bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloablation-associated deletion of ORF4 in a human coronavirus 229E infection
Authors: Greninger Alexander L. , Pepper Gregory , Shean Ryan C. , Cent Anne , Palileo Isabel , Kuypers Jane M. , Schiffer Joshua T. , Jerome Keith R. 
Published: March 2017

AbstractWe describe metagenomic next-generation sequencing (mNGS) of a human coronavirus 229E from a patient with AML and persistent upper respiratory symptoms, who underwent hematopoietic cell transplantation (HCT). mNGS revealed a 548-nucleotide deletion, which comprised the near entirety of the ORF4 gene, and no minor allele variants were detected to suggest a mixed infection. As part of her pre-HCT conditioning regimen, the patient received myeloablative treatment with cyclophosphamide and 12 Gy total body irradiation. Iterative sequencing and RT-PCR confirmation of 4 respiratory samples over the 4-week peritransplant period revealed that the pre-conditioning strain contained an intact ORF4 gene, while the deletion strain appeared just after conditioning and persisted over a 2.5-week period. This sequence represents one of the largest genomic deletions detected in a human RNA virus and describes large-scale viral mutation associated with myeloablation for HCT.
Cartilage microRNA dysregulation in mouse osteoarthritis overlaps with patient disease candidates
Authors: Kung Louise H. W. , Ravi Varshini , Rowley Lynn , Angelucci Constanza , Fosang Amanda J , Bell Katrina M , Little Christopher B , Bateman John F 
Published: March 2017

ABSTRACTTo explore the role of microRNAs in osteoarthritis (OA), we conducted microRNA expression profiling on micro-dissected tibial cartilage and subchondral bone in a mouse model of OA produced by medial meniscus destabilization (DMM). DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis and osteophyte formation. While subchondral bone showed no microRNA dysregulation, 139 microRNAs were differentially expressed in DMM cartilage at 1 and/or 6 weeks after OA initiation. To prioritize OA-candidates, dysregulated microRNAs with human orthologues were filtered using paired microRNA:mRNA expression analysis to identify those with corresponding changes in mRNA target transcripts in the DMM cartilage. An important cohort overlapped with microRNAs identified in human end-stage OA. Comparisons with microRNAs dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically-ablated demonstrated that all were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Our comprehensive analyses identified high-priority microRNA candidates that have potential as human OA-biomarkers and therapeutic targets.SUMMARYKung et al. conducted global analysis of microRNA dysregulation in joint tissues of a well-established mouse osteoarthritis model. Stringent filtering against human microRNA orthologues, integrated mRNA target analysis and comparison with published studies on human end-stage osteoarthritis identified microRNA candidates of potential clinical relevance.
Intratumor Heterogeneity and Circulating Tumor Cell Clusters
Authors: Ahmed Zafarali , Gravel Simon 
Published: March 2017

SummaryGenetic diversity plays a central role in tumor progression, metastasis, and resistance to treatment. Experiments are shedding light on this diversity at ever finer scales, but interpretation is challenging. Using recent progress in numerical models, we simulate macroscopic tumors to investigate the interplay between growth dynamics, microscopic composition, and circulating tumor cell cluster diversity. We find that modest differences in growth parameters can profoundly change microscopic diversity. Simple outwards expansion leads to spatially segregated clones and low diversity, as expected. However, a modest cell turnover can result in an increased number of divisions and mixing among clones resulting in increased microscopic diversity in the tumor core. Using simulations to estimate power to detect such spatial trends, we find that multiregion sequencing data from contemporary studies is marginally powered to detect the predicted effects. Slightly larger samples, improved detection of rare variants, or sequencing of smaller biopsies or circulating tumor cell clusters would allow one to distinguish between leading models of tumor evolution. The genetic composition of circulating tumor cell clusters, which can be obtained from non-invasive blood draws, is therefore informative about tumor evolution and its metastatic potential.HighlightsNumerical and theoretical models show interaction of front expansion, mutation, and clonal mixing in shaping tumor heterogeneity.Cell turnover increases intratumor heterogeneity.Simulated circulating tumor cell clusters and microbiopsies exhibit substantial diversity with strong spatial trends.Simulations suggest attainable sampling schemes able to distinguish between prevalent tumor growth models.
Signatures of natural selection in the drug metabolizing enzyme genes: Opportunity for developing personalized and precision medicine
Authors: Nizamuddin Sheikh , Thangaraj K. 
Published: March 2017

AbstractModern human experienced various selective pressures; including range of xenobiotics which contributed to heterogeneity of drug response. Many genes involve in pharmacokinetics and dynamics of drug, have been reported under natural selection. However, none of the studies have utilized comprehensive information of drug-centered PharmGKB pathways. We have extended this work and aimed to investigate sweep signals, using 1,798 subjects, from 53 Indian and 15 other world populations. We observed that modifiers which alters the biochemical function of other genes, have excess of natural selection (median std-z score=0.033±0.95; p-value=1.7×10−9-3.7×10−3). Taxane and statin primarily used for chemotherapy and lowering cholesterol level, respectively; and well known for heterogeneous drug response. We observed that pharmacokinetic pathway of taxane and statins are under natural selection (p-value=2.53×10−9and 2.73×10−9-1.09×10−4; q-value=1.28×10−7and 6.91×10−6-1.1×10−3). We also observed signal of selection in Ibuprofen pharmacokinetics (p-value=1.76×10−5; q-value =2.22×10−4), beta-agonist/beta-blocker pharmacodynamics (p-value=4.79×10−4; q-value =4.04×10−4) and Zidovudin pharmacokinetics/dynamic pathway (p-value=7.0×10−4; q-value =5.06×10−4). Hard sweeps signals were observed in a total of 322 loci. Of which, 53 affect mRNA expression (p-value<0.001) and 16 were already reported with therapeutic response. Interestingly, we observed that Africans have experience 2 phases of natural selection, one at ~30,000 another at ~10,000 years before present.
Reduced representation optical methylation mapping (R2OM2)
Authors: Grunwald Assaf , Sharim Hila , Gabrieli Tslil , Michaeli Yael , Torchinsky Dmitry , Arieli Rani , Juhasz Matyas , Wagner Kathryn R , Pevsner Jonathan , Reifenberger Jeff , Hastie Alex R , Cao Han , Weinhold Elmar , Ebenstein Yuval 
Published: March 2017

AbstractReduced representation methylation analysis utilizes a subset of CpGs in order to report the overall methylation status of the probed genomic regions. Here, we use this concept in order to create fluorescent optical methylation profiles along chromosomal DNA molecules for epigenetic profiling. Reduced representation optical methylation mapping (R2OM2) in combination with Bionano Genomics next generation genome mapping (NGM) technology provides a hybrid genetic/epigenetic genome map of individual chromosome segments spanning hundreds of kilobase pairs (kbp). These long reads, along with the single-molecule resolution, allow for epigenetic variation calling and methylation analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell next generation sequencing (NGS). We show that in addition to the inherent long-read benefits of R2OM2, it provides genomic methylation patterns comparable to whole genome bisulfite sequencing (WGBS) while retaining single-molecule information. The method is applied here to detect methylation along genes, around regulatory histone marks and to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number and methylation status of the disease-associated, highly repetitive locus onchromosome 4q.
REPARATION: Ribosome Profiling Assisted (Re-)Annotation of Bacterial genomes
Authors: Ndah Elvis , Jonckheere Veronique , Giess Adam , Valen Eivind , Menschaert Gerben , Van Damme Petra 
Published: March 2017

ABSTRACTProkaryotic genome annotation is highly dependent on automated methods, as manual curation cannot keep up with the exponential growth of sequenced genomes. Current automated methods depend heavily on sequence context and often underestimate the complexity of the proteome. We developed REPARATION (RibosomeE Profiling Assisted (Re-)AnnotaTION), ade novoalgorithm that takes advantage of experimental protein translation evidence from ribosome profiling (Ribo-seq) to delineate translated open reading frames (ORFs) in bacteria, independent of genome annotation. REPARATION evaluates all possible ORFs in the genome and estimates minimum thresholds based on a growth curve model to screen for spurious ORFs. We applied REPARATION to three annotated bacterial species to obtain a more comprehensive mapping of their translation landscape in support of experimental data. In all cases, we identified hundreds of novel (small) ORFs including variants of previously annotated ORFs. Our predictions were supported by matching mass spectrometry (MS) proteomics data, sequence composition and conservation analysis. REPARATION is unique in that it makes use of experimental translation evidence to performde novoORF delineation in bacterial genomes irrespective of the sequence context of the reading frame.
Representing Genetic Determinants in Bacterial GWAS with Compacted De Bruijn Graphs
Authors: Jaillard Magali , Tournoud Maud , Lima Leandro , Lacroix Vincent , Veyrieras Jean-Baptiste , Jacob Laurent 
Published: March 2017

AbstractMotivationAntimicrobial resistance has become a major worldwide public health concern, calling for a better characterization of existing and novel resistance mechanisms. GWAS methods applied to bacterial genomes have shown encouraging results for new genetic marker discovery. Most existing approaches either look at SNPs obtained by sequence alignment or consider sets of kmers, whose presence in the genome is associated with the phenotype of interest. While the former approach can only be performed when genomes are similar enough for an alignment to make sense, the latter can lead to redundant descriptions and to results which are hard to interpret.ResultsWe propose an alignment-free GWAS method detecting haplotypes of variable length associated to resistance, using compacted De Bruijn graphs. Our representation is flexible enough to deal with very plastic genomes subject to gene transfers while drastically reducing the number of features to explore compared to kmers, without loss of information. It accomodates polymorphisms in core genes, accessory genes and noncoding regions. Using our representation in a GWAS leads to the selection of a small number of entities which are easier to visualize and interpret than fixed-length kmers. We illustrate the benefit of our approach by describing known as well as potential novel determinants of antimicrobial resistance inP. aeruginosa,a pathogenic bacteria with a highly plastic genome.Availability and implementationThe code and data used in the experiments will be made available upon acceptance of this manuscript.Contactmagali.dancette@biomerieux.com
Development of a Novel CD4+TCR Transgenic Line that Reveals a Dominant Role for CD8+DC and CD40-Signaling in the Generation of Helper and CTL Responses to Blood Stage Malaria
Authors: Fernandez-Ruiz Daniel , Lau Lei Shong , Ghazanfari Nazanin , Jones Claerwen M , Ng Wei Yi , Davey Gayle M , Berthold Dorothee , Holz Lauren , Kato Yu , Bayarsaikhan Ganchimeg , Hendriks Sanne H. , James Kylie R , Cozijnsen Anton , Mollard Vanessa , de Koning-Ward Tania F , Gilson Paul R , Kaisho Tsuneyasu , Haque Ashraful , Crabb Brendan S , Carbone Francis R , McFadden Geoffrey I. , Heath William R 
Published: March 2017

AbstractWe describe an MHC II (IAb)-restricted T cell receptor (TCR) transgenic mouse line that produces CD4+T cells specific forPlasmodiumspecies. This line, termed PbT-II, was derived from a CD4+T cell hybridoma generated to blood-stagePlasmodium bergheiANKA (PbA). PbT-II cells responded to allPlasmodiumspecies and stages tested so far, including rodent (PbA,P. bergheiNK65,P. chabaudiAS andP. yoelii17XNL) and human (P.falciparum)blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of antibody toP. chabaudiinfection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+DC (a subset of XCR1+DC) were the major antigen presenting cell (APC) responsible for activation of both T cell subsets, though other DC also contributed to CD4+T cell responses. Depletion of CD8+DC at the beginning of infection prevented ECM development and impaired both Th1 and Tfh responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+T cell immunity during malaria and provides evidence that CD4+T cell help, acting via CD40L signalling, can promote immunity or pathology to blood stage malaria largely through antigen presentation by CD8+DC.
Rational design of proteins that exchange on functional timescales
Authors: Davey James A. , Damry Adam M. , Goto Natalie K. , Chica Roberto A. 
Published: March 2017

AbstractProteins are intrinsically dynamic molecules that can exchange between multiple conformational states, enabling them to carry out complex molecular processes with extreme precision and efficiency. Attempts to design novel proteins with tailored functions have mostly failed to yield efficiencies matching those found in nature because standard methods do not allow for the design of exchange between necessary conformational states on a functionally-relevant timescale. Here, we develop a broadly-applicable computational method to engineer protein dynamics that we term meta-multistate design. We used this methodology to design spontaneous exchange between two novel conformations introduced into the global fold of Streptococcal protein G domain β1. The designed proteins, named DANCERs, forDynamic And Native Conformational ExchangeRs, are stably folded and exchange between predicted conformational states on the millisecond timescale. The successful introduction of defined dynamics on functional timescales opens the door to new applications requiring a protein to spontaneously access multiple conformational states.
Determinants of participating in training: a Canadian-based analysis
Authors: Weaver Robert , Habibov Nazim 
Published: March 2017

PurposeThe purpose of this paper is to estimate and compare the across-time individual and contextual factors influencing the participation of Canadian residents in adult education and training during the 1990s and the early twenty-first century. This era is characterized by the social investment state (SIS), a policy paradigm adopted by various developed nations throughout the world, including Canada, during the latter part of the twentieth century.Design/methodology/approachThe authors analyzed data obtained from the 1994, 1998, and 2003 versions of the Adult Education and Training Survey, which is administered by Statistics Canada. They employed binomial logit regression so as to predict the likelihood of the respondents participating in training.FindingsParticipants whose level of education was below the post-secondary level were less likely to participate in training, as were adult residents of households in which pre-school children also lived. These findings occurred across all three periods of data collection. Furthermore, urban residents exhibited an increasingly greater likelihood to participate in training across-time.Research limitations/implicationsFuture studies should consider the funding source for training, be it from the public or private sector, and how this may affect participation. The impact that various types of training have on employment and earning patterns in developed nations should also be further assessed.Originality/valueThis study, with its use of the most recent available data to analyze across-time changes in the determinants of participating in training in Canada, has contributed to the knowledge base regarding the SIS in Canada and how it compares to its European counterparts.
Dual recombinant Lactococcus lactis for enhanced delivery of DNA vaccine reporter plasmid pPERDBY
Authors: Yagnik Bhrugu , Sharma Drashya , Padh Harish , Desai Priti 
Published: March 2017

ABSTRACTFood grade Lactococcus lactis has been widely used as an antigen and DNA delivery vehicle. We have previously reported the use of non‐invasive L. lactis to deliver the newly constructed immunostimulatory DNA vaccine reporter plasmid, pPERDBY. In the present report, construction of dual recombinant L. lactis expressing internalin A of Listeria monocytogenes and harboring pPERDBY (LL InlA + pPERDBY) to enhance the efficiency of delivery of DNA by L. lactis is outlined. After confirmation and validation of LL InlA + pPERDBY, its DNA delivery potential was compared with previously developed non‐invasive r‐ L. lactis::pPERDBY. The use of invasive L. lactis resulted in around threefold increases in the number of enhanced green fluorescent protein‐expressing Caco‐2 cells. These findings reinforce the prospective application of invasive strain of L. lactis for delivery of DNA/RNA and antigens.
Caregiver perceptions of inclusive playgrounds targeting toddlers and preschoolers with disabilities: has recent international and national policy improved overall satisfaction?
Authors: Stanton‐Chapman Tina L. , Schmidt Eric L. 
Published: March 2017

The purpose of the current study was to survey and interview caregivers of children with disabilities (ages 2–5 years) to obtain their input as to whether current playground equipment meets their child's needs. A total of 149 participants agreed to participate. Caregivers (i) indicated that their child with a disability could not fully participate in the playground's offerings, (ii) felt that the playground was not appropriate for their child with a disability and (iii) dreamed of a fully inclusive playground that met their child's needs. The results also demonstrate that social participation barriers continue to remain for families who have children with disabilities despite the passing of international human rights standards targeting individuals with disabilities and a global focus in improving the overall well‐being of children with disabilities.
Examining the physical and human dichotomy in geography: existing divisions and possible mergers in pedagogic outlooks
Authors: Dasgupta Rajarshi , Patel Priyank Pravin 
Published: March 2017

AbstractThe physical‐human dichotomy in geography is long standing, revolving around the topics studied and outlooks adopted by the two groups of geographers. Three reasons are identified for its continuation—the present structure of academic geography, constrained interactions between physical and human geographers, and their publication strategies. Critics suggest that physical and human geography have become divergent strains because the physical environment has been accorded little relevance in human geographic studies, also putting forward the failure of physical geographers to integrate the human influence on physical processes and neglecting space in their studies. Citing examples, this paper argues that physical and human geography influence each other. It also demonstrates that physical geographers have sufficiently considered both space and time, and even space‐time, through the concepts of scale and ergodicity. Some measures have been proposed to resuscitate the links between these two branches. These are reconnecting university and school geography, merging departments, teaching courses on geographical philosophies and theory building, engaging in integrative discourses, innovative classroom strategies, joint fieldwork, using geoinformatics, and conducting collaborative research. The paper concludes that physical and human geographers must communicate with each other more and engage in cross‐disciplinary studies. Otherwise, they might undermine their responsibilities as geographers and spatial thinkers/analysts.
Genome‐wide survey of nuclear protein‐coding markers for beetle phylogenetics and their application in resolving both deep and shallow‐level divergences
Authors: Che Li‐Heng , Zhang Shao‐Qian , Li Yun , Liang Dan , Pang Hong , Ślipiński Adam , Zhang Peng 
Published: March 2017

AbstractBeetles (Coleoptera) are the most diverse and species‐rich insect group, representing an impressive explosive radiation in the evolutionary history of insects, and their evolutionary relationships are often difficult to resolve. The amount of ‘traditional markers’ (e.g. mitochondrial genes and nuclearrDNAs) for beetle phylogenetics is small, and these markers often lack sufficient signals in resolving relationships for such a rapidly radiating lineage. Here, based on the available genome data of beetles and other related insect species, we performed a genome‐wide survey to search nuclear protein‐coding (NPC) genes suitable for research on beetle phylogenetics. As a result, we identified 1470 candidate loci, which provided a valuable data resource to the beetle evolutionary research community forNPCmarker development. We randomly chose 180 candidate loci from the database to design primers and successfully developed 95NPCmarkers which can bePCRamplified from standard genomicDNAextracts. These new nuclear markers are universally applicable across Coleoptera, with an average amplification success rate of 90%. To test the phylogenetic utility, we used them to investigate the backbone phylogeny of Coleoptera (18 families sampled) and the family Coccinellidae (39 species sampled). Both phylogenies are well resolved (average bootstrap support >95%), showing that our markers can be used to address phylogenetic questions of various evolutionary depth (from species level to family level). In general, the newly developed nuclear markers are much easier to use and more phylogenetically informative than the ‘traditional markers’, and show great potential to expedite resolution of many parts in the Beetle Tree of Life.
Integrative review of older adult loneliness and social isolation in Aotearoa/New Zealand
Authors: Wright‐St Clair Valerie A , Neville Stephen , Forsyth Vanessa , White Lindsey , Napier Sara 
Published: March 2017

ObjectiveTo conduct an integrative review of empirical studies of loneliness for older people in Aotearoa/New Zealand. Loneliness is a risk factor for older people's poor physical and cognitive health, serious illness and mortality. A national survey showed loneliness rates vary by gender and ethnicity.MethodsA systematic search of health and social science databases was conducted. Of 21 scrutinised articles, nine were eligible for inclusion and subjected to independent quality appraisal. One qualitative and eight quantitative research articles were selected.ResultsReported levels and rates of loneliness vary across age cohorts. Loneliness was significantly related to social isolation, living alone, depression, suicidal ideation, being female, being Māori and having a visual impairment. Qualitatively, older Korean immigrants experienced loneliness and social isolation, along with language and cultural differences.ConclusionAmongst older New Zealanders loneliness is commonly experienced by particular ethnic groups, highlighting a priority for targetted health and social services.