bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting late-onset Alzheimer’s disease from genomic data using deep neural networks
Authors: de Velasco Oriol Javier , Vallejo Edgar E. , Estrada Karol ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: May 2019

AbstractAlzheimer’s disease (AD) is the leading form of dementia. Over 25 million cases have been estimated worldwide and this number is predicted to increase two-fold every 20 years. Even though there is a variety of clinical markers available for the diagnosis of AD, the accurate and timely diagnosis of this disease remains elusive. Recently, over a dozen of genetic variants predisposing to the disease have been identified by genome-wide association studies. However, these genetic variants only explain a small fraction of the estimated genetic component of the disease. Therefore, useful predictions of AD from genetic data could not rely on these markers exclusively as they are not sufficiently informative predictors. In this study, we propose the use of deep neural networks for the prediction of late-onset Alzheimer’s disease from a large number of genetic variants. Experimental results indicate that the proposed model holds promise to produce useful predictions for clinical diagnosis of AD.
Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B1-associated DNA Damage
Authors: St. John Nick , Freedland Julian , Baldino Henri , Doyle Frank , Cera Cinzia , Begley Thomas , Fasullo Michael 
Published: May 2019

ABSTRACTExposure to the mycotoxin aflatoxin B1 (AFB1) strongly correlates with hepatocellular carcinoma. P450 enzymes convert AFB1into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) DNA adducts, which convert to stable mutagenic AFB1formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB1is a weak mutagen but a potent recombinagen. However, few genes have been identified that confer AFB1resistance. Here, we profiled the yeast genome for AFB1resistance. We introduced the human CYP1A2 into ∼90% of the diploid deletion library, and pooled samples from CYP1A2-expressing libraries and the original library were exposed to 50 μM AFB1for 20 hs. By using next generation sequencing to count molecular barcodes, we identified 85 AFB1resistant genes from the CYP1A2-expressing libraries. While functionally diverse genes, including those that function in proteolysis, actin reorganization, and tRNA modification, were identified, those that function in post-replication DNA repair and encode proteins that bind to DNA damage were over-represented, compared to the yeast genome, at large. DNA metabolism genes included those functioning in DNA damage tolerance, checkpoint recovery and replication fork maintenance, emphasizing the potency of the mycotoxin to trigger replication stress. Among genes involved in error-free DNA damage tolerance, we observed thatCSM2, a member of theCSM2(SHU)complex, functioned in AFB1-associated sister chromatid recombination while suppressing AFB1-associated mutations. These studies thus broaden the number of AFB1resistant genes and have elucidated a mechanism of error-free bypass of AFB1-associated DNA adducts.
DNA sequence is a major determinant of tetrasome dynamics
Authors: Ordu O. , Lusser A. , Dekker N. H. 
Published: May 2019

ABSTRACTEukaryotic genomes are hierarchically organized into protein-DNA assemblies for compaction into the nucleus. Nucleosomes, with the (H3-H4)2tetrasome as a likely intermediate, are highly dynamic in nature by way of several different mechanisms. We have recently shown that tetrasomes spontaneously change the direction of their DNA wrapping between left- and right-handed conformations, which may prevent torque build-up in chromatin during active transcription or replication. DNA sequence has been shown to strongly affect nucleosome positioning throughout chromatin. It is not known, however, whether DNA sequence also impacts the dynamic properties of tetrasomes. To address this question, we examined tetrasomes assembled on a high-affinity DNA sequence using freely orbiting magnetic tweezers. In this context, we also studied the effects of mono- and divalent salts on the flipping dynamics. We found that neither DNA sequence nor altered buffer conditions affect overall tetrasome structure. In contrast, tetrasomes bound to high-affinity DNA sequences showed significantly altered flipping kinetics, predominantly via a reduction in the lifetime of the canonical state of left-handed wrapping. Increased mono- and divalent salt concentrations counteracted this behaviour. Thus, our study indicates that high-affinity DNA sequences impact not only the positioning of the nucleosome, but that they also endow the subnucleosomal tetrasome with enhanced conformational plasticity. This may provide a means to prevent histone loss upon exposure to torsional stress, thereby contributing to the integrity of chromatin at high-affinity sites.STATEMENT OF SIGNIFICANCECanonical (H3-H4)2tetrasomes possess high conformational flexibility, as evidenced by their spontaneous flipping between states of left- and right-handed DNA wrapping. Here, we show that these conformational dynamics of tetrasomes cannot be described by a fixed set of rates over all conditions. Instead, an accurate description of their behavior must take into account details of their loading, in particular the underlying DNA sequence.In vivo, differences in tetrasome flexibility could be regulated by modifications of the histone core or the tetrasomal DNA, and as such constitute an intriguing, potentially adjustable mechanism for chromatin to accommodate the torsional stress generated by processes such as transcription and replication.
Developmentally Regulated Genome Editing in Terminally Differentiated N2-Fixing Heterocysts ofAnabaena cylindricaATCC 29414
Authors: Qiu Yeyan , Gu Liping , Tian Shengni , Sidhu Jagdeep , Gibbons Jaimie , Van Den Top Trevor , Gonzalez-Hernandez Jose L. , Zhou Ruanbao 
Published: May 2019

AbstractSome vegetative cells ofAnabaena cylindricaare programed to differentiate semi-regularly spaced, single heterocysts along filaments. Since heterocysts are terminally differentiated non-dividing cells, with the sole known function for solar-powered N2-fixation, is it necessary for a heterocyst to retain the entire genome (≈7.1 Mbp) from its progenitor vegetative cell? By sequencing the heterocyst genome, we discovered and confirmed that at least six DNA elements (≈0.12 Mbp) are deleted during heterocyst development. The six-element deletions led to the restoration of five genes (nifH1,nifD,hupL,primase P4and a hypothetical protein gene) that were interrupted in vegetative cells. The deleted elements contained 172 genes present in the genome of vegetative cells. By sequence alignments of intactnifgenes (nifH,nifDandhupL) from N2-fixing cyanobacteria (multicellular and unicellular) as well as other N2-fixing bacteria (non-cyanobacteria), we found that interruptednifgenes all contain the conserved core sequences that may be required for phage DNA insertion. Here, we discuss thenifgenes interruption which uniquely occurs in heterocyst-forming cyanobacteria. To our best knowledge, this is first time to sequence the genome of heterocyst, a specially differentiated oxic N2-fixing cell. This research demonstrated that (1) different genomes may occur in distinct cell types in a multicellular bacterium; and (2) genome editing is coupled to cellular differentiation and/or cellular function in a heterocyst-forming cyanobacterium.
Computational and experimental optimization of T cell activation
Authors: Aksoy Bulent Arman , Czech Eric , Paulos Chrystal , Hammerbacher Jeff 
Published: May 2019

AbstractBead-based activation is widely-used for ex vivo expansion of T cells for either research or clinical purposes. Despite its wide use, culture conditions that can potentially affect the efficiency of bead-based T cell activation has not been extensively documented. With the help of computationally-driven experimental investigations of basic culturing factors, we found that culture density, bead-to-cell ratio, and debeading time can have a major impact on the efficiency of bead-based T cell activation for short-term cultures. Furthermore, discrepancies across expected and observed activation efficiencies helped discover interesting artifacts of bead-based T cell activation.Human primary T cells were imaged together with activation beads at 20X magnification after three hours of culturing at varying confluencies and bead-to-cell ratios.
Pseudomonas aeruginosalectin LecB impairs keratinocyte fitness by abrogating growth factor signalling
Authors: Landi Alessia , Mari Muriel , Wolf Tobias , Kleiser Svenja , Gretzmeier Christine , Wilhelm Isabel , Kiritsi Dimitra , Thünauer Roland , Geiger Roger , Nyström Alexander , Reggiori Fulvio , Claudinon Julie , Römer Winfried 
Published: May 2019

AbstractLectins are glycan-binding proteins with no catalytic activity and ubiquitously expressed in nature. Numerous bacteria employ lectins to efficiently bind to epithelia, thus facilitating tissue colonisation. Wounded skin is one of the preferred niches forPseudomonas aeruginosa, which has developed diverse strategies to impair tissue repair processes and promote infection.Here, we analyse the effect of theP. aeruginosafucose-binding lectin LecB on human keratinocytes and demonstrate that it triggers events in the host, upon binding to fucosylated residues on cell membrane receptors, that extend beyond its role as an adhesion molecule. We found that LecB associates with several growth factor receptors and dampens their signalling pathways, leading to the arrest of cell cycle. Additionally, we describe a novel LecB-triggered mechanism to downregulate host cell receptors by showing that LecB leads to insulin-like growth factor receptor 1 internalisation, without receptor activation, and subsequent missorting towards intracellular endosomal compartments.Overall, these data highlight that LecB is a multitask virulence factor that, through subversion of several host pathways, has a profound impact on keratinocyte proliferation and survival.
Region-specific magnetic fields structure sea turtle populations
Authors: Cameron Sahmorie J.K. , Baltazar-Soares Miguel , Eizaguirre Christophe 
Published: May 2019

AbstractPhilopatry and long distance migrations are common in the animal kingdom, of which sea turtles are flagship examples. Recent studies have suggested sea turtles use the Earth’s magnetic field to navigate across ocean basins to return to their natal area, yet the mechanisms underlying this process remain unknown. If true though, the genetic structure at nesting sites should positively correlate with differences in location-specific magnetic vectors within nesting regions. Here, we confirm this working hypothesis but only in certain regions of the world and for all sea turtle species nesting in those regions. Reversely, where no correlations were found between genetic differentiation and geomagnetic vectors, this was the case for all nesting sea turtle species. Our approach hence reveals parallel but not universal use of geomagnetic cues in sea turtles. We describe magneto-sensing regions as characterized by sharp clines of total and vertical field intensity vectors offering the navigation cues that increase philopatric accuracy and promote genetic structuring among sea turtle populations.
The Vertebrate Codex Gene Breaking Protein Trap Library For Genomic Discovery and Disease Modeling Applications
Authors: Ichino Noriko , Serres MaKayla , Urban Rhianna , Urban Mark , Schaefbauer Kyle , Greif Lauren , Varshney Gaurav K. , Skuster Kimberly J. , McNulty Melissa , Daby Camden , Wang Ying , Liao Hsin-kai , El-Rass Suzan , Ding Yonghe , Liu Weibin , Schimmenti Lisa A. , Sivasubbu Sridhar , Balciunas Darius , Hammerschmidt Matthias , Farber Steven A. , Wen Xiao-Yan , Xu Xiaolei , McGrail Maura , Essner Jeffrey J. , Burgess Shawn , Clark Karl J. , Ekker Stephen C. 
Published: May 2019

AbstractThe zebrafish is a powerful model to explore the molecular genetics and expression of the vertebrate genome. The gene break transposon (GBT) is a unique insertional mutagen that reports the expression of the tagged member of the proteome while generating Cre-revertible genetic alleles. This 1000+ locus collection represents novel codex expression data from the illuminated mRFP protein trap, with 36% and 87% of the cloned lines showcasing to our knowledge the first described expression of these genes at day 2 and day 4 of development, respectively. Analyses of 183 molecularly characterized loci indicate a rich mix of genes involved in diverse cellular processes from cell signaling to DNA repair. The mutagenicity of the GBT cassette is very high as assessed using both forward and reverse genetic approaches. Sampling over 150 lines for visible phenotypes after 5dpf shows a similar rate of discovery of embryonic phenotypes as ENU and retroviral mutagenesis. Furthermore, five cloned insertions were in loci with previously described phenotypes; embryos homozygous for each of the corresponding GBT alleles displayed strong loss of function phenotypes comparable to published mutants using other mutagenesis strategies (ryr1b,fras1,tnnt2a, edarandhmcn1). Using molecular assessment after positional cloning, to date nearly all alleles cause at least a 99+% knockdown of the tagged gene. Interestingly, over 35% of the cloned loci represent 68 mutants in zebrafish orthologs of human disease loci, including nervous, cardiovascular, endocrine, digestive, musculoskeletal, immune and integument systems. The GBT protein trapping system enabled the construction of a comprehensive protein codex including novel expression annotation, identifying new functional roles of the vertebrate genome and generating a diverse collection of potential models of human disease.
COSPLAY: An expandable toolbox for combinatorial and swift generation of expression plasmids in yeast
Authors: Goulev Youlian , Matifas Audrey , Heyer Vincent , Reina-San-Martin Bernardo , Charvin Gilles 
Published: May 2019

AbstractA large number of genetic studies in yeast rely on the use of expression vectors. To facilitate the experimental approach of these studies, several collections of expression vectors have been generated (YXplac, pRS series, etc.). Subsequently, these collections have been expanded by adding more diversity to many of the plasmid features, including new selection markers and new promoter sequences. However, the ever growing number of plasmid feature makes it unrealistic for research labs to maintain an up-to-date collection of plasmids.. Here, we developed the COSPLAY toolbox: a Golden Gate approach based on the scheme of a simple modular plasmid that recapitulates and completes all the properties of the pRS plasmids. The COSPLAY toolbox contains a basal collection of individual functional modules. Moreover we standardized a simple and rapid, software-assisted protocol which facilitates the addition of new personalized modules. Finally, our toolbox includes the possibility to select a genomic target location and to perform a single copy integration of the expression vector.
Probing the polarity of spontaneous perisomatic GABAergic synaptic transmission during epileptogenesis in the mouse CA3 circuit in vivo
Authors: Dubanet Olivier , Da Silva Arnaldo Ferreira Gomes , Frick Andreas , Hirase Hajime , Beyeler Anna , Leinekugel Xavier 
Published: May 2019

AbstractSeveral studies suggest a contribution of reversed, excitatory GABA to epileptogenesis. But GABAergic transmission critically depends on the very dynamic combination of membrane potential, conductance and occurrence of other synaptic inputs. Taking this complexity into account implies measuring the postsynaptic responses to spontaneously occurring GABAergic events, in vivo, without interfering with neuronal [Cl-]i. Because of technical difficulties, this has not been achieved yet. We have overcome this challenge by combining in vivo extracellular detection of both optogenetically-evoked and spontaneously occurring unitary inhibitory postsynaptic field-potentials (fIPSPs), with the silicon probe recording of neuronal firing activity, with single cell resolution. We report that isolated acute seizures induced a global reversal of the polarity of CA3 hippocampal GABAergic transmission, shifting from inhibitory to excitatory for a duration of several tens of seconds before returning to normal polarity. Nevertheless we observed this reversed polarity only in the post-ictal period during which neurons (including GABAergic interneurons) were silent. Perisomatic inhibition was also affected during the course of epileptogenesis in the Kainate model of chronic epilepsy. One week after Kainate injection, the majority of pyramidal cells escaped inhibitory control by perisomatic GABAergic events. Besides, we did not observe a reversed polarity of fIPSPs, but fIPSPs provided time-locked excitation to a minor subset of CA3 pyramidal neurons. Beside methodological interests, our results suggest that subtle alterations in the regulation of [Cl-]i and perisomatic GABAergic transmission already operate in the hippocampal circuit during the latent period that precedes the establishment of chronic epilepsy.
Pathways to women’s empowerment in Bangladesh
Authors: Zafarullah Habib , Nawaz Faraha 
Published: May 2019

PurposeThe purpose of this paper is to examine two interventions toward women’s empowerment in Bangladesh – formal employment and microfinance, and to highlight two case studies supporting these interventions.Design/methodology/approachThis interpretive-evaluative inquiry of the state of employment and microfinance as important interventions in women’s empowerment in Bangladesh is based on both primary and secondary sources. Theoretical insights and empirical evidence from previous research along with data from various sources inform the arguments.FindingsBangladeshi women are making steady progress toward empowerment through a gradual increase in female participation in the workforce, especially in the ready-made garment manufacturing sector. The expanding microfinance arena has also been providing a growing number of women the opportunity to undertake productive small-scale business ventures that also provide informal employment to unemployed women in rural areas. However, social and cultural constraints and overt conservatism has been a daunting challenge for enterprising women and those in formal employment continue to suffer from discrimination, harassment and unfavorable working conditions.Originality/valueThe paper will be of value to both researchers and policy makers in Bangladesh as it seeks to relate two specific interventions toward women’s empowerment from a broad conceptual perspective and interpretive analysis.
Large frugivores matter: Insights from network and seed dispersal effectiveness approaches
Authors: Naniwadekar Rohit , Chaplod Saniya , Datta Aparajita , Rathore Akanksha , Sridhar Hari 
Published: May 2019

Abstract

While large avian frugivores are known to be key dispersers for large‐seeded tree species, their role in community‐wide plant‐disperser networks is still poorly known. Large avian frugivores are also among the most threatened due to anthropogenic impacts.

We evaluated the role of large avian frugivores in a plant‐disperser community by (a) determining whether the plant‐disperser community was modular, with a distinct community of large frugivores (thereby highlighting their importance), (b) determining relative qualitative and quantitative roles played by large‐bodied frugivores vis‐à‐vis other frugivores and (c) determining impacts of large‐bodied frugivore loss on the plant‐disperser community.

The study was carried out at a tropical forest site in north‐east India, which is part of the Eastern Himalaya Biodiversity Hotspot. We collected tree watch data (20:55 hr) from 46 tree species, which represented 85% of tree species that are predominantly bird‐dispersed in the area.

We found that the plant‐disperser community was modular, with a distinct module of large‐seeded tree species and large frugivores. Intermediate‐sized frugivores such as barbets and bulbuls were the most connected, while large‐sized frugivores, such as hornbills and imperial pigeons, were moderately well connected. Qualitative and quantitative roles played by different dispersers varied across the gradient of frugivore body size. Hornbills, the largest avian frugivores, consumed a significantly greater number of fruits and swallowed larger proportions of fruits compared with other avian groups. In comparison with similar‐sized frugivores, imperial pigeons fed on larger‐sized fruits, highlighting their importance for dispersal of large‐seeded plants. Under simulated extinction scenarios, larger extinction cascades were not necessarily caused by larger frugivores; however, extinctions of certain large‐bodied frugivores (hornbills, imperial pigeons) caused extinction cascades.

Integrating information from networks and seed dispersal effectiveness approaches enabled a better understanding of large frugivore role in a plant‐disperser community. While large‐bodied frugivores may not be playing a central role in plant‐disperser communities, they are crucial as seed dispersal service providers for large‐seeded plants. In conjunction with the reported local extinctions of large frugivores like hornbills from the south Asian region, this study’s findings highlight the irreplaceable quantitative and qualitative impacts that tropical plant communities are likely to experience in the future.
Imagined Corporate Communities: Historical Sources and Discourses
Authors: Heller Michael , Rowlinson Michael 
Published: May 2019

AbstractCorporations can be conceptualized as imagined communities, in which a sense of community is created through textual media rather than face‐to‐face communication. Historically the press, and newspapers in particular, provided texts through which nations could be imagined as communities. By analogy, historically company magazines can be seen as texts in which corporations were imagined as communities of employees. Company magazines were ubiquitous in large corporations by the second half of the twentieth century, and many continue in print or online. Three enduring discourses of ‘imagined corporate communities’ are identified from a sample of company magazines from four UK organizations for 1955, 1985 and 2005 – Royal Mail, Cadbury, the BBC and HSBC (formerly Midland Bank) – as well as periodicals for the professional bodies of magazine editors. These discourses explain the perceived role of company magazines and can be described as: ‘esprit de corps’, in which the corporation is imagined as an extended family, public school or tightly knit military unit with its own distinctive spirit; ‘brand community’, where the magazine's readers are imagined as ambassadors for the brand along with consumers; and ‘democratic polity’, where employees are seen as citizens and the magazine represents an independent voice holding management to account.