bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Two ENU-Induced Mutations Affecting Mouse Skeletal Morphology
Authors: Dauphinee Shauna M , Eva Megan M , Yuki Kyoko E , Herman Melissa , Vidal Silvia M , Malo Danielle 
Published: August 2013

Abstract
Using the N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we have identified two skeletal morphology mutants, Skm1 and Skm2. Positional cloning and candidate gene sequencing localized the causative point mutations within the genes coding for natriuretic peptide receptor C (NPR-C) and filamin b (FLNB), respectively. Mice that carry a mutation in Npr3 exhibit a skeletal overgrowth phenotype, resulting in an elongated body and kyphosis. Skm2 mice, carrying a mutation in Flnb, present with scoliosis and lordosis. These mutant mice will serve as useful models for the study of vertebral malformations.
Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome
Authors: Tanaka Shigekazu , Mizushina Youichi , Kato Yoriko , Tamura Masaru , Shiroishi Toshihiko 
Published: August 2013

Abstract
Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations exhibiting alopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2, whereas human and rat have only one related gene. To date, no skin mutation has been reported for human GSDMA and rat Gsdma as well as mouse Gsdma and Gsdma2. Therefore, it is possible that only Gsdma3 has gain-of-function type mutations to cause dominant skin phenotype. To elucidate functional divergence among the Gsdma-related genes in mice, and to infer the function of the human and rat orthologs, we examined in vivo function of mouse Gsdma by generating Gsdma knockout mice and transgenic mice that overexpress wild-type Gsdma or Gsdma harboring a point mutation (Alanine339Threonine). The Gsdma knockout mice shows no visible phenotype, indicating that Gsdma is not essential for differentiation of epidermal cells and maintenance of the hair cycle, and that Gsdma is expressed specifically both in the inner root sheath of hair follicles and in suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers. By contrast, both types of the transgenic mice exhibited epidermal hyperplasia resembling the Gsdma3 mutations, although the phenotype depended on the genetic background. These results indicate that the mouse Gsdma and Gsdma3 genes share common function to regulate epithelial maintenance and/or homeostasis, and suggest that the function of human GSDMA and rat Gsdma, which are orthologs of mouse Gsdma, is conserved as well.
Identification of a Novel Polymorphism in X-Linked Sterol-4-Alpha-Carboxylate 3-Dehydrogenase (Nsdhl) Associated with Reduced High-Density Lipoprotein Cholesterol Levels in I/LnJ Mice
Authors: Bautz David J , Broman Karl W , Threadgill David W 
Published: August 2013

Abstract
Loci controlling plasma lipid concentrations were identified by performing a quantitative trait locus analysis on genotypes from 233 mice from a F2 cross between KK/HlJ and I/LnJ, two strains known to differ in their high-density lipoprotein (HDL) cholesterol levels. When fed a standard diet, HDL cholesterol concentration was affected by two significant loci, the Apoa2 locus on Chromosome (Chr) 1 and a novel locus on Chr X, along with one suggestive locus on Chr 6. Non-HDL concentration also was affected by loci on Chr 1 and X along with a suggestive locus on Chr 3. Additional loci that may be sex-specific were identified for HDL cholesterol on Chr 2, 3, and 4 and for non-HDL cholesterol on Chr 5, 7, and 14. Further investigation into the potential causative gene on Chr X for reduced HDL cholesterol levels revealed a novel, I/LnJ-specific nonsynonymous polymorphism in Nsdhl, which codes for sterol-4-alpha-carboxylate 3-dehydrogenase in the cholesterol synthesis pathway. Although many lipid quantitative trait locus have been reported previously, these data suggest there are additional genes left to be identified that control lipid levels and that can provide new pharmaceutical targets.
Drosophila Embryonic Cell-Cycle Mutants
Authors: Unhavaithaya Yingdee , Park Eugenia A , Royzman Irena , Orr-Weaver Terry L 
Published: August 2013

AbstractNearly all cell division mutants in Drosophila were recovered in late larval/pupal lethal screens, with less than 10 embryonic lethal mutants identified, because larval development occurs without a requirement for cell division. Only cells in the nervous system and the imaginal cells that generate the adult body divide during larval stages, with larval tissues growing by increasing ploidy rather than cell number. Thus, most mutants perturbing mitosis or the cell cycle do not manifest a phenotype until the adult body differentiates in late larval and pupal stages. To identify cell-cycle components whose maternal pools are depleted in embryogenesis or that have specific functions in embryogenesis, we screened for mutants defective in cell division during embryogenesis. Five new alleles of Cyclin E were recovered, ranging from a missense mutation that is viable to stop codons causing embryonic lethality. These permitted us to investigate the requirements for Cyclin E function in neuroblast cell fate determination, a role previously shown for a null Cyclin E allele. The mutations causing truncation of the protein affect cell fate of the NB6-4 neuroblast, whereas the weak missense mutation has no effect. We identified mutations in the pavarotti (pav) and tumbleweed (tum) genes needed for cytokinesis by a phenotype of large and multinucleate cells in the embryonic epidermis and nervous system. Other mutations affecting the centromere protein CAL1 and the kinetochore protein Spc105R caused mitotic defects in the nervous system.
When Females Produce Sperm: Genetics ofC. elegansHermaphrodite Reproductive Choice
Authors: Bahrami Adam K , Zhang Yun 
Published: August 2013

AbstractReproductive behaviors have manifold consequences on evolutionary processes. Here, we explore mechanisms underlying female reproductive choice in the nematode Caenorhabditis elegans, a species in which females have evolved the ability to produce their own self-fertilizing sperm, thereby allowing these "hermaphrodites" the strategic choice to self-reproduce or outcross with males. We report that hermaphrodites of the wild-type laboratory reference strain N2 favor self-reproduction, whereas a wild isolate CB4856 (HW) favors outcrossing. To characterize underlying neural mechanisms, we show that N2 hermaphrodites deficient in mechanosensation or chemosensation (e.g., mec-3 and osm-6 mutants) exhibit high mating frequency, implicating hermaphrodite perception of males as a requirement for low mating frequency. Within chemosensory networks, we find opposing roles for different sets of neurons that express the cyclic GMP-gated nucleotide channel, suggesting both positive and negative sensory-mediated regulation of hermaphrodite mating frequency. We also show that the ability to self-reproduce negatively regulates hermaphrodite mating. To map genetic variation, we created recombinant inbred lines and identified two QTL that explain a large portion of N2 × HW variation in hermaphrodite mating frequency. Intriguingly, we further show that ∼40 wild isolates representing C. elegans global diversity exhibit extensive and continuous variation in hermaphrodite reproductive outcome. Together, our findings demonstrate that C. elegans hermaphrodites actively regulate the choice between selfing and crossing, highlight the existence of natural variation in hermaphrodite choice, and lay the groundwork for molecular dissection of this evolutionarily important trait.
Population Growth Inflates the Per-Individual Number of Deleterious Mutations and Reduces Their Mean Effect
Authors: Gazave Elodie , Chang Diana , Clark Andrew G , Keinan Alon 
Published: August 2013

AbstractThis study addresses the question of how purifying selection operates during recent rapid population growth such as has been experienced by human populations. This is not a straightforward problem because the human population is not at equilibrium: population genetics predicts that, on the one hand, the efficacy of natural selection increases as population size increases, eliminating ever more weakly deleterious variants; on the other hand, a larger number of deleterious mutations will be introduced into the population and will be more likely to increase in their number of copies as the population grows. To understand how patterns of human genetic variation have been shaped by the interaction of natural selection and population growth, we examined the trajectories of mutations with varying selection coefficients, using computer simulations. We observed that while population growth dramatically increases the number of deleterious segregating sites in the population, it only mildly increases the number carried by each individual. Our simulations also show an increased efficacy of natural selection, reflected in a higher fraction of deleterious mutations eliminated at each generation and a more efficient elimination of the most deleterious ones. As a consequence, while each individual carries a larger number of deleterious alleles than expected in the absence of growth, the average selection coefficient of each segregating allele is less deleterious. Combined, our results suggest that the genetic risk of complex diseases in growing populations might be distributed across a larger number of more weakly deleterious rare variants.
Rate of Adaptation in Sexuals and Asexuals: A Solvable Model of the Fisher–Muller Effect
Authors: Park Su-Chan , Krug Joachim 
Published: August 2013

AbstractThe adaptation of large asexual populations is hampered by the competition between independently arising beneficial mutations in different individuals, which is known as clonal interference. In classic work, Fisher and Muller proposed that recombination provides an evolutionary advantage in large populations by alleviating this competition. Based on recent progress in quantifying the speed of adaptation in asexual populations undergoing clonal interference, we present a detailed analysis of the Fisher–Muller mechanism for a model genome consisting of two loci with an infinite number of beneficial alleles each and multiplicative (nonepistatic) fitness effects. We solve the deterministic, infinite population dynamics exactly and show that, for a particular, natural mutation scheme, the speed of adaptation in sexuals is twice as large as in asexuals. This result is argued to hold for any nonzero value of the rate of recombination. Guided by the infinite population result and by previous work on asexual adaptation, we postulate an expression for the speed of adaptation in finite sexual populations that agrees with numerical simulations over a wide range of population sizes and recombination rates. The ratio of the sexual to asexual adaptation speed is a function of population size that increases in the clonal interference regime and approaches 2 for extremely large populations. The simulations also show that the imbalance between the numbers of accumulated mutations at the two loci is strongly suppressed even by a small amount of recombination. The generalization of the model to an arbitrary number L of loci is briefly discussed. If each offspring samples the alleles at each locus from the gene pool of the whole population rather than from two parents, the ratio of the sexual to asexual adaptation speed is approximately equal to L in large populations. A possible realization of this scenario is the reassortment of genetic material in RNA viruses with L genomic segments.
Targeted Heritable Mutation and Gene Conversion by Cas9-CRISPR in Caenorhabditis elegans
Authors: Katic Iskra , Großhans Helge 
Published: August 2013

Abstract
We have achieved targeted heritable genome modification in Caenorhabditis elegans by injecting mRNA of the nuclease Cas9 and Cas9 guide RNAs. This system rapidly creates precise genomic changes, including knockouts and transgene-instructed gene conversion.
Selecting Informative Traits for Multivariate Quantitative Trait Locus Mapping Helps to Gain Optimal Power
Authors: Cheng Riyan , Borevitz Justin , Doerge R W 
Published: August 2013

Abstract
A major consideration in multitrait analysis is which traits should be jointly analyzed. As a common strategy, multitrait analysis is performed either on pairs of traits or on all of traits. To fully exploit the power of multitrait analysis, we propose variable selection to choose a subset of informative traits for multitrait quantitative trait locus (QTL) mapping. The proposed method is very useful for achieving optimal statistical power for QTL identification and for disclosing the most relevant traits. It is also a practical strategy to effectively take advantage of multitrait analysis when the number of traits under consideration is too large, making the usual multivariate analysis of all traits challenging. We study the impact of selection bias and the usage of permutation tests in the context of variable selection and develop a powerful implementation procedure of variable selection for genome scanning. We demonstrate the proposed method and selection procedure in a backcross population, using both simulated and real data. The extension to other experimental mapping populations is straightforward.
Identification of Mob2, a Novel Regulator of Larval Neuromuscular Junction Morphology, in Natural Populations of Drosophila melanogaster
Authors: Campbell Megan , Ganetzky Barry 
Published: August 2013

Abstract
Although evolutionary changes must take place in neural connectivity and synaptic architecture as nervous systems become more complex, we lack understanding of the general principles and specific mechanisms by which these changes occur. Previously, we found that morphology of the larval neuromuscular junction (NMJ) varies extensively among different species of Drosophila but is relatively conserved within a species. To identify specific genes as candidates that might underlie phenotypic differences in NMJ morphology among Drosophila species, we performed a genetic analysis on one of two phenotypic variants we found among 20 natural isolates of Drosophila melanogaster. We discovered genetic polymorphisms for both positive and negative regulators of NMJ growth segregating within the variant line. Focusing on one subline, that displayed NMJ overgrowth, we mapped the phenotype to Mob2 [Monopolar spindle (Mps) one binding protein 2)], a gene encoding a Nuclear Dbf2 (Dumbbell formation 2)-Related (NDR) kinase activator. We confirmed this identification by transformation rescue experiments and showed that presynaptic expression of Mob2 is necessary and sufficient to regulate NMJ growth. Mob2 interacts in a dominant, dose-dependent manner with tricornered but not with warts, to cause NMJ overgrowth, suggesting that Mob2 specifically functions in combination with the former NDR kinase to regulate NMJ development. These results demonstrate the feasibility and utility of identifying genetic variants affecting NMJ morphology in natural populations of Drosophila. These variants can lead to discovery of new genes and molecular mechanisms that regulate NMJ development while also providing new information that can advance our understanding of mechanisms that underlie nervous system evolution.
Highly Efficient Targeted Mutagenesis in Mice Using TALENs
Authors: Panda Sudeepta Kumar , Wefers Benedikt , Ortiz Oskar , Floss Thomas , Schmid Bettina , Haass Christian , Wurst Wolfgang , Kühn Ralf 
Published: August 2013

Abstract
Targeted mouse mutants are instrumental for the analysis of gene function in health and disease. We recently provided proof-of-principle for the fast-track mutagenesis of the mouse genome, using transcription activator-like effector nucleases (TALENs) in one-cell embryos. Here we report a routine procedure for the efficient production of disease-related knockin and knockout mutants, using improved TALEN mRNAs that include a plasmid-coded poly(A) tail (TALEN-95A), circumventing the problematic in vitro polyadenylation step. To knock out the C9orf72 gene as a model of frontotemporal lobar degeneration, TALEN-95A mutagenesis induced sequence deletions in 41% of pups derived from microinjected embryos. Using TALENs together with mutagenic oligodeoxynucleotides, we introduced amyotrophic lateral sclerosis patient-derived missense mutations in the fused in sarcoma (Fus) gene at a rate of 6.8%. For the simple identification of TALEN-induced mutants and their progeny we validate high-resolution melt analysis (HRMA) of PCR products as a sensitive and universal genotyping tool. Furthermore, HRMA of off-target sites in mutant founder mice revealed no evidence for undesired TALEN-mediated processing of related genomic sequences. The combination of TALEN-95A mRNAs for enhanced mutagenesis and of HRMA for simplified genotyping enables the accelerated, routine production of new mouse models for the study of genetic disease mechanisms.
Pneumococcal Meningitis in Children: Epidemiology, Serotypes, and Outcomes From 1997–2010 in Utah
Authors: Stockmann Chris , Ampofo Krow , Byington Carrie L. , Filloux Francis , Hersh Adam L. , Blaschke Anne J. , Cowan Priscilla , Korgenski Kent , Mason Edward O. , Pavia Andrew T. 
Published: August 2013

BACKGROUND:After licensure of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, the incidence of pediatric pneumococcal meningitis decreased significantly. However, cases continue to occur. It is unknown whether meningitis due to PCV7 and non-PCV7 serotypes causes similar morbidity and mortality.METHODS:We performed a retrospective cohort study of laboratory-confirmed pneumococcal meningitis among Utah children from 1997 to 2010. We reviewed medical records and obtained clinical data during the acute illness and follow-up data on neurologic sequelae.RESULTS:Sixty-eight cases of meningitis were identified. PCV7 serotypes caused 64% of cases before and 25% of cases after licensure of PCV7 (P &lt; .01). The age range was similar before and after PCV7 licensure (P = .5). The overall case fatality rate was 13% and was similar among cases caused by PCV7 and non-PCV7 serotypes (P = .7). Children with PCV7 serotypes were more likely to require mechanical ventilation (68% vs 34%; P &lt; .01). Of all survivors, 63% had neurologic sequelae, and the proportion was similar after infection with PCV7 or non-PCV7 serotypes (P = .1). More than one-half (54%) of all children who developed pneumococcal meningitis in the PCV7 period were eligible for PCV7 and had not been immunized.CONCLUSIONS:Pneumococcal meningitis continues to be associated with high mortality and morbidity; death and neurologic sequelae are common with both PCV7 and non-PCV7 serotype meningitis. The substantial burden of this disease and continued cases among unimmunized children reinforce the need for more effective immunization strategies and continued surveillance in the era of PCV13.
Interventions to Modify Health Care Provider Adherence to Asthma Guidelines: A Systematic Review
Authors: Okelo Sande O. , Butz Arlene M. , Sharma Ritu , Diette Gregory B. , Pitts Samantha I. , King Tracy M. , Linn Shauna T. , Reuben Manisha , Chelladurai Yohalakshmi , Robinson Karen A. 
Published: August 2013

BACKGROUND AND OBJECTIVE:Health care provider adherence to asthma guidelines is poor. The objective of this study was to assess the effect of interventions to improve health care providers’ adherence to asthma guidelines on health care process and clinical outcomes.METHODS:Data sources included Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Educational Resources Information Center, PsycINFO, and Research and Development Resource Base in Continuing Medical Education up to July 2012. Paired investigators independently assessed study eligibility. Investigators abstracted data sequentially and independently graded the evidence.RESULTS:Sixty-eight eligible studies were classified by intervention: decision support, organizational change, feedback and audit, clinical pharmacy support, education only, quality improvement/pay-for-performance, multicomponent, and information only. Half were randomized trials (n = 35). There was moderate evidence for increased prescriptions of controller medications for decision support, feedback and audit, and clinical pharmacy support and low-grade evidence for organizational change and multicomponent interventions. Moderate evidence supports the use of decision support and clinical pharmacy interventions to increase provision of patient self-education/asthma action plans. Moderate evidence supports use of decision support tools to reduce emergency department visits, and low-grade evidence suggests there is no benefit for this outcome with organizational change, education only, and quality improvement/pay-for-performance.CONCLUSIONS:Decision support tools, feedback and audit, and clinical pharmacy support were most likely to improve provider adherence to asthma guidelines, as measured through health care process outcomes. There is a need to evaluate health care provider-targeted interventions with standardized outcomes.
Primary Care Interventions to Prevent Tobacco Use in Children and Adolescents: U.S. Preventive Services Task Force Recommendation Statement
Authors: Moyer Virginia A. 
Published: August 2013

Description:
Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation on primary care interventions to prevent tobacco use in children and adolescents.

Methods:
The USPSTF reviewed the evidence on the effectiveness of primary care interventions on the rates of initiation or cessation of tobacco use in children and adolescents and on health outcomes, such as respiratory health, dental and oral health, and adult smoking. The USPSTF also reviewed the evidence on the potential harms of these interventions.

Population:
This recommendation applies to school-aged children and adolescents. The USPSTF has issued a separate recommendation statement on tobacco use counseling in adults and pregnant women.

Recommendation:
The USPSTF recommends that primary care clinicians provide interventions, including education or brief counseling, to prevent initiation of tobacco use in school-aged children and adolescents.
Molecular Dynamics Study of Cu Thin Film Deposition onβ-Ta
Authors: Klaver Peter , Thijsse Barend J. 
Published: August 2013

AbstractMolecular Dynamics simulations were performed to study Cu film deposition on β-Ta. Three different β-Ta surfaces were used, two being atomically flat, and one resulting from Ta on Ta growth. We find that the Cu films develop a (111) texture with vertical grain boundaries between grains having different epitaxial relations with the β-Ta substrate. The epitaxial rotation angles were determined, as 5.2° and 10-13°, and the resulting strain reductions in the Cu films were identified. The effects of the substrate differences on the interfacial Ta/Cu intermixing and the epitaxy and grain boundary structure of the films are discussed.