bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic overlap in the contribution of individual genes to CNV pathogenicity revealed by cross-species computational analysis of single-gene mutations in humans, mice and zebrafish
Authors: Doelken Sandra C. , Köhler Sebastian , Mungall Christopher J. , Gkoutos Georgios V. , Ruef Barbara J. , Smith Cynthia , Smedley Damian , Bauer Sebastian , Klopocki Eva , Schofield Paul N. , Westerfield Monte , Robinson Peter N. , Lewis Suzanna E. 
Published: October 2012

Summary
Numerous disease syndromes are associated with regions of copy number variation (CNV) in the human genome and, in most cases, the pathogenicity of the CNV is thought to be related to altered dosage of the genes contained within the affected segment. However, establishing the contribution of individual genes to the overall pathogenicity of CNV syndromes is difficult and often relies on the identification of potential candidates through manual searches of the literature and online resources. We describe here the development of a computational framework to comprehensively search phenotypic information from model organisms and single-gene human hereditary disorders, and thus speed the interpretation of the complex phenotypes of CNV disorders. There are currently more than 5000 human genes about which nothing is known phenotypically but for which detailed phenotypic information for the mouse and/or zebrafish orthologs is available. Here, we present an ontology-based approach to identify similarities between human disease manifestations and the mutational phenotypes in characterized model organism genes; this approach can therefore be used even in cases where there is little or no information about the function of the human genes. We applied this algorithm to detect candidate genes for 27 recurrent CNV disorders and identified 802 gene-phenotype associations, approximately half of which involved genes that were previously reported to be associated with the individual phenotypic features and half of which were novel candidates. A total of 431 associations were made solely on the basis of model organism phenotype data. Additionally, we observed a striking, statistically significant tendency for individual disease phenotypes to be associated with multiple genes located within a single CNV region, a phenomenon that we denote as pheno-clustering. Many of the clusters also display statistically significant similarities in protein function or vicinity within the protein-protein interaction network. Our results provide a basis for understanding previously un-interpretable genotype-phenotype correlations in pathogenic CNVs and for mobilizing the large amount of model organism phenotype data to provide insights into human genetic disorders.
Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage
Authors: Lévesque Mathieu , Feng Yi , Jones Rebecca , Martin Paul 
Published: October 2012

SummaryIn humans, skin is the largest organ serving as a barrier between our body and the outside world. Skin protects our internal organs from external pathogens and other contaminants, and melanocytes within the skin protect the body from damage by ultraviolet light. These same pigment cells also determine our skin colour and complexion. Skin wounding triggers a repair response that includes a robust recruitment of inflammatory cells, which function to kill invading microbes and clear away cell and matrix debris. Once at the wound site, these innate immune cells release a barrage of cytokines that direct the activities of other cells during the repair process. Tissue damage and repair also frequently lead to alterations in skin pigmentation, in particular to wound hyperpigmentation. In this study, we describe a model of wound hyperpigmentation in the translucent zebrafish larva, where we can live-image the recruitment of melanocytes and their precursors, melanoblasts, to the wound site. We show that these pigment cells are drawn in after the initial recruitment of innate immune cells and that the inflammatory response is essential for wound hyperpigmentation. This new model will allow us to uncover the molecular link between immune and pigment cells during tissue repair and to screen for potential therapeutics to dampen wound hyperpigmentation.
The emerging role of Polycomb repressors in the response to DNA damage
Authors: Vissers Joseph H. A. , van Lohuizen Maarten , Citterio Elisabetta 
Published: October 2012

SummaryPolycomb group (PcG) genes encode chromatin modifiers that are involved in the maintenance of cell identity and in proliferation, processes that are often deregulated in cancer. Interestingly, besides a role in epigenetic gene silencing, recent studies have begun to uncover a function for PcG proteins in the cellular response to DNA damage. In particular, PcG proteins have been shown to accumulate at sites of DNA double-strand breaks (DSBs). Several signaling pathways contribute to the recruitment of PcG proteins to DSBs, where they catalyze the ubiquitylation of histone H2A. The relevance of these findings is supported by the fact that loss of PcG genes decreases the efficiency of cells to repair DSBs and renders them sensitive to ionizing radiation. The recruitment of PcG proteins to DNA breaks suggests that they have a function in coordinating gene silencing and DNA repair at the chromatin flanking DNA lesions. In this Commentary, we discuss the current knowledge of the mechanisms that allow PcG proteins to exert their positive functions in genome maintenance.
Does the MRI or MRI contrast medium gadopentetate dimeglumine change the oxidant and antioxidant status in humans?
Authors: Olmaz Refik , Turgutalp Kenan , Oguz Ebru Gok , Horoz M , Ozhan Onur , Muslu Necati , Sungur Mehmet A , Kiykim Ahmet 
Published: October 2012

BackgroundIt has become evident that gadolinium-based contrast agents (GBCA) may have nephrotoxic potential. Oxidative stress is one of the most important pathways in the pathogenesis of iodinated contrast-induced nephropathy.PurposeTo investigate the effects of static magnetic fields and gadopentetate dimeglumine (Magnevist®) on oxidant/antioxidant status via measurement of total antioxidant capacity (TAC), total oxidant status (TOS), and serum malondialdehide (MDA).Material and MethodsTwo age- and sex-matched groups of patients not under oxidative stress conditions that underwent magnetic resonance imaging (MRI) were recruited to this study. While contrast-enhanced (Magnevist®, 0.2 mmol/kg) MRI was performed in group 1, MRI without GBCA was performed in group 2. Fasting blood glucose, C-reactive protein, serum creatinine, liver enzymes, uric acid, and lipid parameters were examined in all patients. Peripheral venous blood samples in order to determine TAC, TOS, and MDA were collected before and 6, 24, and 72 h after the MRI procedures. The TOS:TAC ratio was used as the oxidative stress index (OSI). Patients were followed up to 72 h.ResultsThere were no significant changes in serum TAC, TOS, and MDA levels (Δserum TAC, Δserum TOS, and ΔMDA) in either group 6, 24, or 72 h after the procedures (P > 0.05). Furthermore, OSI did not change after the procedures in either group (P > 0.05).ConclusionMagnetic field and gadopentetate dimeglumine (Magnevist®) do not change the oxidant or antioxidant status at a dose of 0.2 mmol/kg.
Restoring shoulder abduction in children with Erb’s palsy
Authors: Abdelaziz T. H. , Samir S. , Magdy W. 
Published: October 2012

A total of 35 children with Erb’s palsy and shoulder abduction of < 90° underwent transfer of teres major. In 18 cases (group 1) a trapezius transfer was added (combined procedure). In 17 cases (group 2) teres major transfer was carried out in isolation (single procedure). The mean gain in abduction was 67.2° (60° to 80°) in group 1 and 37.6° (20° to 70°) in group 2, which reached statistical significance (p < 0.001). Group 2 was further divided into those who had deltoid power of < M3 (group 2a) and those with deltoid power ≥ M3 (group 2b). The difference in improvement of abduction between groups 2a and group 2b was statistically significant (p < 0.001) but the difference between group 2b and group 1 was not (p = 0.07). We recommend the following protocol of management: in children with abduction ≥ 90° a single procedure is indicated. In children with abduction < 90°: a combined procedure is indicated if deltoid power is < M3 and a single procedure is indicated if deltoid power is ≥ M3. If no satisfactory improvement is achieved, the trapezius can be transferred at a later stage.
Empirical Bayesian Selection of Hypothesis Testing Procedures for Analysis of Sequence Count Expression Data
Authors: Pounds Stanley B. , Gao Cuilan L. , Zhang Hui 
Published: October 2012

Abstract
Differential expression analysis of sequence-count expression data involves performing a large number of hypothesis tests that compare the expression count data of each gene or transcript across two or more biological conditions. The assumptions of any specific hypothesis-testing method will probably not be valid for each of a very large number of genes. Thus, computational evaluation of assumptions should be incorporated into the analysis to select an appropriate hypothesis-testing method for each gene. Here, we generalize earlier work to introduce two novel procedures that use estimates of the empirical Bayesian probability (EBP) of overdispersion to select or combine results of a standard Poisson likelihood ratio test and a quasi-likelihood test for each gene. These EBP-based procedures simultaneously evaluate the Poisson-distribution assumption and account for multiple testing. With adequate power to detect overdispersion, the new procedures select the standard likelihood test for each gene with Poisson-distributed counts and the quasi-likelihood test for each gene with overdispersed counts. The new procedures outperformed previously published methods in many simulation studies. We also present a real-data analysis example and discuss how the framework used to develop the new procedures may be generalized to further enhance performance. An R code library that implements the methods is freely available at www.stjuderesearch.org/depts/biostats/software.
Detecting Differential Expression in RNA-sequence Data Using Quasi-likelihood with Shrunken Dispersion Estimates
Authors: Lund Steven P. , Nettleton Dan , McCarthy Davis J. , Smyth Gordon K. 
Published: October 2012

Abstract
Next generation sequencing technology provides a powerful tool for measuring gene expression (mRNA) levels in the form of RNA-sequence data. Method development for identifying differentially expressed (DE) genes from RNA-seq data, which frequently includes many low-count integers and can exhibit severe overdispersion relative to Poisson or binomial distributions, is a popular area of ongoing research. Here we present quasi-likelihood methods with shrunken dispersion estimates based on an adaptation of Smyth's (2004) approach to estimating gene-specific error variances for microarray data. Our suggested methods are computationally simple, analogous to ANOVA and compare favorably versus competing methods in detecting DE genes and estimating false discovery rates across a variety of simulations based on real data.
Optimization of Algorithms for Modeling Protein Structural Transitions from Sparse Long-Range Spin-Label Distance Constraints
Authors: Jeschke Gunnar 
Published: October 2012

Abstract
Function-related structural transitions of proteins are often large-scale conformational changes that are related to essential dynamics of a protein, which in turn proceeds along a small number of slow normal modes. Hence, it should be possible to characterize such transitions by an equally small number of distance constraints. These constraints should contain the information how the backbone coordinates move along the active normal modes. Such an approach based on residue-level elastic network models for the protein backbone is optimized with respect to the fit algorithm, constraint selection, and parametrization of the elastic network model. A stable fitting algorithm can be based on energy equipartitioning among the modes in the active space. This stabilization allows for extending active space dimension beyond the number of available constraints, which improves fit quality for transitions with a normal mode spectrum of only slowly increasing frequencies. In constraint selection, discrimination between the active normal modes appears to be more important than achieving large distance changes between initial and final structure. Parametrization of the network model has only a small influence on fit quality, as long as scaling of force constants with the inverse sixth power of the distance between network nodes is maintained. Elastic network models with a uniform force constant below a cutoff distance perform significantly worse. With 50 distance constraints, the optimized approach covers more than 50% of the structural change for 44% of all test cases, between 25 and 50% for 22% of the cases, and it fails for 33%.
Engineering Silkworms for Resistance to Baculovirus Through Multigene RNA Interference
Authors: Subbaiah Edupalli V , Royer Corinne , Kanginakudru Sriramana , Satyavathi Valluri V , Babu Adari Sobhan , Sivaprasad Vankadara , Chavancy Gérard , DaRocha Martine , Jalabert Audrey , Mauchamp Bernard , Basha Ibrahim , Couble Pierre , Nagaraju Javaregowda 
Published: October 2012

Abstract
Bombyx mori nucleopolyhedrovirus (BmNPV) that infects the silkworm, B. mori, accounts for &gt;50% of silk cocoon crop losses globally. We speculated that simultaneous targeting of several BmNPV essential genes in transgenic silkworm would elicit a stable defense against the virus. We introduced into the silkworm germline the vectors carrying short sequences of four essential BmNPV genes in tandem, either in sense or antisense or in inverted-repeat arrangement. The transgenic silkworms carrying the inverted repeat-containing transgene showed stable protection against high doses of baculovirus infection. Further, the antiviral trait was incorporated to a commercially productive silkworm strain highly susceptible to BmNPV. This led to combining the high-yielding cocoon and silk traits of the parental commercial strain and a very high level of refractoriness (&gt;75% survival rate as compared to &lt;15% in nontransgenic lines) to baculovirus infection conferred by the transgene. We also observed impaired infectivity of the occlusion bodies derived from the transgenic lines as compared to the wild-type ones. Currently, large-scale exploitation of these transgenic lines is underway to bring about economic transformation of sericulture.
Depleting Gene Activities in Early Drosophila Embryos with the “Maternal-Gal4–shRNA” System
Authors: Staller Max V , Yan Dong , Randklev Sakara , Bragdon Meghan D , Wunderlich Zeba B , Tao Rong , Perkins Lizabeth A , DePace Angela H , Perrimon Norbert 
Published: October 2012

Abstract
In a developing Drosophila melanogaster embryo, mRNAs have a maternal origin, a zygotic origin, or both. During the maternal–zygotic transition, maternal products are degraded and gene expression comes under the control of the zygotic genome. To interrogate the function of mRNAs that are both maternally and zygotically expressed, it is common to examine the embryonic phenotypes derived from female germline mosaics. Recently, the development of RNAi vectors based on short hairpin RNAs (shRNAs) effective during oogenesis has provided an alternative to producing germline clones. Here, we evaluate the efficacies of: (1) maternally loaded shRNAs to knockdown zygotic transcripts and (2) maternally loaded Gal4 protein to drive zygotic shRNA expression. We show that, while Gal4-driven shRNAs in the female germline very effectively generate phenotypes for genes expressed maternally, maternally loaded shRNAs are not very effective at generating phenotypes for early zygotic genes. However, maternally loaded Gal4 protein is very efficient at generating phenotypes for zygotic genes expressed during mid-embryogenesis. We apply this powerful and simple method to unravel the embryonic functions of a number of pleiotropic genes.
Evolutionary Branching in a Finite Population: Deterministic Branching vs. Stochastic Branching
Authors: Wakano Joe Yuichiro , Iwasa Yoh 
Published: October 2012

Abstract
Adaptive dynamics formalism demonstrates that, in a constant environment, a continuous trait may first converge to a singular point followed by spontaneous transition from a unimodal trait distribution into a bimodal one, which is called “evolutionary branching.” Most previous analyses of evolutionary branching have been conducted in an infinitely large population. Here, we study the effect of stochasticity caused by the finiteness of the population size on evolutionary branching. By analyzing the dynamics of trait variance, we obtain the condition for evolutionary branching as the one under which trait variance explodes. Genetic drift reduces the trait variance and causes stochastic fluctuation. In a very small population, evolutionary branching does not occur. In larger populations, evolutionary branching may occur, but it occurs in two different manners: in deterministic branching, branching occurs quickly when the population reaches the singular point, while in stochastic branching, the population stays at singularity for a period before branching out. The conditions for these cases and the mean branching-out times are calculated in terms of population size, mutational effects, and selection intensity and are confirmed by direct computer simulations of the individual-based model.
Effect of Porphyromonas gingivalis on Citrullination of Proteins by Macrophages In Vitro
Authors: Marchant Ceilidh , Smith Malcolm D. , Proudman Susanna , Haynes David R. , Bartold P. Mark 
Published: October 2012

Background: Citrullination of proteins within inflamed periodontal tissues may provide an important link between periodontitis and rheumatoid arthritis. The aim of this study is to determine whether the presence of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) can influence citrullination of proteins by either increasing the amount of local citrullinated protein or influencing the peptidylarginine deiminase (PAD) enzymes found in the monocyte/macrophage population.Methods: Human peripheral blood monocytes and macrophages were incubated in the presence of live or heat‐killed P. gingivalis. Expression of PAD2 and PAD4, PPAD, and citrullinated proteins were assessed by either a combination of real‐time polymerase chain reaction, Western blotting, or a colorimetric assay.Results: PPAD was detected only in mononuclear cells incubated in the presence of live P. gingivalis and resulted in increased extracellular citrullination. Endogenous PAD (mRNA and protein) expression was detected in monocytes and macrophages but was not affected by P. gingivalis.Conclusion: Although P. gingivalis produces a PAD that can citrullinate extracellular proteins and may contribute to the citrullinated protein load in gingival tissues, it does not appear to affect PAD expression or citrullination by host monocytes or macrophages.
Investigation of forelimb hoof wall strains and hoof shape in unshod horses exercised on a treadmill at various speeds and gaits
Authors: Bellenzani Maria C. R. , Merritt Jonathan S. , Clarke Sandy , Davies Helen M. S. 
Published: October 2012

Abstract
Objective—To investigate forelimb hoof wall strains and shape changes in unshod horses undergoing regular moderate exercise on a treadmill at selected speeds and gaits.
Animals—6 horses of various body types.
Procedures—Each horse was exercised on a treadmill (walking, trotting, and cantering, with or without galloping at 12.5 m/s) 3 times a week for 4 consecutive weeks; duration of each exercise session ranged from 10 to 14 minutes. During the 4-week period, the proximal hoof circumference (PHC) and toe angle (TA) of each forelimb hoof were measured weekly with a flexible measuring tape and a hoof gauge, respectively. Forelimb hoof wall strains were measured bilaterally at the toe and each quarter (3 strain gauges) immediately before the first and after the last exercise session.
Results—Strain measurements revealed a consistent pattern of deformation of the hoof wall in both forelimbs at all gaits; strains increased during the stance phase of the stride. Strain values were dependent on site and gait. Compared with initial findings, mean TA increased significantly, whereas mean PHC did not, after the 4-week exercise period. A relationship between TA changes and hoof wall strains could not be established.
Conclusions and Clinical Relevance—In unshod horses, forelimb hoof wall strains were affected by site and gait, but not by discrete changes in TA; PHC did not change in response to moderate regular exercise. The pattern of hoof loading was consistent despite significant changes in TA.
Mitochondrial dysfunction in myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy
Authors: Sleeper Meg M. , Rosato Bradley P. , Bansal Seema , Avadhani Narayan G. 
Published: October 2012

Abstract
Objective—To compare mitochondrial complex I and complex IV activity in myocardial mitochondria of clinically normal dogs, clinically normal dogs exposed to inhalation anesthesia, and dogs affected with dilated cardiomyopathy.
Sample—Myocardial samples obtained from 21 euthanized dogs (6 clinically normal [control] dogs, 5 clinically normal dogs subjected to inhalation anesthesia with isoflurane prior to euthanasia, 5 dogs with juvenile-onset dilated cardiomyopathy, and 5 dogs with adult-onset dilated cardiomyopathy).
Procedures—Activity of mitochondrial complex I and complex IV was assayed spectrophotometrically in isolated mitochondria from left ventricular tissue obtained from the 4 groups of dogs.
Results—Activity of complex I and complex IV was significantly decreased in anesthetized dogs, compared with activities in the control dogs and dogs with juvenile-onset or adult-onset dilated cardiomyopathy.
Conclusions and Clinical Relevance—Inhalation anesthesia disrupted the electron transport chain in the dogs, which potentially led to an outburst of reactive oxygen species that caused mitochondrial dysfunction. Inhalation anesthesia depressed mitochondrial function in dogs, similar to results reported in other species. This effect is important to consider when anesthetizing animals with myocardial disease and suggested that antioxidant treatments may be beneficial in some animals. Additionally, this effect should be considered when designing studies in which mitochondrial enzyme activity will be measured. Additional studies that include a larger number of animals are warranted.