bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal Dynamics of Stream Fish Assemblages Over Four Decades
Authors: Zbinden Zachery D.
Published: March 2019

Fish assemblage structure was compared between 1974 and 2014 at 33 sampling locations in the Muddy Boggy River drainage, OK. The two main objectives for this comparison were to first quantify change in assemblage structure, and, second, to test for a relationship between compositional change and spatial scale. Spatial scale was manipulated by pooling assemblage data into groups ranging from K=33 pairs (i.e., local scale) to K=1 pair (i.e., global scale). Local assemblages varied in the degree of assemblage change over 4 decades (range=10-99% dissimilarity; mean=66%). The global assemblage remained quantitatively and qualitatively similar: most species persisted through time and those that did not were rare, and several diversity measures were not significantly different between time periods. Pooling assemblage data into consecutively larger groups and assessing the resultant compositional change revealed interesting patterns indicative of domains of spatial scaling. A discontinuity in the relationship between compositional change and spatial scale occurred at K=15, and this grouping is roughly the size of the headwater/tributary drainages of the Muddy Boggy system. This result suggests assemblages are more predictable when defined at scales larger than a stream reach, and a domain of higher predictability exists at a scale smaller than the entire drainage.
Co-occurrence of multiple CRISPRs andcasclusters suggests epistatic interactions
Authors: Bernheim Aude , Bikard David , Touchon Marie , Rocha Eduardo PC
Published: March 2019

Prokaryotes use CRISPR-Cas for adaptive immunity, but the reasons for the existence of multiple CRISPR andcasclusters remain poorly understood. We found that more than 40% of the genomes encoding a system show atypical genetic organizations. Their analysis revealed negative and positive epistatic interactions between Cas subtypes. The latter often result in one single complex locus with a shared adaptation module and diverse interference mechanisms, presumably to produce more effective immune systems. We typed CRISPRs that could not be unambiguously associated with acascluster and found that such complex loci tend to have unique type I repeats in multiple CRISPRs. In contrast, under-represented co-occurrences caused by functional interference or redundancy may lead to CRISPRs distant fromcasgenes. To investigate the origin of atypical CRISPR-Cas organizations, we analyzed plasmids and phages. Sets of nearly 2000 phages and 10000 prophages were almost devoid of CRISPR-Cas systems, but a sizeable fraction of plasmids had them. Isolated CRISPRs in plasmids were often compatible with the chromosomalcasclusters, suggesting that plasmids use CRISPRs to subvert host immunity. These results point to an important role for the interactions between multiple CRISPR and Cas in the function and evolution of bacterial immunity.
Drivers of amphibian population dynamics and asynchrony at local and continental scales
Authors: Cayuela Hugo , Griffiths Richard A. , Zakaria Nurul , Arntzen Jan W. , Priol Pauline , Léna Jean-Paul , Besnard Aurélien , Joly Pierre
Published: March 2019

Identifying the drivers of population fluctuations in spatially distinct populations remains a significant challenge for ecologists. Whereas regional climatic factors may generate population synchrony (i.e., Moran effect), local factors including the level of density-dependence may reduce the level of synchrony. Although divergences in the scaling of population synchrony and spatial environmental variation have been observed, the regulatory factors that underlie such mismatches are poorly understood.

No previous studies have investigated how density-dependent processes and population-specific responses to weather variation influence spatial synchrony at both local and continental scales. We addressed this issue in a pond-breeding amphibian, the great crested newt (Triturus cristatus). We used capture-recapture data collected through long-term surveys in fiveT. cristatuspopulations in Western Europe.

We found a low level of demographic synchrony at both local and continental levels. Weather has weak and spatially variable effects on survival, recruitment and population growth rate. In contrast, density-dependence was a common phenomenon (at least for population growth) in almost all populations and subpopulations.

Our findings support the idea that Moran’s effect is low in species where the population dynamics more closely depends on local factors (e.g. population density and habitat characteristics) than on large-scale environmental fluctuation (e.g. regional climatic variation). Those demographic feature likely have far-reaching consequences for the long-term viability of the spatially structured populations and their ability to response to large-scale climatic anomalies.
Differences in sodium channel densities in the apical dendrites of pyramidal cells of the electrosensory lateral line lobe
Authors: Motipally Sree I. , Allen Kathryne M. , Williamson Daniel K. , Marsat Gary
Published: March 2019

Heterogeneity of neural properties within a given neural class is ubiquitous in the nervous system and permits different sub-classes of neurons to specialize for specific purposes. This principle has been thoroughly investigated in the hindbrain of the weakly electric fishA. leptorhynchusin the primary electrosensory area, the Electrosensory Lateral Line lobe (ELL). The pyramidal cells that receive inputs from tuberous electroreceptors are organized in three maps in distinct segments of the ELL. The properties of these cells vary greatly across maps due to differences in connectivity, receptor expression, and ion channel composition. These cells are a seminal example of bursting neurons and their bursting dynamic relies on the presence of voltage-gated Na+channels in the extensive apical dendrites of the superficial pyramidal cells. Other ion channels can affect burst generation and their expression varies across ELL neurons and segments. For example, SK channels cause hyperpolarizing after-potentials decreasing the likelihood of bursting, yet bursting propensity is similar across segments. We question whether the depolarizing mechanism that generates the bursts presents quantitative differences across segments that could counterbalance other differences having the opposite effect. Although their presence and role are established, the distribution and density of the apical dendrites’ Na+channels have not been quantified and compared across ELL maps. Therefore, we test the hypothesis that Na+channel density varies across segment by quantifying their distribution in the apical dendrites of immunolabeled ELL sections. We found the Na+channels to be two-fold denser in the lateral segment than in the centro-medial segment, the centro-lateral segment being intermediate. Our results imply that this differential expression of voltage-gated Na+channels could counterbalance or interact with other aspects of neuronal physiology that vary across segments (e.g. SK channels). We argue that burst coding of sensory signals, and the way the network regulates bursting, should be influenced by these variations in Na+channel density.
Convergent genes shape budding yeast pericentromeres
Authors: Paldi Flora , Alver Bonnie , Robertson Daniel , Schalbetter Stephanie A. , Kerr Alastair , Kelly David A. , Neale Matthew J. , Baxter Jonathan , Marston Adele L.
Published: March 2019

The 3D architecture of the genome governs its maintenance, expression and transmission. The conserved ring-shaped cohesin complex organises the genome by topologically linking distant loci on either a single DNA molecule or, after DNA replication, on separate sister chromatids to provide the cohesion that resists the pulling forces of spindle microtubules during mitosis1,2. Cohesin is highly enriched in specialized chromosomal domains surrounding centromeres, called pericentromeres3-7. However, the structural organisation of pericentromeres and implications for chromosome segregation are unknown. Here we report the 3D structure of budding yeast pericentromeres and establish the relationship between genome organisation and function. We find that convergent genes mark pericentromere borders and, together with core centromeres, define their structure and function by positioning cohesin. Centromeres load cohesin and convergent genes at pericentromere borders trap it. Each side of the pericentromere is organised into a looped conformation, with border convergent genes at the base. Microtubule attachment extends a single pericentromere loop, size-limited by convergent genes at its borders. Re-orienting genes at borders into a tandem configuration repositions cohesin, enlarges the pericentromere and impairs chromosome biorientation in mitosis. Thus, the linear arrangement of transcriptional units together with targeted cohesin loading at centromeres shapes pericentromeres into a structure competent for chromosome segregation during mitosis. Our results reveal the architecture of the chromosomal region within which kinetochores are embedded and the re-structuring caused by microtubule attachment. Furthermore, we establish a direct, causal relationship between 3D genome organization of a specific chromosomal domain and cellular function.
Opposing chromatin remodelers control transcription initiation frequency and start site selection
Authors: Kubik Slawomir , Challal Drice , Bruzzone Maria Jessica , Dreos René , Mattarocci Stefano , Bucher Philipp , Libri Domenico , Shore David
Published: March 2019

Precise nucleosome organization at eukaryotic promoters is thought to be generated by multiple chromatin remodeler (CR) enzymes and to affect transcription initiation. Using an integrated analysis of chromatin remodeler binding and nucleosome displacement activity following rapid remodeler depletion, we investigate the interplay between these enzymes and their impact on transcription in budding yeast. We show that many promoters are acted upon by multiple CRs that operate either cooperatively or in opposition to position the key transcription start site-associated +1 nucleosome. Functional assays suggest that +1 nucleosome positioning often reflects a trade-off between maximizing RNA Polymerase II recruitment and minimizing transcription initiation at incorrect sites. Finally, we show that nucleosome movement following CR inactivation usually results from the activity of another CR and that in the absence of any remodeling activity +1 nucleosomes maintain their positions. Our results provide a detailed picture of fundamental mechanisms linking promoter nucleosome architecture to transcription initiation.
Conditional GWAS analysis identifies putative disorder-specific SNPs for psychiatric disorders
Authors: Byrne Enda M , Zhu Zhihong , Qi Ting , Skene Nathan G , Bryois Julien , Pardinas Antonio F , Stahl Eli , Smoller Jordan W , Rietschel Marcella ,   Bipolar Working Group of the Psychiatric Genomics Consortium,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Owen Michael J , Walters James T.R. , O’Donovan Michael C , McGrath John G , Hjerling-Leffler Jens , Sullivan Patrick F , Goddard Michael E , Visscher Peter M , Yang Jian , Wray Naomi R
Published: March 2019

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium – schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genom-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. In addition, we identified a number of variants that approached genome-wide significance in the original GWAS and have larger conditional effect sizes after conditioning on the other disorders. We show that decreased expression ofVPS29in the brain may increase risk to SCZ only and increased expression ofCSE1Lis associated with SCZ and MD, but not with BIP. Likewise, decreased expression ofPCDHA7in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen injection as a proof of principle
Authors: Shen Hanyuan , Qu Zhipeng , Harata-Lee Yuka , Cui Jian , Aung Thazin Nwe , Wang Wei , Kortschak R. Daniel , Adelson David L.
Published: March 2019

Drug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs. We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.
MARGO (Massively Automated Real-time GUI for Object-tracking), a platform for high-throughput ethology
Authors: Werkhoven Zach , Rohrsen Christian , Qin Chuan , Brembs Björn , de Bivort Benjamin
Published: March 2019

Fast object tracking in real time allows convenient tracking of very large numbers of animals and closed-loop experiments that control stimuli for multiple animals in parallel. We developed MARGO, a real-time animal tracking suite for custom behavioral experiments. We demonstrated that MARGO can rapidly and accurately track large numbers of animals in parallel over very long timescales. We incorporated control of peripheral hardware, and implemented a flexible software architecture for defining new experimental routines. These features enable closed-loop delivery of stimuli to many individuals simultaneously. We highlight MARGO’s ability to coordinate tracking and hardware control with two custom behavioral assays (measuring phototaxis and optomotor response) and one optogenetic operant conditioning assay. There are currently several open source animal trackers. MARGO’s strengths are 1) robustness, 2) high throughput, 3) flexible control of hardware and 4) real-time closed-loop control of sensory and optogenetic stimuli, all of which are optimized for large-scale experimentation.
Increased molecular plasticity along the septotemporal axis of the hippocampus is associated with network functioning
Authors: Sotiriou Evangelos , Angelatou Fevronia , Papatheodoropoulos Costas
Published: March 2019

Molecular plasticity crucially supports adaptive cellular and network functioning in the brain. Variations in molecular plasticity may yield important differences in neuronal network dynamics between discrete brain subregions. In the present study we show that the gradual development of sharp waves (SPWs), a spontaneous network activity that is organized under normalin vitroconditions in the CA1 field of ventral but not dorsal hippocampal slices, is associated with region selective molecular reorganization. In particular, increased levels of mRNAs for specific GABAAreceptor subunits (α1, β2, γ2) occurred in ventral hippocampal CA1 field during the development of SPWs. These mRNA changes were followed by a clear increase in GABAAreceptor number in ventral hippocampus, as shown by [3H]muscimol binding. An increase in mRNAs was also observed in dorsal slices for α2 and α5 subunits, not followed by quantitative GABAAreceptor changes. Furthermore, full development of SPWs in the CA1 field (at 3 hours of slice maintenancein vitro) was followed by increased expression of immediate early genes c-fos and zif-268 in ventral hippocampal slices (measured at 5 hoursin vitro). No change in c-fos and zif-268 levels is observed in the CA1 field of dorsal slices, which do not develop spontaneous activity. These results suggest that generation of SPWs could trigger specific molecular reorganization in the VH that may be related to the functional roles of SPWs. Correspondingly, the revealed increased potentiality of the ventral hippocampus for molecular reorganization may provide a clue to mechanisms that underlie the regulated emergence of SPWs along the longitudinal axis of the hippocampus. Furthermore, the present evidence suggests that dynamic tuning between spontaneous neuronal activity and molecular organization may importantly contribute to the functional segregation/heterogeneity seen along the hippocampus.
CGGBP1 regulates chromatin barrier activity and CTCF occupancy at repeats
Authors: Patel Divyesh , Patel Manthan , Singh Umashankar
Published: March 2019

CGGBP1 is a repeat-binding protein with diverse functions in regulation of gene expression, cytosine methylation, repeat silencing and genomic integrity. CGGBP1 has also been identified as a cooperator factor in histone modifying complexes and as a component of protein complexes that form the enhancer-promoter loops. Here we report that the occupancy of CTCF at repeats and the chromatin barrier function of these repeat sequences depends on CGGBP1. Using ChIP-sequencing for CTC we describe CTCF binding on repetitive DNA. Our results show that CGGBP1 determines the CTCF occupancy preference for repeats over canonical CTCF-motif. By combining CTCF ChIP-sequencing results with ChIP-sequencing for three different kinds of histone modifications (H3K4me3, H3K9me3 and H3K27me3) we uncover insulator-like chromatin barrier activities of the repeat-rich CTCF-binding sites. This work shows that CGGBP1 is a regulator of CTCF occupancy and posits it as a regulator of barrier functions of CTCF-binding sites.
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

RNA-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

Objective

Concealable, 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.

Methods

Starting 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.

Results

The 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.

Conclusion

When the nodes are optimally placed, WESNs do not significantly suffer from EEG miniaturization effects in the case of AAD.

Significance

WESN-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

Maximal 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

Schistosomiasis 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.
Whole genome duplication potentiates inter-specific hybridisation and niche shifts in Australian burrowing frogs Neobatrachus
Authors: Novikova Polina Yu. , Brennan Ian G. , Booker William , Mahony Michael , Doughty Paul , Lemmon Alan R. , Lemmon Emily Moriarty , Yant Levi , Van de Peer Yves , Keogh J. Scott , Donnellan Stephen C.
Published: March 2019

Polyploidy has played an important role in evolution across the tree of life but it is still unclear how polyploid lineages may persist after their initial formation. While both common and well-studied in plants, polyploidy is rare in animals and generally less well-understood. The Australian burrowing frog genus Neobatrachus is comprised of six diploid and three polyploid species and offers a powerful animal polyploid model system. We generated exome-capture sequence data from 87 individuals representing all nine species of Neobatrachus to investigate species-level relationships, the origin and inheritance mode of polyploid species, and the population genomic effects of polyploidy on genus-wide demography. We resolve the phylogenetic relationships among Neobatrachus species and provide further support that the three polyploid species have independent autotetraploid origins. We document higher genetic diversity in tetraploids, resulting from widespread gene flow specifically between the tetraploids, asymmetric inter-ploidy gene flow directed from sympatric diploids to tetraploids, and current isolation of diploid species from each other. We also constructed models of ecologically suitable areas for each species to investigate the impact of climate variation on frogs with differing ploidy levels. These models suggest substantial change in suitable areas compared to past climate, which in turn corresponds to population genomic estimates of demographic histories. We propose that Neobatrachus diploids may be suffering the early genomic impacts of climate-induced habitat loss, while tetraploids appear to be avoiding this fate, possibly due to widespread gene flow into tetraploid lineages specifically. Finally, we demonstrate that Neobatrachus is an attractive model to study the effects of ploidy on the evolution of adaptation in animals.
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

Alzheimer 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

Patient-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

Transposable 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

The 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

Tradeoffs 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

A 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

How 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

The 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 Summary

Cutimycin, 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

Pat1 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.
Detection of Spacer Precursors Formed In Vivo During Primed CRISPR Adaptation
Authors: Shiriaeva Anna A. , Savitskaya Ekaterina , Datsenko Kirill A. , Vvedenskaya Irina O. , Fedorova Iana , Morozova Natalia , Metlitskaya Anastasia , Sabantsev Anton , Nickels Bryce E. , Severinov Konstantin , Semenova Ekaterina
Published: March 2019

Type I CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas (CRISPR associated) loci provide prokaryotes with a nucleic-acid-based adaptive immunity against foreign DNA1. Immunity involves “adaptation,” the integration of ~30-bp DNA fragments into the CRISPR array as “spacer” sequences, and “interference,” the targeted degradation of DNA containing a “protospacer” sequence mediated by a complex containing a spacer-derived CRISPR RNA (crRNA)1–4. Specificity for targeting interference to protospacers, but not spacers, occurs through recognition of a 3-bp protospacer adjacent motif (PAM)5 by the crRNA-containing complex6. Interference-driven DNA degradation of protospacer-containing DNA can be coupled with “primed adaptation,” ill which spacers are acquired from DNA surrounding the targeted protospacer in a bidirectional, orientation-dependent manner2,3,7. Here we construct a robust in vivo model for primed adaptation consisting of an Escherichia coli type I-E CRISPR-Cas “self-targeting” locus encoding a crRNA that targets a chromosomal protospacer. We develop a strand-specific, high-throughput-sequencing method for analysis of DNA fragments, “FragSeq,” and use this method to detect short fragments derived from DNA surrounding the targeted protospacer. The detected fragments have sequences matching spacers acquired during primed adaptation, contain ~3- to 4-nt overhangs derived from excision of genomic DNA within a PAM, are generated in a bidirectional, orientation-dependent manner relative to the targeted protospacer, require the functional integrity of machinery for interference and adaptation to accumulate, and function as spacer precursors when exogenously introduced into cells by transformation. DNA fragments with a similar structure accumulate in cells undergoing primed adaptation in a type I-F CRISPR-Cas self-targeting system. We propose the DNA fragments detected in this work are products of universal steps of spacer precursor processing in type I CRISPR-Cas systems.
Improving Democratic Discourse in UK General Election and Referendum Campaigns
Authors: Crines Andrew S.
Published: March 2019

This 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

The 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.