bluuebunny/crossref_metadata_2025_split huggingface dataset:
Familial hypophosphatemic rickets caused by a large deletion in PHEX gene
Authors: Saito Tasuku , Nishii Yutaka , Yasuda Toshiyuki , Ito Nobuaki , Suzuki Hisanori , Igarashi Takashi , Fukumoto Seiji , Fujita Toshiro 
Published: July 2009

ContextX-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated.ObjectiveTo clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets.Design and patientsThe proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected.ResultsSequencing of all coding exons and exon–intron junctions of DMP1 and FGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1–3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism.ConclusionCareful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.
Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study
Authors: Völzke Henry , Ittermann Till , Schmidt Carsten O , Dörr Marcus , John Ulrich , Wallaschofski Henri , Stricker Bruno H C , Felix Stephan B , Rettig Rainer 
Published: July 2009

ObjectivesThere is current controversy on the association between subclinical hyperthyroidism and hypertension. Data from cohort studies have not been available yet. The present study was designed to longitudinally investigate possible associations of subclinical hyperthyroidism with blood pressure, pulse pressure and the risk of hypertension.MethodsWe used data from the population-based, prospective cohort Study of Health in Pomerania and included 2910 subjects (1469 women) aged 20–79 years with completed 5-year examination follow-up. Subjects with increased serum TSH levels or overt hyperthyroidism were excluded. Serum TSH levels below 0.25 mIU/l with free triiodothyronine and free thyroxine levels within the reference range were defined as subclinical hyperthyroidism. Blood pressure was measured according to standard methods.ResultsMultivariable analyses adjusted for age, sex, overweight, obesity, smoking status and time between the examinations did not reveal any statistically significant association between subclinical hyperthyroidism and any of the blood pressure-related variables in the whole study population. Although the 5-year hypertension incidence was higher in subjects with subclinical hyperthyroidism compared with those without (31.4 vs 19.2%; risk ratio 1.64; 95% confidence interval (CI) 1.17–2.28, P=0.006), both groups did not differ with respect to the risk of hypertension, after analyses were adjusted for confounders (relative risk 1.23, 95% CI 0.91–1.68, P=0.182). Analyses yielded similar results in subjects without thyroid disease and in those who took no antihypertensive medication.ConclusionSubclinical hyperthyroidism is not associated with changes in blood pressure, pulse pressure or incident hypertension.
Ancestral Population Genomics: The Coalescent Hidden Markov Model Approach
Authors: Dutheil Julien Y , Ganapathy Ganesh , Hobolth Asger , Mailund Thomas , Uyenoyama Marcy K , Schierup Mikkel H 
Published: July 2009

AbstractWith incomplete lineage sorting (ILS), the genealogy of closely related species differs along their genomes. The amount of ILS depends on population parameters such as the ancestral effective population sizes and the recombination rate, but also on the number of generations between speciation events. We use a hidden Markov model parameterized according to coalescent theory to infer the genealogy along a four-species genome alignment of closely related species and estimate population parameters. We analyze a basic, panmictic demographic model and study its properties using an extensive set of coalescent simulations. We assess the effect of the model assumptions and demonstrate that the Markov property provides a good approximation to the ancestral recombination graph. Using a too restricted set of possible genealogies, necessary to reduce the computational load, can bias parameter estimates. We propose a simple correction for this bias and suggest directions for future extensions of the model. We show that the patterns of ILS along a sequence alignment can be recovered efficiently together with the ancestral recombination rate. Finally, we introduce an extension of the basic model that allows for mutation rate heterogeneity and reanalyze human–chimpanzee–gorilla–orangutan alignments, using the new models. We expect that this framework will prove useful for population genomics and provide exciting insights into genome evolution.
Is There Variation in Crossover Interference Levels Among Chromosomes From Human Males?
Authors: Housworth E A , Stahl F W 
Published: July 2009

Abstract
We demonstrate that recent data from human males are consistent with constant interference levels among chromosomes under the two-pathway model, whereas inappropriately fitting shape parameters of Gamma distributions to immunofluorescent interfoci distances observed on finite chromosomes generates false interpretations of higher levels of interference on shorter chromosomes. We provide appropriate statistical methodology.
KlAft, the Kluyveromyces lactis Ortholog of Aft1 and Aft2, Mediates Activation of Iron-Responsive Transcription Through the PuCACCC Aft-Type Sequence
Authors: Conde e Silva Natalia , Gonçalves Isabelle R , Lemaire Marc , Lesuisse Emmanuel , Camadro Jean Michel , Blaiseau Pierre Louis 
Published: July 2009

Abstract
Iron homeostasis in fungi is regulated at the transcriptional level by two different mechanisms. It is mediated by a conserved GATA-type repressor in most fungi except in the yeast Saccharomyces cerevisiae, where it is controlled by the transcription activators Aft1 and Aft2. These activators are encoded by the paralogous genes AFT1 and AFT2, which result from the whole-genome duplication. Here, we explore regulation of iron homeostasis in the yeast Kluyveromyces lactis that diverged from S. cerevisiae before this event. We identify an ortholog of AFT1/AFT2, designated KlAFT, whose deletion leads to the inability to grow under iron limitation. We show with quantitative real-time PCR analysis that KlAft activates the transcription of all homologs of the Aft1-target genes involved in the iron transport at the cell surface in response to iron limitation. However, homologs of Aft2-specific target genes encoding intracellular iron transporters are regulated neither by KlAft nor by iron. Both bioinformatic and DNA binding and transcription analyses demonstrate that KlAft activates iron-responsive gene expression through the PuCACCC Aft-type sequence. Thus, K. lactis is the first documented species with a positive iron-transcriptional control mediated by only one copy of the Aft-type regulator. This indicates that this function was acquired before the whole-genome duplication and was then diversified into two regulators in S. cerevisiae.
Polymorphisms in Multiple Genes Contribute to the Spontaneous Mitochondrial Genome Instability ofSaccharomyces cerevisiaeS288C Strains
Authors: Dimitrov Lazar N , Brem Rachel B , Kruglyak Leonid , Gottschling Daniel E 
Published: July 2009

AbstractThe mitochondrial genome (mtDNA) is required for normal cellular function; inherited and somatic mutations in mtDNA lead to a variety of diseases. Saccharomyces cerevisiae has served as a model to study mtDNA integrity, in part because it can survive without mtDNA. A measure of defective mtDNA in S. cerevisiae is the formation of petite colonies. The frequency at which spontaneous petite colonies arise varies by ∼100-fold between laboratory and natural isolate strains. To determine the genetic basis of this difference, we applied quantitative trait locus (QTL) mapping to two strains at the opposite extremes of the phenotypic spectrum: the widely studied laboratory strain S288C and the vineyard isolate RM11-1a. Four main genetic determinants explained the phenotypic difference. Alleles of SAL1, CAT5, and MIP1 contributed to the high petite frequency of S288C and its derivatives by increasing the formation of petite colonies. By contrast, the S288C allele of MKT1 reduced the formation of petite colonies and compromised the growth of petite cells. The former three alleles were found in the EM93 strain, the founder that contributed ∼88% of the S288C genome. Nearly all of the phenotypic difference between S288C and RM11-1a was reconstituted by introducing the common alleles of these four genes into the S288C background. In addition to the nuclear gene contribution, the source of the mtDNA influenced its stability. These results demonstrate that a few rare genetic variants with individually small effects can have a profound phenotypic effect in combination. Moreover, the polymorphisms identified in this study open new lines of investigation into mtDNA maintenance.
Candidate Gene Association Mapping of Arabidopsis Flowering Time
Authors: Ehrenreich Ian M , Hanzawa Yoshie , Chou Lucy , Roe Judith L , Kover Paula X , Purugganan Michael D 
Published: July 2009

Abstract
The pathways responsible for flowering time in Arabidopsis thaliana comprise one of the best characterized genetic networks in plants. We harness this extensive molecular genetic knowledge to identify potential flowering time quantitative trait genes (QTGs) through candidate gene association mapping using 51 flowering time loci. We genotyped common single nucleotide polymorphisms (SNPs) at these genes in 275 A. thaliana accessions that were also phenotyped for flowering time and rosette leaf number in long and short days. Using structured association techniques, we find that haplotype-tagging SNPs in 27 flowering time genes show significant associations in various trait/environment combinations. After correction for multiple testing, between 2 and 10 genes remain significantly associated with flowering time, with CO arguably possessing the most promising associations. We also genotyped a subset of these flowering time gene SNPs in an independent recombinant inbred line population derived from the intercrossing of 19 accessions. Approximately one-third of significant polymorphisms that were associated with flowering time in the accessions and genotyped in the outbred population were replicated in both mapping populations, including SNPs at the CO, FLC, VIN3, PHYD, and GA1 loci, and coding region deletions at the FRI gene. We conservatively estimate that ∼4–14% of known flowering time genes may harbor common alleles that contribute to natural variation in this life history trait.
The Population Genomics of Trans-Specific Inversion Polymorphisms in Anopheles gambiae
Authors: White Bradley J , Cheng Changde , Sangaré Djibril , Lobo Neil F , Collins Frank H , Besansky Nora J 
Published: July 2009

Abstract
In the malaria mosquito Anopheles gambiae polymorphic chromosomal inversions may play an important role in adaptation to environmental variation. Recently, we used microarray-based divergence mapping combined with targeted resequencing to map nucleotide differentiation between alternative arrangements of the 2La inversion. Here, we applied the same technique to four different polymorphic inversions on the 2R chromosome of An. gambiae. Surprisingly, divergence was much lower between alternative arrangements for all 2R inversions when compared to the 2La inversion. For one of the rearrangements, 2Ru, we successfully mapped a very small region (∼100 kb) of elevated divergence. For the other three rearrangements, we did not identify any regions of significantly high divergence, despite ample independent evidence from natural populations of geographic clines and seasonal cycling, and stable heterotic polymorphisms in laboratory populations. If these inversions are the targets of selection as hypothesized, we suggest that divergence between rearrangements may have escaped detection due to retained ancestral polymorphism in the case of the youngest 2R rearrangements and to extensive gene flux in the older 2R inversion systems that segregate in both An. gambiae and its sibling species An. arabiensis.
Spp382p Interacts with Multiple Yeast Splicing Factors, Including Possible Regulators of Prp43 DExD/H-Box Protein Function
Authors: Pandit Shatakshi , Paul Sudakshina , Zhang Li , Chen Min , Durbin Nicole , Harrison Susan M W , Rymond Brian C 
Published: July 2009

Abstract
Prp43p catalyzes essential steps in pre-mRNA splicing and rRNA biogenesis. In splicing, Spp382p stimulates the Prp43p helicase to dissociate the postcatalytic spliceosome and, in some way, to maintain the integrity of the spliceosome assembly. Here we present a dosage interference assay to identify Spp382p-interacting factors by screening for genes that when overexpressed specifically inhibit the growth of a conditional lethal prp38-1 spliceosome assembly mutant in the spp382-1 suppressor background. Identified, among others, are genes encoding the established splicing factors Prp8p, Prp9p, Prp11p, Prp39p, and Yhc1p and two poorly characterized proteins with possible links to splicing, Sqs1p and Cwc23p. Sqs1p copurifies with Prp43p and is shown to bind Prp43p and Spp382p in the two-hybrid assay. Overexpression of Sqs1p blocks pre-mRNA splicing and inhibits Prp43p-dependent steps in rRNA processing. Increased Prp43p levels buffer Sqs1p cytotoxicity, providing strong evidence that the Prp43p DExD/H-box protein is a target of Sqs1p. Cwc23p is the only known yeast splicing factor with a DnaJ motif characteristic of Hsp40-like chaperones. We show that similar to SPP382, CWC23 activity is critical for efficient pre-mRNA splicing and intron metabolism yet, surprisingly, this activity does not require the canonical DnaJ/Hsp40 motif. These and related data establish the value of this dosage interference assay for finding genes that alter cellular splicing and define Sqs1p and Cwc23p as prospective modulators of Spp382p-stimuated Prp43p function.
Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders
Authors: Atladóttir Hjördís Ó. , Pedersen Marianne G. , Thorsen Poul , Mortensen Preben Bo , Deleuran Bent , Eaton William W. , Parner Erik T. 
Published: July 2009

OBJECTIVES: Recent studies suggest that familial autoimmunity plays a part in the pathogenesis of ASDs. In this study we investigated the association between family history of autoimmune diseases (ADs) and ASDs/infantile autism. We perform confirmatory analyses based on results from previous studies, as well as various explorative analyses.
METHODS: The study cohort consisted of all of the children born in Denmark from 1993 through 2004 (689 196 children). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry. Information on ADs in parents and siblings of the cohort members was obtained from the Danish National Hospital Register. The incidence rate ratio of autism was estimated by using log-linear Poisson regression.
RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes.
CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.
No Change in the Age of Diagnosis for Fragile X Syndrome: Findings From a National Parent Survey
Authors: Bailey Donald B. , Raspa Melissa , Bishop Ellen , Holiday David 
Published: July 2009

OBJECTIVE: To determine recent trends in the diagnosis of children with fragile X syndrome (FXS) and identify factors associated with the timing of diagnosis.
METHODS: More than 1000 families of children with FXS participated in a national survey. Of these, 249 had their first child (213 boys, 36 girls) diagnosed between 2001 and 2007 and did not know about FXS in their family before diagnosis. These parents answered questions about the average age of first concerns, developmental delays, early intervention, and the FXS diagnosis. They also provided other information about their child and family, reported who made the diagnosis, and described ramifications for other children and extended family members.
RESULTS: The average age of FXS diagnosis of boys remained relatively stable across the 7-year period at ∼35 to 37 months. The 36 girls with full mutation were given the diagnosis at an average age of 41.6 months. A trend was noted in earlier diagnosis of developmental delay for boys in more recent years. Approximately 25% of the families of male children had a second child with the full mutation before the diagnosis was given to the first child; 14 (39%) of the 36 families of female children had a second child with the full mutation before the diagnosis.
CONCLUSIONS: Despite patient advocacy, professional recommendations regarding prompt referral for genetic testing, and increased exposure to information about FXS in the pediatric literature, no changes were detected in the age of diagnosis of FXS during the time period studied. Earlier identification in the absence of systematic screening will likely continue to be a challenge.
Decline and Change in Seasonality of US Rotavirus Activity After the Introduction of Rotavirus Vaccine
Authors: Tate Jacqueline E. , Panozzo Catherine A. , Payne Daniel C. , Patel Manish M. , Cortese Margaret M. , Fowlkes Ashley L. , Parashar Umesh D. 
Published: July 2009

BACKGROUND: In 2006, routine immunization of US infants against rotavirus was initiated. We assessed national, regional, and local trends in rotavirus testing and detection before and after vaccine introduction.
METHODS: We examined data for July 2000 through June 2008 from a national network of ∼70 US laboratories to compare geographical and temporal aspects of rotavirus season timing and peak activity. To assess trends in rotavirus testing and detection, we restricted the analyses to 33 laboratories that reported for ≥26 weeks per season from 2000 to 2008.
RESULTS: Nationally, the onset and peak of the 2007–2008 rotavirus season were delayed 15 and 8 weeks, respectively, compared with prevaccine seasons from 2000–2006. Delays were observed in each region. The 2007–2008 rotavirus season lasted 14 weeks compared with a median of 26 weeks during the prevaccine era. Of 33 laboratories, 32 reported fewer positive results and a lower proportion of positive test results in 2007–2008 compared with the median in 2000–2006, with a 67% decline in the number and a 69% decline in the proportion of rotavirus-positive test results. The proportion of positive test results in 2007–2008 compared with the median in 2000–2006 declined &gt;50% in 79% of the laboratories and &gt;75% in 39% of the laboratories.
CONCLUSIONS: The 2007–2008 US rotavirus season seems substantially delayed, shorter, and diminished in magnitude compared with seasons before vaccine implementation. The extent of change seems greater than expected on the basis of estimated vaccine coverage, suggesting indirect benefits to unvaccinated individuals. Monitoring in future seasons is needed to confirm these trends.
Gender Differences in Research Grant Applications for Pediatric Residents
Authors: Gordon Mary Beth , Osganian Stavroula K. , Emans S. Jean , Lovejoy Frederick H. 
Published: July 2009

OBJECTIVE: Recent studies have reported gender differences in research grant applications and funding outcomes for medical school faculty. Our goal was to determine whether similar patterns exist at the resident level and, if so, to explore possible explanations.
METHODS: We conducted a retrospective review of all applications to an internal, mentored research grant fund at a large academic pediatric residency program from 2003 to 2008. We determined whether gender differences existed for application characteristics and outcomes and defined significant predictors of success.
RESULTS: During the 5-year period, the fund supported 42 (66%) of 64 applications. Among all applicants, men were more likely than women to hold an advanced research degree. Men requested more money than women and obtained more favorable application scores. Funding success rates were not statistically different between male and female applicants. Among funded applicants, men received higher awards than women, although the percentage of requests funded was the same. In a multiple regression analysis, advanced degree was the significant independent predictor of successful funding outcome. Controlling for advanced degree attenuated the association between gender and timing of application, type of project, dollars requested, and dollars awarded; however, even after controlling for advanced degree, women had inferior grant scores compared with men.
CONCLUSIONS: Gender differences existed in research grant applications and funding among pediatric residents that mirrored faculty patterns. Among residents, these differences were explained in part by the correlation of male gender with holding an advanced research degree.