1-(2,6,6-trimethyi-4-hydroxycyclohexenyl)-1,3-butanedione, a norcarotenoid referred to herein as β-diketone. The β-diketone was released extracellularly in a single "pulse" during the stationary phase of growth, and irradiance and temperature are important in controlling its maximum extracellular concentration. Different concentrations were obtained depending on the limiting nutrient. If cells were P deficient, the final extracellular concentration was twice that of N-deficient cultures. Iron-deficient growth further reduced the amount of the β-diketone produced. The ambient nitrate concentration in the medium had a strong influence on the maximum amount of the β-diketone produced. None of the environmental factors affected the temporal pattern of production. That the β-diketone is an antibiotic metabolite active against marine bacteria is shown by the reduction of the growth rate of three of four marine isolates and the inhibition of the heterotrophic uptake of glucose. The β-diketone in the natural environment may serve to reduce degradation of algae by physically associated bacteria.
Geochemical Pathways and Biological Uptake of Radium in Small Canadian Shield Lakes
Authors: Hesslein R. H. , Slavicek E.
Published: June 2008

The sediment–water interactions and biological uptake of226Ra are described for four small Canadian Shield lakes at the Experimental Lakes Area, Kenora, Ont. A single addition of226Ra was made to each lake between 1970 and 1976. Approximately 90% of the added226Ra initially sorbed to the sediments. Outflow from the lakes showed losses of only 5–11%226Ra per year. Models are proposed for adsorption and outflow of226Ra from lakes. Biological uptake and long-term226Ra concentrations were measured in three species of macrophytes, crayfish, and five species of fish. Bioaccumulation ranged from 1100 to 5000 in macrophytes, 750 in crayfish, from 30 to 80 in large adult lake trout (Salvelinus namaycush), white sucker (Catostomus commersoni), and lake whitefish (Coregonus clupeaformis), and from 230 to 1200 in fathead minnows (Pimephales promelas), pearl dace (Semotilus margarita), and northern redbelly dace (Chrosomus eos). The concept of Ra/Ca ratio in organisms versus water and food is used to explain the differences in bioaccumulation.226Ra is discriminated against versus calcium by fish but favored by macrophytes and crayfish.
Changes in the Selection of Microhabitat by Juvenile Atlantic Salmon (Salmo salar) at the Summer–Autumn Transition in a Small River
Authors: Rimmer D. M. , Paim U. , Saunders R. L.
Published: June 2008

Over three summers we used direct underwater observation to examine the summer to autumn differences in seven microhabitat properties of three age-classes of juvenile Atlantic salmon (Salmo salar) in the Little Sevogle River of northeastern New Brunswick. Salmon of all three age-classes occupied a wide range of water depths during summer, but were concentrated mainly in depths of 24–36 cm. In autumn, they occurred in this range almost exclusively. The streambed stones most closely associated with the individual positions of all ages were always <20 cm in summer and mostly (84–92%) <10 cm in diameter. In autumn, all ages were associated with home stones up to 40 cm in diameter, with 65–83% of the stones exceeding 20 cm; the size of home stones selected increased with fish age in autumn. There was no apparent relationship between the water depth and home stone size distributions occupied by all age-classes and available in the stream during either summer or autumn. Summer focal water velocity (velocity at the fish's snout) was predominantly 10–30 cm∙s−1 for 0+, 10–40 cm∙s−1 for 1+, and 30–50 cm∙s−1 for 2+ salmon, but during autumn it was almost always <10 cm∙s−1 for all ages. The bottom and surface water velocities as well as the maximum water velocity within 1 m of fish stations increased with fish age during summer and autumn. At the summer–autumn transition, 0+ salmon selected higher bottom, surface, and maximum water velocities, 2+ salmon selected lower velocities, but selection by 1+ salmon remained unchanged. We view substrate size followed by water depth as the primary properties influencing stream suitability for juvenile Atlantic salmon in autumn.
Inter- and Intra-Population Variation in the Fecundity of Chinook Salmon (Oncorhynchus tshawytscha) and its Relevance to Life History Theory
Authors: Healey M. C. , Heard W. R.
Published: June 2008

Chinook salmon (Oncorhynchus tshawytscha) varied significantly in fecundity both between years within populations and between populations throughout their range. Generally less than 50% of the variation in fecundity between individuals within populations could be explained by variation in length. A small additional amount of variation could be attributed to racial differences (e.g. red or white fleshed types) but age, seasonal timing of subpopulations, and stream or ocean type life history pattern did not contribute significantly to variation in fecundity beyond their correlation with length. A great deal of individual variation in fecundity remains to be explained in chinook salmon. The slopes of the regression of fecundity on length for all populations were low in comparison with other fishes, indicating that fecundity increases slowly with increasing size in chinook. The mean age of reproducing females varied among populations, and populations that reproduced at an older age were more fecund at a common length than populations that reproduced at a younger age. The increase in fecundity with increasing age of maturity was consistent with theoretical predictions of the trade-off between fecundity and mortality in fish of reproductive age. The mean age of reproduction within a population, however, was considerably older than the predicted optimum age of reproduction based on the trade-off between increasing fecundity with age and natural mortality. These observations suggest that chinook have sacrificed fecundity for increased size in the allocation of surplus energy, a life history characteristic that is consistent with the survival value of size in anadromous salmon.
Population Dynamics of Western Arctic Bowhead Whales (Balaena mysticetus)
Authors: Breiwsck Jeffrey M. , Eberhardt L. Lee , Braham Howard W.
Published: June 2008

Leslie-type projection matrices were used to model the western Arctic bowhead whale (Balaena mysticetus) population in two stages: (1) from 1848 to 1970 and (2) from 1970 to 2000. Several constraints were imposed on adult and immature survival rates, and several assumptions were made about combinations of age through which immature survival applies (a), age at sexual maturity (m), and maximum age (w). Fecundity was derived by assuming that the population was stationary in 1848 (start of commercial exploitation). Estimates of numbers of animals killed and struck and lost, as well as an assumed mortality rate for whales struck and lost, were used to solve for the 1848 population size assuming that the 1970 level was 4000 bowheads. The 1970 level (4000) was then projected forward to the year 2000 with constant kill regimes for 1983–2000 of 0, 20, and 40 animals per year. Results indicate that there is an apparent incompatibility between the observed proportion of immature whales in the population and the proportions predicted by population modeling. Improved estimates of calf production and of the proportion of immature bowheads in the population are therefore needed. Calculated maximum net productivity rate is very sensitive to adult survival rate and thus, accurate estimates of the current growth rate of the bowhead whale population are not possible at present. Due to the many uncertainties about relevant biological features of the population, it would be prudent to restrict future total removals to no greater than the levels prior to 1970.
A Gastric Evacuation Model for Young Yellow Perch, Perca flavescens
Authors: Mills Edward L. , Ready Richard C. , Jahncke Michael , Hanger Clare R. , Trowbridge Cynthia
Published: June 2008

Gastric evacuation times for age 0+ yellow perch (Perca flavescens) (20–69 mm total length) fed continuous meals of zooplankton were measured in the laboratory. The pattern of gastric emptying was described using a segmented regression with two linear sections joined at a fish length of 36.5 mm. It was assumed that evacuation time (hours) is dependent on the amount of food in the stomach; the variables prey size and meal size were the primary determinants of stomach food volume. A gastric evacuation time model was developed; model parameters of evacuation time were quantified as functions of fish size, prey size, and numbers of prey in the stomach. For fish <36.5 mm, all three variables improved the regression model (P < 0.05), while for larger fish, only the number of prey in the stomach and fish length contributed (P < 0.05) to the explained variance in evacuation time. Estimates of evacuation time were applied to a model of prey consumption and it was found that predicted food intake did not differ significantly from direct counts (P > 0.05).
Use of a Self-Cleaning, In-line Filter to Continuously Monitor Phytoplankton Nutrient Uptake Rates
Authors: Parslow J. S. , Harrison P. J. , Thompson P. A.
Published: June 2008

Our new technique allows the decline in ambient ammonium concentration to be followed continuously during phytoplankton uptake experiments. A self-cleaning, in-line filter permits the continuous separation of cells from the medium for nutrient determination by an autoanalyzer. The technique works well with laboratory cultures of the marine diatoms Thalassiosira pseudonana and Skeletonema costatum. Changes in uptake rate on time scales of 1 min or longer can be resolved, the resolution being limited by the response characteristics of the autoanalyzer.
Influence of Various Sources of Error and Community Interactions on Quota Management of Fish Stocks
Authors: Koonce Joseph F. , Shuter Brian J.
Published: June 2008

We compare the performance of fishery control systems based on population and surplus production models. We show that the population method is superior to a surplus production method over a wide range of observational and structural error conditions. We also show that adaptive fishery control systems have potential to reduce uncertainty surrounding management of fisheries like the walleye (Stizostedion vitreum vitreum) fishery of western Lake Erie where unknown bias and error in harvest statistics combine with environmental variability to contribute substantial uncertainty to the quota derivation process.