bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual working memory is independent of the cortical spacing between memoranda
Authors: Harrison William J. , Bays Paul M.
Published: November 2017

The sensory recruitment hypothesis states that visual short term memory is maintained in the same visual cortical areas that initially encode a stimulus’ features. Although it is well established that the distance between features in visual cortex determines their visibility, a limitation known as crowding, it is unknown whether short term memory is similarly constrained by the cortical spacing of memory items. Here we investigated whether the cortical spacing between sequentially presented memoranda affects the fidelity of memory in humans (of both sexes). In a first experiment, we varied cortical spacing by taking advantage of the log-scaling of visual cortex with eccentricity, sequentially presenting memoranda in peripheral vision along either the radial or tangential visual axis with respect to the fovea. In a second experiment, we sequentially presented memoranda either within or beyond the critical spacing of visual crowding, a distance within which visual features cannot be perceptually distinguished due to their nearby cortical representations. In both experiments and across multiple measures, we found strong evidence that the ability to maintain visual features in memory is unaffected by cortical spacing. These results indicate that the neural architecture underpinning working memory has properties inconsistent with the known behaviour of sensory neurons in visual cortex. Instead, the dissociation between perceptual and memory representations supports a role of higher cortical areas, such as posterior parietal or prefrontal regions, or may involve an as yet unspecified mechanism in visual cortex in which stimulus features are bound to their temporal order.

Significance Statement

Although much is known about the resolution with which we can remember visual objects, the cortical representation of items held in short term memory remains contentious. A popular hypothesis suggests that memory of visual features is maintained via the recruitment of the same neural architecture in sensory cortex that encodes stimuli. We investigated this claim by manipulating the spacing in visual cortex between sequentially presented memoranda such that some items shared cortical representations more than others, while preventing perceptual interference between stimuli. We found clear evidence that short term memory is independent of the intra-cortical spacing of memoranda, revealing a dissociation between perceptual and memory representations. Our data indicate that working memory relies on different neural mechanisms from sensory perception.
Russian doll genes and complex chromosome rearrangements inOxytricha trifallax
Authors: Braun Jasper , Nabergall Lukas , Neme Rafik , Landweber Laura F. , Saito Masahico , Jonoska Nataša
Published: November 2017

Ciliates have two different types of nuclei per cell, with one acting as a somatic, transcriptionally active nucleus (macronucleus; abbr. MAC) and another serving as a germline nucleus (micronucleus; abbr. MIC). Furthermore,Oxytricha trifallaxundergoes extensive genome rearrangements during sexual conjugation and post-zygotic development of daughter cells. These rearrangements are necessary because the precursor MIC loci are often both fragmented and scrambled, with respect to the corresponding MAC loci. Such genome architectures are remarkably tolerant of encrypted MIC loci, because RNA-guided processes during MAC development reorganize the gene fragments in the correct order to resemble the parental MAC sequence. Here, we describe the germline organization of several nested and highly scrambled genes inOxytricha trifallax. These include cases with multiple layers of nesting, plus highly interleaved or tangled precursor loci that appear to deviate from previously described patterns. We present mathematical methods to measure the degree of nesting between precursor MIC loci, and revisit a method for a mathematical description of scrambling. After applying these methods to the chromosome rearrangement maps ofO. trifallaxwe describe cases of nested arrangements with up to five layers of embedded genes, as well as the most scrambled loci inO. trifallax.
Breaking the spell of nestedness
Authors: Payrató Borrás Clàudia , Hernández Laura , Moreno Yamir
Published: November 2017

Mutualistic interactions, which are beneficial for both interacting species, are recurrently present in ecosystems. Observations of natural systems showed that, if we draw mutualistic relationships as binary links between species, the resulting bipartite network of interactions displays a widespread particular ordering called nestedness [1]. On the other hand, theoretical works have shown that a nested structure has a positive impact on a number of relevant features ranging from species coexistence [2], to a higher structural stability of communities and biodiversity [3,4]. However, how nestedness emerges and what are its determinants, are still open challenges that have led to multiple debates to date [5–7]. Here, we show, by applying a theoretical approach to the analysis of 167 real mutualistic networks, that nestedness is not an irreducible feature, but a consequence of the degree sequences of both guilds of the mutualistic network. Remarkably, we find that an outstanding majority of the analyzed networks does not show statistical significant nestedness. These findings point to the need of revising previous claims about the role of nestedness and might contribute to expand our understanding of how evolution shapes mutualistic interactions and communities by placing the focus on the local properties rather than on global quantities.
The application of zeta diversity as a continuous measure of compositional change in ecology
Authors: Mcgeoch Melodie A. , Latombe Guillaume , Andrew Nigel R. , Nakagawa Shinichi , Nipperess David A. , Roige Mariona , Marzinelli Ezequiel M. , Campbell Alexandra H. , Vergés Adriana , Thomas Torsten , Steinberg Peter D. , Selwood Katherine E. , Hui Cang
Published: November 2017

Zeta diversity provides the average number of shared species acrossnsites (or shared operational taxonomic units (OTUs) acrossncases). It quantifies the variation in species composition of multiple assemblages in space and time to capture the contribution of the full suite of narrow, intermediate and wide-ranging species to biotic heterogeneity. Zeta diversity was proposed for measuring compositional turnover in plant and animal assemblages, but is equally relevant for application to any biological system that can be characterised by a row by column incidence matrix. Here we illustrate the application of zeta diversity to explore compositional change in empirical data, and how observed patterns may be interpreted. We use 10 datasets from a broad range of scales and levels of biological organisation – from DNA molecules to microbes, plants and birds – including one of the original data sets used by R.H. Whittaker in the 1960’s to express compositional change and distance decay using beta diversity. The applications show (i) how different sampling schemes used during the calculation of zeta diversity may be appropriate for different data types and ecological questions, (ii) how higher orders of zeta may in some cases better detect shifts, transitions or periodicity, and importantly (iii) the relative roles of rare versus common species in driving patterns of compositional change. By exploring the application of zeta diversity across this broad range of contexts, our goal is to demonstrate its value as a tool for understanding continuous biodiversity turnover and as a metric for filling the empirical gap that exists on spatial or temporal change in compositional diversity.
The cost of enforcing a marine protected area to achieve ecological targets for the recovery of fish biomass
Authors: Brown Christopher J , Parker Brett , Ahmadia Gabby N , Ardiwijaya Rizya , Purwanto  , Game Edward T
Published: November 2017

Protected areas are the primary management tool for conserving ecosystems, yet their intended outcomes may often be compromised by poaching. Consequently, many protected areas are ineffective ‘paper parks’ that contribute little towards conserving ecosystems. Poaching can be prevented through enforcement and engaging with community members so they support protected areas. It is not clear how much needs to be spent on enforcement and engagement to ensure they are frequent enough to be effective at conserving biodiversity. We develop models of enforcement against illegal fishing in marine protected areas. We apply the models to data on fishing rates and fish biomass from a marine protected area in Raja Ampat, Indonesia and explore how frequent enforcement patrols need to be to achieve targets for coral reef fish biomass. Achieving pristine levels of reef fish biomass required almost year-round enforcement of the protected area. Surveillance of the protected area may also be enhanced if local fishers who support the reserve report on poaching. The opportunity for local fishing boats to participate in surveillance was too small for it to have much benefit for total reef fish biomass, which increases slowly. However, specific functional groups of fish have much higher population growth rates and their biomass was predicted to increase markedly with community surveillance. We conclude that budgets for park management must balance the cost of conducting frequent patrols against supporting alternative activities, like education to build community support. Optimized budgets will be much more likely to achieve ecological targets for recovering fish biomasses and will contribute to fiscal sustainability of protected areas.
Condensin’s ATPase Machinery Drives and Dampens Mitotic Chromosome Condensation
Authors: Elbatsh Ahmed M.O. , Raaijmakers Jonne A. , van der Weide Robin H. , Kuit de Bos Jelmi , Teunissen Hans , Bravo Sol , Medema René H. , de Wit Elzo , Haering Christian H. , Rowland Benjamin D.
Published: November 2017

Chromosome condensation by condensin is essential for faithful chromosome segregation. Metazoans have two complexes, named condensin I and II. Both are thought to act by creating looped structures in DNA, but how they do so is unknown. Condensin’s SMC subunits together form a composite ATPase with two pseudo-symmetric ATPase sites. We reveal that these sites have opposite functions in the condensation process. One site drives condensation, while the other site rather has a dampening function. Mutation of this dampener site hyperactivates both condensin I and II complexes. We find that hyperactive condensin I efficiently shortens chromosomes in the total absence of condensin II. The two complexes form loops with different lengths, and specifically condensin II is key to the decatenation of sister chromatids and the formation of a straight chromosomal axis.
Improving the calling of non-invasive prenatal testing on 13-/18-/21-trisomy by support vector machine discrimination
Authors: Yang Jianfeng , Ding Xiaofan , Zhu Weidong
Published: November 2017

With the advance of next-generation sequencing technologies, non-invasive prenatal testing (NIPT) has been developed and employed in fetal aneuploidy screening on 13-/18-/21-trisomies through detecting cell-free fetal DNA (cffDNA) in maternal blood. Although Z test is widely used in NIPT nowadays, there is still necessity to improve its accuracy for removing a) false negatives and false positives, and b) the ratio of unclassified data, so as to reduce the potential harm to patients caused by these inaccuracies as well as the induced cost of retests.

Employing multiple Z tests with machine-learning algorithm could provide a better prediction on NIPT data. Combining the multiple Z values with indexes of clinical signs and quality control, features were collected from the known samples and scaled for model training in support vector machine (SVM) discrimination. The trained model was applied to predict the unknown samples, which showed significant improvement. In 4752 qualified NIPT data, our method reached 100% accuracies on all three chromosomes, including 151 data that were grouped as unclassified by one-Z-value based method. Moreover, four false positives and four false negatives were corrected by using this machine-learning model.

To our knowledge, this is the first study to employ support vector machine in NIPT data analysis. It is expected to replace the current one-Z-value based NIPT analysis in clinical use.
DiscoSnp-RAD: de novo detection of small variants for population genomics
Authors: Gauthier Jèrèmy , Mouden Charlotte , Suchan Tomasz , Alvarez Nadir , Arrigo Nils , Riou Chloé , Lemaitre Claire , Peterlongo Pierre
Published: November 2017

We present an original method to de novo call variants for Restriction site associated DNA Sequencing (RAD-Seq). RAD-Seq is a technique characterized by the sequencing of specific loci along the genome, that is widely employed in the field of evolutionary biology since it allows to exploit variants (mainly SNPs) information from entire populations at a reduced cost. Common RAD dedicated tools, as STACKS or IPyRAD, are based on all-versus-all read comparisons, which require consequent time and computing resources. Based on the variant caller DiscoSnp, initially designed for shotgun sequencing, DiscoSnp-RAD avoids this pitfall as variants are detected by exploring the De Bruijn Graph built from all the read datasets. We tested the implementation on RAD data from 259 specimens of Chiastocheta flies, morphologically assigned to 7 species. All individuals were successfully assigned to their species using both STRUCTURE and Maximum Likelihood phylogenetic reconstruction. Moreover, identified variants succeeded to reveal a within species structuration and the existence of two populations linked to their geographic distributions. Furthermore, our results show that DiscoSnp-RAD is at least one order of magnitude faster than state-of-the-art tools. The overall results show that DiscoSnp-RAD is suitable to identify variants from RAD data, and stands out from other tools due to his completely different principle, making it significantly faster, in particular on large datasets.

License

GNU Affero general public license

Availability

https://github.com/GATB/DiscoSnp

Contact

jeremy.gauthier@inria.fr
GrapeTree: Visualization of core genomic relationships among 100,000 bacterial pathogens
Authors: Zhou Zhemin , Alikhan Nabil-Fareed , Sergeant Martin J. , Luhmann Nina , Vaz Cátia , Francisco Alexandre P. , Carriço João André , Achtman Mark
Published: November 2017

Current methods struggle to reconstruct and visualise the genomic relationships of ≥100,000 bacterial genomes.

GrapeTree facilitates the analyses of allelic profiles from 10,000’s of core genomes within a web browser window.

GrapeTree implements a novel minimum spanning tree algorithm to reconstruct genetic relationships despite missing data together with a static “GrapeTree Layout” algorithm to render interactive visualisations of large trees.

GrapeTree is a stand-along package for investigating Newick trees plus associated metadata and is also integrated into EnteroBase to facilitate cutting edge navigation of genomic relationships among >160,000 genomes from bacterial pathogens.

The GrapeTree package was released under the GPL v3.0 Licence.
A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection
Authors: Singhania Akul , Verma Raman , Graham Christine M. , Lee Jo , Trang Tran , Richardson Matthew , Lecine Patrick , Leissner Philippe , Berry Matthew P.R. , Wilkinson Robert J. , Kaiser Karine , Rodrigue Marc , Woltmann Gerrit , Haldar Pranabashis , O’Garra Anne
Published: November 2017

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise information from the entire transcriptome, which includes over-abundance of type I interferon-inducible genes and under-abundance ofIFNGandTBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals, or those with acute viral and bacterial infections. We suggest methods targeting gene selection across multiple discriminant modules can improve development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.
Asubstratefor modular, extensible data-visualization
Authors: Matelsky Jordan K , Downs Joseph , Cowley Hannah , Wester Brock , Gray-Roncal William
Published: November 2017

As the scope of scientific questions increase and datasets grow larger, the visualization of relevant information correspondingly becomes more difficult and complex. Sharing visualizations amongst collaborators and with the public can be especially onerous, as it is challenging to reconcile software dependencies, data formats, and specific user needs in an easily accessible package. We presentsubstrate, a data-visualization framework designed to simplify communication and code reuse across diverse research teams. Our platform provides a simple, powerful, browser-based interface for scientists to rapidly build effective three-dimensional scenes and visualizations. We aim to reduce the gap of existing systems, which commonly prescribe a limited set of high-level components, that are rarely optimized for arbitrarily large data visualization or for custom data types. To further engage the broader scientific community and enable seamless integration with existing scientific workflows, we also presentpytri, a Python library that bridges the use ofsubstratewith the ubiquitous scientific computing platform,Jupyter. Our intention is to reduce the activation energy required to transition between exploratory data analysis, data visualization, and publication-quality interactive scenes.
Mantis: A Fast, Small, and Exact Large-Scale Sequence-Search Index
Authors: Pandey Prashant , Almodaresi Fatemeh , Bender Michael A. , Ferdman Michael , Johnson Rob , Patro Rob
Published: November 2017

Motivation

Sequence-level searches on large collections of RNA-seq experiments, such as the NIH Sequence Read Archive (SRA), would enable one to ask many questions about the expression or variation of a given transcript in a population. Bloom filter-based indexes and variants, such as the Sequence Bloom Tree, have been proposed in the past to solve this problem. However, these approaches suffer from fundamental limitations of the Bloom filter, resulting in slow build and query times, less-than-optimal space usage, and large numbers of false positives.

Results

This paper introduces Mantis, a space-efficient data structure that can be used to index thousands of rawread experiments and facilitate large-scale sequence searches on those experiments. Mantis uses counting quotient filters instead of Bloom filters, enabling rapid index builds and queries, small indexes, andexactresults, i.e., no false positives or negatives. Furthermore, Mantis is also a colored de Bruijn graph representation, so it supports fast graph traversal and other topological analyses in addition to large-scale sequence-level searches.

In our performance evaluation, index construction with Mantis is 4.4× faster and yields a 20% smaller index than the state-of-the-art split sequence Bloom tree (SSBT). For queries, Mantis is 6× –108× faster than SSBT and has no false positives or false negatives. For example, Mantis was able to search for all 200,400 known human transcripts in an index of 2652 human blood, breast, and brain RNA-seq experiments in one hour and 22 minutes; SBT took close to 4 days and AllSomeSBT took about eight hours.

Mantis is written inC++11and is available athttps://github.com/splatlab/mantis.
Overlooked polyploidies in lycophytes generalize their roles during the evolution of vascular plants
Authors: Wang Jinpeng , Yu Jigao , Sun Pengchuan , Li Chao , Song Xiaoming , Lei Tianyu , Li Yuxian , Yuan Jiaqing , Sun Sangrong , Ding Hongling , Duan Xueqian , Shen Shaoqi , Shen Yanshuang , Li Jing , Meng Fanbo , Xie Yangqin , Wang Jianyu , Hou Yue , Zhang Jin , Zhang Xianchun , Wang Xiyin
Published: November 2017

Seed plants and lycophytes constitute the extant vascular plants. As a model lycophyte, Selaginalla moellendroffii was deciphered its genome, previously proposed to have avoided polyploidies, as key events contributing to the origination and fast expansion of seed plants. Here, using a gold-standard streamline recently proposed to deconvolute complex genomes, we reanalyzed the S. moellendroffii genome. To our surprise, we found clear evidence of multiple paleo-polyploidies, with one being recent (~ 13-15 millions of years ago or Mya), another one occurring about ~125-142 Mya, during the evolution of lycophytes, and at least 2 or 3 events being more ancient. Besides, comparison of reconstructed ancestral genomes of lycophytes and angiosperms shows that lycophytes were likely much more affected by paleo-polyploidies than seed plants. The present analysis here provides clear and solid evidence that polyploidies have contributed the successful establishment of all vascular plants on earth.
Integrative construction of regulatory region networks in 127 human reference epigenomes by matrix factorization
Authors: Liu Dianbo , Davila-Velderrain Jose , Zhang Zhizhuo , Kellis Manolis
Published: November 2017

Despite large experimental and computational efforts aiming to dissect the mechanisms underlying disease risk, mapping cis-regulatory elements to target genes remains a challenge. Here, we introduce a matrix factorization framework to integrate physical and functional interaction data of genomic segments. The framework was used to predict a regulatory network of chromatin interaction edges linking more than 20,000 promoters and 1.8 million enhancers across 127 human reference epigenomes, including edges that are present in any of the input datasets. Our network integrates functional evidence of correlated activity patterns from epigenomic data and physical evidence of chromatin interactions. An important contribution of this work is the representation of heterogeneous data with different qualities as networks. We show that the unbiased integration of independent data sources suggestive of regulatory interactions produces meaningful associations supported by existing functional and physical evidence, correlating with expected independent biological features.
Modified antibiotic adjuvant ratios can slow and steer the evolution of resistance: co-amoxiclav as a case study
Authors: Allen Richard C. , Brown Sam P.
Published: November 2017

As the spread of antibiotic resistance outstrips the introduction of new antibiotics, reusing existing antibiotics is increasingly important. One promising method is to combine antibiotics with synergistically acting adjuvants that inhibit resistance mechanisms, allowing drug killing. Here we use co-amoxiclav (a commonly used and clinically important drug combination of the β-lactam antibiotic amoxicillin and the β-lactamase inhibitor clavulanate) to ask whether treatment efficacy and resistance evolution can be decoupled via component dosing modifications.

A simple mathematical model predicts that different ratios of these two drug components can produce distinct evolutionary responses despite similar initial levels of control. We test this hypothesis by selecting Escherichia coli with a plasmid encoded β-lactamase (ESBL CTX-M-14), against different proportions of amoxicillin and clavulanate. Consistent with our theory, we found that while resistance evolved under all conditions, the component ratio influenced both the rate and mechanism of resistance evolution. Specifically, we found that the current clinical practice of high amoxicillin to clavulanate ratios resulted in the most rapid failure due to the evolution of gene dosing responses. Increased plasmid copy number allowed E. coli to increase β-lactamase dosing and effectively titrate out the low quantities of clavulanate, restoring amoxicillin resistance. In contrast, we found high clavulanate ratios were more robust - plasmid copy number did not increase, although porin or efflux resistance mechanisms were found, as in all drug ratios. Our results indicate that by changing the ratio of adjuvant to antibiotic we can slow and steer the path of resistance evolution. We therefore suggest the use of increased clavulanate dosing regimens to slow the rate of resistance evolution.
Microbial community structure and microbial networks correspond to nutrient gradients within coastal wetlands of the Laurentian Great Lakes
Authors: Horton Dean J. , Theis Kevin R. , Uzarski Donald G. , Learman Deric R.
Published: November 2017

Microbial communities within the soil of Laurentian Great Lakes coastal wetlands drive biogeochemical cycles and provide several other ecosystems services. However, there exists a lack of understanding of how microbial communities respond to nutrient gradients and human activity in these systems. This research sought to address the lack of understanding through exploration of relationships between nutrient gradients, microbial community diversity, and microbial networks. Significant differences in microbial community structure were found among coastal wetlands within the western basin of Lake Erie and all other wetlands studied (three regions within Saginaw Bay and one region in the Beaver Archipelago). These diversity differences coincided with higher nutrient levels within the Lake Erie region. Site-to-site variability also existed within the majority of the regions studied, suggesting site-scale heterogeneity may impact microbial community structure. Several subnetworks of microbial communities and individual community members were related to chemical gradients among wetland regions, revealing several candidate indicator communities and taxa which may be useful for Great Lakes coastal wetland management. This research provides an initial characterization of microbial communities among Great Lakes coastal wetlands and demonstrates that microbial communities could be negatively impacted by anthropogenic activities.
Hospitalized premature infants are colonized by related bacterial strains with distinct proteomic profiles
Authors: Brown Christopher. T. , Xiong Weili , Olm Matthew R. , Thomas Brian C. , Baker Robyn , Firek Brian , Morowitz Michael J. , Hettich Robert L. , Banfield Jillian F.
Published: November 2017

During the first weeks of life, microbial colonization of the gut impacts human immune system maturation and other developmental processes. In premature infants, aberrant colonization has been implicated in the onset of necrotizing enterocolitis (NEC), a life-threatening intestinal disease. To study the premature infant gut colonization process, genome-resolved metagenomics was conducted on 343 fecal samples collected during the first three months of life from 35 premature infants housed in a neonatal intensive care unit, 14 of which developed NEC, and metaproteomic measurements were made on 87 samples. Microbial community composition and proteomic profiles remained relatively stable on the time scale of a week, but the proteome was more variable. Although genetically similar organisms colonized many infants, most infants were colonized by distinct strains with metabolic profiles that could be distinguished using metaproteomics. Microbiome composition correlated with infant, antibiotics administration, and NEC diagnosis. Communities were found to cluster into seven primary types, and community type switched within infants, sometimes multiple times. Interestingly, some communities sampled from the same infant at subsequent time points clustered with those of other infants. In some cases, switches preceded onset of NEC; however, no species or community type could account for NEC across the majority of infants. In addition to a correlation of protein abundances with organism replication rates, we found that organism proteomes correlated with overall community composition. Thus, this genome-resolved proteomics study demonstrates that the contributions of individual organisms to microbiome development depend on microbial community context.

Importance

Humans are colonized by microbes at birth, a process that is important to health and development. However, much remains to be known about the fine-scale microbial dynamics that occur during the colonization period. We conducted a genome-resolved study of microbial community composition, replication rates, and proteomes during the first three months of life of both healthy and sick premature infants. Infants were found to be colonized by similar microbes, but each underwent a distinct colonization trajectory.

Interestingly, related microbes colonizing different infants were found to have distinct proteomes, indicating that microbiome function is not only driven by which organisms are present, but also largely depends on microbial responses to the unique set of physiological conditions in the infant gut.
Circuit models of low dimensional shared variability in cortical networks
Authors: Huang Chengcheng , Ruff Douglas A. , Pyle Ryan , Rosenbaum Robert , Cohen Marlene R. , Doiron Brent
Published: November 2017

Trial-to-trial variability is a reflection of the circuitry and cellular physiology that makeup a neuronal network. A pervasive yet puzzling feature of cortical circuits is that despite their complex wiring, population-wide shared spiking variability is low dimensional with all neurons fluctuating en masse. Previous model cortical networks are at loss to explain this global variability, and rather assume it is from external sources. We show that if the spatial and temporal scales of inhibitory coupling match known physiology, model spiking neurons internally generate low dimensional shared variability that captures the properties ofin vivopopulation recordings along the visual pathway. Shifting spatial attention into the receptive field of visual neurons has been shown to reduce low dimensional shared variability within a brain area, yet increase the variability shared between areas. A top-down modulation of inhibitory neurons in our network provides a parsimonious mechanism for this attentional modulation, providing support for our theory of cortical variability. Our work provides a critical and previously missing mechanistic link between observed cortical circuit structure and realistic population-wide shared neuronal variability and its modulation.
Don’t throw out the sympatric species with the crater lake water: fine-scale investigation of introgression provides weak support for functional role of secondary gene flow in one of the clearest examples of sympatric speciation
Authors: Richards Emilie J. , Poelstra Jelmer W. , Martin Christopher H.
Published: November 2017

Genomic data has revealed complex histories of colonization and repeated gene flow previously unrecognized in some of the most celebrated examples of sympatric speciation and radiation. However, much of the evidence for secondary gene flow into these radiations comes from genome-wide tests, which tells us little about how gene flow potentially influenced sympatric diversification. Here we investigated whole genomes of Barombi Mbo crater lake cichlids for fine-scale patterns of introgression between species with neighboring riverine cichlid populations. We did find evidence of secondary gene flow into the radiation scattered across < 0.24% of the genome; however, the functional and genetic diversity in these regions paint no clear picture of how that variation could have contributed to the ecological and morphological diversity found in the lake. Our results suggest that either variation in novel genetic pathways introduced during secondary gene flow contributed to the radiation, or that secondary gene flow was predominantly neutral with respect to the diversification processes. We also found evidence for differential assortment of ancestral polymorphism found in riverine populations between sympatric sister species, suggesting the presence of a hybrid swarm in the past. While the history of gene flow and colonization appears to be more complicated than once thought, the lack of compelling evidence for secondary gene flow influencing diversification suggests that we should not yet rule out one of the most celebrated examples of sympatric speciation in nature.
Quadratic Programming Data Descriptors for Abnormal Beat Detection in ECG Recordings
Authors: Minhas Fayyaz ul Amir Afsar
Published: November 2017

This paper analyzes the efficacy of applying one class classifiers (OCCs) to the problem of abnormal beat detection in ECG. It also proposes a novel OCC called Quadratic Programming Dissimilarity representation based Data Descriptor (QPDDD). A comparison of the proposed classification technique with existing classifiers over the MIT-BIH arrhythmia database is presented. Results show that OCCs coupled with wavelet domain features present a practical, robust and scalable solution for handling inter-individual variability in ECG patterns of different types of cardiac beats. An equal error rate of 90-95% was obtained for the MIT-BIH arrhythmia database depending upon the amount of training data used. A major advantage of the proposed scheme is that it requires only normal beats during its training. Another advantage is that it is able to handle inter-individual differences in ECG morphologies as the training takes place separately for each individual.
An agent-based model of cattle grazing toxic Geyer’s larkspur
Authors: Jablonski Kevin E. , Boone Randall B. , Meiman Paul J.
Published: November 2017

By killing cattle and otherwise complicating management, the many species of larkspur (Delphiniumspp.) present a serious, intractable, and complex challenge to livestock grazing management in the western United States. Among the many obstacles to improving our understanding of cattle-larkspur dynamics has been the difficulty of testing different grazing management strategies in the field, as the risk of dead animals is too great. Agent-based models (ABMs) provide an effective method of testing alternate management strategies without risk to livestock. ABMs are especially useful for modeling complex systems such as livestock grazing management, and allow for realistic bottom-up encoding of cattle behavior. Here, we introduce a spatially-explicit, behavior-based ABM of cattle grazing in a pasture with a dangerous amount of Geyer’s larkspur (D. geyeri). This model tests the role of herd cohesion and stocking density in larkspur intake, finds that both are key drivers of larkspur-induced toxicosis, and indicates that alteration of these factors within realistic bounds can mitigate risk. Crucially, the model points to herd cohesion, which has received little attention in the discipline, as playing an important role in lethal acute toxicosis. As the first ABM to model grazing behavior at realistic scales, this study also demonstrates the tremendous potential of ABMs to illuminate grazing management dynamics, including fundamental aspects of livestock behavior amidst ecological heterogeneity.
Electrophysiological signatures of spatial boundaries in the human subiculum
Authors: Lee Sang Ah , Miller Jonathan F. , Watrous Andrew J. , Sperling Michael , Sharan Ashwini , Worrell Gregory A. , Berry Brent M , Jobst Barbara C. , Davis Kathryn A. , Gross Robert E. , Lega Bradley , Sheth Sameer , Das Sandhitsu R. , Stein Joel M. , Gorniak Richard , Rizzuto Daniel S. , Jacobs Joshua
Published: November 2017

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly-related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. While studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. Here we present direct intracranial recordings from the hippocampal formation of surgical epilepsy patients while they performed a virtual spatial navigation task. Our results suggest that encoding target locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, or movement. These findings provide the first direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homologue of the hippocampal subregion in which most rodent boundary cells are found.

Significance Statement

Spatial computations using environmental boundaries are an integral part of the brain’s spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to fMRI studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions we identified, for the first time in humans, a neural marker of boundary representation in the subiculum.
The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment
Authors: Li Ding , Finley Stacey D.
Published: November 2017

Multiple promoters and inhibitors mediate angiogenesis, the formation of new blood vessels, and these factors represent potential targets for impeding vessel growth in tumors. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor targeted in anti-angiogenic cancer therapies. In addition, thrombospondin-1 (TSP1) is a major endogenous inhibitor of angiogenesis, and TSP1 mimetics are being developed as an alternative type of anti-angiogenic agent. The combination of bevacizumab, an anti-VEGF agent, and ABT-510, a TSP1 mimetic, has been tested in clinical trials to treat advanced solid tumors. However, the patients’ responses are highly variable and show disappointing outcomes. To obtain mechanistic insight into the effects of this combination anti-angiogenic therapy, we have constructed a novel whole-body systems biology model including the VEGF and TSP1 reaction networks. Using this molecular-detailed model, we investigated how the combination anti-angiogenic therapy changes the amounts of pro-angiogenic and anti-angiogenic complexes in cancer patients. We particularly focus on answering the question of how the effect of the combination therapy is influenced by tumor receptor expression, one aspect of patient-to-patient variability. Overall, this model complements the clinical administration of combination anti-angiogenic therapy, highlights the role of tumor receptor variability in the heterogeneous responses to anti-angiogenic therapy, and identifies the tumor receptor profiles that correlate with a high likelihood of a positive response to the combination therapy. Our model provides novel understanding of the VEGF-TSP1 balance in cancer patients at the systems-level and could be further used to optimize combination anti-angiogenic therapy.
Easy quantification of template-directed CRISPR/Cas9 editing
Authors: Brinkman Eva K. , Kousholt Arne Nedergaard , Harmsen Tim , Leemans Christ , Chen Tao , Jonkers Jos , van Steensel Bas
Published: November 2017

Template-directed CRISPR/Cas9 editing is a powerful tool for introducing subtle mutations in genomes. However, the success rate of incorporation of the desired mutations at the target site is difficult to predict and therefore must be empirically determined. Here, we adapted the widely used TIDE method for quantification of templated editing events, including point mutations. The resulting TIDER method is a rapid, cheap and accessible tool for testing and optimization of template-directed genome editing strategies.
Transposon insertional mutagenesis in Saccharomyces uvarum reveals trans-acting effects influencing species-dependent essential genes
Authors: Sanchez Monica R. , Payen Celia , Cheong Frances , Hovde Blake T. , Bissonnette Sarah , Arkin Adam P. , Skerker Jeffrey M. , Brem Rachel B. , Caudy Amy A. , Dunham Maitreya J.
Published: November 2017

To understand how complex genetic networks perform and regulate diverse cellular processes, the function of each individual component must be defined. Comprehensive phenotypic studies of mutant alleles have been successful in model organisms in determining what processes depend on the normal function of a gene. These results are often ported to newly sequenced genomes by using sequence homology. However, sequence similarity does not always mean identical function or phenotype, suggesting that new methods are required to functionally annotate newly sequenced species. We have implemented comparative analysis by high-throughput experimental testing of gene dispensability in Saccharomyces uvarum, a sister species of S. cerevisiae. We created haploid and heterozygous diploid Tn7 insertional mutagenesis libraries in S. uvarum to identify species dependent essential genes, with the goal of detecting genes with divergent functions and/or different genetic interactions. Comprehensive gene dispensability comparisons with S. cerevisiae predicted diverged dispensability at 12% of conserved orthologs, and validation experiments confirmed 22 differentially essential genes. Surprisingly, despite their differences in essentiality, these genes were capable of cross-species complementation, demonstrating that trans-acting factors that are background-dependent contribute to differential gene essentiality. This study demonstrates that direct experimental testing of gene disruption phenotypes across species can inform comparative genomic analyses and improve gene annotation. Our method can be widely applied in microorganisms to further our understanding of genome evolution.
Antimicrobial resistant Klebsiella pneumoniae carriage and infection in specialized geriatric care wards linked to acquisition in the referring hospital
Authors: Gorrie Claire L. , Mirceta Mirjana , Wick Ryan R. , Judd Louise M. , Wyres Kelly L. , Thomson Nicholas R. , Strugnell Richard A. , Pratt Nigel F. , Garlick Jill S. , Watson Kerrie M. , Hunter Peter C. , McGloughlin Steve A. , Spelman Denis W. , Jenney Adam W. J. , Holt Kathryn E.
Published: November 2017

Background

Klebsiella pneumoniae is a leading cause of extended-spectrum beta-lactamase (ESBL) producing hospital-associated infections, for which elderly patients are at increased risk.

Methods

We conducted a 1-year prospective cohort study, in which a third of patients admitted to two geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole genome sequencing and antimicrobial susceptibility testing.

Results

K. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8% and ESBL carriage 1.7%. K. pneumoniae infection incidence was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15and belonged to clones associated with hospital-acquired ESBL infections in other countries (ST29, ST323, ST340).

One also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital.

Conclusions

The data suggest the major source of K. pneumoniae was the patient’s own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection control. Rectal screening for ESBL organisms upon admission to geriatric wards could help inform patient management and infection control in such facilities.

Patients’ own gut microbiota were the major source of K. pneumoniae, but extended-spectrum beta-lactamase strains were acquired in the referring hospital. This highlights the potential for rectal screening, and the importance of the wider hospital network, for local risk management.
Regulation of vocal precision by local noradrenergic modulation of a motor nucleus
Authors: Glaze Christopher M , Castelino Christina B , Bibu Steve P , Yau Elvina , Schmidt Marc F
Published: November 2017

Recent theories of norepinephrine (NE) function suggest that NE modulates the transition between stereotyped, goal-directed behavior and more variable exploratory behaviors that facilitate learning and adaptation. We provide evidence for context dependent switching by NE that is analogous to this explore/exploit strategy in the vocal system of the zebra finch (Taeniopygia guttata). Stimulation of the locus coeruleus, the major source of norepinephrine in the brain, decreases song trial-to-trial variability transforming the variable, exploratory “undirected” song into song that resembles the more stereotyped, exploitative “directed” song males sing to females. This behavioral switch is mediated by NE acting directly on a cortical motor nucleus that integrates inputs from a premotor cortical nucleus and a basal ganglia circuit necessary for vocal motor learning. These findings suggest that norepinephrine can act directly on the motor system to influence the transition between exploratory and exploitative behavioral strategies.
The role of telomere shortening in carcinogenesis: A hybrid stochastic-deterministic approach
Authors: Rodriguez-Brenes Ignacio A. , Komarova Natalia L. , Wodarz Dominik
Published: November 2017

Genome instability is a characteristic of most cancers, contributing to the acquisition of genetic alterations that drive tumor progression. One important source of genome instability is linked to telomere dysfunction in cells with critically short telomeres that lack p53-mediated surveillance of genomic integrity. Here we research the probability that cancer emerges through an evolutionary pathway that includes a telomere-induced phase of genome instability. To implement our models we use a hybrid stochastic-deterministic approach, which allows us to perform large numbers of simulations using biologically realistic population sizes and mutation rates, circumventing the traditional limitations of fully stochastic algorithms. The hybrid methodology should be easily adaptable to a wide range of evolutionary problems. In particular, we model telomere shortening and the acquisition of two mutations: Telomerase activation and p53 inactivation. We find that the death rate of unstable cells, and the number of cell divisions that p53 mutants can sustain beyond the normal senescence setpoint determine the likelihood that the first double mutant originates in a cell with telomere-induced instability. The model has applications to an influential telomerase-null mouse model and p16 silenced human cells. We end by discussing algorithmic performance and a measure for the accuracy of the hybrid approximation.