bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Stock Market in the Driver's Seat! Implications for R&D and Marketing
Authors: Chakravarty Anindita , Grewal Rajdeep 
Published: March 2011

The budgets for research and development (R&D) and marketing should be determined by managers to attain product market advantages. However, in response to investor expectations for short-term stock returns, managers may modify these budgets myopically to avoid unexpected short-term earnings shortfalls, at the cost of long-term profitability. We propose that the past behavior of firm stock returns and volatility may create investor expectations of short-term financial performance, which drives managers to modify either R&D or marketing budgets or both. In the context of high-technology firms, a Bayesian vector autoregression model, supported by content analysis, shows that few firms exhibit high levels of managerial myopia by simultaneously cutting both R&D and marketing budgets; instead, firms display moderate myopic reactions, in the form of unanticipated decreases in R&D budgets but increased budgets for marketing functions. The tendency to manage myopically in response to past stock returns and volatility increases as firm size or industry concentration decrease. This paper was accepted by Pradeep Chintagunta and Preyas Desai, special issue editors. This paper was accepted by Pradeep Chintagunta and Preyas Desai, special issue editors.
Overconfidence by Bayesian-Rational Agents
Authors: Van den Steen Eric 
Published: March 2011

This paper derives two mechanisms through which Bayesian-rational individuals with differing priors will tend to be relatively overconfident about their estimates and predictions, in the sense of overestimating the precision of these estimates. The intuition behind one mechanism is slightly ironic: In trying to update optimally, Bayesian agents overweight information of which they overestimate the precision and underweight in the opposite case. This causes overall an overestimation of the precision of the final estimate, which tends to increase as agents get more data. This paper was accepted by Teck Ho, decision analysis.
Der Zweitspracherwerb des deutschen Kasus in der Präpositionalphrase
Authors: Turgay Katharina 
Published: March 2011

Abstract
Case is one of the grammatical categories that pose great challenges to children acquiring German, both in first and second language acquisition. The paper examines the special case of the second language acquisition of case within prepositional phrases (PPs). A prototypical German PP consists of a preposition selecting a determiner phrase (DP) whose case is governed by the prepositional head. One problem is that the case assigned by a preposition and its semantics are not related to each other, while in the case of socalled two-way prepositions, the semantics of the PP and the case within the DP are closely connected. This conflict between arbitrariness and semantically driven case assignment could pose an additional obstacle for learners of German. I have conducted an experiment in which I examined how case within PPs is acquired by 56 primary school children whose first language is not German. My study shows that the children have great difficulties regarding the dative and that the accusative is used instead very often. This overgeneralization decreases with an increase in age.
Allomorphy in the German genitive. A paradigmatic account
Authors: Fehringer Carol 
Published: March 2011

Abstract
This paper investigates the distribution of the genitive singular allomorphs -es and -s in modern standard German, in the light of current theories of the mental lexicon. It will be shown, using current electronic corpora, that the preference that native speakers demonstrate for one genitive allomorph over the other is determined by a number of interacting factors: phonological, morphological, semantic and frequency-based, and that this preference should not be seen in terms of a simple two-way opposition but is a more subtle matter of degree. Primarily, the paper will argue that: i) the choice of genitive allomorph in non-derived nouns is determined by the token frequency of that noun; ii) the choice of genitive allomorph on the head of compound words is determined by semantic transparency, so that compound heads showing a clear semantic association with the corresponding free-standing noun mirror the behaviour of that noun with respect to their genitive form (e.g. Hundes ‘dog’ – Blindenhundes ‘guide dog’). By contrast, compounds with more opaque meanings tend to act as independent items with respect to genitive allomorph allocation. It will be argued that such data provide evidence for the wholesale lexical listing of genitive forms in the lexicon, which are related to other members of their (inflectional and derivational) paradigm by lexical connections of varying strength.
Identification and functional characterization of a missense mutation in resistin in two patients with severe obesity and insulin resistance
Authors: Beckers Sigri , de Freitas Fenna , Zegers Doreen , Verrijken An , Peeters Armand V , Peiffer Frida , Verhulst Stijn L , Massa Guy , Mertens Ilse L , Desager Kristine N , Van Gaal Luc F , Van Hul Wim 
Published: March 2011

ObjectiveIn this study, we hypothesized that mutations in the resistin encoding gene, RETN, may cause a monogenic form of obesity.Design/methodsWe screened the coding region of RETN in 81 morbidly obese adults, 263 overweight and obese children/adolescents, and 116 healthy lean subjects. In vitro experiments include qPCR, ELISA, and western blot for WT and mutant resistin transfected into 3T3-L1 adipocytes.ResultsMutation analysis identified five sequence variants in our patient populations: 3′-UTR +87 G/A, 3′-UTR +100 A/G, T73T, IV3-61 C/A, and C78S. In our control population, we only found the 3′-UTR +87 G/A variant. We started functional experiments for the C78S mutation that was found in a 20-year-old obese male (body mass index (BMI)=39.7 kg/m2) and his obese mother (BMI=31.9 kg/m2). In vitro testing demonstrated that the mutation does not impair mRNA expression. We identified a 100-fold lower extracellular protein concentration for mutant resistin compared with WT levels using a resistin ELISA on cell culture medium (P=4.87×10−6). We also detected a decreased intracellular concentration for the mutant protein (tenfold lower relative levels, P=0.007). The plasma resistin levels of the proband and his mother, however, did not differ significantly from lean control individuals.ConclusionsIn conclusion, we identified the first missense mutation in resistin in a morbidly obese proband and his obese mother. Functional testing of the mutant protein suggests that the C78S mutant protein is degraded, possibly resulting in a decreased extracellular concentration, which may predispose to obesity.
Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families
Authors: Nandagopal Radha , Sinaii Ninet , Avila Nilo A , Van Ryzin Carol , Chen Wuyan , Finkielstain Gabriela P , Mehta Sneha P , McDonnell Nazli B , Merke Deborah P 
Published: March 2011

ObjectiveTo comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.DesignGenotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.ResultsOf the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56–364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27–54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found.ConclusionsParents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.
A Link Between Impaired Purine Nucleotide Synthesis and Apoptosis in Drosophila melanogaster
Authors: Holland Catherine , Lipsett David B , Clark Denise V 
Published: March 2011

Abstract
The biosynthetic pathways and multiple functions of purine nucleotides are well known. However, the pathways that respond to alterations in purine nucleotide synthesis in vivo in an animal model organism have not been identified. We examined the effects of inhibiting purine de novo synthesis in vivo and in cultured cells of Drosophila melanogaster. The purine de novo synthesis gene ade2 encodes phosphoribosylformylglycinamidine synthase (EC 6.3.5.3). An ade2 deletion, generated by P-element transposon excision, causes lethality in early pupal development, with darkening, or necrosis, of leg and wing imaginal disc tissue upon disc eversion. Together with analysis of a previously isolated weaker allele, ade24, and an allele of the Prat gene, which encodes an enzyme for the first step in the pathway, we determined that the lethal arrest and imaginal disc phenotypes involve apoptosis. A transgene expressing the baculovirus caspase inhibitor p35, which suppresses apoptosis caused by other stresses such as DNA damage, suppresses both the imaginal disc tissue darkening and the pupal lethality of all three purine de novo synthesis mutants. Furthermore, we showed the presence of apoptosis at the cellular level in both ade2 and Prat mutants by detecting TUNEL-positive nuclei in wing imaginal discs. Purine de novo synthesis inhibition was also examined in tissue culture by ade2 RNA interference followed by analysis of genome-wide changes in transcript levels. Among the upregulated genes was HtrA2, which encodes an apoptosis effector and is thus a candidate for initiating apoptosis in response to purine depletion.
O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans
Authors: Mondoux Michelle A , Love Dona C , Ghosh Salil K , Fukushige Tetsunari , Bond Michelle , Weerasinghe Gayani R , Hanover John A , Krause Michael W 
Published: March 2011

AbstractIn a variety of organisms, including worms, flies, and mammals, glucose homeostasis is maintained by insulin-like signaling in a robust network of opposing and complementary signaling pathways. The hexosamine signaling pathway, terminating in O-linked-N-acetylglucosamine (O-GlcNAc) cycling, is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling in Caenorhabditis elegans. Here we demonstrate that O-GlcNAc cycling and insulin signaling are both essential components of the C. elegans response to glucose stress. A number of insulin-dependent processes were found to be sensitive to glucose stress, including fertility, reproductive timing, and dauer formation, yet each of these differed in their threshold of sensitivity to glucose excess. Our findings suggest that O-GlcNAc cycling and insulin signaling are both required for a robust and adaptable response to glucose stress, but these two pathways show complex and interdependent roles in the maintenance of glucose–insulin homeostasis.
Germline Fitness-Based Scoring of Cancer Mutations
Authors: Fischer Andrej , Greenman Chris , Mustonen Ville 
Published: March 2011

AbstractA key goal in cancer research is to find the genomic alterations that underlie malignant cells. Genomics has proved successful in identifying somatic variants at a large scale. However, it has become evident that a typical cancer exhibits a heterogenous mutation pattern across samples. Cases where the same alteration is observed repeatedly seem to be the exception rather than the norm. Thus, pinpointing the key alterations (driver mutations) from a background of variations with no direct causal link to cancer (passenger mutations) is difficult. Here we analyze somatic missense mutations from cancer samples and their healthy tissue counterparts (germline mutations) from the viewpoint of germline fitness. We calibrate a scoring system from protein domain alignments to score mutations and their target loci. We show first that this score predicts to a good degree the rate of polymorphism of the observed germline variation. The scoring is then applied to somatic mutations. We show that candidate cancer genes prone to copy number loss harbor mutations with germline fitness effects that are significantly more deleterious than expected by chance. This suggests that missense mutations play a driving role in tumor suppressor genes. Furthermore, these mutations fall preferably onto loci in sequence neighborhoods that are high scoring in terms of germline fitness. In contrast, for somatic mutations in candidate onco genes we do not observe a statistically significant effect. These results help to inform how to exploit germline fitness predictions in discovering new genes and mutations responsible for cancer.
Circumventing Heterozygosity: Sequencing the Amplified Genome of a Single HaploidDrosophila melanogasterEmbryo
Authors: Langley Charles H , Crepeau Marc , Cardeno Charis , Corbett-Detig Russell , Stevens Kristian 
Published: March 2011

AbstractHeterozygosity is a major challenge to efficient, high-quality genomic assembly and to the full genomic survey of polymorphism and divergence. In Drosophila melanogaster lines derived from equatorial populations are particularly resistant to inbreeding, thus imposing a major barrier to the determination and analyses of genomic variation in natural populations of this model organism. Here we present a simple genome sequencing protocol based on the whole-genome amplification of the gynogenetically derived haploid genome of a progeny of females mated to males homozygous for the recessive male sterile mutation, ms(3)K81. A single “lane” of paired-end sequences (2 × 76 bp) provides a good syntenic assembly with &gt;95% high-quality coverage (more than five reads). The amplification of the genomic DNA moderately inflates the variation in coverage across the euchromatic portion of the genome. It also increases the frequency of chimeric clones. But the low frequency and random genomic distribution of the chimeric clones limits their impact on the final assemblies. This method provides a solid path forward for population genomic sequencing and offers applications to many other systems in which small amounts of genomic DNA have unique experimental relevance.
Modeling of Identity-by-Descent Processes Along a Chromosome Between Haplotypes and Their Genotyped Ancestors
Authors: Druet Tom , Farnir Frederic Paul 
Published: March 2011

Abstract
Identity-by-descent probabilities are important for many applications in genetics. Here we propose a method for modeling the transmission of the haplotypes from the closest genotyped relatives along an entire chromosome. The method relies on a hidden Markov model where hidden states correspond to the set of all possible origins of a haplotype within a given pedigree. Initial state probabilities are estimated from average genetic contribution of each origin to the modeled haplotype while transition probabilities are computed from recombination probabilities and pedigree relationships between the modeled haplotype and the various possible origins. The method was tested on three simulated scenarios based on real data sets from dairy cattle, Arabidopsis thaliana, and maize. The mean identity-by-descent probabilities estimated for the truly inherited parental chromosome ranged from 0.94 to 0.98 according to the design and the marker density. The lowest values were observed in regions close to crossing over or where the method was not able to discriminate between several origins due to their similarity. It is shown that the estimated probabilities were correctly calibrated. For marker imputation (or QTL allele prediction for fine mapping or genomic selection), the method was efficient, with 3.75% allelic imputation error rates on a dairy cattle data set with a low marker density map (1 SNP/Mb). The method should prove useful for situations we are facing now in experimental designs and in plant and animal breeding, where founders are genotyped with relatively high markers densities and last generation(s) genotyped with a lower-density panel.
Insights Into Mutagenesis Using Escherichia coli Chromosomal lacZ Strains That Enable Detection of a Wide Spectrum of Mutational Events
Authors: Seier Tracey , Padgett Dana R , Zilberberg Gal , Sutera Vincent A , Toha Noor , Lovett Susan T 
Published: March 2011

Abstract
Strand misalignments at DNA repeats during replication are implicated in mutational hotspots. To study these events, we have generated strains carrying mutations in the Escherichia coli chromosomal lacZ gene that revert via deletion of a short duplicated sequence or by template switching within imperfect inverted repeat (quasipalindrome, QP) sequences. Using these strains, we demonstrate that mutation of the distal repeat of a quasipalindrome, with respect to replication fork movement, is about 10-fold higher than the proximal repeat, consistent with more common template switching on the leading strand. The leading strand bias was lost in the absence of exonucleases I and VII, suggesting that it results from more efficient suppression of template switching by 3′ exonucleases targeted to the lagging strand. The loss of 3′ exonucleases has no effect on strand misalignment at direct repeats to produce deletion. To compare these events to other mutations, we have reengineered reporters (designed by Cupples and Miller 1989) that detect specific base substitutions or frameshifts in lacZ with the reverting lacZ locus on the chromosome rather than an F′ element. This set allows rapid screening of potential mutagens, environmental conditions, or genetic loci for effects on a broad set of mutational events. We found that hydroxyurea (HU), which depletes dNTP pools, slightly elevated templated mutations at inverted repeats but had no effect on deletions, simple frameshifts, or base substitutions. Mutations in nucleotide diphosphate kinase, ndk, significantly elevated simple mutations but had little effect on the templated class. Zebularine, a cytosine analog, elevated all classes.
Differential Contributions of Histone H3 and H4 Residues to Heterochromatin Structure
Authors: Yu Qun , Olsen Lars , Zhang Xinmin , Boeke Jef D , Bi Xin 
Published: March 2011

AbstractTranscriptional silencing in Saccharomyces cerevisiae is mediated by heterochromatin. There is a plethora of information regarding the roles of histone residues in transcriptional silencing, but exactly how histone residues contribute to heterochromatin structure is not resolved. We address this question by testing the effects of a series of histone H3 and H4 mutations involving residues in their aminoterminal tails, on the solvent-accessible and lateral surfaces of the nucleosome, and at the interface of the H3/H4 tetramer and H2A/H2B dimer on heterochromatin structure and transcriptional silencing. The general state, stability, and conformational heterogeneity of chromatin are examined with a DNA topology-based assay, and the primary chromatin structure is probed by micrococcal nuclease. We demonstrate that the histone mutations differentially affect heterochromatin. Mutations of lysine 16 of histone H4 (H4-K16) and residues in the LRS (loss of rDNA silencing) domain of nucleosome surface markedly alter heterochromatin structure, supporting the notion that H4-K16 and LRS play key roles in heterochromatin formation. Deletion of the aminoterminal tail of H3 moderately alters heterochromatin structure. Interestingly, a group of mutations in the globular domains of H3 and H4 that abrogate or greatly reduce transcriptional silencing increase the conformational heterogeneity and/or reduce the stability of heterochromatin without affecting its overall structure. Surprisingly, yet another series of mutations abolish or reduce silencing without significantly affecting the structure, stability, or conformational heterogeneity of heterochromatin. Therefore, histone residues may contribute to the structure, stability, conformational heterogeneity, or other yet-to-be-characterized features of heterochromatin important for transcriptional silencing.
Nitrogen Metabolite Repression of Metabolism and Virulence in the Human Fungal Pathogen Cryptococcus neoformans
Authors: Lee I Russel , Chow Eve W L , Morrow Carl A , Djordjevic Julianne T , Fraser James A 
Published: March 2011

Abstract
Proper regulation of metabolism is essential to maximizing fitness of organisms in their chosen environmental niche. Nitrogen metabolite repression is an example of a regulatory mechanism in fungi that enables preferential utilization of easily assimilated nitrogen sources, such as ammonium, to conserve resources. Here we provide genetic, transcriptional, and phenotypic evidence of nitrogen metabolite repression in the human pathogen Cryptococcus neoformans. In addition to loss of transcriptional activation of catabolic enzyme-encoding genes of the uric acid and proline assimilation pathways in the presence of ammonium, nitrogen metabolite repression also regulates the production of the virulence determinants capsule and melanin. Since GATA transcription factors are known to play a key role in nitrogen metabolite repression, bioinformatic analyses of the C. neoformans genome were undertaken and seven predicted GATA-type genes were identified. A screen of these deletion mutants revealed GAT1, encoding the only global transcription factor essential for utilization of a wide range of nitrogen sources, including uric acid, urea, and creatinine—three predominant nitrogen constituents found in the C. neoformans ecological niche. In addition to its evolutionarily conserved role in mediating nitrogen metabolite repression and controlling the expression of catabolic enzyme and permease-encoding genes, Gat1 also negatively regulates virulence traits, including infectious basidiospore production, melanin formation, and growth at high body temperature (39°–40°). Conversely, Gat1 positively regulates capsule production. A murine inhalation model of cryptococcosis revealed that the gat1Δ mutant is slightly more virulent than wild type, indicating that Gat1 plays a complex regulatory role during infection.