bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Balamuthia survivor
Authors: Vollmer Michael Eric , Glaser Carol 
Published: March 2016

Introduction:
This case report describes a human survivor of Balamuthia mandrillaris infection. This is a free-living amoeba that can cause infection with the devastating consequence of near universally fatal encephalitis. We report this case to demonstrate the possibility of recovery.

Case presentation:
A 26-year-old Hispanic male, a landscape gardener, presented to the hospital in March 2010 with a two month history of headache, visual disturbances and new-onset seizures. Brain imaging identified two enhancing central lesions and Balamuthia mandrillaris was later identified by brain biopsy. He received several months of various antimicrobials including miltefosine, a novel use of the drug in this disease at the time. Seven weeks into therapy, considerations were made to switch him to ‘comfort care’ because of worsening clinical status and seemingly lack of response to treatment. The patient finally demonstrated clinical and radiological improvement after eight weeks with modified therapy, despite experiencing some debilitating toxic effects likely to be related to antibiotics. Two years after his initial presentation he made a complete recovery.

Conclusion:

Balamuthia mandrillaris amoebic encephalitis is considered an almost universally fatal disease; this case demonstrates the possibility of recovery. This report outlines his treatment, drug toxicities and includes additional information regarding the therapeutic use of the drug miltefosine. Whether his survival is related to the specific antimicrobials used in this case is unknown and further investigation is warranted.
Topologically associated domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation
Authors: Harmston Nathan , Ing-Simmons Elizabeth , Tan Ge , Perry Malcolm , Merkenschlager Matthias , Lenhard Boris 
Published: March 2016

AbstractIn vertebrates and other Metazoa, developmental genes are found surrounded by dense clusters of highly conserved noncoding elements (CNEs). CNEs exhibit extreme levels of sequence conservation of unexplained origin, with many acting as long-range enhancers during development. Clusters of CNEs, termed genomic regulatory blocks (GRBs), define the span of regulatory interactions for many important developmental regulators. The function and genomic distribution of these elements close to important regulatory genes raises the question of how they relate to the 3D conformation of these loci. We show that GRBs, defined using clusters of CNEs, coincide strongly with the patterns of topological organisation in metazoan genomes, predicting the boundaries of topologically associating domains (TADs) at hundreds of loci. The set of TADs that are associated with high levels of non-coding conservation exhibit distinct properties compared to TADs called in chromosomal regions devoid of extreme non-coding conservation. The correspondence between GRBs and TADs suggests that TADs around developmental genes are ancient, slowly evolving genomic structures, many of which have had conserved spans for hundreds of millions of years. This relationship also explains the difference in TAD numbers and sizes between genomes. While the close correspondence between extreme conservation and the boundaries of this subset of TADs does not reveal the mechanism leading to the conservation of these elements, it provides a functional framework for studying the role of TADs in long-range transcriptional regulation.
RNA-seq based analysis of population structure within the maize inbred B73
Authors: Liang Zhikai , Schnable James C. 
Published: March 2016

AbstractB73 is a variety of maize (Zea mays ssp. mays) widely used in genetic, genomic, and phenotypic research around the world. B73 was also served as the reference genotype for the original maize genome sequencing project. The advent of large-scale RNA-sequencing as a method of measuring gene expression presents a unique opportunity to assess the level of relatedness among individuals identified as variety B73. The level of haplotype conservation and divergence across the genome were assessed using 27 RNA-seq data sets from 20 independent research groups in three countries. Several clearly distinct clades were identified among putatively B73 samples. A number of these blocks were defined by the presence of clearly defined genomic blocks containing a haplotype which did not match the published B73 reference genome. In a number of cases the relationship among B73 samples generated by different research groups recapitulated mentor/mentee relationships within the maize genetics community. A number of regions with distinct, dissimilar, haplotypes were identified in our study. However, when considering the age of the B73 accession – greater than 40 years – and the challenges of maintaining isogenic lines of a naturally outcrossing species, a strikingly high overall level of conservation was exhibited among B73 samples from around the globe.
Bridging the gap between genes and language deficits in schizophrenia: an oscillopathic approach
Authors: Murphy Elliot , Benítez-Burraco Antonio 
Published: March 2016

AbstractSchizophrenia is characterised by marked language deficits, but it is not clear how these deficits arise from gene mutations linked to or associated with the disease. The goal of this paper is to aid the bridging of the gap between genes and schizophrenia and, ultimately, give support to the view that it represents an abnormal ontogenetic itinerary for the human faculty of language, heavily rooted in the evolutionary processes that brought about modern language. To that end we will focus on how the schizophrenia brain processes language and, particularly, on its distinctive oscillatory profile during language processing: We will argue that brain rhythms constitute the best route to interpret language deficits in this condition and map them to neural dysfunction and risk alleles of the genes. Additionally, we will show that candidate genes for schizophrenia are overrepresented among the set of genes that are believed are important for the evolution of human language. These genes crucially include (and are related to) genes involved in brain rhythmicity. We will claim that this translational effort and the links we uncover may help develop an understanding of language evolution, along with the aetiology of schizophrenia, its clinical/linguistic profile, and its high prevalence among modern populations.
Using reciprocity for relating the simulation of transcranial current stimulation to the EEG forward problem
Authors: Wagner S. , Lucka F. , Vorwerk J. , Herrmann C.S. , Nolte G. , Burger M. , Wolters C.H. 
Published: March 2016

AbstractTo explore the relationship between transcranial current stimulation (tCS) and the electroencephalography (EEG) forward problem, we investigate and compare accuracy and efficiency of a reciprocal and a direct EEG forward approach for dipolar primary current sources both based on the finite element method (FEM), namely the adjoint approach (AA) and the partial integration approach in conjunction with a transfer matrix concept (PI). By analyzing numerical results, comparing to analytically derived EEG forward potentials and estimating computational complexity in spherical shell models, AA turns out to be essentially identical to PI. It is then proven that AA and PI are also algebraically identical even for general head models. This relation offers a direct link between the EEG forward problem and tCS. We then demonstrate how the quasi-analytical EEG forward solutions in sphere models can be used to validate the numerical accuracies of FEM-based tCS simulation approaches. These approaches differ with respect to the ease with which they can be employed for realistic head modeling based on MRI-derived segmentations. We show that while the accuracy of the most easy to realize approach based on regular hexahedral elements is already quite high, it can be significantly improved if a geometry-adaptation of the elements is employed in conjunction with an isoparametric FEM approach. While the latter approach does not involve any additional difficulties for the user, it reaches the high accuracies of surface-segmentation based tetrahedral FEM, which is considerably more difficult to implement and topologically less flexible in practice. Finally, in a highly realistic head volume conductor model and when compared to the regular alternative, the geometry-adapted hexahedral FEM is shown to result in significant changes in tCS current flow orientation and magnitude up to 45 degrees and a factor of 1.66, respectively.
Complex ancient genetic structure and cultural transitions in southern African populations
Authors: Montinaro Francesco , Busby George BJ , Gonzalez-Santos Miguel , Oosthuitzen Ockie , Oosthuizen Erika , Anagnostou Paolo , Destro-Bisol Giovanni , Pascali Vincenzo L , Capelli Cristian 
Published: March 2016

AbstractThe characterization of the structure of southern Africa populations has been the subject of numerous genetic, medical, linguistic, archaeological and anthropological investigations. Current diversity in the subcontinent is the result of complex episodes of genetic admixture and cultural contact between the early inhabitants and the migrants that have arrived in the region over the last 2,000 years. Here we analyze 1,856 individuals from 91 populations, comprising novel and available genotype data to characterize the genetic ancestry profiles of 631 individuals from 51 southern African populations. Combining local ancestry and allele frequency analyses we identify a tripartite, ancient, Khoesan-related genetic structure, which correlates with geography, but not with linguistic affiliation or subsistence strategy. The fine mapping of these components in southern African populations reveals admixture dynamics and episodes of cultural reversion involving several Khoesan groups and highlights different mixtures of ancestral components in Bantu speakers and Coloured individuals.
Synlet: an R package for systemically analyzing synthetic lethal RNA interference screen data
Authors: Shao Chunxuan , Westermann Frank , Höfer Thomas 
Published: March 2016

AbstractSummaryHigh-throughput synthetic lethal RNA interference (RNAi) screen experiments shed important insights on the filed of cancer researches and drug discovery, but a comprehensive software for analyzing the data was not available yet. We present synlet, an R package provided a complete pipeline to process the synthetic lethal RNAi screens data. Synlet provides several methods to access the screen quality, including Z’ factor and data visualization. B-score and fraction of control or samplesnormalizationmethods are implemented in the package. More importantly, synlet facilitates the process of hits selection by implementing several algorithms, providing the possibility to identify high confidence targets.AvailabilityThe source code is freely available in Bioconductor (http://bioconductor.org/).Contactc.shao@Dkfz-Heidelberg.de
Hybrid Discrete-Continuum Cellular Automaton (HCA) model of Prostate to Bone Metastasis
Authors: Araujo Arturo , Basanta David 
Published: March 2016

AbstractProstate to bone metastases induce a “vicious cycle” by promoting excessive osteoclast and osteoblast mediated bone degradation and formation that in turn yields factors that drive cancer growth. Recent advances defining the molecular mechanisms that control the vicious cycle have revealed new therapeutic targeting opportunities. However, given the complex temporal and simultaneous cellular interactions occurring in the bone microenvironment, assessing the impact of putative therapies is challenging. To this end, we have integrated biological and computational approaches to generate an accurate model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model faithfully reproduces the basic multicellular unit (BMU) bone coupling process and introduction of a single prostate cancer cell yields a vicious cycle that is similar in cellular composition and pathophysiology to models of prostate to bone metastasis.
The evolutionary fates of a large segmental duplication in mouse
Authors: Morgan Andrew P , Holt J Matthew , McMullan Rachel C , Bell Timothy A , Clayshulte Amelia M-F , Didion John P , Yadgary Liran , Thybert David , Odom Duncan T , Flicek Paul , McMillan Leonard , de Villena Fernando Pardo-Manuel 
Published: March 2016

ABSTRACTGene duplication and loss are major sources of genetic polymorphism in populations, and are important forces shaping the evolution of genome content and organization. We have reconstructed the origin and history of a 127 kbp segmental duplication,R2d, in the house mouse (Mus musculus). R2dcontains a single protein-coding gene,Cwc22. De novoassembly of both the ancestral (R2d1) and the derived (R2d2) copies reveals that they have been subject to non-allelic gene conversion events spanning tens of kilobases.R2d2is also a hotspot for structural variation: its diploid copy number ranges from zero in the mouse reference genome to more than 80 in wild mice sampled from around the globe. Hemizgyosity for high-copy-number alleles ofR2d2is associated inciswith meiotic drive, suppression of meiotic crossovers, and copy-number instability, with a mutation rate in excess of 1 per 100 transmissions in laboratory populations. We identify an additional 57 loci covering 0.8% of the mouse genome with patterns of sequence variation similar to those atR2d1andR2d2. Our results provide a striking example of allelic diversity generated by duplication and demonstrate the value ofde novoassembly in a phylogenetic context for understanding the mutational processes affecting duplicate genes.
Tissue culture as a source of replicates in non-model plants: variation in cold tolerance inArabidopsis lyratassp.petraea
Authors: Kenta Tanaka , Edwards Jessica E.M. , Butlin Roger K. , Burke Terry , Quick W. Paul , Urwin Peter , Davey Matthew P. 
Published: March 2016

AbstractWhilst genotype–environment interaction is increasingly receiving attention by ecologists and evolutionary biologists, such studies need genetically homogeneous replicates—a challenging hurdle in outcrossing plants. This could potentially be overcome by using tissue culture techniques. However, plants regenerated from tissue culture may show aberrant phenotypes and “somaclonal” variation. Here we examined the somaclonal variation due to tissue culturing using the response of the photosynthetic efficiency (chlorophyll fluorescence measurements forFv/Fm,Fv’/Fm’ and ΦPSII, representing maximum efficiency of photosynthesis for dark‐ and light-adapted leaves, and the actual electron transport operating efficiency, respectively) to cold treatment, compared to variation among half-sibling seedlings from three different families ofArabidopsis lyratassp.petraea. Somaclonal variation was limited and we could successfully detect within-family variation in change in chlorophyll fluorescence by cold shock with the help of tissue-culture derived replicates. Icelandic and Norwegian families exhibited higher chlorophyll fluorescence, suggesting higher cold tolerance, than a Swedish family. Although the main effect of tissue culture onFv/Fm,Fv’/Fm’ and ΦPSIIwas small, there were significant interactions between tissue culture and family, suggesting that the effect of tissue culture is genotype–specific. Tissue-cultured plantlets were less affected by cold treatment than seedlings, but to a different extent in each family. These interactive effects, however, were comparable to, or much smaller than the single effect of family. These results suggest that tissue culture is a useful method for obtaining genetically homogenous replicates for studying genotype–environment interaction related to adaptively relevant phenotypes, such as cold tolerance, in non-model outcrossing plants.
A little walk from physical to biological complexity: protein folding and stability
Authors: Pucci Fabrizio , Rooman Marianne 
Published: March 2016

AbstractAs an example of topic where biology and physics meet, we present the issue of protein folding and stability, and the development of thermodynamics-based bioinformatics tools that predict the stability and thermal resistance of proteins and the change of these quantities upon amino acid substitutions. These methods are based on knowledge-driven statistical potentials, derived from experimental protein structures using the inverse Boltzmann law. We also describe an application of these predictors, which contributed to the understanding of the mechanisms of aggregation of a particular protein known to cause a neuronal disease.
Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet
Authors: Viner Coby , Ishak Charles A. , Johnson James , Walker Nicolas J. , Shi Hui , Sjöberg-Herrera Marcela K. , Shen Shu Yi , Lardo Santana M. , Adams David J. , Ferguson-Smith Anne C. , De Carvalho Daniel D. , Hainer Sarah J. , Bailey Timothy L. , Hoffman Michael M. 
Published: March 2016

AbstractTranscription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult.Here, we developed methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We developed Cytomod to create modified genomic sequences and enhanced the Multiple EM for Motif Elicitation (MEME) Suite by adding the capacity to handle custom alphabets. We adapted the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet.Using these methods, we identified modification-sensitive transcription factor binding motifs. We confirmed established binding preferences, such as the preference of ZFP57 and C/EBPβ for methylated motifs and the preference of c-Myc for unmethylated E-box motifs. Using known binding preferences to tune model parameters, we discovered novel modified motifs for a wide array of transcription factors. Finally, we validated predicted binding preferences of OCT4 using cleavage under targets and release using nuclease (CUT&RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications.
Findingde novomethylated DNA motifs
Authors: Ngo Vu , Wang Mengchi , Wang Wei 
Published: March 2016

AbstractIncreasing evidence has shown that posttranslational modifications (PTMs) such as methylation and hydroxymethylation on cytosine would greatly impact the binding of transcription factors (TFs). However, there is a lack of motif finding algorithms with the function to search for motifs with PTMs. In this study, we expend on our previous motif finding pipeline Epigram to provide systematicde novomotif discovery and performance evaluation on methylated DNA motifs. Using the tool, we were able to identified methylated motifs inArabidopsisDAP-seq data that were previously demonstrated to contain such motifs1. When applied to TF ChIP-seq and DNA methylome data in H1 and GM12878, our method successfully identified novel methylated motifs that can be recognized by the TFs or their co-factors. We also observed spacing constraint between the canonical motif of the TF and the newly discovered methylated motifs, which suggests operative recognition of these cis-elements by collaborative proteins.
Hierarchical Association Coefficient Algorithm
Authors: Kim Bongsong 
Published: March 2016

AbstractSuppose that members in a universal set categorized based on observations, and that categories can be stratified based on the average of observations within each category. Two sorting extremes can be obtained from the perspective of arbitrariness of an order of observations. The first sorting extreme is an increasing order of observations on ascendingly stratified categories. The second sorting extreme is a decreasing order of observations on ascendingly stratified categories. Hierarchical association coefficient (HA-coefficient) algorithm is based on a principle that any order of observations in stratified categorization can be placed between the two sorting extremes. The algorithm produces a proportion of how much an order of observations in stratified categorization is close to the first sorting extreme, or how much an order of categorized observations is distant from the second sorting extreme. This paper introduces a theory about the HA-coefficient algorithm, and shows its applications with example data. In addition, proving a reliability of the algorithm is shown through a simulation.
Rethinking urban destination marketing
Authors: Heeley John 
Published: March 2016

Purpose
– The purpose of this paper is to trace the emergence of a dominant paradigm from within which academics and practitioners alike currently describe and otherwise explain urban destination marketing. The paradigm has been dubbed the “theory of marketing competitive advantage (CA)” by the author, and by others as the “4P’s marketing paradigm”. To effectively market themselves as tourism destinations, this paradigm requires towns and cities to differentiate themselves through the provision of more or less unique products, based on which they subsequently undertake branding, market positioning, distribution and other activities through bespoke destination marketing organisations (DMOs).

Design/methodology/approach
– The paper summarises the findings of: first, a review of the academic and practitioner literature on urban destination marketing; second, an online investigation of urban destination marketing in 62 European towns and cities, consulting the corporate and consumer pages of the relevant DMO website; and third, in-depth interviews with 20 senior DMO departmental executives. Each interview was recorded digitally for subsequent transcribing, and was conducted on the basis of a semi-structured interview schedule.

Findings
– Theory, as enshrined in the “4P’s marketing paradigm” rarely holds up in practice. Irrespective of whether or not a town or city possesses CA (and few do), DMO marketing gravitates almost inexorably towards a “marketing of everything”. Moreover, much the greater part of urban destination marketing is ineffective, failing to create visitors and deliver the commercial and economic returns on which it is premised. Against a backdrop of DMO marginality and ineffectiveness and a reluctance by them to market what is special and different about places, the continued existence of DMOs and the destination marketing they undertake is thrown into serious question.

Research limitations/implications
– Interpretation is unavoidably subjective in parts, drawing on personal experience as well as research undertaken.

Originality/value
– This paper is intended to give the reader an understanding of why success is so problematic in urban destination marketing, serving as an antidote to the prevailing idealised, normative and unproblematic picture of the DMO world as this is depicted from within the prevailing “4P’s marketing paradigm”. The research method provides a basis on which to unite theory and practice in the field of urban destination marketing in a more systematic and verifiable manner than has hitherto ever been the case.