bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Community Supports for Individuals With Co-Occurring Disabilities After Traumatic Brain Injury: Cost Effectiveness and Project-Based Intervention
Authors: Ylvisaker Mark , Feeney Timothy , Capo Melissa
Published: February 2008

Outcome studies have established that successful community living is compromised in the population of individuals with traumatic brain injury and chronic behavioural difficulties along with a co-occurring diagnosis of substance abuse and/or mental health disorder. Two studies are presented. The first was aimed at describing long-term outcome of a sample of individuals (N= 51) served by the New York State Department of Health TBI Medicaid Waiver Program. Each of the participants was diagnosed with TBI plus either substance abuse or a mental health disorder, or both. Because of significant behavioural challenges, all of the participants were in a restrictive living setting the year before enrolment in the waiver program (e.g., nursing or correctional facility). Data on community living arrangement, self-reported community integration experiences, and costs are presented. Results indicate that most of the participants (41 of the 46 who were alive and living in state) continued to live in the community 8 to 9 years after commencement of community support services. The participants' community integration responses were generally positive and cost data demonstrate substantial savings to the state for this cohort. Comparing prewaiver costs in residential settings with most recent (2005) costs for community supports, there was an average daily cost savings of US$137 per person for the 1996 cohort and US$144 per person for the 1997 cohort. The second study explored the use of project-oriented interventions and supports in an agency that provides community support services to this dual diagnosis population. Project-oriented services are described as meeting many needs common to this dual-diagnosis population. Clinical staff (N= 11) and a sample of waiver participants (N= 7) were surveyed. Results suggest that the use of personally meaningful projects can become a clinical habit for staff and that projects are generally judged by participants to be a meaningful use of time, and significant in giving them an opportunity to play an expert role and to help others.
Psychological Wellbeing in Three Groups of Skilled Immigrants to New Zealand
Authors: Alpass Fiona , Flett Ross , Trlin Andrew , Henderson Anne , North Nicola , Skinner Monica , Wright Sarah
Published: February 2008

The present study sought to investigate the current levels of psychological wellbeing in three immigrant groups to New Zealand. In addition, we sought to determine whether aspects of the acculturation process were related to mental health outcomes. This is a cross–sectional study from the fifth wave of annual in-depth interviews with three groups of recently arrived skilled immigrants from India, the People's Republic of China and South Africa. Interviews focused on international contacts and the migration of relatives and friends, housing, language, qualifications and employment, and social participation. Participants were also asked about health difficulties, homesickness, and whether they felt settled in New Zealand. The SF-36 Health Status Questionnaire (Ware, 1997), assessed the respondent's functional status and wellbeing in relation to four health concepts: vitality, social functioning, role limitations due to emotional health, and general mental wellbeing. The immigrant group differed significantly from the New Zealand population on only one of the four mental health scales, Vitality, with immigrants reporting higher levels. Different acculturation factors were found to predict different mental health subscales in regression analyses. Gender, home contact and health difficulty explained 22% of the unique variance in Vitality; employment status and health difficulty explained 18% of the variance in Social Functioning; health difficulty significantly contributed to the explained variance (14%) in the Role limitations due to emotional health subscale; gender, home contact and health difficulty explained 27% of the variance in the Mental Health subscale. There was little evidence for lower levels of psychological wellbeing for the three immigrant groups compared to the general New Zealand population, nor for differences between the three groups. However, results highlight the importance of differential predictors in the understanding of psychological health in migrant groups.
Identifying and Developing Effective Interventions in Rehabilitation Settings: Recognising the Limits of the Evidence-Based Practice Approach
Authors: Murphy Gregory C. , King Neville J. , Ollendick Thomas H.
Published: February 2008

The evidence-based practice movement has led to higher quality intervention studies being reported in the health sciences literature (see, for example, Mosely et al., 2002), and consequently being available for uptake by practising health professionals. Yet interventions in applied settings need to satisfy more than the methodologically-based criteria associated with being categorised as a ‘well-established treatment’ (Chambless et al., 1996). Some of these additional criteria were recently described by King and Ollendick (2007). The current article extends these criteria so as to include attributes of interventions that (ideally) are required when designing or delivering services within rehabilitation settings.
The Role of Pet Ownership and Attachment in Older Adults
Authors: Watt Deidre , Pachana Nancy A.
Published: February 2008

Australia is preparing for a population increase in persons aged over 65 years, which will likely result in increased mental health needs for this group. Sub-clinical levels of depression, anxiety and loneliness are common in older adults. Older adults are also more likely than any other age group to live alone. Research has suggested that older adults living on their own often report companion animals as providing important social support. Thirty-two community-dwelling older adults, between 60 and 75+ years of age, took part in this study examining attachment to pets in an older cohort. Previous or current pet ownership was a requirement for inclusion in the study in order to account for possible bias of nonpet owners on reporting pets as a positive influence on wellbeing. Results found support for the psychometric properties of a relatively new attachment scale designed for older adults. Results also indicated limited support for a relationship between pet attachment and quality of life in the study group. Implications for clinical work with older adults and areas for future research are discussed.
Is the Second Twin at Risk in Vaginal Delivery?
Authors: Derom Robert
Published: February 2008

In a normal delivery the second-born twin experiences a slight degree of hypoxia, which, as a rule, has no clinical importance. It is the oxygen debt everybody makes by running 30 metres.
Rescue From Oculocutaneous Albinism Type 4 Using Medaka slc45a2 cDNA Driven by Its Own Promoter
Authors: Fukamachi Shoji , Kinoshita Masato , Tsujimura Taro , Shimada Atsuko , Oda Shoji , Shima Akihiro , Meyer Axel , Kawamura Shoji , Mitani Hiroshi
Published: February 2008

Patients and vertebrate mutants with oculocutaneous albinism type 4 (OCA4) have mutations in the solute carrier family 45 member 2 (slc45a2) gene. However, there is no empirical evidence for this gene–phenotype relationship. There is a unique OCA4 mutant in medaka (b) that exhibits albinism only in the skin, but the mechanism underlying this phenotype is also unknown. In this study, we rescued medaka OCA4 phenotypes, in both the eyes and the skin, by micro-injection of an slc45a2-containing genomic fragment or slc45a2 cDNA driven by its own 0.9-kb promoter. We also identified a spontaneous nucleotide change of 339 bp in the promoter as the b mutation. There are multiple transcription start sites in medaka slc45a2, as in its human ortholog, and only the shortest and eye-specific mRNA is transcribed with the b mutation. Interestingly, we further revealed a conserved pyrimidine (Py)-rich sequence of ∼10 bp in the promoter by medaka–pufferfish comparative genomics and verified that it plays an indispensable role for expression of slc45a2 in the skin. Further studies of the 0.9-kb promoter identified in this study should provide insights into the cis/trans-regulatory mechanisms underlying the ocular and cutaneous expression of slc45a2.
Linkage Disequilibrium Under Skewed Offspring Distribution Among Individuals in a Population
Authors: Eldon Bjarki , Wakeley John
Published: February 2008

Correlations in coalescence times between two loci are derived under selectively neutral population models in which the offspring of an individual can number on the order of the population size. The correlations depend on the rates of recombination and random drift and are shown to be functions of the parameters controlling the size and frequency of these large reproduction events. Since a prediction of linkage disequilibrium can be written in terms of correlations in coalescence times, it follows that the prediction of linkage disequilibrium is a function not only of the rate of recombination but also of the reproduction parameters. Low linkage disequilibrium is predicted if the offspring of a single individual frequently replace almost the entire population. However, high linkage disequilibrium can be predicted if the offspring of a single individual replace an intermediate fraction of the population. In some cases the model reproduces the standard Wright–Fisher predictions. Contrary to common intuition, high linkage disequilibrium can be predicted despite frequent recombination, and low linkage disequilibrium under infrequent recombination. Simulations support the analytical results but show that the variance of linkage disequilibrium is very large.
The Genetics of Domestication of the Azuki Bean (Vigna angularis)
Authors: Kaga Akito , Isemura Takehisa , Tomooka Norihiko , Vaughan Duncan A
Published: February 2008

Genetic differences between azuki bean (Vigna angularis var. angularis) and its presumed wild ancestor (V. angularis var. nipponensis) were resolved into QTL for traits associated with adaptation to their respective distinct habits. A genetic linkage map constructed using progenies from a cross between Japanese cultivated and wild azuki beans covers 92.8% of the standard azuki bean linkage map. A reciprocal translocation between cultivated and wild azuki bean parents was identified on the basis of the linkage map having a pseudolinkage group and clustering of seed productivity-related QTL with large effect near the presumed breakpoints. In total, 162 QTL were identified for 46 domestication-related traits. Domestication of azuki bean has involved a trade-off between seed number and seed size: fewer but longer pods and fewer but larger seeds on plants with shorter stature in cultivated azuki bean being at the expense of overall seed yield. Genes found related to germination and flowering time in cultivated azuki bean may confer a selective advantage to the hybrid derivatives under some ecological conditions and may explain why azuki bean has evolved as a crop complex in Japan.
Catalytic-Site Mutations in the MYST Family Histone Acetyltransferase Esa1
Authors: Decker Peter V , Yu David Y , Iizuka Masayoshi , Qiu Qifeng , Smith M Mitchell
Published: February 2008

Esa1 is the only essential histone acetyltransferase (HAT) in budding yeast. It is the catalytic subunit of at least two multiprotein complexes, NuA4 and Piccolo NuA4 (picNuA4), and its essential function is believed to be its catalytic HAT activity. To examine the role of Esa1 in DNA damage repair, we isolated viable esa1 mutants with a range of hypersensitivities to the toposide camptothecin. Here we show that the sensitivity of these mutants to a variety of stresses is inversely proportional to their level of histone H4 acetylation, demonstrating the importance of Esa1 catalytic activity for resistance to genotoxic stress. Surprisingly, individual mutations in two residues directly involved in catalysis were not lethal even though the mutant enzymes appear catalytically inactive both in vivo and in vitro. However, the double-point mutant is lethal, demonstrating that the essential function of Esa1 relies on residues within the catalytic pocket but not catalysis. We propose that the essential function of Esa1 may be to bind acetyl-CoA or lysine substrates and positively regulate the activities of NuA4 and Piccolo NuA4.
Maternal Effects as the Cause of Parent-of-Origin Effects That Mimic Genomic Imprinting
Authors: Hager Reinmar , Cheverud James M , Wolf Jason B
Published: February 2008

Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles.
Synergistic Fitness Interactions and a High Frequency of Beneficial Changes Among Mutations Accumulated Under Relaxed Selection inSaccharomyces cerevisiae
Authors: Dickinson W Joseph
Published: February 2008

Spontaneous mutations were accumulated for ∼4800 generations in 48 lines of yeast protected from effective selection by frequent passage through single-cell bottlenecks. Changes in fitness were evaluated by direct competition with matched parental stocks differing only at a selectively neutral marker locus. Average fitness declined by ∼5% over the course of the experiment. The rate of change increased sharply in later generations, strongly suggesting synergistic epistasis. Divergence among lines increased rapidly relative to the change in average fitness and also at an accelerating pace. Both results are well matched by a model assuming that fitness cost increases exponentially (approximately second order) with the number of accumulated mutations. This result is consistent with fitness loss due primarily to interactions between specific pairs of gene products. I also estimate that ∼25% of the mutations with detectable fitness effects were beneficial. This result can be explained by the fact that the effects of most mutations are small relative to the distance from a local fitness optimum.
Bayesian Variable Selection for Detecting Adaptive Genomic Differences Among Populations
Authors: Riebler Andrea , Held Leonhard , Stephan Wolfgang
Published: February 2008

We extend an Fst-based Bayesian hierarchical model, implemented via Markov chain Monte Carlo, for the detection of loci that might be subject to positive selection. This model divides the Fst-influencing factors into locus-specific effects, population-specific effects, and effects that are specific for the locus in combination with the population. We introduce a Bayesian auxiliary variable for each locus effect to automatically select nonneutral locus effects. As a by-product, the efficiency of the original approach is improved by using a reparameterization of the model. The statistical power of the extended algorithm is assessed with simulated data sets from a Wright–Fisher model with migration. We find that the inclusion of model selection suggests a clear improvement in discrimination as measured by the area under the receiver operating characteristic (ROC) curve. Additionally, we illustrate and discuss the quality of the newly developed method on the basis of an allozyme data set of the fruit fly Drosophila melanogaster and a sequence data set of the wild tomato Solanum chilense. For data sets with small sample sizes, high mutation rates, and/or long sequences, however, methods based on nucleotide statistics should be preferred.
Functional Interactions Between Sae2 and the Mre11 Complex
Authors: Kim Hee-Sook , Vijayakumar Sangeetha , Reger Mike , Harrison Jacob C , Haber James E , Weil Clifford , Petrini John H J
Published: February 2008

The Mre11 complex functions in double-strand break (DSB) repair, meiotic recombination, and DNA damage checkpoint pathways. Sae2 deficiency has opposing effects on the Mre11 complex. On one hand, it appears to impair Mre11 nuclease function in DNA repair and meiotic DSB processing, and on the other, Sae2 deficiency activates Mre11-complex-dependent DNA-damage-signaling via the Tel1–Mre11 complex (TM) pathway. We demonstrate that SAE2 overexpression blocks the TM pathway, suggesting that Sae2 antagonizes Mre11-complex checkpoint functions. To understand how Sae2 regulates the Mre11 complex, we screened for sae2 alleles that behaved as the null with respect to Mre11-complex checkpoint functions, but left nuclease function intact. Phenotypic characterization of these sae2 alleles suggests that Sae2 functions as a multimer and influences the substrate specificity of the Mre11 nuclease. We show that Sae2 oligomerizes independently of DNA damage and that oligomerization is required for its regulatory influence on the Mre11 nuclease and checkpoint functions.
Accelerated Mitochondrial Evolution and “Darwin's Corollary”: Asymmetric Viability of Reciprocal F1 Hybrids in Centrarchid Fishes
Authors: Bolnick Daniel I , Turelli Michael , López-Fernández Hernán , Wainwright Peter C , Near Thomas J
Published: February 2008

Reciprocal crosses between species can yield hybrids with different viabilities. The high frequency of this asymmetric hybrid viability (“Darwin's corollary”) places it alongside Haldane's rule and the “large-X effect” as a general feature of postmating reproductive isolation. Recent theory suggests that reciprocal cross asymmetries can arise from stochastic substitutions in uniparentally inherited loci such as mitochondrial genomes, although large systematic differences in mitochondrial substitution rates can also contribute to asymmetries. Although the magnitude of asymmetry will be relatively insensitive to unequal rates of mitochondrial evolution in diverging species, we show here that rate asymmetries can have a large effect on the direction of viability asymmetries. In reciprocal crosses between species, the maternal parent with faster mitochondrial evolution will tend to produce less viable F1 hybrids owing to an increased probability of mito-nuclear incompatibilities. We test this prediction using data on reciprocal hybrid viability and molecular evolution rates from a clade of freshwater fishes, Centrarchidae. As predicted, species with accelerated mitochondrial evolution tend to be the worse maternal parent for F1 hybrids, providing the first comparative evidence for a systematic basis to Darwin's corollary. This result is consistent with the hypothesis that mito-nuclear incompatibilities can play an important role in reproductive isolation. Such asymmetrical reproductive isolation may help explain the asymmetrical mitochondrial introgression observed between many hybridizing species. However, as with any comparative study, we cannot rule out the possibility that our results arise from a mutual correlation with a third variable such as body size.
Drosophila Importin α1 Performs Paralog-Specific Functions Essential For Gametogenesis
Authors: Ratan R , Mason D A , Sinnot B , Goldfarb D S , Fleming R J
Published: February 2008

Importin α's mediate nuclear transport by linking nuclear localization signal (NLS)-containing proteins to importin β1. Animal genomes encode three conserved groups of importin α's, α1's, α2's, and α3's, each of which are competent to bind classical NLS sequences. Using Drosophila melanogaster we describe the isolation and phenotypic characterization of the first animal importin α1 mutant. Animal α1's are more similar to ancestral plant and fungal α1-like genes than to animal α2 and α3 genes. Male and female importin α1 (Dα1) null flies developed normally to adulthood (with a minor wing defect) but were sterile with defects in gametogenesis. The Dα1 mutant phenotypes were rescued by Dα1 transgenes, but not by Dα2 or Dα3 transgenes. Genetic interactions between the ectopic expression of Dα1 and the karyopherins CAS and importin β1 suggest that high nuclear levels of Dα1 are deleterious. We conclude that Dα1 performs paralog-specific activities that are essential for gametogenesis and that regulation of subcellular Dα1 localization may affect cell fate decisions. The initial expansion and specialization of the animal importin α-gene family may have been driven by the specialized needs of gametogenesis. These results provide a framework for studies of the more complex mammalian importin α-gene family.
An Investigation of Heterochromatin Domains on the Fourth Chromosome ofDrosophila melanogaster
Authors: Riddle Nicole C , Leung Wilson , Haynes Karmella A , Granok Howard , Wuller Jo , Elgin Sarah C R
Published: February 2008

The banded portion of Drosophila melanogaster chromosome 4 exhibits euchromatic and heterochromatic characteristics. Reminiscent of heterochromatin, it contains a high percentage of repetitive elements, does not undergo recombination, and exhibits high levels of HP1 and histone-3 lysine-9 dimethylation. However, in the distal 1.2 Mb, the gene density is typical of euchromatin, and this region is polytene in salivary gland nuclei. Using P-element reporters carrying a copy of hsp70-white, alternative chromatin packaging domains can be distinguished by the eye color phenotype. Mapping studies identified the repetitive element 1360 as a candidate for heterochromatin targeting in the fourth chromosome Hcf region. We report here two new screens using this reporter to look for additional heterochromatin target sites. We confirm that reporter elements within 10 kb of 1360 are usually packaged as heterochromatin; however, heterochromatin packaging occurs in the sv region in the absence of 1360. Analyses of the sequences adjacent to P-element reporters show no simple association between specific repeated elements and transgene expression phenotype on a whole chromosome level. The data require that heterochromatin formation as a whole depends on a more complex pattern of sequence organization rather than the presence of a single sequence element.
Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility
Authors: Fergestad Tim , Olson Lisa , Patel Khelan P , Miller Rosie , Palladino Michael J , Ganetzky Barry
Published: February 2008

Genetic factors are known to contribute to seizure susceptibility, although the long-term effects of these predisposing factors on neuronal viability remain unclear. To examine the consequences of genetic factors conferring increased seizure susceptibility, we surveyed a class of Drosophila mutants that exhibit seizures and paralysis following mechanical stimulation. These bang-sensitive seizure mutants exhibit shortened life spans and age-dependent neurodegeneration. Because the increased seizure susceptibility in these mutants likely results from altered metabolism and since the Na+/K+ ATPase consumes the majority of ATP in neurons, we examined the effect of ATPα mutations in combination with bang-sensitive mutations. We found that double mutants exhibit strikingly reduced life spans and age-dependent uncoordination and inactivity. These results emphasize the importance of proper cellular metabolism in maintaining both the activity and viability of neurons.
A Drosophila Gain-of-Function Screen for Candidate Genes Involved in Steroid-Dependent Neuroendocrine Cell Remodeling
Authors: Zhao Tao , Gu Tingting , Rice Heather C , McAdams Kathleen L , Roark Kimberly M , Lawson Kaylan , Gauthier Sebastien A , Reagan Kathleen L , Hewes Randall S
Published: February 2008

The normal functioning of neuroendocrine systems requires that many neuropeptidergic cells change, to alter transmitter identity and concentration, electrical properties, and cellular morphology in response to hormonal cues. During insect metamorphosis, a pulse of circulating steroids, ecdysteroids, governs the dramatic remodeling of larval neurons to serve adult-specific functions. To identify molecular mechanisms underlying metamorphic remodeling, we conducted a neuropeptidergic cell-targeted, gain-of-function genetic screen. We screened 6097 lines. Each line permitted Gal4-regulated transcription of flanking genes. A total of 58 lines, representing 51 loci, showed defects in neuropeptide-mediated developmental transitions (ecdysis or wing expansion) when crossed to the panneuropeptidergic Gal4 driver, 386Y-Gal4. In a secondary screen, we found 29 loci that produced wing expansion defects when crossed to a crustacean cardioactive peptide (CCAP)/bursicon neuron-specific Gal4 driver. At least 14 loci disrupted the formation or maintenance of adult-specific CCAP/bursicon cell projections during metamorphosis. These include components of the insulin and epidermal growth factor signaling pathways, an ecdysteroid-response gene, cabut, and an ubiquitin-specific protease gene, fat facets, with known functions in neuronal development. Several additional genes, including three micro-RNA loci and two factors related to signaling by Myb-like proto-oncogenes, have not previously been implicated in steroid signaling or neuronal remodeling.
Multiple Pathways Influence Mitochondrial Inheritance in Budding Yeast
Authors: Frederick Rebecca L , Okamoto Koji , Shaw Janet M
Published: February 2008

Yeast mitochondria form a branched tubular network. Mitochondrial inheritance is tightly coupled with bud emergence, ensuring that daughter cells receive mitochondria from mother cells during division. Proteins reported to influence mitochondrial inheritance include the mitochondrial rho (Miro) GTPase Gem1p, Mmr1p, and Ypt11p. A synthetic genetic array (SGA) screen revealed interactions between gem1Δ and deletions of genes that affect mitochondrial function or inheritance, including mmr1Δ. Synthetic sickness of gem1Δ mmr1Δ double mutants correlated with defective mitochondrial inheritance by large buds. Additional studies demonstrated that GEM1, MMR1, and YPT11 each contribute to mitochondrial inheritance. Mitochondrial accumulation in buds caused by overexpression of either Mmr1p or Ypt11p did not depend on Gem1p, indicating these three proteins function independently. Physical linkage of mitochondria with the endoplasmic reticulum (ER) has led to speculation that distribution of these two organelles is coordinated. We show that yeast mitochondrial inheritance is not required for inheritance or spreading of cortical ER in the bud. Moreover, Ypt11p overexpression, but not Mmr1p overexpression, caused ER accumulation in the bud, revealing a potential role for Ypt11p in ER distribution. This study demonstrates that multiple pathways influence mitochondrial inheritance in yeast and that Miro GTPases have conserved roles in mitochondrial distribution.
Global Screening of Genes Essential for Growth in High-Pressure and Cold Environments: Searching for Basic Adaptive Strategies Using a Yeast Deletion Library
Authors: Abe Fumiyoshi , Minegishi Hiroaki
Published: February 2008

Microorganisms display an optimal temperature and hydrostatic pressure for growth. To establish the molecular basis of piezo- and psychroadaptation, we elucidated global genetic defects that give rise to susceptibility to high pressure and low temperature in Saccharomyces cerevisiae. Here we present 80 genes including 71 genes responsible for high-pressure growth and 56 responsible for low-temperature growth with a significant overlap of 47 genes. Numerous previously known cold-sensitive mutants exhibit marked high-pressure sensitivity. We identified critically important cellular functions: (i) amino acid biosynthesis, (ii) microautophagy and sorting of amino acid permease established by the exit from rapamycin-induced growth arrest/Gap1 sorting in the endosome (EGO/GSE) complex, (iii) mitochondrial functions, (iv) membrane trafficking, (v) actin organization mediated by Drs2-Cdc50, and (vi) transcription regulated by the Ccr4-Not complex. The loss of EGO/GSE complex resulted in a marked defect in amino acid uptake following high-pressure and low-temperature incubation, suggesting its role in surface delivery of amino acid permeases. Microautophagy and mitochondrial functions converge on glutamine homeostasis in the target of rapamycin (TOR) signaling pathway. The localization of actin requires numerous associated proteins to be properly delivered by membrane trafficking. In this study, we offer a novel route to gaining insights into cellular functions and the genetic network from growth properties of deletion mutants under high pressure and low temperature.
Templated Mutagenesis in Bacteriophage T4 Involving Imperfect Direct or Indirect Sequence Repeats
Authors: Schultz Gary E , Drake John W
Published: February 2008

Some mutations arise in association with a potential sequence donor that consists of an imperfect direct or reverse repeat. Many such mutations are complex; that is, they consist of multiple close sequence changes. Current models posit that the primer terminus of a replicating DNA molecule dissociates, reanneals with an ectopic template, extends briefly, and then returns to the cognate template, bringing with it a locally different sequence; alternatively, a hairpin structure may form the mutational intermediate when processed by mismatch repair. This process resembles replication repair, in which primer extension is blocked by a lesion in the template; in this case, the ectopic template is the other daughter strand, and the result is error-free bypass of the lesion. We previously showed that mutations that impair replication repair can enhance templated mutagenesis. We show here that the intensity of templated mutation can be exquisitely sensitive to its local sequence, that the donor and recipient arms of an imperfect inverse repeat can exchange roles, and that double mutants carrying two alleles, each affecting both templated mutagenesis and replication repair, can have unexpected phenotypes. We also record an instance in which the mutation rates at two particular sites change concordantly with a distant sequence change, but in a manner that appears unrelated to templated mutagenesis.
Targeted Gene Deletion and Phenotypic Analysis of theDrosophila melanogasterSeminal Fluid Protease Inhibitor Acp62F
Authors: Mueller Jacob L , Linklater Jon R , Ravi Ram Kristipati , Chapman Tracey , Wolfner Mariana F
Published: February 2008

Internally fertilizing organisms transfer a complex assortment of seminal fluid proteins, a substantial fraction of which are proteolysis regulators. In mammals, some seminal protease inhibitors have been implicated in male infertility and these same molecular classes of protease inhibitors are also found in Drosophila seminal fluid. Here, we tested the reproductive functions of the Drosophila melanogaster seminal fluid protease inhibitor Acp62F by generating a precise deletion of the Acp62F gene. We did not detect a nonredundant function for Acp62F in modulating the egg laying, fertility, remating frequency, or life span of mated females. However, loss of Acp62F did alter a male's defensive sperm competitive ability, consistent with the localization of Acp62F to sperm storage organs. In addition, the processing of at least one seminal protein, the ovulation hormone ovulin, is slower in the absence of Acp62F.
Identification of Drosophila Mutants Altering Defense of and Endurance to Listeria monocytogenes Infection
Authors: Ayres Janelle S , Freitag Nancy , Schneider David S
Published: February 2008

We extended the use of Drosophila beyond being a model for signaling pathways required for pattern recognition immune signaling and show that the fly can be used to identify genes required for pathogenesis and host–pathogen interactions. We performed a forward genetic screen to identify Drosophila mutations altering sensitivity to the intracellular pathogen Listeria monocytogenes. We recovered 18 mutants with increased susceptibility to infection, none of which were previously shown to function in a Drosophila immune response. Using secondary screens, we divided these mutants into two groups: In the first group, mutants have reduced endurance to infections but show no change in bacterial growth. This is a new fly immunity phenotype that is not commonly studied. In the second group, mutants have a typical defense defect in which bacterial growth is increased and survival is decreased. By further challenging mutant flies with L. monocytogenes mutants, we identified subgroups of fly mutants that affect specific stages of the L. monocytogenes life cycle, exit from the vacuole, or actin-based movement. There is no overlap between our genes and the hundreds of genes identified in Drosophila S2 cells fighting L. monocytogenes infection, using genomewide RNAi screens in vitro. By using a whole-animal model and screening for host survival, we revealed genes involved in physiologies different from those that were found in previous screens, which all had defects in defensive immune signaling.
A Role for Chd1 and Set2 in Negatively Regulating DNA Replication in Saccharomyces cerevisiae
Authors: Biswas Debabrata , Takahata Shinya , Xin Hua , Dutta-Biswas Rinku , Yu Yaxin , Formosa Tim , Stillman David J
Published: February 2008

Chromatin-modifying factors regulate both transcription and DNA replication. The yFACT chromatin-reorganizing complex is involved in both processes, and the sensitivity of some yFACT mutants to the replication inhibitor hydroxyurea (HU) is one indication of a replication role. This HU sensitivity can be suppressed by disruptions of the SET2 or CHD1 genes, encoding a histone H3(K36) methyltransferase and a chromatin remodeling factor, respectively. The additive effect of set2 and chd1 mutations in suppressing the HU sensitivity of yFACT mutants suggests that these two factors function in separate pathways. The HU suppression is not an indirect effect of altered regulation of ribonucleotide reductase induced by HU. set2 and chd1 mutations also suppress the HU sensitivity of mutations in other genes involved in DNA replication, including CDC2, CTF4, ORC2, and MEC1. Additionally, a chd1 mutation can suppress the lethality normally caused by disruption of either MEC1 or RAD53 DNA damage checkpoint genes, as well as the lethality seen when a mec1 sml1 mutant is exposed to low levels of HU. The pob3 defect in S-phase progression is suppressed by set2 or chd1 mutations, suggesting that Set2 and Chd1 have specific roles in negatively regulating DNA replication.
The Contribution of Social Effects to Heritable Variation in Finishing Traits of Domestic Pigs (Sus scrofa)
Authors: Bergsma R , Kanis E , Knol E F , Bijma P
Published: February 2008

Social interactions among individuals are ubiquitous both in animals and in plants, and in natural as well as domestic populations. These interactions affect both the direction and the magnitude of responses to selection and are a key factor in evolutionary success of species and in the design of breeding schemes in agriculture. At present, however, very little is known of the contribution of social effects to heritable variance in trait values. Here we present estimates of the direct and social genetic variance in growth rate, feed intake, back fat thickness, and muscle depth in a population of 14,032 domestic pigs with known pedigree. Results show that social effects contribute the vast majority of heritable variance in growth rate and feed intake in this population. Total heritable variance expressed relative to phenotypic variance was 71% for growth rate and 70% for feed intake. These values clearly exceed the usual range of heritability for those traits. Back fat thickness and muscle depth showed no heritable variance due to social effects. Our results suggest that genetic improvement in agriculture can be substantially advanced by redirecting breeding schemes, so as to capture heritable variance due to social effects.
Adaptive Evolution of the Insulin Two-Gene System in Mouse
Authors: Shiao Meng-Shin , Liao Ben-Yang , Long Manyuan , Yu Hon-Tsen
Published: February 2008

Insulin genes in mouse and rat compose a two-gene system in which Ins1 was retroposed from the partially processed mRNA of Ins2. When Ins1 originated and how it was retained in genomes still remain interesting problems. In this study, we used genomic approaches to detect insulin gene copy number variation in rodent species and investigated evolutionary forces acting on both Ins1 and Ins2. We characterized the phylogenetic distribution of the new insulin gene (Ins1) by Southern analyses and confirmed by sequencing insulin genes in the rodent genomes. The results demonstrate that Ins1 originated right before the mouse–rat split (∼20 MYA), and both Ins1 and Ins2 are under strong functional constraints in these murine species. Interestingly, by examining a range of nucleotide polymorphisms, we detected positive selection acting on both Ins2 and Ins1 gene regions in the Mus musculus domesticus populations. Furthermore, three amino acid sites were also identified as having evolved under positive selection in two insulin peptides: two are in the signal peptide and one is in the C-peptide. Our data suggest an adaptive divergence in the mouse insulin two-gene system, which may result from the response to environmental change caused by the rise of agricultural civilization, as proposed by the thrifty-genotype hypothesis.
Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines
Authors: Pichichero Michael E. , Gentile Angela , Giglio Norberto , Umido Veronica , Clarkson Thomas , Cernichiari Elsa , Zareba Grazyna , Gotelli Carlos , Gotelli Mariano , Yan Lihan , Treanor John
Published: February 2008

OBJECTIVES. Thimerosal is a mercurial preservative that was widely used in multidose vaccine vials in the United States and Europe until 2001 and continues to be used in many countries throughout the world. We conducted a pharmacokinetic study to assess blood levels and elimination of ethyl mercury after vaccination of infants with thimerosal-containing vaccines.

METHODS. Blood, stool, and urine samples were obtained before vaccination and 12 hours to 30 days after vaccination from 216 healthy children: 72 newborns (group 1), 72 infants aged 2 months (group 2), and 72 infants aged 6 months (group 3). Total mercury levels were measured by atomic absorption. Blood mercury pharmacokinetics were calculated by pooling the data on the group and were based on a 1-compartment first-order pharmacokinetics model.

RESULTS. For groups 1, 2, and 3, respectively, (1) mean ± SD weights were 3.4 ± 0.4, 5.1 ± 0.6, and 7.7 ± 1.1 kg; (2) maximal mean ± SD blood mercury levels were 5.0 ± 1.3, 3.6 ± 1.5, and 2.8 ± 0.9 ng/mL occurring at 0.5 to 1 day after vaccination; (3) maximal mean ± SD stool mercury levels were 19.1 ± 11.8, 37.0 ± 27.4, and 44.3 ± 23.9 ng/g occurring on day 5 after vaccination for all groups; and (4) urine mercury levels were mostly nondetectable. The blood mercury half-life was calculated to be 3.7 days and returned to prevaccination levels by day 30.

CONCLUSIONS. The blood half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter than that of oral methyl mercury in adults. Increased mercury levels were detected in stools after vaccination, suggesting that the gastrointestinal tract is involved in ethyl mercury elimination. Because of the differing pharmacokinetics of ethyl and methyl mercury, exposure guidelines based on oral methyl mercury in adults may not be accurate for risk assessments in children who receive thimerosal-containing vaccines.
Effect of a Short Course of Prednisolone in Infants With Oxygen-Dependent Bronchopulmonary Dysplasia
Authors: Bhandari Anita , Schramm Craig M. , Kimble Claudia , Pappagallo Mariann , Hussain Naveed
Published: February 2008

OBJECTIVE. The purpose of this work was to determine whether oral prednisolone is effective in weaning infants with bronchopulmonary dysplasia, after 36 weeks' postmenstrual age, off supplemental oxygen and to identify factors associated with successful weaning.

METHODS. Data were abstracted from a standardized prospectively collected database at the John Dempsey Hospital NICU. Logistic regression and receiver operating curve analyses were used.

RESULTS. Of 385 infants, 131 (34%) received oral prednisolone and 254 (66%) did not. There was no significant difference in race, gender, birth weight, or gestational age between the groups receiving and not receiving oral prednisolone. Infants in the oral prednisolone group were more likely to have received previous dexamethasone therapy, had longer duration of mechanical ventilation, had longer length of hospital stay, and were more likely to be discharged from the hospital on oxygen. Of those in the oral prednisolone group, 63% responded to treatment. Pulmonary acuity score and Pco2 were the only parameters that remained significant on multiple logistic regression analyses. The oral prednisolone-responsive group had a lower pulmonary acuity score compared with the oral prednisolone-nonresponsive group. A pulmonary acuity score value of ≤0.5 had a sensitivity of 20% and specificity of 97.4%, with positive and negative predictive values of 94.1% and 42.1%, respectively. Capillary Pco2 values were significantly lower in the oral prednisolone-responsive group compared with the oral prednisolone-nonresponsive group. In predicting a successful response to oral prednisolone, a capillary Pco2 value of <48.5 mmHg had a sensitivity of 50% and specificity of 89.7%, with positive and negative predictive values of 89.1% and 51.8%, respectively.

CONCLUSIONS. Oral prednisolone therapy is effective in weaning off supplemental oxygen in a postterm infant with oxygen-dependent bronchopulmonary dysplasia who has a pulmonary acuity score of <0.5 and Pco2 of <48.5 mmHg. In addition, if a single course of prednisolone fails, there is no clear benefit of using multiple courses.
Burden and Economic Cost of Group A Streptococcal Pharyngitis
Authors: Pfoh Elizabeth , Wessels Michael R. , Goldmann Donald , Lee Grace M.
Published: February 2008

OBJECTIVE. Our aim was to describe the morbidity, medical costs, and nonmedical costs associated with group A streptococcal pharyngitis in school-aged children.

METHODS. Our study population included parents of children diagnosed as having group A streptococcal pharyngitis at 2 pediatric practice sites in the Boston, Massachusetts, metropolitan area. Telephone interviews were conducted with parents of eligible children, who were asked questions about health care utilization, medications, and time missed from work or school, for calculation of medical and nonmedical costs associated with illness.

RESULTS. One hundred thirty-five parents completed interviews between October 2005 and January 2006. Older children were significantly more likely to present with headache, compared with those ≤5 years of age. No significant differences between older and younger children were found for rates of sore throat, fever, abdominal pain/nausea/vomiting, or rash. Children missed a mean of 1.9 days (range: 0–7 days) of school/day care, and 42% of parents missed a mean of 1.8 days of work. A second parent or caregiver also missed a mean of 1.5 days in 14% of families. The total societal cost per case of group A streptococcal pharyngitis was $205 (medical: $118; nonmedical: $87).

CONCLUSIONS. The societal cost of group A streptococcal pharyngitis is substantial, with almost one half being attributable to nonmedical costs. Through extrapolation from this experience, the total cost of group A streptococcal pharyngitis among children in the United States ranges from $224 to $539 million per year.
Why Do Adolescents Say They Are Less Healthy Than Their Parents Think They Are? The Importance of Mental Health Varies by Social Class in a Nationally Representative Sample
Authors: Johnson Sara B. , Wang Constance
Published: February 2008

OBJECTIVE. We sought to (1) confirm the discrepancy between parent-reported and youth-reported adolescent health in a nationally representative sample, (2) compare the predictors of parent-reported and adolescent self-reported health, and (3) determine whether the discrepancy between the 2 ratings differed by sociodemographic characteristics, particularly income.

METHODS. Data were from the 2001–2002 National Health and Nutrition Examination Survey. A total of 1157 adolescents aged 12 to 15 years, representative of 16227827 US youth, were included. Youth and their parents reported on the youth's health status along with other indicators of health and illness and sociodemographic characteristics. To examine predictors of self-rated and parent-rated adolescent health (excellent to poor), bivariate analyses were conducted, followed by multiple linear regression adjusted for relevant covariates. All of the analyses were stratified by income (standardized poverty income index: ≤1 vs >1).

RESULTS. Parents and youth differed in subjective judgments regarding the child's health, even when these differences were not supported by other health indicators (days of school missed because of illness or injury or days of poor mental or physical health). Poor adolescents reported worse self-rated health than higher-income youth, and their parents did also. In income-stratified multiple regression models, higher-income adolescents' and their parents' ratings were predicted by indicators of physical health. In contrast, poor youth and parent ratings were better predicted by mental health care use. Poor youth with a mental health visit in the last year reported better health, but their parents saw these mental health visits as an indication of poor health.

CONCLUSIONS. The findings suggest that social class differences in subjective ratings of adolescents' health are related to the differential ways that youth and parents determine what constitutes health and are not simply a reflection of objective health status.