bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal reconfigurattion of distribution systems by considering switch and wind turbine placements to enhance reliability and efficiency
Authors: Zare Mohsen , Azizipanah‐Abarghooee Rasoul , Hooshmand Rahmat‐Allah , Malekpour Mostafa
Published: September 2017

Reconfiguration and smart control of remote‐controlled sectionalising switches in distribution networks are considered as the major solutions for loss mitigation, interruption time reduction and reliability improvement after events. That is because these automation tools bring about changes in the topology of the network, isolate the faulted regions, operate distributed generators for local load satisfaction and restore the un‐faulted regions as rapidly as possible. Thus, a new solution methodology for solving the simultaneous optimal wind turbines (WTs)/switches placement as well as network reconfiguration is developed to enhance the distribution network's efficiency and reliability. Power losses, voltage deviation index, switch cost and reliability cost based on expected customer interruption cost are considered as the objective functions. The approach profits from a new multi‐objective algorithm based on modified artificial bee colony for providing the best compromise solution. The presented framework is shown to provide superior results when applied to the IEEE 69‐node test feeder. Finally, different scenarios based on feeder reconfiguration, switch placement and WT placement problems are constructed and presented in Section 5.
Creeping discharges features propagating in air at atmospheric pressure on various materials under positive lightning impulse voltage – part 2: modelling and computation of discharges’ parameters
Authors: Douar Mohammed Adnane , Beroual Abderrahmane , Souche Xavier
Published: September 2017

In this paper, the propagation mechanism of creeping discharges up to flashover for short air gaps is examined and described on various materials based on laboratory de‐noised data (namely current, voltage and captured images). The main parameters considered for investigating the development of creeping discharges and their characteristics deal with the measurement, modelling and calculation of (i) their final/stopping length and morphology, (ii) their propagation velocity and (iii) the electric field distribution including the maximal magnitude (Emax) and the geometric coefficient (β) estimation. The obtained results evidenced that both length and velocity of discharges are emphasised for polyamide‐based materials (namely PA6/50 and PA66/50) whereas their ignition remains inhibited for filled cycloaliphatic epoxy resin (FCEP) and ethylene propylene diene monomere (EPDM) surfaces. As the electric field is concerned, both analytical and numerical models are developed and their results are compared and discussed. It has been shown that the presence of a polymer acts as a barrier when being incorporated between an electrodes gap whose dielectric strength depends strongly on the used material. Moreover, the FCEP barrier, in comparison to other materials, exhibits a marked dielectric reinforcement and an enhanced stability of the system making it suitable to provide a better protection to high‐voltage equipment against discharges effects.
Dual‐band planar antenna loaded with CRLH unit cell for WLAN/WiMAX application
Authors: Li Haixiong , Zheng Qi , Ding Jun , Guo Chenjiang
Published: September 2017

A dual‐band planar antenna based on composite right and left handed (CRLH) metamaterial is presented. The proposed antenna is comprised of a host folded planar monopole antenna and a CRLH transmission line unit cell. Due to another resonance frequency generated from the loaded CRLH unit cell, the presented antenna is actually a planar antenna with dual resonance bands at the centre frequency of 2.50 and 5.80 GHz, respectively, which can be regulated independently. The developed antenna also has different polarisations, the linear polarisation at the lower band and the circular polarisation at the upper resonance band. Rather than the complicated structure as before, this antenna is fabricated easily for the simple configuration without holes and the interdigital capacitances. The results of this study show that the reflection coefficient and radiation pattern have a good agreement between the simulation and measurement, the simulated relative bandwidth is 22.8% (2.22–2.79 GHz) and 10.8% (5.42–6.04 GHz), which meet the Wi‐Fi/Worldwide Interoperability for Microwave Access (WiMAX) specification very well.
Additive manufacturing of Ku/K‐band waveguide filters: a comparative analysis among selective‐laser melting and stereo‐lithography
Authors: Peverini Oscar A. , Addamo Giuseppe , Lumia Mauro , Virone Giuseppe , Calignano Flaviana , Lorusso Massimo , Manfredi Diego
Published: September 2017

This study describes an experimental research activity on the manufacturing of passive waveguide components by means of two additive technologies, namely the selective‐laser melting and the stereo‐lithography processes. The former is a power‐bed fusion process, for which aluminium, titanium, and steel powders have been considered in this study. The latter is based on the photopolymerisation of a resin vat. This technology has been applied in conjunction with an acrylonitrile–butadiene–styrene‐like polymer and a subsequent electrolytic copper plating for the metallisation of the internal channels. Wideband filters operating in Ku/K band have been developed as benchmarks, for which detailed comparisons between simulations and measurements are reported.
Design of a single‐mode photonic crystal fibre with ultra‐low material loss and large effective mode area in THz regime
Authors: Ahmed Kawsar , Paul Bikash Kumar , Chowdhury Sawrab , Sen Shuvo , Islam Md. Ibadul , Islam Md. Shadidul , Hasan Md. Rabiul , Asaduzzaman Sayed
Published: September 2017

A novel low‐loss photonic crystal fibre (PCF) has been suggested for THz spectral applications. The proposed PCF contains five layers cladding with three layers core. The cladding and core region of the fibre are arranged in the octagonal and porous manner, respectively, where both the core and cladding vicinity are constituted by circular air cavities. The optical properties of the PCF are investigated by utilising the full vectorial finite‐element method along with the perfect match layers boundary condition. All numerical outcomes show the ultra‐low effective material loss of 0.049 cm−1 and large effective area of 3 × 10−7 m2 at 1 THz operating frequency. The power fraction is also considered as another significant parameter to design a low loss fibre. The almost more than half of the useful power (about 53.78% at f  = 1 THz) goes through the core over the wider operating frequency. In addition this, the proposed single‐mode PCF can be fabricated using the sol–gel method and is useful not only for high data traffic transmission applications but also for THz waveguide applications.
Fault detection of HVDC cable in multi‐terminal offshore wind farms using transient sheath voltage
Authors: Ashrafi Niaki Seyed Hassan , Hosseini Seyyed Mehdi , Abdoos Ali Akbar
Published: September 2017

With respect to rapid growth of offshore wind power, multi‐terminal HVDC system is going to be an attractive way of the power transmission for remote and large offshore wind farms. Since the HVDC cables are the vital component of the multi‐terminal HVDC transmission system, an accurate and fast fault detection method is necessary for protection and maintaining uninterrupted power delivery to the main grid. This study presents a novel method to diagnose HVDC cable faults and unbalancing of DC capacitor bank in multi‐terminal voltage source converter HVDC systems for offshore wind farms. Transient voltage of cable sheath is investigated as a main parameter for detecting types of cable faults. Extensive simulations are performed on EMTDC‐PSCAD platform and the results show the effectiveness of the proposed technique.
Optimal design with materials selection for thermal energy storages in high temperature concentrating solar power
Authors: Berrhazi Samir , Ahmed Ouammi , Benchrifa Rachid , Zejli Driss
Published: September 2017

This study proposes a comprehensive decision support framework to optimally select the solid medium and heat transfer tubes material composing the thermal energy storage (TES). The proposed decision model aims to maximise the net present value (NPV) associated with the TES investment over a given time horizon. Compared with related works in the literature, the authors’ design accounts for various practical investment costs and design parameters that are the number of heat transfer tubes, storage module length, and the storage unit diameter. The decision problem, which maximises the NPV is formulated as an optimisation problem to find out the optimal combination among a set of solid media and heat transfer tube materials considering their thermo‐physical characteristics. The proposed design is evaluated through case studies to test its concrete practices and to evaluate the impacts of the design parameters on the TES investment costs.
Impact of grid‐tied large‐scale photovoltaic system on dynamic voltage stability of electric power grids
Authors: Refaat Shady S. , Abu‐Rub Haitham , Sanfilippo Antonio P. , Mohamed Amira
Published: September 2017

Perfect power system voltage stability is not possible in practice. Generally, the power grid is continually exposed to changes in its load and operating conditions. Therefore, dynamic stability analysis is one the most important and effective elements for greater security, stability and reliability of planning, design, operation and economic aspects of electric power networks. This study investigates and reports on the dynamic stability of the power system with a large‐scale photovoltaic system (L‐S PV). Two different scenarios with centralised PV power plants are considered in the medium voltage level without voltage regulation capabilities. Simulation results with these scenarios will show how the voltage instability decreases with the L‐S PV based on the bus status, disturbance location, and disturbance duration. In addition, the study discusses network terminal voltage, generator's rotor angle, generator's terminal current, generator's reactive power and electrical power output. This study is an extension of the earlier published conference paper.
Optimal unit commitment based on second‐order cone programming in high wind power penetration scenarios
Authors: Dui Xiaowei , Zhu Guiping
Published: September 2017

With the increase in wind power integration in power systems, wind power uncertainty can no longer be neglected in the determination of the day‐ahead power generation schedules. Aiming to achieve the best economy of power generation of the system, this study proposes a unit commitment (UC) optimal model for thermal plants, considering the fuel costs required for compensating for the wind power below schedule. The AC power flow equations are included as constraints based on the second‐order cone programming (SOCP) method. SOCP is further improved here by considering line loss as constraint to guarantee the validity of its solution. Research shows that generators with lower minimum‐output and fuel‐cost rates are preferred to be online and that reasonable wind curtailment is beneficial for reducing the generation cost. Finally, AC power flow verification is carried out and the results suggest that the improved SOCP method could model the AC power flow equations correctly. The proposed methodology can be effective in making UC decisions for power grids with high wind power penetration.
Development of expertise in elite and sub‐elite British rugby league players: A comparison of practice experiences
Authors: Rothwell Martyn , Stone Joseph A. , Davids Keith , Wright Craig
Published: September 2017

Previous studies have investigated how individuals reach an expert level by counting the number of hours engaged in specific practice types. Here we sought to understand and compare the microstructure (e.g. practice tasks undertaken) of these practice hours experienced by elite and sub‐elite British rugby league players. Semi‐structured interviews explored the practice experiences of eight international and eight domestic level players. A two‐staged thematic analysis was used to interpret the data. The analysis revealed that both player groups experienced a rich and narrow landscape of affordances and were exposed to early diversification of sports experiences during childhood. Differences were identified in domestic level players’ experiences of amateur and professional sports, where episodes of negative developmental environments were reported. International players’ practice experiences revealed differences in their professional careers, where exposure to scenario‐based practice and dynamic learning environments were reported. The findings suggest that insights from ecological dynamics provide a suitable theoretical framework to guide coaches in the design of practice environments that should consider the physical, psychological, emotional and social dimensions of expertise acquisition.
OncomiR: an online resource for exploring pan-cancer microRNA dysregulation
Authors: Wong Nathan W , Chen Yuhao , Chen Shuai , Wang Xiaowei
Published: September 2017

Dysregulation of microRNAs (miRNAs) is extensively associated with cancer development and progression. miRNAs have been shown to be biomarkers for predicting tumor formation and outcome. However, identification of the relationships between miRNA expression and tumor characteristics can be difficult and time-consuming without appropriate bioinformatics expertise. To address this issue, we present OncomiR, an online resource for exploring miRNA dysregulation in cancer. Using combined miRNA-seq, RNA-seq and clinical data from The Cancer Genome Atlas, we systematically performed statistical analyses to identify dysregulated miRNAs that are associated with tumor development and progression in most major cancer types. Additional analyses further identified potential miRNA-gene target interactions in tumors. These results are stored in a backend database and presented through a web server interface. Moreover, through a backend bioinformatics pipeline, OncomiR can also perform dynamic analysis with custom miRNA selections for in-depth characterization of miRNAs in cancer.

Availability and implementation

The OncomiR website is freely accessible at www.oncomir.org.

Supplementary information

Supplementary data are available at Bioinformatics online.
Phylodynamic assessment of intervention strategies for the West African Ebola virus outbreak
Authors: Dellicour Simon , Baele Guy , Dudas Gytis , Faria Nuno R. , Pybus Oliver G. , Suchard Marc A. , Rambaut Andrew , Lemey Philippe
Published: September 2017

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100046). The recent Ebola virus (EBOV) outbreak in West Africa witnessed considerable efforts to obtain viral genomic data as the epidemic was unfolding. If such data can be deployed in real-time, molecular epidemiological investigations could play a role in complementing contact tracing undertaken by public health agencies. Analysing the EBOV genomes accumulated to date can also deliver insights into epidemic dynamics. Such analyses have been shown that metapopulation dynamics were critical for EBOV dispersal between rural and urban areas during the epidemic, but the implications for specific intervention scenarios remain unclear. Here, we address this issue using a collection of phylodynamic approaches. We show that long-distance dispersal events (between administrative areas >250 km apart) were not crucial for epidemic expansion and that preventing viral lineage movement to any given administrative area would, in most cases, have had little impact. However, urban areas – specifically those encompassing the three capital cities and their suburbs – were critical in attracting and further disseminating the virus: preventing viral lineage movement to all three simultaneously would have contained epidemic size by two-thirds. Using continuous phylogeographic reconstructions we estimate a distance kernel for EBOV spread and reveal considerable heterogeneity in dispersal velocity through time. We also show that announcements of border closures were followed by a significant but transient effect on international virus dispersal. By quantifying the hypothetical impact of different intervention strategies as well as the impact of barriers on dispersal frequency, our study illustrates how phylodynamic analyses can help to address specific epidemiological and outbreak control questions.
Reconstructing the Molecular Life History of Gliomas
Authors: Barthel Floris P. , Wesseling Pieter , Verhaak Roel G.W.
Published: September 2017

At the time of clinical presentation, the very heterogeneous group of pediatric and adult gliomas carry a wide range of diverse somatic genomic alterations. These include chromosome-sized gains and losses, focal amplification and deletions, rearrangements resulting in transcript fusions, small insertions/deletions, and point mutations. Tumor cells pay a penalty for maintaining these abnormalities which therefore must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model for gliomagenesis consisting of five consecutive phases that glioma cells have traversed prior to diagnosis. Tumor growth is repressed by activated DNA damage response pathways and dysfunctional telomeres in physiological conditions. Disruption of the p16-RB-p53 pathway and the acquisition of a telomere maintenance mechanism can bypass these bottlenecks. We relate somatic alterations to each of these steps, in order to reconstruct the life history of glioma. Understanding the story that each glioma tells at presentation may facilitate the design of novel, more effective therapeutic approaches.

Key Concepts

Glioma initiating event: The first event that initiates the clonal expansion of cells

Oncogene-induced senescence: Durable growth arrest triggered by continued oncogene exposure

Replicative senescence: Durable growth arrest triggered via telomere dysfunction and activated DNA damage pathways

Crisis: Widespread cell death triggered via telomere dysfunction

Senescence bypass event: Any molecular alteration that bypasses or suppresses oncogene-induced senescence

Senescence-associated secretory phenotype (SASP): Senescent cells secrete various immunogenic cytokines, growth factors and proteases into the microenvironment

Functional redundancy: Used to describe two or more genomic changes that provide overlapping functional effect

Neutral evolution:changes due to stochastic allelic variation that do not affect fitness

Selective sweep:The elimination of genetic variation following strong positive selection effectively reducing the tumor to a single clone

Clonal event: Somatic mutation or copy number event that is conserved across all tumor cells

Subclonal event: Somatic mutation or copy number event that is only present in a subset (subclone) of tumor cells

Chromothripsis: A punctuated shattering of genomic DNA

Kataegis: Clustered regions of hypermutation

Polyploidization: The multiplication of chromosome content in a cell

Breakage fusion bridge (BFB) cycle: Cyclic fusion of uncapped telomeres, bridge formation during anaphase and subsequent breakage leading to unequal inheritance of DNA

Dicentric chromosome: Two fused chromosomes span across the mitotic spindle in anaphase, called dicentric because it has two centromeres

Double minute (DM) chromosome: Extra-chromosomal circular DNA segment lacking centromere(s) and telomeres

Immortalization event: The last straw in the immortalization process that directly leads to telomere stabilization
BldC delays entry into development to produce a sustained period of vegetative growth inStreptomyces venezuelae
Authors: Bush Matthew J. , Chandra Govind , Al-Bassam Mahmoud M. , Findlay Kim C. , Buttner Mark J.
Published: September 2017

Streptomycetes are filamentous bacteria that differentiate by producing spore-bearing reproductive structures called aerial hyphae. The transition from vegetative to reproductive growth is controlled by thebld(bald) loci, and mutations inbldgenes prevent the formation of aerial hyphae, either by blocking entry into development (typically mutations in activators) or by inducing precocious sporulation in the vegetative mycelium (typically mutations in repressors). One of thebldgenes,bldC, encodes a 68-residue DNA-binding protein related to the DNA-binding domain of MerR-family transcription factors. Recent work has shown that BldC binds DNA by a novel mechanism, but there is less insight into its impact onStreptomycesdevelopment. Here we used ChIP-seq coupled with RNA-seq to define the BldC regulon in the model speciesStreptomyces venezuelae, showing that BldC can function both as a repressor and as an activator of transcription. Using electron microscopy and time-lapse imaging, we show thatbldCmutants are bald because they initiate development prematurely, bypassing the formation of aerial hyphae. This is consistent with the premature expression of BldC target genes encoding proteins with key roles in development (e.g.whiD,whiI,sigF), chromosome condensation and segregation (e.g.smeA-sffA,hupS), and sporulation-specific cell division (e.g.dynAB), suggesting that BldC-mediated repression is critical to maintain a sustained period of vegetative growth prior to sporulation. We discuss the possible significance of BldC as an evolutionary link between MerR family transcription factors and DNA architectural proteins.

IMPORTANCE

Understanding the mechanisms that drive bacterial morphogenesis depends on the dissection of the regulatory networks that underpin the cell biological processes involved. Recently,Streptomyces venezuelaehas emerged as an attractive new model system for the study of morphological differentiation inStreptomyces. This has led to significant progress in identifying the genes controlled by the transcription factors that regulate aerial mycelium formation (Bld regulators) and sporulation (Whi regulators). Taking advantage ofS. venezuelae, we used ChIP-seq coupled with RNA-seq to identify the genes directly under the control of BldC. BecauseS. venezuelaesporulates in liquid culture, the complete spore-to-spore life cycle can be examined using time-lapse microscopy, and we applied this technique to thebldCmutant. These combined approaches reveal BldC to be a member of an emerging class of Bld regulators that function principally to repress key sporulation genes, thereby extending vegetative growth and blocking the onset of morphological differentiation.
A multi-locus association analysis method integrating phenotype and expression data reveals multiple novel associations to flowering time variation in wild-collectedArabidopsis thaliana
Authors: Zan Yanjun , Carlborg Örjan
Published: September 2017

Abstract

When a species adapts to a new habitat, selection for the fitness traits often result in a confounding between genome-wide genotype and adaptive alleles. It is a major statistical challenge to detect such adaptive polymorphisms if the confounding is strong, or the effects of the adaptive alleles are weak. Here, we describe a novel approach to dissect polygenic traits in natural populations. First, candidate adaptive loci are identified by screening for loci that are directly associated to the trait or control the expression of genes known to affect it. Then, the multi-locus genetic architecture is inferred using a backward elimination association analysis across all the candidate loci using an adaptive false-discovery rate based threshold. Effects of population stratification are controlled by corrections for population structure in the pre-screening step and by simultaneously testing all candidate loci in the multi-locus model. We illustrate the method by exploring the polygenic basis of an important adaptive trait, flowering time inArabidopsis thaliana, using public data from the 1,001 genomes project. Our method revealed associations between 33 (29) loci and flowering time at 10 (16)°C in this collection of natural accessions, where standard genome wide association analysis methods detected 5 (3) loci. The 33 (29) loci explained approximately 55 (48)% of the total phenotypic variance of the respective traits. Our work illustrates how the genetic basis of highly polygenic adaptive traits in natural populations can be explored in much greater detail by using new multi-locus mapping approaches taking advantage of prior biological information as well as genome and transcriptome data.
Induction and Relief of Curiosity Elicit Parietal and Frontal Activity
Authors: van Lieshout Lieke L. F. , Vandenbroucke Annelinde R. E. , Müller Nils C. J. , Cools Roshan , de Lange Floris P.
Published: September 2017

Curiosity is a basic biological drive, but little is known about its behavioral and neural mechanisms. We can be curious about several types of information. On the one hand, curiosity is a function of the expected value of information, serving primarily to help us maximize reward. On the other hand, curiosity can be a function of the uncertainty of information, helping us to update what we know. In the current studies, we aimed to disentangle the contribution of information uncertainty and expected value of rewards to curiosity in humans of either sex. To this end, we designed a lottery task in which uncertainty and expected value of trial outcomes were manipulated independently, and examined how neural activity and behavioral measures of curiosity were modulated by these factors. Curiosity increased linearly with increased outcome uncertainty, both when curiosity was explicitly probed as well as when it was implicitly tested by people’s willingness to wait. Increased expected value, however, did not strongly relate to these curiosity measures. Neuroimaging results showed greater BOLD response with increasing outcome uncertainty in parietal cortex at the time of curiosity induction. Outcome updating when curiosity was relieved resulted in an increased signal in the insula, orbitofrontal cortex and parietal cortex. Furthermore, the insula showed a linear increase corresponding to the size of the information update. These results suggest that curiosity is monotonically related to the uncertainty about one’s current world model, the induction and relief of which are associated with activity in parietal and insular cortices respectively.

Significance statement

Humans are curious by nature. When you hear your phone beep, you probably feel the urge to check the message right away, even though the message itself likely doesn’t give you a direct reward. In this study, we demonstrated that curiosity can be driven by outcome uncertainty, irrespective of reward. The induction of curiosity was accompanied by increased activity in the parietal cortex, whereas the information update at the time of curiosity relief was associated with activity in insular cortex. These findings advance our understanding of the behavioral and neural underpinnings of curiosity, which lies at the core of human information-seeking and serves to optimize the individual’s current world-model.
Employing single-stranded DNA donors for the high-throughput production of conditional knockout alleles in mice
Authors: Lanza Denise G. , Gaspero Angelina , Lorenzo Isabel , Liao Lan , Zheng Ping , Wang Ying , Deng Yu , Cheng Chonghui , Zhang Chuansheng , Rasband Matthew N. , Seavitt John R. , DeMayo Francisco J. , Xu Jianming , Dickinson Mary E. , Beaudet Arthur L. , Heaney Jason D.
Published: September 2017

The International Mouse Phenotyping Consortium is generating null allele mice for every protein-coding gene in the genome and characterizing these mice to identify gene-phenotype associations. To test the feasibility of using CRISPR/Cas9 gene editing to generate conditional knockout mice for this large-scale resource, we employed Cas9-mediated homology driven repair (HDR) with short and long single-stranded oligodeoxynucleotides (ssODNs and lssODNs). Using pairs of guides and ssODNs donating loxP sites, we obtained putative conditional allele founder mice, harboring both loxP sites, for 23 of 30 genes targeted. LoxP sites integratedin cisin at least one F0 for 18 of 23 targeted genes. However, loxP sites were mutagenized in 4 of 18in cislines. HDR efficiency correlated with Cas9 cutting efficiency but was not influenced by ssODN homology arm symmetry. By contrast, using pairs of guides and a single lssODN to introduce a loxP-flanked exon, conditional allele founders were generated for all 4 genes targeted. Our studies demonstrate that Cas9-mediated HDR with pairs of ssODNs can generate conditional null alleles at many loci, but reveal inefficiencies when applied at scale. In contrast, lssODNs are amenable to high-throughput production of conditional alleles when they can be employed.
Desert Tortoises in the Genomic Age: Population Genetics and the Landscape
Authors: Shaffer H. Bradley , McCartney-Melstad Evan , Ralph Peter L. , Bradburd Gideon , Lundgren Erik , Vu Jannet , Hagerty Bridgette , Sandmeier Fran , Weitzman Chava , Tracy C. Richard
Published: September 2017

The California Department of Fish and Wildlife (CDFW) provided research funds to study the conservation genomics and landscape genomics of the Mojave desert tortoise, Gopherus agassizii, in response to the Desert Renewable Energy Conservation Plan (DRECP). To do this, we consolidated tissue samples of the desert tortoise from across the species range within California and southern Nevada, generated a DNA dataset consisting of full genomes of 270 tortoises, and analyzed the way in which the environment of the desert tortoise has determined modern patterns of relatedness and genetic diversity across the landscape. Here we present the implications of these results for the conservation and landscape genomics of the desert tortoise. Our work strongly indicates that several well-defined genetic groups exist within the species, including a primary north-south genetic discontinuity at the Ivanpah Valley and another separating western from eastern Mojave samples. We also use existing desert tortoise habitat modeling data with a novel extension of genetic "resistance distance" using geographic maps of continuous space to predict the relative impacts of five proposed development alternatives within the DRECP and rank them with respect to their likely impacts on desert tortoise gene flow and connectivity in the Mojave. Finally, we analyzed the impacts of each of the 214 distinct proposed development area "chunks", derived from the proposed development polygons, and ranked each chunk in terms of its range-wide impacts on desert tortoise gene flow.
High-throughput creation and functional profiling of eukaryotic DNA sequence variant libraries using CRISPR/Cas9
Authors: Guo Xiaoge , Chavez Alejandro , Tung Angela , Chan Yingleong , Cecchi Ryan , Garnier Santiago Lopez , Kaas Christian , Kelsic Eric , Schubert Max , DiCarlo James E. , Collins James J. , Church George M.
Published: September 2017

Construction of genetic variant libraries with phenotypic measurement is central to advancing today’s functional genomics, and remains a grand challenge. Here, we introduce a Cas9-based approach for generating pools of mutants with defined genetic alterations (deletions, substitutions and insertions), along with methods for tracking their fitnessen masse. We demonstrate the utility of our approach in performing focused analysis of hundreds of mutants of a single protein and in investigating the biological function of an entire family of poorly characterized genetic elements. Our platform allows fundamental biology questions to be investigated in a quick, easy and affordable manner.
PHENOS: a high-throughput and flexible tool for microorganism growth phenotyping on solid media
Authors: Barton David B. H. , Georghiou Danae , Dave Neelam , Alghamdi Majed , Walsh Thomas A. , Louis Edward J. , Foster Steven S.
Published: September 2017

BACKGROUND

Microbial arrays, with a large number of different strains on a single plate printed with robotic precision, underpin an increasing number of genetic and genomic approaches. These include Synthetic Genetic Array analysis, high-throughput Quantitative Trait Loci (QTL) analysis and 2-hybrid techniques. Measuring the growth of individual colonies within these arrays is an essential part of many of these techniques but is useful for any work with arrays. Measurement is typically done using intermittent imagery fed into complex image analysis software, which is not especially accurate and is challenging to use effectively. We have developed a simple and fast alternative technique that uses a pinning robot and a commonplace microplate reader to continuously measure the thickness of colonies growing on solid agar, complemented by a technique for normalizing the amount of cells initially printed to each spot of the array in the first place. We have developed software to automate the process of combining multiple sets of readings, subtracting agar absorbance, and visualizing colony thickness changes in a number of informative ways.

RESULTS

The “PHENOS” pipeline (PHENotyping On Solid media), optimized forSaccharomycesyeasts, produces highly reproducible growth curves and is particularly sensitive to low-level growth. We have empirically determined a formula to estimate colony cell count from an absorbance measurement, and shown this to be comparable with estimates from measurements in liquid. We have also validated the technique by reproducing the results of an earlier QTL study done with conventional liquid phenotyping, and found PHENOS to be considerably more sensitive.

CONCLUSIONS

“PHENOS” is a cost effective and reliable high-throughput technique for quantifying growth of yeast arrays, and is likely to be equally very useful for a range of other types of microbial arrays. A detailed guide to the pipeline and software is provided with the installation files athttps://github.com/gact/phenos.
Visual evidence accumulation guides decision-making in unrestrained mice
Authors: Odoemene Onyekachi , Pisupati Sashank , Nguyen Hien , Churchland Anne K.
Published: September 2017

The ability to manipulate neural activity with precision is an asset in uncovering neural circuits for decision-making. Diverse tools for manipulating neurons are available for mice, but the feasibility of mice for decision-making studies remains unclear, especially when decisions require accumulating visual evidence. For example, whether mice’ decisions reflect leaky accumulation is not established, and the relevant and irrelevant factors that influence decisions are unknown. Further, causal circuits for visual evidence accumulation have not been established. To address these issues, we measured >500,000 decisions in 27 mice trained to judge the fluctuating rate of a sequence of flashes. Information throughout the 1000ms trial influenced choice, but early information was most influential. This suggests that information persists in neural circuits for ~1000ms with minimal accumulation leak. Further, while animals primarily based decisions on current stimulus rate, they were unable to entirely suppress additional factors: total stimulus brightness and the previous trial’s outcome. Next, we optogenetically inhibited anteromedial (AM) visual area using JAWS. Importantly, light activation biased choices in both injected and uninjected animals, demonstrating that light alone influences behavior. By varying stimulus-response contingency while holding stimulated hemisphere constant, we surmounted this obstacle to demonstrate that AM suppression biases decisions. By leveraging a large dataset to quantitatively characterize decision-making behavior, we establish mice as suitable for neural circuit manipulation studies, including the one here. Further, by demonstrating that mice accumulate visual evidence, we demonstrate that this strategy for reducing uncertainty in decision-making is employed by animals with diverse visual systems.

Significance statement

To connect behaviors to their underlying neural mechanism, a deep understanding of the behavioral strategy is needed. This understanding is incomplete in mouse studies, in part because existing datasets have been too small to quantitatively characterize decision-making behavior. To surmount this, we measured the outcome of over 500,000 decisions made by 27 mice trained to judge visual stimuli. Our analyses offer new insights into mice’ decision-making strategies and compares them with those of other species. We then disrupted neural activity in a candidate neural structure and examined the effect on decisions. Our findings establish mice as a suitable organism for visual accumulation of evidence decisions. Further, the results highlight similarities in decision-making strategies across very different species.
Simultaneous representation of a spectrum of dynamically changing value estimates during decision making
Authors: Meder David , Kolling Nils , Verhagen Lennart , Wittmann Marco K , Scholl Jacqueline , Madsen Kristoffer H , Hulme Oliver J , Behrens Timothy EJ , Rushworth Matthew FS
Published: September 2017

Decisions are based on value expectations derived from experience. We show that dorsal anterior cingulate cortex and three other brain regions hold multiple representations of choice value based on different time-scales of experience organized in terms of systematic gradients across the cortex. Some parts of each area represent value estimates based on recent reward experience while others represent value estimates based on experience over the longer term. The value estimates within these four brain areas interact with one another according to their temporal scaling. Some aspects of the representations change dynamically as the environment changes. The spectrum of value estimates may act as a flexible selection mechanism for combining experience-derived value information with other aspects of value to allow flexible and adaptive decisions in changing environments.
Evaluation of MRI sequences for quantitative T1 brain mapping
Authors: Tsialios P , Thrippleton M , Pernet C
Published: September 2017

T1 mapping constitutes a quantitative MRI technique finding significant application in brain imaging. It allows improved evaluation of contrast uptake, blood perfusion, volume, and provides more specific biomarkers of disease progression compared to conventional T1-weighted images. While there are many techniques for T1-mapping, there is also a wide range of reported T1-values in tissues, raising the issue of protocols’ reproducibility and standardization. The gold standard for obtaining T1-maps is based on acquiring IR-SE sequence. Widely used alternative sequences are IR-SE-EPI, VFA (DESPOT), DESPOT-HIFI and MP2RAGE that speed up scanning and fitting procedures. A custom MRI phantom was used to assess the reproducibility and accuracy of the different methods. All scans were performed using a 3T Siemens Prisma scanner. The acquired data were processed using two different codes. The main difference was observed for VFA (DESPOT) which grossly overestimated T1 relaxation time by 214 ms [CI: 126 270 ms] compared to the IR-SE sequence. MP2RAGE and DESPOT-HIFI sequences gave slightly shorter T1 than IR-SE (∼20 to 30ms) and can be considered as alternative and time-efficient methods for acquiring accurate T1 maps of the human brain, while IR-SE-EPI gave identical results, at a cost of a lower image quality.
Karrikin-sensing protein KAI2 is a new player in regulating root growth patterns
Authors: Swarbreck Stéphanie M. , Guerringue Yannick , Matthus Elsa , Jamieson Fiona J. C. , Davies Julia M.
Published: September 2017

Roots form highly complex systems varying in growth direction and branching pattern to forage for nutrients efficiently. Here mutations in the KAI2 (KARRIKIN INSENSITIVE) α/β-fold hydrolase and the MAX2 (MORE AXILLARY GROWTH 2) F-box leucine-rich protein, which together perceive karrikins (smoke-derived butenolides), caused alteration in root growth direction (root skewing and waving) ofArabidopsis thaliana. This exaggerated root skewing was independent of endogenous strigolactone perception by the D14 α/β-fold hydrolase and MAX2. Thus KAI2/MAX2’s regulation of root growth may be through perception of endogenous KAI2-ligands, which have yet to be identified. Degradation targets of the KAI2/MAX2 complex, SMAX1 (SUPPRESSOR OF MAX2-1) and SMXL6,7,8 (SUPPRESSOR OF MAX2-1-LIKE) are also involved in the regulation of root skewing. Genetic data reveal a new potential target for degradation, as mutation in the SKS3 (SKU5 similar) but not the SKU5/SKS17 root plasma membrane glycoprotein suppresses the exaggerated root skewing induced by the lack of MAX2. InArabidopsis thalianatherefore, the KAI2 karrikin-sensing protein acts to limit root skewing, and we propose a mechanism involving root radial expansion as the mutant’s gravitropic and mechano-sensing responses remained largely unaffected.
Metabolic characterization of menopause: cross-sectional and longitudinal evidence
Authors: Wang Qin , Santos Ferreira Diana L , Nelson Scott M , Sattar Naveed , Ala-Korpela Mika , Lawlor Debbie A
Published: September 2017

Background

It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging. Well-conducted longitudinal studies are required to determine this. The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status defined according to the 2012 Stages of Reproductive Aging Workshop criteria with 74 metabolic biomarkers, and establish whether any associations are independent of age related changes.

Methods

We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women. In a subgroup of 1,492 women who had repeat assessments after 2.5 years, we assessed how change in reproductive status was associated with the changes in metabolic biomarkers. Metabolic profiles were measured by high-throughput quantitative serum NMR metabolomics. In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive status category change to that in the reference of being pre-menopausal at both time points. As all women aged by a similar amount during follow-up, these analyses contribute to distinguish age related changes from those related to change in reproductive status.

Results

Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting transition to menopause induces multiple metabolic changes independent of chronological aging. The metabolic changes included increased concentrations of very small VLDL, IDL and LDL subclasses, remnant and LDL cholesterol, and reduced LDL particle size, all towards an atherogenic lipoprotein profile. Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein. Also, levels of glutamine and albumin were increased during the transition. Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years.

Conclusions

Transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory. The adverse changes in multiple apolipoprotein-B containing lipoprotein subclasses and increased inflammation may underlie women’s increased cardiometabolic risk in post-menopausal years.

Abbreviations

ALSPAC

Avon Longitudinal Study of Parents and Children

BMI

body mass index

CRP

high sensitive C-reactive protein

CVD

cardiovascular diseases

HDL

high-density lipoprotein

HRT

hormone replacement therapy

IDL

intermediate-density lipoprotein

LDL

low-density lipoprotein

SD

standard deviation

STRAW

Stages of Reproductive Aging Workshop

SWAN

The Study of Women’s health Across the Nation

VLDL

very low-density lipoprotein
Discovery of physiological and cancer-related regulators of 3’ UTR processing with KAPAC
Authors: Gruber Andreas J. , Schmidt Ralf , Ghosh Souvik , Martin Georges , Gruber Andreas R. , van Nimwegen Erik , Zavolan Mihaela
Published: September 2017

3’ UTR length is regulated in relation to cellular state. To uncover key regulators of poly(A) site (PAS) use in specific conditions, we have developed PAQR, a method for quantifying PAS use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on PAS choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovered sequence motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to Polypyrimidine tract binding protein 1 as a regulator of PAS choice in glioblastoma.
CRISPR-Based DNA Imaging in Living Cells Reveals Cell Cycle-Dependent Chromosome Dynamics
Authors: Ma Hanhui , Tu Li-Chun , Naseri Ardalan , Chung Yu-Chieh , Grunwald David , Zhang Shaojie , Pederson Thoru
Published: September 2017

In contrast to the well-studied condensation and folding of chromosomes during mitosis, their dynamics in interphase are less understood. We developed a sensitive, multicolor system, CRISPR-Sirius, allowing the real-time tracking of the dynamics of chromosomal loci. We tracked loci kilobases to megabases apart and found significant variation in the inter-locus distances of each pair, indicating differing degrees of DNA contortion. We resolved two distinct modes of dynamics of loci: saltatory local movements as well as translational movements of the domain. The magnitude of both of these modes of movements increased from early to late G1, whereas the translational movements were reduced in early S. The local fluctuations decreased slightly in early S and more markedly in mid-late S. These newly observed movements and their cell cycle-dependence are indicative of a hitherto unrecognized compaction-relaxation dynamic of the chromosomal fiber operating concurrently with changes in the extent of observed genomic domain movements.

IN BRIEF

Distinct chromosome folding and dynamics during cell cycle progression were dissected by CRISPR-Sirius DNA imaging in living cells.

HIGHLIGHTS

CRISPR-Sirius allows tracking of pairs of chromosomal loci having kilobase to megabase inter-locus distances

Pair-wise tracking of loci allows measurement of both local and domain dynamics

Chromosomal fiber relaxation is positively correlated with local dynamics

Genomic region size contributes to local and domain movements

Distinct chromosome dynamics were uncovered during cell cycle progression in interphase