bluuebunny/crossref_metadata_2025 huggingface dataset:
The Changing Face of Antibiotic Prescribing: The Mutant Selection Window
Authors: Epstein Benjamin J , Gums John G , Drlica Karl
Published: September 2004

OBJECTIVE

To describe the mutant selection window, discuss supporting evidence and limitations, and suggest potential applications for clinical practice.

DATA SOURCES

A MEDLINE search (1990–December 2003) of the English-language literature was conducted using the key words antibiotic, antimicrobial, resistance, mutant, selection window, prevention, MPC, and MSW in various combinations. Original investigations and reviews evaluating the mutant selection window, including abstracts and proceedings, were considered for inclusion. Published articles were also cross-referenced, and experts were contacted to locate additional pertinent data.

STUDY SELECTION AND DATA EXTRACTION

All data sources identified were evaluated and all information deemed relevant was included.

DATA SYNTHESIS

Until recently, physicians have had few ways to preserve antimicrobials from resistance other than by prescribing the agents less often. The mutant selection window hypothesis may modify this paradigm by shifting the focus to dosing strategies that reduce the growth of resistant mutants. Conventional dosing strategies have been formulated on the likelihood of curing an individual patient. Unfortunately, doses that cure patients appear to enrich resistant subpopulations of bacteria, thus promoting resistance. Antimicrobial—pathogen combinations can be identified that minimize mutant selection and cure patients while possibly restricting the progression of resistance.

CONCLUSIONS

The mutant selection window hypothesis provides a framework for considering the contribution of dosing to resistance, and it offers ideas for restricting the enrichment of resistant mutants and antimicrobial resistance.
Lumiracoxib Does Not Affect Methotrexate Pharmacokinetics in Rheumatoid Arthritis Patients
Authors: Hartmann Stefan N , Rordorf Christiane M , Milosavljev Slavica , Branson Janice M , Chales Gérard H , Juvin Robert R , Lafforgue Pierre , Le Parc Jean Marie , Tavernier Christian G , Meyer Olivier C
Published: September 2004

BACKGROUND

Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA).

OBJECTIVE

To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA.

METHODS

This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5–15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment).

RESULTS

Plasma methotrexate pharmacokinetics (AUC0–t, maximum concentration [Cmax], time to Cmax) and methotrexate protein binding were similar for methotrexate alone (108.0 ng•h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng•h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng•h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7–OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and Cmax, although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated.

CONCLUSIONS

Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.
Recombinant Factor VIIa for Refractory Bleeding Following Orthotopic Heart Transplantation
Authors: Flynn Jeremy D , Pajoumand Mehrnaz , Camp Phillip C , Jahania M Salik , Ramaiah Chand , Akers Wendell S
Published: September 2004

OBJECTIVE

To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation.

Case Summary

A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 μg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition.

DISCUSSION

Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients.

CONCLUSIONS

rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.
A German Source of Inspiration? Locus Standi and Remediation Duties under the Soil Protection Act, the Environmental Liability Act and the Draft Environmental Code
Authors: Rehbinder Eckard
Published: September 2004

German public law has developed a far-reaching, strict and unlimited responsibility mainly of polluters and owners for investigation and remediation of contaminated sites as well as prevention of future contamination. In this liability system, which is now codified in the federal Soil Protection Act, the responsible persons and the competent agency are the major players. It is not the polluter who bears the primary responsibility for contaminated sites but the present landowner. Therefore, the recognition of limits to the responsibility of the owner (based on grounds of proportionality) by a recent decision of the German Constitutional Court is of major importance. As to the setting of thresholds for investigation and remediation, German law has taken a pragmatic stance relativising, the basic concept of prevention of danger by recourse to the exercised or admissible use of the affected land. Trigger and remediation standards are designed to ensure a fair degree of uniformity in the investigation and remediation practice. The draft Environmental Code would introduce a new element into the public law liability regime for environmental harm. It proposes to extend the strict liability to pure ecological harm although limited in certain respects. Whilst restoration and replacement are the primary duties of the responsible persons, the draft would also introduce monetary compensation for remaining ecological harm. Moreover, it would deviate, in some cases, from the traditional model of enforcement discretion by obliging the authorities to require remediation. Following an introduction the author examines the legal basis for investigating and managing risks originating from contaminated sites before looking at the position of contaminated sites under both public and private law and finally offering his conclusions.
Defensive Use of a Co-Accused's Confession and the Criminal Justice Act 2003
Authors: Hartshorne John
Published: September 2004

The Criminal Justice Act 2003 introduces statutory provisions regulating the extent to which a defendant may adduce a co-defendant's confession in a joint trial. The relevant provisions are based upon the recommendations of the Law Commission. In this article it is argued that the Law Commission's analysis was overly narrow, and that as a consequence the emerging legislation is unsatisfactory in several significant respects, to the extent that it may even be incompatible with Article 6 of the European Convention on Human Rights. The potential for curing the highlighted deficiencies within the legislation is considered. The article also discusses the extent to which a defendant may continue to adduce a co-accused's confession as a previous inconsistent statement.
The Isoazimuthal Perception of Sounds across Distance: A Preliminary Investigation into the Location of the Audio Egocenter
Authors: Neelon Michael F. , Brungart Douglas S. , Simpson Brian D.
Published: September 2004

Evidence indicates that both visual and auditory input may be represented in multiple frames of reference at different processing stages in the nervous system. Most models, however, have assumed that unimodal auditory input is first encoded in a head-centered reference frame. The present work tested this conjecture by measuring the subjective auditory egocenter in six blindfolded listeners who were asked to match the perceived azimuths of sounds that were alternately played between a surrounding arc of far-field speakers and a hand-held point source located three different distances from the head. If unimodal auditory representation is head centered, then “isoazimuth” lines fitted to the matching estimates across distance should intersect near the midpoint of the interaural axis. For frontomedially arranged speakers, isoazimuth lines instead converged in front of the interaural axis for all listeners, often at a point between the two eyes. As far-field sources moved outside the visual field, however, the auditory egocenter location implied by the intersection of the isoazimuth lines retreated toward or even behind the interaural axis. Physiological and behavioral evidence is used to explain this change from an eye-centered to a head-centered auditory egocenter as a function of source laterality.
Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease
Authors: Canals Josep M. , Pineda José R. , Torres-Peraza Jesús F. , Bosch Miquel , Martín-Ibañez Raquel , Muñoz M. Teresa , Mengod Guadalupe , Ernfors Patrik , Alberch Jordi
Published: September 2004

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression ofbdnfin a transgenic mouse model by cross-matingbdnf+/ -mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.

Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.
Impaired Repression at a Vasopressin Promoter Polymorphism Underlies Overexpression of Vasopressin in a Rat Model of Trait Anxiety
Authors: Murgatroyd Chris , Wigger Alexandra , Frank Elisabeth , Singewald Nicolas , Bunck Mirjam , Holsboer Florian , Landgraf Rainer , Spengler Dietmar
Published: September 2004

Two inbred rat lines have been developed that show either high (HAB) or low (LAB) anxiety-related behavior. The behavioral phenotype correlates with arginine vasopressin (AVP) expression at the level of the hypothalamic paraventricular nucleus (PVN), but not supraoptic nucleus, with HAB animals overexpressing the neuropeptide in both magnocellular and parvocellular subdivisions of the PVN. We detected a number of single nucleotide polymorphisms (SNPs) in the AVP locus that differ between the HAB and LAB animals, two of which were embedded incis-regulatory elements. The HAB-specific allele of the AVP gene promoter occurs in 1.5% of outbred Wistar rats and is more transcriptionally activein vivo, as revealed by allele-specific transcription studies in cross-mated HAB/LAB F1 animals. Interestingly, one specific SNP [A(-1276)G] conferred reduced binding of the transcriptional repressor CArG binding factor A (CBF-A) in the HAB allele, the consequent differential regulation of the AVP promoter resulting in an overexpression of AVPin vitroandin vivo. Furthermore, CBF-A is highly coexpressed in AVP-containing neurons of the PVN supporting an important role for regulation of AVP gene expressionin vivo. Taken together, our results demonstrate a role for an AVP gene polymorphism and CBF-A in elevated AVP expression in the PVN of HAB rats likely to contribute to their behavioral and neuroendocrine phenotype.
Reduction in Size of Perforated Postsynaptic Densities in Hippocampal Axospinous Synapses and Age-Related Spatial Learning Impairments
Authors: Nicholson Daniel A. , Yoshida Rie , Berry Robert W. , Gallagher Michela , Geinisman Yuri
Published: September 2004

A central problem in the neurobiology of normal aging is why learning is preserved in some aged individuals yet impaired in others. To investigate this issue, we examined whether age-related deficits in spatial learning are associated with a reduction in postsynaptic density (PSD) area in hippocampal excitatory synapses (i.e., with a structural modification that is likely to have a deleterious effect on synaptic function). A hippocampus-dependent version of the Morris water maze task was used to separate Long-Evans male rats into young adult, aged learning-unimpaired, and equally aged learning-impaired groups. Axospinous synapses from the CA1 stratum radiatum were analyzed using systematic random sampling and serial section analyses. We report that aged learning-impaired rats exhibit a marked (∼30%) and significant reduction in PSD area, whereas aged learning-unimpaired rats do not. The observed structural alteration involves a substantial proportion of perforated synapses but is not observed in nonperforated synapses. These findings support the notion that many hippocampal perforated synapses become less efficient in aged learning-impaired rats, which may contribute to cognitive decline during normal aging.
Hippocampal Plasticity across Multiple Days of Exposure to Novel Environments
Authors: Frank Loren M. , Stanley Garrett B. , Brown Emery N.
Published: September 2004

The hippocampus is essential for learning complex spatial relationships, but little is known about how hippocampal neural activity changes as animals learn about a novel environment. We studied the formation of new place representations in rats by examining the changes in place-specific firing of neurons in the CA1 region of the hippocampus and the relationship between these changes and behavioral change across multiple days of exposure to novel places. We found that many neurons showed very rapid changes on the first day of exposure to the novel place, including many cases in which a previously silent neuron developed a place field over the course of a single pass through the environment. Across the population, the largest changes in neural activity occurred on day 2 of exposure to a novel place, but only if the animal had little experience (<4 min) in that location on day 1. Longer exposures on day 1 were associated with smaller changes on day 2, suggesting that hippocampal neurons required 5-6 min of experience to form a stable spatial representation. Even after the representation stabilized, the animals' behavior remained different in the novel places, suggesting that other brain regions continued to distinguish novel from familiar locations. These results show that the hippocampus can form new spatial representations quickly but that stable hippocampal representations are not sufficient for a place to be treated as familiar.
GABA Release and Uptake Regulate Neuronal Precursor Migration in the Postnatal Subventricular Zone
Authors: Bolteus Anna J. , Bordey Angélique
Published: September 2004

In the postnatal subventricular zone (SVZ), astrocyte-like cells tightly encapsulate chains of migrating neuronal precursors, although an influence of the astrocyte-like cells on precursor migration has not yet been demonstrated. Cell migration was studied in acute sagittal brain slices to determine whether GABA signaling between astrocyte-like cells and neuronal precursors controls the speed of neuronal precursor migration in the anterior SVZ and rostral migratory stream of juvenile and adult mice. Application of GABA at 10 μm, a nondesensitizing concentration for GABAAreceptors (GABAARs), reduced the rate (mean of ∼50 μm/hr) of cell migration by 21% via GABAAR activation. Application of the GABAAR antagonist bicuculline enhanced the migration rate by 30%, suggesting that endogenous GABA tonically reduces the speed of cell migration via GABAAR activation. Using immunohistochemistry, we found that astrocyte-like cells express the high-affinity GABA transporter subtype GAT4 on processes ensheathing neuronal precursors that contain GABA. Inhibition of GABA uptake into astrocyte-like cells or enhancement of GABA release from neuronal precursors during high K+application further reduced the migration rate by increasing ambient GABA levels. GABA altered the migration speed by interfering with intracellular Ca2+signaling independently of cell depolarization, because high K+application did not alter the speed of cell migration in the presence of bicuculline. These data indicate that astrocyte-like cells create a microenvironment in which their uniquely positioned GABA transporters control the degree of GABAAR activation and the migration of neuronal precursors.
Neutralization of Transthyretin Reverses the Neuroprotective Effects of Secreted Amyloid Precursor Protein (APP) in APPSwMice Resulting in Tau Phosphorylation and Loss of Hippocampal Neurons: Support for the Amyloid Hypothesis
Authors: Stein Thor D. , Anders Nicholas J. , DeCarli Charles , Chan Sic L. , Mattson Mark P. , Johnson Jeffrey A.
Published: September 2004

Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of β-amyloid (Aβ). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Aβ can be toxic, the α-secretase cleaved APP (sAPPα) is neuroprotective. However, the mechanism of sAPPα protection is unknown. Here, we show that sAPPα increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Aβ-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPα-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Aβ-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPα and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APPSw) leads to increased Aβ, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPα and protects APPSwmice from developing many of the neuropathologies observed in AD.
Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization
Authors: Dang Vu C. , Williams John T.
Published: September 2004

Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-β-d-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.
Olfactory Receptor Proteins in Axonal Processes of Chemosensory Neurons
Authors: Strotmann Joerg , Levai Olga , Fleischer Joerg , Schwarzenbacher Karin , Breer Heinz
Published: September 2004

Olfactory receptors are supposed to act not only as molecular sensors for odorants but also as cell recognition molecules guiding the axons of olfactory neurons to their appropriate glomerulus in the olfactory bulb. This concept implies that olfactory receptor proteins are located in sensory cilia and in the axons. To approach this critical issue, antibodies were generated against two peptides, one derived from olfactory receptor mOR256-17, one derived from the “mOR37” subfamily. By means of immunohistochemistry and double-labeling studies using transgenic mouse lines as well as Western blot analyses, it was demonstrated that the newly generated antibodies specifically recognized the receptor proteins. To scrutinize the hypothesis that olfactory receptor proteins may also be present in the axonal processes and the nerve terminals, serial sections through the olfactory bulb were probed with the antibodies. Two glomeruli in each bulb were stained by anti-mOR256-17, one positioned in the medial, one in the lateral hemisphere. Fiber bundles approaching the glomeruli through the outer nerve layer also displayed intense immunofluorescence. A similar picture emerged for the antibody anti-mOR37, a small number of glomeruli in the ventral domain of the bulb was stained. On serial sections through the olfactory bulb of mOR37-transgenic mouse lines, double-labeling experiments demonstrated that distinct immunoreactive glomeruli corresponded to glomeruli that were targeted by neurons expressing a particular member of the mOR37 receptor subfamily. These data indicate that olfactory receptor (OR) proteins are indeed present in the axonal processes and nerve terminals of olfactory sensory neurons, thus supporting the notion that ORs may participate in the molecular processes underlying the fasciculation and targeting of olfactory axons.
Suprachiasmatic GABAergic Inputs to the Paraventricular Nucleus Control Plasma Glucose Concentrations in the Rat via Sympathetic Innervation of the Liver
Authors: Kalsbeek Andries , La Fleur Susanne , Van Heijningen Caroline , Buijs Ruud M.
Published: September 2004

Daily peak plasma glucose concentrations are attained shortly before awakening. Previous experiments indicated an important role for the biological clock, located in the suprachiasmatic nuclei (SCN), in the genesis of this anticipatory rise in plasma glucose concentrations by controlling hepatic glucose production. Here, we show that stimulation of NMDA receptors, or blockade of GABA receptors in the paraventricular nucleus of the hypothalamus (PVN) of conscious rats, caused a pronounced increase in plasma glucose concentrations. The local administration of TTX in brain areas afferent to the PVN revealed that an important part of the inhibitory inputs to the PVN was derived from the SCN. Using a transneuronal viral-tracing technique, we showed that the SCN is connected to the liver via both branches of the autonomic nervous system (ANS). The combination of a blockade of GABA receptors in the PVN with selective removal of either the sympathetic or parasympathetic branch of the hepatic ANS innervation showed that hyperglycemia produced by PVN stimulation was primarily attributable to an activation of the sympathetic input to the liver. We propose that the daily rise in plasma glucose concentrations is caused by an SCN-mediated withdrawal of GABAergic inputs to sympathetic preautonomic neurons in the PVN, resulting in an increased hepatic glucose production. The remarkable resemblance of the presently proposed control mechanism to that described previously for the control of daily melatonin rhythm suggests that the GABAergic control of sympathetic preautonomic neurons in the PVN is an important pathway for the SCN to control peripheral physiology.
Significance Tests and Weighted Values for AFLP Similarities, Based on Arabidopsis in Silico AFLP Fragment Length Distributions
Authors: Koopman Wim J M , Gort Gerrit
Published: September 2004

Many AFLP studies include relatively unrelated genotypes that contribute noise to data sets instead of signal. We developed: (1) estimates of expected AFLP similarities between unrelated genotypes, (2) significance tests for AFLP similarities, enabling the detection of unrelated genotypes, and (3) weighted similarity coefficients, including band position information. Detection of unrelated genotypes and use of weighted similarity coefficients will make the analysis of AFLP data sets more informative and more reliable. Test statistics and weighted coefficients were developed for total numbers of shared bands and for Dice, Jaccard, Nei and Li, and simple matching (dis)similarity coefficients. Theoretical and in silico AFLP fragment length distributions (FLDs) were examined as a basis for the tests. The in silico AFLP FLD based on the Arabidopsis thaliana genome sequence was the most appropriate for angiosperms. The G + C content of the selective nucleotides in the in silico AFLP procedure significantly influenced the FLD. Therefore, separate test statistics were calculated for AFLP procedures with high, average, and low G + C contents in the selective nucleotides. The test statistics are generally applicable for angiosperms with a G + C content of ∼35–40%, but represent conservative estimates for genotypes with higher G + C contents. For the latter, test statistics based on a rice genome sequence are more appropriate.
Sex-Specific Meiotic Drive and Selection at an Imprinted Locus
Authors: Úbeda Francisco , Haig David
Published: September 2004

We present a one-locus model that breaks two symmetries of Mendelian genetics. Whereas symmetry of transmission is breached by allowing sex-specific segregation distortion, symmetry of expression is breached by allowing genomic imprinting. Simple conditions for the existence of at least one polymorphic stable equilibrium are provided. In general, population mean fitness is not maximized at polymorphic equilibria. However, mean fitness at a polymorphic equilibrium with segregation distortion may be higher than mean fitness at the corresponding equilibrium with Mendelian segregation if one (or both) of the heterozygote classes has higher fitness than both homozygote classes. In this case, mean fitness is maximized by complete, but opposite, drive in the two sexes. We undertook an extensive numerical analysis of the parameter space, finding, for the first time in this class of models, parameter sets yielding two stable polymorphic equilibria. Multiple equilibria exist both with and without genomic imprinting, although they occurred in a greater proportion of parameter sets with genomic imprinting.
Maximum-Likelihood Estimation of Rates of Recombination Within Mating-Type Regions
Authors: Takebayashi Naoki , Newbigin Ed , Uyenoyama Marcy K
Published: September 2004

Features common to many mating-type regions include recombination suppression over large genomic tracts and cosegregation of genes of various functions, not necessarily related to reproduction. Model systems for homomorphic self-incompatibility (SI) in flowering plants share these characteristics. We introduce a method for the exact computation of the joint probability of numbers of neutral mutations segregating at the determinant of mating type and at a linked marker locus. The underlying Markov model incorporates strong balancing selection into a two-locus coalescent. We apply the method to obtain a maximum-likelihood estimate of the rate of recombination between a marker locus, 48A, and S-RNase, the determinant of SI specificity in pistils of Nicotiana alata. Even though the sampled haplotypes show complete allelic linkage disequilibrium and recombinants have never been detected, a highly significant deficiency of synonymous substitutions at 48A compared to S-RNase suggests a history of recombination. Our maximum-likelihood estimate indicates a rate of recombination of perhaps 3 orders of magnitude greater than the rate of synonymous mutation. This approach may facilitate the construction of genetic maps of regions tightly linked to targets of strong balancing selection.
Application of Coalescent Methods to Reveal Fine-Scale Rate Variation and Recombination Hotspots
Authors: Fearnhead Paul , Harding Rosalind M , Schneider Julie A , Myers Simon , Donnelly Peter
Published: September 2004

There has been considerable recent interest in understanding the way in which recombination rates vary over small physical distances, and the extent of recombination hotspots, in various genomes. Here we adapt, apply, and assess the power of recently developed coalescent-based approaches to estimating recombination rates from sequence polymorphism data. We apply full-likelihood estimation to study rate variation in and around a well-characterized recombination hotspot in humans, in the β-globin gene cluster, and show that it provides similar estimates, consistent with those from sperm studies, from two populations deliberately chosen to have different demographic and selectional histories. We also demonstrate how approximate-likelihood methods can be used to detect local recombination hotspots from genomic-scale SNP data. In a simulation study based on 80 100-kb regions, these methods detect 43 out of 60 hotspots (ranging from 1 to 2 kb in size), with only two false positives out of 2000 subregions that were tested for the presence of a hotspot. Our study suggests that new computational tools for sophisticated analysis of population diversity data are valuable for hotspot detection and fine-scale mapping of local recombination rates.
Comparative Mapping of a Major Aluminum Tolerance Gene in Sorghum and Other Species in the Poaceae
Authors: Magalhaes Jurandir V , Garvin David F , Wang Yihong , Sorrells Mark E , Klein Patricia E , Schaffert Robert E , Li Li , Kochian Leon V
Published: September 2004

In several crop species within the Triticeae tribe of the grass family Poaceae, single major aluminum (Al) tolerance genes have been identified that effectively mitigate Al toxicity, a major abiotic constraint to crop production on acidic soils. However, the trait is quantitatively inherited in species within other tribes, and the possible ancestral relationships between major Al tolerance genes and QTL in the grasses remain unresolved. To help establish these relationships, we conducted a molecular genetic analysis of Al tolerance in sorghum and integrated our findings with those from previous studies performed in crop species belonging to different grass tribes. A single locus, AltSB, was found to control Al tolerance in two highly Al tolerant sorghum cultivars. Significant macrosynteny between sorghum and the Triticeae was observed for molecular markers closely linked to putatively orthologous Al tolerance loci present in the group 4 chromosomes of wheat, barley, and rye. However, AltSB was not located within the homeologous region of sorghum but rather mapped near the end of sorghum chromosome 3. Thus, AltSB not only is the first major Al tolerance gene mapped in a grass species that does not belong to the Triticeae, but also appears to be different from the major Al tolerance locus in the Triticeae. Intertribe map comparisons suggest that a major Al tolerance QTL on rice chromosome 1 is likely to be orthologous to AltSB, whereas another rice QTL on chromosome 3 is likely to correspond to the Triticeae group 4 Al tolerance locus. Therefore, this study demonstrates a clear evolutionary link between genes and QTL encoding the same trait in distantly related species within a single plant family.
Selection in ContextSequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AF016760, AF016761, AF016762, AF016763, AF016764, AF016765, AF016766, AF016767, AF016768, AF016769, AF016770, AF016771, AF016772, AF016773, AF016774, AF016775, AF016776, AF016777, AF016778, AF016779, AF016780, AF016781, AF016782, AF016783, AF016784, AF016785, AF016786, AF016787, AF016788, AF016789, AF016790, AF016791, AF016792, AF016793, AF016794, AF016795, AF016796, AF016797, AF016798, AF016799, AF016800, AF016801, AF016802, AF016803, AF016804, AF016805, AF016806, AF016807, AF016808, AF016809, AF016810, AF016811, AF016812, AF016813, AF016814, AF016815, AF016816, AF016817, AF016818, AF016819, AF016820, AF016821, AF016822, AF016823, AF016824, AF016825 and AF089109, AF089708.
Authors: Templeton Alan R , Reichert Rebecca A , Weisstein Anton E , Yu Xiao-Fang , Markham Richard B
Published: September 2004

Evolution of the HIV-1 V3 loop was monitored in 15 subjects over a period of 5 years at ∼6-month intervals. Putative recombination was detected in many of the sequences. Evolutionary trees were estimated from the nonrecombinant viral sequences found in each individual. Selection and altered demographic regimes were detected with logit and other contingency analyses in a highly context-dependent fashion. Mutations leading to amino acid substitutions are subject to positive selection over a broad range of clinical conditions in the nonsyncytium-inducing (NSI) form, and the growth rates of the NSI strains and their level of genetic subdivision change little in going from a healthy immune system to a severely compromised immune system. In contrast, the SI form has a significant increase in growth rate as the immune system goes from healthy to compromised, particularly in those subjects who did not receive any antiviral drug therapy. This increase in SI growth rate results in a significant growth advantage of SI over NSI when the immune system is compromised. The SI strains also show more demographic subdivision when the immune system is healthy than when the immune system is compromised, and the SI form has greater demographic subdivision than NSI in subjects with healthy immune systems who also are not receiving antiviral drug therapy. Positive selection on amino-acid-changing mutations weakens and then intensifies again in the SI strains in going from healthy to compromised immune systems. These patterns are consistent with other studies that suggest that NSI strains inhibit replication of SI strains, that the V3 loop is more hidden from the immune system in the NSI form, that evolution in the V3 loop influences cell tropism and coreceptor usage, that substrate for replication of SI forms increases as the disease progresses, and that death of CD8 cells is influenced by the type of coreceptor usage typically found in SI but not in NSI strains. Finally, the transition between NSI and SI forms is associated with a burst of evolutionary change due to strong positive selection at sites other than those that define the NSI/SI phenotypes.
The Aspergillus nidulans npkA Gene Encodes a Cdc2-Related Kinase That Genetically Interacts With the UvsBATR KinaseSequence data from this article have been deposited with the NCBI under accession no. AY166593.
Authors: Fagundes Marcia R V Z Kress , Lima Joel Fernandes , Savoldi Marcela , Malavazi Iran , Larson Roy E , Goldman Maria H S , Goldman Gustavo H
Published: September 2004

The DNA damage response is a protective mechanism that ensures the maintenance of genomic integrity. We have used Aspergillus nidulans as a model system to characterize the DNA damage response caused by the antitopoisomerase I drug, camptothecin. We report the molecular characterization of a p34Cdc2-related gene, npkA, from A. nidulans. The npkA gene is transcriptionally induced by camptothecin and other DNA-damaging agents, and its induction in the presence of camptothecin is dependent on the uvsBATR gene. There were no growth defects, changes in developmental patterns, increased sensitivity to DNA-damaging agents, or effects on septation or growth rate in the A. nidulans npkA deletion strain. However, the ΔnpkA mutation can partially suppress HU sensitivity caused by the ΔuvsBATR and uvsD153ATRIP checkpoint mutations. We demonstrated that the A. nidulans uvsBATR gene is involved in DNA replication and the intra-S-phase checkpoints and that the ΔnpkA mutation can suppress its intra-S-phase checkpoint deficiency. There is a defect in both the intra-S-phase and DNA replication checkpoints due to the npkA inactivation when DNA replication is slowed at 6 mm HU. Our results suggest that the npkA gene plays a role in cell cycle progression during S-phase as well as in a DNA damage signal transduction pathway in A. nidulans.
Translating Available Food Into the Number of Eggs Laid by Drosophila melanogaster
Authors: Terashima Jun , Bownes Mary
Published: September 2004

In Drosophila and other insects egg production is related to the nutrients available. Somehow the nutritional status of the environment is translated into hormonal signs that can be “read” by each individual egg chamber, influencing the decision to either develop into an egg or die. We have shown that BR-C is a control gene during oogenesis and that the differential expression of BR-C isoforms plays a key role in controlling whether the fate of the egg chamber is to develop or undergo apoptosis.
Intralocus Sexual Conflict Can Drive the Evolution of Genomic Imprinting
Authors: Day Troy , Bonduriansky Russell
Published: September 2004

Genomic imprinting is a phenomenon whereby the expression of an allele differs depending upon its parent of origin. There is an increasing number of examples of this form of epigenetic inheritance across a wide range of taxa, and imprinting errors have also been implicated in several human diseases. Various hypotheses have been put forward to explain the evolution of genomic imprinting, but there is not yet a widely accepted general hypothesis for the variety of imprinting patterns observed. Here a new evolutionary hypothesis, based on intralocus sexual conflict, is proposed. This hypothesis provides a potential explanation for much of the currently available empirical data, and it also makes new predictions about patterns of genomic imprinting that are expected to evolve but that have not, as of yet, been looked for in nature. This theory also provides a potential mechanism for the resolution of intralocus sexual conflict in sexually selected traits and a novel pathway for the evolution of sexual dimorphism.
Transposition of Reversed Ac Element Ends Generates Chromosome Rearrangements in Maize
Authors: Zhang Jianbo , Peterson Thomas
Published: September 2004

In classical “cut-and-paste” transposition, transposons are excised from donor sites and inserted at new locations. We have identified an alternative pathway in which transposition involves the 5′ end of an intact Ac element and the 3′ end of a nearby terminally deleted fAc (fractured Ac). The Ac and fAc elements are inserted at the maize p1 locus on chromosome 1s in the same orientation; the adjacent ends of the separate elements are thus in reversed orientation with respect to each other and are separated by a distance of ∼13 kb. Transposition involving the two ends in reversed orientation generates inversions, deletions, and a novel type of local rearrangement. The rearrangement breakpoints are bounded by the characteristic footprint or target site duplications typical of Ac transposition reactions. These results demonstrate a new intramolecular transposition mechanism by which transposons can greatly impact genome evolution.
Mapping of Multiple Quantitative Trait Loci Affecting Bovine Spongiform Encephalopathy
Authors: Zhang Chi , de Koning Dirk-Jan , Hernández-Sánchez Jules , Haley Chris S , Williams John L , Wiener Pamela
Published: September 2004

A whole-genome scan was conducted to map quantitative trait loci (QTL) for BSE resistance or susceptibility. Cows from four half-sib families were included and 173 microsatellite markers were used to construct a 2835-cM (Kosambi) linkage map covering 29 autosomes and the pseudoautosomal region of the sex chromosome. Interval mapping by linear regression was applied and extended to a multiple-QTL analysis approach that used identified QTL on other chromosomes as cofactors to increase mapping power. In the multiple-QTL analysis, two genome-wide significant QTL (BTA17 and X/Yps) and four genome-wide suggestive QTL (BTA1, 6, 13, and 19) were revealed. The QTL identified here using linkage analysis do not overlap with regions previously identified using TDT analysis. One factor that may explain the disparity between the results is that a more extensive data set was used in the present study. Furthermore, methodological differences between TDT and linkage analyses may affect the power of these approaches.
Extensive Sex-Specific Nonadditivity of Gene Expression in Drosophila melanogaster
Authors: Gibson Greg , Riley-Berger Rebecca , Harshman Larry , Kopp Artyom , Vacha Scott , Nuzhdin Sergey , Wayne Marta
Published: September 2004

Assessment of the degree to which gene expression is additive and heritable has important implications for understanding the maintenance of variation, adaptation, phenotypic divergence, and the mapping of genotype onto phenotype. We used whole-genome transcript profiling using Agilent long-oligonucleotide microarrays representing 12,017 genes to demonstrate that gene transcription is pervasively nonadditive in Drosophila melanogaster. Comparison of adults of two isogenic lines and their reciprocal F1 hybrids revealed 5820 genes as significantly different between at least two of the four genotypes in either males or females or across both sexes. Strikingly, while 25% of all genes differ between the two parents, 33% differ between both F1's and the parents, averaged across sexes. However, only 5% of genes show overdominance, suggesting that heterosis for expression is rare.
Enhancer Choice in Cis and in Trans in Drosophila melanogaster
Authors: Morris James R , Petrov Dmitri A , Lee Anne M , Wu Chao-ting
Published: September 2004

Eukaryotic enhancers act over very long distances, yet still show remarkable specificity for their own promoter. To better understand mechanisms underlying this enhancer-promoter specificity, we used transvection to analyze enhancer choice between two promoters, one located in cis to the enhancer and the other in trans to the enhancer, at the yellow gene of Drosophila melanogaster. Previously, we demonstrated that enhancers at yellow prefer to act on the cis-linked promoter, but that mutation of core promoter elements in the cis-linked promoter releases enhancers to act in trans. Here, we address the mechanism by which these elements affect enhancer choice. We consider and explicitly test three models that are based on promoter competency, promoter pairing, and promoter identity. Through targeted gene replacement of the endogenous yellow gene, we show that competency of the cis-linked promoter is a key parameter in the cis-trans choice of an enhancer. In fact, complete replacement of the yellow promoter with both TATA-containing and TATA-less heterologous promoters maintains enhancer action in cis.
A Single-Amino-Acid Change of the Gustatory Receptor Gene, Gr5a, Has a Major Effect on Trehalose Sensitivity in a Natural Population of Drosophila melanogaster
Authors: Inomata Nobuyuki , Goto Hiroki , Itoh Masanobu , Isono Kunio
Published: September 2004

Variation in trehalose sensitivity and nucleotide sequence polymorphism of the Gr5a gene encoding the gustatory receptor to sugar trehalose were investigated in 152 male lines of Drosophila melanogaster collected from a natural population. Among the observed 59 segregating sites, some pairs of sites showed significant linkage disequilibrium. A single SNP, which results in the Ala218Thr amino acid change, was significantly associated with trehalose sensitivity, as previously suggested. Threonine at amino acid position 218 was found to be the ancestral form in D. melanogaster, suggesting that low trehalose sensitivity was an ancestral form with respect to the receptor function. There was large genetic variation in trehalose sensitivity. It was continuously distributed, indicating that trehalose sensitivity measured by the behavioral assay is a quantitative trait. These results suggest that apart from the Gr5a gene, other genetic factors contribute to variation in trehalose sensitivity. Nucleotide diversity (π) and nucleotide variation (θ) per site were 0.00874 and 0.00590, respectively. Fu and Li's test and the MK test showed no significant departure from the expectation of selective neutrality in the Gr5a gene. However, we rejected selective neutrality by Tajima's test and Fay and Wu's test with the observed level of recombination. We discuss possible causes of the observed pattern of nucleotide variation in the gustatory receptor Gr5a gene.
The Speed of Adaptation in Large Asexual Populations
Authors: Wilke Claus O
Published: September 2004

In large asexual populations, beneficial mutations have to compete with each other for fixation. Here, I derive explicit analytic expressions for the rate of substitution and the mean beneficial effect of fixed mutations, under the assumptions that the population size N is large, that the mean effect of new beneficial mutations is smaller than the mean effect of new deleterious mutations, and that new beneficial mutations are exponentially distributed. As N increases, the rate of substitution approaches a constant, which is equal to the mean effect of new beneficial mutations. The mean effect of fixed mutations continues to grow logarithmically with N. The speed of adaptation, measured as the change of log fitness over time, also grows logarithmically with N for moderately large N, and it grows double-logarithmically for extremely large N. Moreover, I derive a simple formula that determines whether at given N beneficial mutations are expected to compete with each other or go to fixation independently. Finally, I verify all results with numerical simulations.