bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping Bias Overestimates Reference Allele Frequencies at the HLA Genes in the 1000 Genomes Project Phase I Data
Authors: Brandt Débora Y C , Aguiar Vitor R C , Bitarello Bárbara D , Nunes Kelly , Goudet Jérôme , Meyer Diogo 
Published: March 2015

Abstract
Next-generation sequencing (NGS) technologies have become the standard for data generation in studies of population genomics, as the 1000 Genomes Project (1000G). However, these techniques are known to be problematic when applied to highly polymorphic genomic regions, such as the human leukocyte antigen (HLA) genes. Because accurate genotype calls and allele frequency estimations are crucial to population genomics analyses, it is important to assess the reliability of NGS data. Here, we evaluate the reliability of genotype calls and allele frequency estimates of the single-nucleotide polymorphisms (SNPs) reported by 1000G (phase I) at five HLA genes (HLA-A, -B, -C, -DRB1, and -DQB1). We take advantage of the availability of HLA Sanger sequencing of 930 of the 1092 1000G samples and use this as a gold standard to benchmark the 1000G data. We document that 18.6% of SNP genotype calls in HLA genes are incorrect and that allele frequencies are estimated with an error greater than ±0.1 at approximately 25% of the SNPs in HLA genes. We found a bias toward overestimation of reference allele frequency for the 1000G data, indicating mapping bias is an important cause of error in frequency estimation in this dataset. We provide a list of sites that have poor allele frequency estimates and discuss the outcomes of including those sites in different kinds of analyses. Because the HLA region is the most polymorphic in the human genome, our results provide insights into the challenges of using of NGS data at other genomic regions of high diversity.
Quantitative Genetics of Migration-Related Traits in Rainbow and Steelhead Trout
Authors: Hecht Benjamin C , Hard Jeffrey J , Thrower Frank P , Nichols Krista M 
Published: March 2015

Abstract
Rainbow trout (Oncorhynchus mykiss) exhibit remarkable life history diversity throughout their native range, and among the most evident is variation in migratory propensity. Although some populations and ecotypes will remain resident in freshwater habitats throughout their life history, others have the ability to undertake tremendous marine migrations. Those that migrate undergo a suite of behavioral, morphological, and physiological adaptations in a process called smoltification. We describe a quantitative genetic analysis of 22 growth, size, and morphological traits in addition to overall life history classification (resident or migrant) over the temporal process of smoltification in a large multi-generation experimental pedigree (n = 16,139) of migratory and resident rainbow trout derived from a wild population, which naturally segregates for migratory propensity. We identify significant additive genetic variance and covariance among the suite of traits that make up a component of the migratory syndrome in this species. Additionally, we identify high heritability estimates for the life history classifications and observe a strong negative genetic correlation between the migratory and resident life history trajectories. Given the large heritability estimates of all of the traits that segregate between migratory and resident rainbow trout, we conclude that these traits can respond to selection. However, given the high degree of genetic correlation between these traits, they do not evolve in isolation, but rather as a suite of coordinated characters in a predictable manner.
Charged/Polar-Residue Scanning of the Hydrophobic Face of Transmembrane Domain 9 of the Yeast Glutathione Transporter, Hgt1p, Reveals a Conformationally Critical Region for Substrate Transport
Authors: Thakur Anil , Bachhawat Anand K 
Published: March 2015

Abstract
Unraveling the mechanistic workings of membrane transporters has remained a challenging task. We describe a novel strategy that involves subjecting the residues of the hydrophobic face of a transmembrane helix to a charged/polar scanning mutagenesis. TMD9 of the yeast glutathione transporter, Hgt1p, has been identified as being important in substrate binding, and two residues, F523 and Q526, are expected to line the substrate translocation channel while the other face is hydrophobic. The hydrophobic face of TMD9 helix consists of residues A509, V513, L517, L520, I524, and I528, and these were mutated to lysine, glutamine, and glutamic acid. Among the 16 charged mutants created, six were nonfunctional, revealing a surprising tolerance of charged residues in the hydrophobic part of TM helices. Furthermore, the only position that did not tolerate any charged residue was I524, proximal to the substrate binding residues. However, P525, also proximal to the substrate binding residues, did tolerate charged/polar residues, suggesting that mere proximity to the substrate binding residues was not the only factor. The I524K/E/Q mutants expressed well and localized correctly despite lacking any glutathione uptake capability. Isolation of suppressors for all nonfunctional mutants yielded second-site suppressors only for I524K and I524Q, and suppressors for these mutations appeared at G202K/I and G202K/Q, respectively. G202 is in the hydrophilic loop between TMD3 and TMD4. The results suggest that I524 in the hydrophobic face interacts with this region and is also in a conformationally critical region for substrate translocation.
The Maintenance of Single-Locus Polymorphism by Maternal Selection
Authors: Spencer Hamish G , Chiew Kai X 
Published: March 2015

AbstractPopulation geneticists have long been interested in the ability of natural selection to maintain the levels of standing variation observed in natural populations. Here, we study the polymorphism-maintaining properties of maternal selection, in which the fitness of an individual is a function of its own and its mother’s genotype. Using a model proposed by Gavrilets, we first estimate the proportion of parameter/state space that preserves allelic variation, before investigating the construction of polymorphism over time through the joint action of mutation and selection. These two methods, the “parameter-space” and “constructionist” approaches, respectively, enable us to draw some general conclusions. We argue that, even though the proportion of parameter-state space allowing multiallele polymorphism is greater under maternal selection than under the standard model of constant viability selection, the former is, in fact, less likely to maintain large numbers of alleles. Nevertheless, variation that is balanced by maternal selection is likely to show elements of heterozygous advantage and be resistant to depletion by genetic drift. We observe that the population mean fitness frequently decreases after the successful invasion of a new mutation, but such declines are usually temporary.
Discs large 5, an Essential Gene inDrosophila, Regulates Egg Chamber Organization
Authors: Reilly Eve , Changela Neha , Naryshkina Tatyana , Deshpande Girish , Steward Ruth 
Published: March 2015

AbstractDiscs large 5 (Dlg5) is a member of the MAGUK family of proteins that typically serve as molecular scaffolds and mediate signaling complex formation and localization. In vertebrates, Dlg5 has been shown to be responsible for polarization of neural progenitors and to associate with Rab11-positive vesicles in epithelial cells. In Drosophila, however, the function of Dlg5 is not well-documented. We have identified dlg5 as an essential gene that shows embryonic lethality. dlg5 embryos display partial loss of primordial germ cells (PGCs) during gonad coalescence between stages 12 and 15 of embryogenesis. Loss of Dlg5 in germline and somatic stem cells in the ovary results in the depletion of both cell lineages. Reduced expression of Dlg5 in the follicle cells of the ovary leads to a number of distinct phenotypes, including defects in egg chamber budding, stalk cell overgrowth, and ectopic polar cell induction. Interestingly, loss of Dlg5 in follicle cells results in abnormal distribution of a critical component of cell adhesion, E-cadherin, shown to be essential for proper organization of egg chambers.
Gefitinib and Erlotinib in Metastatic Non-Small Cell Lung Cancer: A Meta-Analysis of Toxicity and Efficacy of Randomized Clinical Trials
Authors: Burotto Mauricio , Manasanch Elisabet E. , Wilkerson Julia , Fojo Tito 
Published: March 2015

Abstract

Background.
Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC.

Methods.
We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies.

Results.
We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations.

Conclusion.
Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC.
Aprepitant and Fosaprepitant: A 10-Year Review of Efficacy and Safety
Authors: Aapro Matti , Carides Alexandra , Rapoport Bernardo L. , Schmoll Hans-Joachim , Zhang Li , Warr David 
Published: March 2015

AbstractChemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT3) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK1 RA) aprepitant and its prodrug fosaprepitant. NK1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV. This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented.
Changes in Gene Expression in Responders and Nonresponders to a Low-Intensity Walking Intervention
Authors: Osler Megan E. , Fritz Tomas , Caidahl Kenneth , Krook Anna , Zierath Juleen R. , Wallberg-Henriksson Harriet 
Published: March 2015

OBJECTIVE
Daily physical activity remains an effective strategy to prevent obesity and type 2 diabetes. However, the metabolic response to exercise training is variable, and the precise clinical and molecular determinants that mark the metabolic improvements remain unknown. We tested the hypothesis that clinical improvements in glucose control after low-intensity exercise in individuals with impaired glucose tolerance (IGT) are coupled to alterations in skeletal muscle gene expression.

RESEARCH DESIGN AND METHODS
We investigated 14 overweight individuals with IGT before and after a 4-month low-intensity unsupervised walking exercise intervention. Clinical and anthropometric measurements and glucose tolerance were determined before and after the intervention. Skeletal muscle biopsy specimens were obtained for mRNA expression analysis.

RESULTS
Waist circumference and work capacity during cycle ergometry were improved in individuals who achieved normal glucose tolerance (NGT) after exercise training (IGT-NGT; n = 9) but in not individuals who remained IGT (IGT-IGT; n = 5). Pretraining glycemic control was better in IGT-NGT compared with IGT-IGT. mRNA expression of mitochondrial markers and transcription factors was increased in IGT-NGT after exercise intervention and normalized to levels measured in a separate cohort of nonexercised individuals with NGT. Conversely, these markers were unaltered after exercise intervention in IGT-IGT.

CONCLUSIONS
Normalization of metabolic control can be achieved after low-intensity exercise in individuals with IGT. This can be tracked with increased mRNA expression of mitochondrial and metabolic genes in skeletal muscle. However, for individuals presenting with a greater derangement in glycemia, the potential for clinical and metabolic improvements after this low-intensity unsupervised exercise protocol appears to be limited.
Réécritures posthumes de Tchicaya U Tam’si entre Brazzaville et Pointe-Noire
Authors: Leroux Pierre 
Published: March 2015

L'œuvre théâtrale de l'auteur congolais Tchicaya U Tam'si (1931-1988) se résume à trois textes : Le Zulu, Le Destin glorieux du Maréchal Nnikon-Nniku prince qu'on sort et Le Bal de Ndinga. Cependant, les nombreuses adaptations pour la scène de romans, nouvelles et autres ensembles de poésies témoignent de la volonté qu'ont eue certains artistes congolais ou français de se réapproprier l'héritage du « père de notre rêve ». Au travers de l'examen de trois spectacles montés à Brazzaville et à Pointe-Noire, cet article tente de montrer comment la scène transforme les textes et comment l'auteur lui-même devient un personnage représenté et fantasmé.
Le Kongo de Sony Labou Tansi
Authors: Gahungu Céline 
Published: March 2015

Les textes inédits de Sony Labou Tansi proposent une réflexion sur l’histoire, et plus singulièrement sur celle du Kongo. Le souvenir du prestigieux royaume apparaît dès les premiers manuscrits, composés au début des années 1970. Loin d’être circonscrit aux écrits de jeunesse, le Kongo surgit sous de multiples formes dans le dédale des textes rédigés au cours des années suivantes. Cette fascination pousse l’écrivain dans une dynamique de recherche esthétique : comment évoquer cet illo tempore mythique sans sacrifier à une historicité convenue ? Comment inventer une écriture en mesure de rendre compte du fabuleux royaume ?L’analyse littéraire ne peut cependant faire fi du contexte politique dans lequel Sony Labou Tansi s’inscrit. Outre sa dimension historique et toponymique, Kongo est un ethnonyme dont l’auteur s’est réclamé. Celui-ci a revendiqué à de nombreuses reprises son appartenance à une identité kongo au point de s’être engagé, à la fin des années 1980, dans les rangs du MCDDI1. Ce discours identitaire et l’adhésion à un parti ethnique ont troublé l’image d’un auteur volontiers perçu comme un démocrate véritable. Est-il possible d’articuler le Kongo littéraire et le Kongo politique ? Le Kongo, dont l’ombre portée apparaît dans les manuscrits littéraires mais également dans les articles et les déclarations politiques, pourrait-il nous aider à saisir les enjeux de l’écriture protéiforme de Sony Labou Tansi ?
La bande dessinée Congo 50 ou la mémoire collective d’une indépendance difficile
Authors: Federici Sandra 
Published: March 2015

Dans la bande dessinée Congo 50, Roularta Books et Africalia, 2010, publiée à l’occasion du cinquantenaire de l’indépendance du Congo, huit auteurs de l’association BD Kin Label racontent l’histoire des cinquante ans d’indépendance de leur pays, sous la coordination du scénariste français Alain Brezault et la direction artistique du dessinateur congolais Asimba Bathy. Recueilli dans des archives numériques, le processus de genèse des idées et de la fabrication de l’album se fonde sur la recherche d’un équilibre entre le rôle et le poids respectifs des différents agents qui ont contribué au projet. Cette œuvre collective peut être considérée comme paradigmatique d’un type de production artistique assez pratiquée en Afrique, qui consiste en la création de produits culturels « du Sud » sous l’impulsion d’une commande institutionnelle « du Nord ».
Silencing IFN-γ Binding/Signaling in Astrocytes versus Microglia Leads to Opposite Effects on Central Nervous System Autoimmunity
Authors: Ding Xiaoli , Yan Yaping , Li Xing , Li Ke , Ciric Bogoljub , Yang Jingxian , Zhang Yuan , Wu Shuai , Xu Hui , Chen Wanjun , Lovett-Racke Amy E. , Zhang Guang-Xian , Rostami Abdolmohamad 
Published: March 2015

Abstract
IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-γ binding/signaling in astrocytes and microglia, and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-γ binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells.
Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region
Authors: He Minghui , Cortizas Elena M. , Verdun Ramiro E. , Severinson Eva 
Published: March 2015

Abstract
Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (&lt;3.5 h), a total cell cycle time of ∼11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.
Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules
Authors: Sadeghi Hengameh , Lockmann Anike , Hund Anna-Carina , Samavedam Unni K. S. R. L. , Pipi Elena , Vafia Katerina , Hauenschild Eva , Kalies Kathrin , Pas Hendri H. , Jonkman Marcel F. , Iwata Hiroaki , Recke Andreas , Schön Michael P. , Zillikens Detlef , Schmidt Enno , Ludwig Ralf J. 
Published: March 2015

Abstract
Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R–deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti–IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R–deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1–stimulated, but not on TNF-α–stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11–deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti–IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.