bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNase H1 and H2 are differentially regulated to eliminate RNA-DNA hybrids
Authors: Lockhart Arianna , Pires Vanessa Borges , Bento Fabio , Kellner Vanessa , Luke-Glaser Sarah , Luke Brian 
Published: March 2019

SUMMARYRNA-DNA hybrids are tightly regulated to ensure genome integrity. The RNase H enzymes, RNase H1 and H2, contribute to chromosomal stability through the removal of RNA-DNA hybrids. Loss of RNase H2 function is implicated in human diseases of the nervous system and cancer. To better understand RNA-DNA hybrid dynamics, we have focused on elucidating the regulation of the RNase H enzymes themselves. Using yeast as a model system, we demonstrate that RNase H1 and H2 are controlled in different manners. RNase H2 is regulated in a strict cell cycle dependent manner, both in terms of its R-loop removal, and ribonucleotide excision repair functions. RNase H1, however, can function independent of cell cycle stage to remove R-loops, but appears to become activated in response to high R-loop loads. These results provide us with a more complete understanding of how and when RNA-DNA hybrids are acted upon by the RNase H enzymes.
Analysis of miniaturization effects and channel selection strategies for EEG sensor networks with application to auditory attention detection
Authors: Narayanan Abhijith Mundanad , Bertrand Alexander 
Published: March 2019

AbstractObjectiveConcealable, miniaturized electroencephalo-graphy (‘mini-EEG’) recording devices are crucial enablers towards long-term ambulatory EEG monitoring. However, the resulting miniaturization limits the inter-electrode distance and the scalp area that can be covered by a single device. The concept of wireless EEG sensor networks (WESNs) attempts to overcome this limitation by placing a multitude of these mini-EEG devices at various scalp locations. We investigate whether optimizing the WESN topology can compensate for miniaturization effects in an auditory attention detection (AAD) paradigm.MethodsStarting from standard full-cap high-density EEG data, we emulate several candidate mini-EEG sensor nodes which locally collect EEG data with embedded electrodes separated by short distances. We propose a greedy group-utility based channel selection strategy to select a subset of these candidate nodes, to form a WESN. We compare the AAD performance of this WESN with the performance obtained using long-distance EEG recordings.ResultsThe AAD performance using short-distance EEG measurements is comparable to using an equal number of long-distance EEG measurements if in both cases the optimal electrode positions are selected. A significant increase in performance was found when using nodes with three electrodes over nodes with two electrodes.ConclusionWhen the nodes are optimally placed, WESNs do not significantly suffer from EEG miniaturization effects in the case of AAD.SignificanceWESN-like platforms allow to achieve similar AAD performance as with long-distance EEG recordings, while adhering to the stringent miniaturization constraints for ambulatory EEG. Their applicability in an AAD task is important for the design of neuro-steered auditory prostheses.
Maximal homology alignment: A new method based on two-dimensional homology
Authors: Erives Al 
Published: March 2019

ABSTRACTMaximal homology alignment is a new biologically-relevant approach to DNA sequence alignment that maps the internal dispersed microhomology of individual sequences onto two dimensions. It departs from the current method of gapped alignment, which uses a simplified binary state model of nucleotide position. In gapped alignment nucleotide positions have either no relationship (1-to-None) or else orthological relationship (1-to-1) with nucleotides in other sequences. Maximal homology alignment, however, allows additional states such as 1-to-Many and Many-to-Many, thus modeling both orthological and paralogical relationships, which together comprise the main homology types. Maximal homology alignment collects dispersed microparalogy into the same alignment columns on multiple rows, and thereby generates a two-dimensional representation of a single sequence. Sequence alignment then proceeds as the alignment of two-dimensional topological objects. The operations of producing and aligning two-dimensional auto-alignments motivate a need for tests of two-dimensional homological integrity. Here, I work out and implement basic principles for computationally testing the two dimensions of positional homology, which are inherent to biological sequences due to replication slippage and related errors. I then show that maximal homology alignment is more informative than gapped alignment in modeling the evolution of genetic sequences. In general, MHA is more suited when small insertions and deletions predominantly originate as local microparalogy. These results show that both conserved and non-conserved genomic sequences are enriched with a signature of replication slippage relative to their random permutations.
A library of cell-surface and secreted proteins fromSchistosoma mansoniidentifies early serological markers of infection
Authors: Crosnier Cécile , Protasio Anna V. , Rinaldi Gabriel , Wilson Shona , Berriman Matthew , Wright Gavin J. 
Published: March 2019

AbstractSchistosomiasis is a major global health problem caused by blood-dwelling parasitic worms and is currently treated by the mass administration of the drug praziquantel. Appropriate drug treatment strategies are informed by diagnostics that establish the prevalence and intensity of infection, which, in regions of low transmission should be highly sensitive. To identify sensitive new serological markers ofSchistosoma mansoniinfections, we have compiled a recombinant protein library of 115 parasite cell surface and secreted proteins expressed in mammalian cells. The vast majority of them were shown to be immunoreactive and to contain heat-labile conformational epitopes when tested against pooled human sera from endemic regions. After probing the library against a time series of sera samples from experimental infections in mice, we identified several markers of infection, the majority of which belong to the saposin-domain-containing and cathepsin families of proteins. These new markers will be a valuable tool to detect ongoing and previousS. mansoniinfections, including in regions of low transmission. We envisage that this new recombinant protein resource will be used in a wide range of cellular and molecular assays to further our understanding ofSchistosomabiology.
A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain
Authors: Del-Aguila Jorge L. , Li Zeran , Dube Umber , Mihindukulasuriya Kathie A. , Budde John P , Fernandez Maria Victoria , Ibanez Laura , Bradley Joseph , Wang Fengxian , Bergmann Kristy , Davenport Richard , Morris John C. , Holtzman David M. , Perrin Richard J. , Benitez Bruno A. , Dougherty Joseph , Cruchaga Carlos , Harari Oscar 
Published: March 2019

AbstractAlzheimer Disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single cell resolution. To do so, we generated unsorted single-nuclei RNA-sequencing data from brain tissue. We leveraged tissue donated from a carrier of a Mendelian genetic mutation and two family members who suffer from AD, but do not have the same mutation. We evaluated alternative alignment approaches to maximize the titer of reads, genes and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses. We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from human brains recapitulate the expression profile of Disease Associated Microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data it is critical to control for biases introduced by donor specific expression profiles. In conclusion, we propose a collection of best practices to generate a highly-detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.
Patient-specific haemodynamic simulations of complex aortic dissections informed by commonly available clinical datasets
Authors: Bonfanti Mirko , Franzetti Gaia , Maritati Gabriele , Homer-Vanniasinkam Shervanthi , Balabani Stavroula , Díaz-Zuccarini Vanessa 
Published: March 2019

AbstractPatient-specific computational fluid-dynamics (CFD) can assist the clinical decision-making process for Type-B aortic dissection (AD) by providing detailed information on the complex intra-aortic haemodynamics. This study presents a new approach for the implementation of personalised CFD models using non-invasive, and oftentimes minimal, datasetscommonlycollected for AD monitoring. An innovative way to account for arterial compliance in rigid-wall simulations using a lumped capacitor is introduced, and a parameter estimation strategy for boundary conditions calibration is proposed. The approach was tested on three complex cases of AD, and the results were successfully compared against invasive blood pressure measurements. Haemodynamics results (e.g. intraluminal pressures, flow partition between the lumina, wall shear-stress based indices) provided information that could not be obtained using imaging alone, providing insight into the state of the disease. It was noted that small tears in the distal intimal flap induce disturbed flow in both lumina. Moreover, oscillatory pressures across the intimal flap were often observed in proximity to the tears in the abdominal region, which could indicate a risk of dynamic obstruction of the true lumen.This study shows how combining commonly available clinical data with computational modelling can be a powerful tool to enhance clinical understanding of AD.
Transposable temperate phages promote the evolution of divergent social strategies inPseudomonas aeruginosapopulations
Authors: O’Brien Siobhán , Kümmerli Rolf , Paterson Steve , Winstanley Craig , Brockhurst Michael A. 
Published: March 2019

AbstractTransposable temperate phages randomly insert into bacterial genomes, providing increased supply and altered spectra of mutations available to selection, thus opening alternative evolutionary trajectories. Transposable phages accelerate bacterial adaptation to new environments, but their effect on adaptation to the social environment is unclear. Here we show, using experimental evolution ofPseudomonas aeruginosain iron-limited and iron-rich environments causing differential expression of siderophore cooperation, that transposable phages promoted divergence into extreme siderophore production phenotypes in iron-limited populations. Iron-limited populations with transposable phages evolved siderophore over-producing clones alongside siderophore non-producing cheats. Low siderophore production was associated with parallel mutations inpvdgenes, encoding pyoverdine biosynthesis, andpqsgenes, encoding quinolone signaling, while high siderophore production was associated with parallel mutations in phenazine-associated gene clusters. Notably, some of these parallel mutations were caused by phage insertional inactivation. These data suggest that transposable phages, which are widespread in microbial communities, can mediate the evolutionary divergence of social strategies.
Meta-MultiSKAT: Multiple phenotype meta-analysis for region-based association test
Authors: Dutta Diptavo , Gagliano Taliun Sarah A. , Weinstock Joshua S. , Zawistowski Matthew , Sidore Carlo , Fritsche Lars G. , Cucca Francesco , Schlessinger David , Abecasis Gonçalo R. , Brummett Chad M. , Lee Seunggeun 
Published: March 2019

AbstractThe power of genetic association analyses can be increased by jointly meta-analyzing multiple correlated phenotypes. Here, we develop a meta-analysis framework, Meta-MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of effects between studies through a kernel matrix and performs a variance component test for association. Using a genotype kernel, our approach can test for rare-variants and the combined effects of both common and rare-variants. To achieve robust power, within Meta-MultiSKAT, we developed fast and accurate omnibus tests combining different models of genetic effects, functional genomic annotations, multiple correlated phenotypes and heterogeneity across studies. Additionally, Meta-MultiSKAT accommodates situations where studies do not share exactly the same set of phenotypes or have differing correlation patterns among the phenotypes. Simulation studies confirm that Meta-MultiSKAT can maintain type-I error rate at exome-wide level of 2.5×10−6. Further simulations under different models of association show that Meta-MultiSKAT can improve power of detection from 23% to 38% on average over single phenotype-based meta-analysis approaches. We demonstrate the utility and improved power of Meta-MultiSKAT in the meta-analyses of four white blood cell subtype traits from the Michigan Genomics Initiative (MGI) and SardiNIA studies.
Single Nucleotide Mapping of the Locally Accessible Trait Space in Yeast Reveals Pareto Fronts that Constrain Initial Adaptation
Authors: Li Yuping , Petrov Dmitri A. , Sherlock Gavin 
Published: March 2019

AbstractTradeoffs constrain the improvement of performance of multiple traits simultaneously. Such tradeoffs define Pareto fronts, which represent a set of optimal individuals that cannot be improved in any one trait without reducing performance in another. Surprisingly, experimental evolution often yields genotypes with improved performance in all measured traits, perhaps indicating an absence of tradeoffs at least in the short-term. Here we densely sample adaptive mutations inS. cerevisiaeto ask whether first-step adaptive mutations result in tradeoffs during the growth cycle. We isolated thousands of adaptive clones evolved under carefully chosen conditions and quantified their performances in each part of the growth cycle. We too find that some first-step adaptive mutations can improve all traits to a modest extent. However, our dense sampling allowed us to identify tradeoffs and establish the existence of Pareto fronts between fermentation and respiration, and between respiration and stationary phases. Moreover, we establish that no single mutation in the ancestral genome can circumvent the detected tradeoffs. Finally, we sequenced hundreds of these adaptive clones, revealing novel targets of adaptation and defining the genetic basis of the identified tradeoffs.
Prokaryotic SPHINX sequences are conserved in mammalian brain and participate in neurodegeneration
Authors: Szigeti-Buck Klara , Manuelidis Laura 
Published: March 2019

ABSTRACTA new class of circular mammalian “SPHINX” DNAs, represented by the 1.8 and 2.4kb elements, were discovered in highly infectious cytoplasmic particles isolated from Creutzfeldt-Jakob Disease (CJD) and scrapie samples. These DNAs contained replication initiation sequences (REPs) with ∼70% homology to Acinetobacter phage REP segments. Antibodies against REP peptides from the 1.8kb DNA highlighted a 41kDa protein (spx) on Western blots, and in-situ studies revealed its tissue and cell-type specific expression, e.g., in pancreatic islet cells, keratinocytes and kidney tubules but not pancreatic exocrine cells, alveoli, and striated muscle. An intense spx signal in oocytes implicated maternal inheritance of the SPHINX 1.8 genome, a feature known only for bacterially derived mitochondrial DNA in mammals. To determine if spx concentrated at specific neurons and synapses, and also maintained a conserved pattern of architectural organization in mammals, we evaluated mouse, rat, hamster, Guinea Pig and human brains. Most outstanding was the cross-species concentration of spx in huge excitatory synapses of mossy fibers and small internal granule neuron synapses, the only excitatory neuron within the cerebellum. This synaptic localization was also demonstrable at the ultrastructural level. Vacuolar loss of these synaptic complexes, thinning of the internal granule cell layer, and pathological fibrillar spx accumulations within Purkinje neurons were obvious in CJD Guinea pig brains. In rats, these fibrillar changes marked hippocampal Pyramidal neurons and preceded prion protein misfolding. Spx may define different causes or processes of neurodegeneration. The evolutionary origin, persistence and modulation of SPHINX 1.8 opens an unexpected chapter in mammalian symbiosis.
Cohesin disrupts polycomb-dependent chromosome interactions
Authors: Rhodes JDP , Feldmann A , Hernández-Rodríguez B , Díaz N , Brown JM , Fursova NA , Blackledge NP , Prathapan P , Dobrinic P , Huseyin M , Szczurek A , Kruse K , Nasmyth KA , Buckle VJ , Vaquerizas JM , Klose RJ 
Published: March 2019

AbstractHow chromosome organisation is related to genome function remains poorly understood. Cohesin, loop-extrusion, and CTCF have been proposed to create structures called topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find as in other cell types that cohesin is required to create TADs and regulate A/B compartmentalisation. However, in the absence of cohesin we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system, depend on PRC1, and we discover that cohesin counteracts these interactions. This disruptive activity is independent of CTCF and TADs, and regulates gene repression by the polycomb system. Therefore, in contrast to the proposal that cohesin creates structure in chromosomes, we discover a new role for cohesin in disrupting polycomb-dependent chromosome interactions to regulate gene expression.
Cutibacterium acnesantibiotic production shapes niche competition in the human skin microbiome
Authors: Claesen Jan , Spagnolo Jennifer B , Ramos Stephany Flores , Kurita Kenji L , Byrd Allyson L , Aksenov Alexander A , Melnik Alexey V , Wong Weng R , Wang Shuo , Hernandez Ryan D , Donia Mohamed S , Dorrestein Pieter C , Kong Heidi H , Segre Julia A , Linington Roger G , Fischbach Michael A , Lemon Katherine P 
Published: March 2019

AbstractThe composition of the skin microbiome varies widely among individuals sampled at the same body site. A key question is which molecular factors determine strain-level variability within sub-ecosystems of the skin. We used a genomics-guided approach to identify an antibacterial biosynthetic gene cluster inCutibacterium acnes(formerlyPropionibacterium acnes) that is widely distributed across individuals and skin sites. Experimental characterization of this cluster enabled the identification of a new thiopeptide antibiotic, cutimycin. Analysis of individual human skin hair follicles showed that cutimycin is an important factor regulating colonization resistance againstStaphylococcusspecies.One Sentence SummaryCutimycin, a thiopeptide antibiotic produced by a widespread skin commensal, reducesStaphylococcuscolonization of human follicles.
Pat1 activates late steps in mRNA decay by multiple mechanisms
Authors: Lobel Joseph H. , Tibble Ryan W. , Gross John D. 
Published: March 2019

ABSTRACTPat1 is a hub for mRNA metabolism, acting in pre-mRNA splicing, translation repression and mRNA decay. A critical step in all 5’-3’ mRNA decay pathways is removal of the 5’ cap structure, which precedes and permits digestion of the RNA body by conserved exonucleases. During bulk 5’-3’ decay, the Pat1/Lsm1-7 complex engages mRNA at the 3’ end and promotes hydrolysis of the cap structure by Dcp1/Dcp2 at the 5’ end through an unknown mechanism. We reconstitute Pat1 with 5’ and 3’ decay factors and show how it activates multiple steps in late mRNA decay. First, we find that Pat1 stabilizes binding of the Lsm1-7 complex to RNA using two conserved short-linear interaction motifs. Secondly, Pat1 directly activates decapping by binding elements in the disordered C-terminal extension of Dcp2, alleviating autoinhibition and promoting substrate binding. Our results uncover the molecular mechanism of how separate domains of Pat1 coordinate the assembly and activation of a decapping mRNP that promotes 5’-3’ mRNA degradation.
Improving Democratic Discourse in UK General Election and Referendum Campaigns
Authors: Crines Andrew S. 
Published: March 2019

AbstractThis article is a short overview of the recently released report entitled Doing Democracy Better published by the Constitution Unit based at University College London. The report makes a series of interesting and useful observations about the health of democratic discourse within the UK and advances a selection of recommendations for its improvement. Whilst noting the value of the report as a piece of substantive research, there are a number of further questions which need to be addressed. As such, this report should be seen as the starting point of a broader discussion that takes a more nuanced approach to improving democratic discourse and a less London‐centric approach to conceptualising the UK's political institutions and language.
School tracking and its role in social reproduction: reinforcing educational inheritance and the direct effects of social origin
Authors: Reichelt Malte , Collischon Matthias , Eberl Andreas 
Published: March 2019

AbstractThe degree of social reproduction varies considerably between industrialized countries, raising the question of which institutional regulations promote or restrict this process. Education is considered the main mediator of social reproduction. Because school tracking – the sorting of children according to ability and interest at different ages – is known to affect educational attainment and the degree of tracking varies strongly across countries, it may thus account for differences in social reproduction. However, empirical studies are scarce, and the total impact of tracking on social reproduction remains ambiguous. Using the European Social Survey (ESS) 2012 and 2014 from 24 countries, we demonstrate that school tracking is strongly associated with higher degrees of social reproduction. Decomposing the process of social reproduction into educational inheritance, educational returns and direct effects of social origin, we find that although all channels contribute to social reproduction, the impact of tracking seems to be exerted through educational inheritance and to a similar degree through direct effects of social origin, whereas educational returns do not seem to be affected. Even net of educational attainment, social origin thus has a stronger effect on social status in tracked systems. We ascribe this effect to differences in qualitative choices within educational tracks, such as fields of study.