bluuebunny/crossref_metadata_2025 huggingface dataset:
High transmission Ni compound refractive lens for high energy X-rays
Authors: Brancewicz M. , Itou M. , Sakurai Y. , Andrejczuk A. , Chiba S. , Kayahara Y. , Inoue T. , Nagamine M.
Published: August 2016

We present a new planar Ni compound refractive lens for high energy X-rays (116 keV). The lens is composed of identical plano-concave elements with longitudinal parabolic grooves manufactured by a punch technique. In order to increase the lens transmission, the thickness of the single lens at the parabolic groove vertex was reduced to less than 5 μm and the radius of curvature was reduced to about 20 μm. The small radius of curvature allowed us to reduce the number of single elements needed to get the focal length of 3 m to 54 single lenses. The gain parameter has been significantly improved compared to the previous lenses due to higher transmission, but the focused beam size and its gain are not as good as expected, mostly due to the aberrations caused by the lens shape imperfections.
The Causal Effect of Education on Farm‐related Disability: Evidence from a Compulsory Schooling Reform in Taiwan
Authors: Chang Hung‐Hao , Meyerhoefer Chad D.
Published: August 2016

We investigate the causal effect of education on the incidence and severity of farm‐related disability. Our dataset is comprised of 75,708 farmers drawn from the Taiwanese Agriculture Census supplemented with administrative data on farmer disability. Approximately 46% of the farmers in our sample were affected by legislation expanding compulsory schooling from the primary school level to the junior high school level. Utilizing the compulsory schooling reform as a natural experiment for identification, we estimated an instrumental variable two‐part model of the incidence and severity of disability, where the latter is measured using the number of disabled days for farmers aged from 35 to 45. We find that greater educational attainment significantly reduced the likelihood of farm‐related disability as well as the severity of disability. Two potential mechanisms for this effect were fewer on‐farm work days and less use of chemical inputs to farm production among more educated farmers.
scphaser: haplotype inference using single-cell RNA-seq data
Authors: Edsgärd Daniel , Reinius Björn , Sandberg Rickard
Published: August 2016

Summary: Determination of haplotypes is important for modelling the phenotypic consequences of genetic variation in diploid organisms, including cis-regulatory control and compound heterozygosity. We realized that single-cell RNA-seq (scRNA-seq) data are well suited for phasing genetic variants, since both transcriptional bursts and technical bottlenecks cause pronounced allelic fluctuations in individual single cells. Here we present scphaser, an R package that phases alleles at heterozygous variants to reconstruct haplotypes within transcribed regions of the genome using scRNA-seq data. The devised method efficiently and accurately reconstructed the known haplotype for ≥93% of phasable genes in both human and mouse. It also enables phasing of rare and de novo variants and variants far apart within genes, which is hard to attain with population-based computational inference.

Availability and Implementation: scphaser is implemented as an R package. Tutorial and code are available at https://github.com/edsgard/scphaser

Contact:  rickard.sandberg@ki.se

Supplementary information:  Supplementary data are available at Bioinformatics online.
genipe: an automated genome-wide imputation pipeline with automatic reporting and statistical tools
Authors: Lemieux Perreault Louis-Philippe , Legault Marc-André , Asselin Géraldine , Dubé Marie-Pierre
Published: August 2016

Summary: Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most recent publicly available reference datasets can require considerable computation power and the management of hundreds of large intermediate files. We have developed genipe, a complete genome-wide imputation pipeline which includes automatic reporting, imputed data indexing and management, and a suite of statistical tests for imputed data commonly used in genetic epidemiology (Sequence Kernel Association Test, Cox proportional hazards for survival analysis, and linear mixed models for repeated measurements in longitudinal studies).

Availability and Implementation: The genipe package is an open source Python software and is freely available for non-commercial use (CC BY-NC 4.0) at https://github.com/pgxcentre/genipe. Documentation and tutorials are available at http://pgxcentre.github.io/genipe.

Contact:  louis-philippe.lemieux.perreault@statgen.org or marie-pierre.dube@statgen.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
A novel copy number variants kernel association test with application to autism spectrum disorders studies
Authors: Zhan Xiang , Girirajan Santhosh , Zhao Ni , Wu Michael C. , Ghosh Debashis
Published: August 2016

Motivation: Copy number variants (CNVs) have been implicated in a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and schizophrenia. Recent advances in high-throughput genomic technologies have enabled rapid discovery of many genetic variants including CNVs. As a result, there is increasing interest in studying the role of CNVs in the etiology of many complex diseases. Despite the availability of an unprecedented wealth of CNV data, methods for testing association between CNVs and disease-related traits are still under-developed due to the low prevalence and complicated multi-scale features of CNVs.

Results: We propose a novel CNV kernel association test (CKAT) in this paper. To address the low prevalence, CNVs are first grouped into CNV regions (CNVR). Then, taking into account the multi-scale features of CNVs, we first design a single-CNV kernel which summarizes the similarity between two CNVs, and next aggregate the single-CNV kernel to a CNVR kernel which summarizes the similarity between two CNVRs. Finally, association between CNVR and disease-related traits is assessed by comparing the kernel-based similarity with the similarity in the trait using a score test for variance components in a random effect model. We illustrate the proposed CKAT using simulations and show that CKAT is more powerful than existing methods, while always being able to control the type I error. We also apply CKAT to a real dataset examining the association between CNV and autism spectrum disorders, which demonstrates the potential usefulness of the proposed method.

Availability and Implementation: A R package to implement the proposed CKAT method is available at http://works.bepress.com/debashis_ghosh/.

Contacts:  xzhan@fhcrc.org or debashis.ghosh@ucdenver.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Metrics for rapid quality control in RNA structure probing experiments
Authors: Choudhary Krishna , Shih Nathan P. , Deng Fei , Ledda Mirko , Li Bo , Aviran Sharon
Published: August 2016

Motivation: The diverse functionalities of RNA can be attributed to its capacity to form complex and varied structures. The recent proliferation of new structure probing techniques coupled with high-throughput sequencing has helped RNA studies expand in both scope and depth. Despite differences in techniques, most experiments face similar challenges in reproducibility due to the stochastic nature of chemical probing and sequencing. As these protocols expand to transcriptome-wide studies, quality control becomes a more daunting task. General and efficient methodologies are needed to quantify variability and quality in the wide range of current and emerging structure probing experiments.

Results: We develop metrics to rapidly and quantitatively evaluate data quality from structure probing experiments, demonstrating their efficacy on both small synthetic libraries and transcriptome-wide datasets. We use a signal-to-noise ratio concept to evaluate replicate agreement, which has the capacity to identify high-quality data. We also consider and compare two methods to assess variability inherent in probing experiments, which we then utilize to evaluate the coverage adjustments needed to meet desired quality. The developed metrics and tools will be useful in summarizing large-scale datasets and will help standardize quality control in the field.

Availability and Implementation: The data and methods used in this article are freely available at: http://bme.ucdavis.edu/aviranlab/SPEQC_software.

Contact:  saviran@ucdavis.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
WebSTAR3D: a web server for RNA 3D structural alignment
Authors: Holzhauser Erwin , Ge Ping , Zhang Shaojie
Published: August 2016

Summary: The WebSTAR3D web server is a user-friendly online interface for the alignment of RNA 3D structures. The website takes as input two files, each of which can be in either PDB or mmCIF format, containing the desired structures to align, via a PDB code or user upload. In return, the user is presented with a visualization of the aligned structures in Jmol or JSmol, along with the corresponding sequence alignment, and the option to download the nucleotide mapping of the structures and a PDB file containing the aligned, superimposed structures.

Availability and Implementation: The WebSTAR3D is available at http://rna.ucf.edu/WebSTAR3D.

Contact:  shzhang@cs.ucf.edu
The ‘business of community development’ and the right to the city: reflections on the neoliberalization processes in urban community development
Authors: Fursova Julia
Published: August 2016

The paper explores emerging contradictions in community development, a subset of non-profit sector, within the context of neoliberalization. I examine non-profit sector as a site that has a potential for articulating counter-hegemonic discourse alternative to neoliberalism. Conversely, non-profit sector itself has been subjected to neoliberal co-optation and restructuring that resulted in restricted autonomy of the sector and decreased capacity to advocate for progressive social change. Drawing on my experience as a community engagement worker in one of Toronto's neighbourhood improvement areas, I problematize community development, posing questions about the role of the non-profit agencies in the production of specific socio-economic configurations that may, albeit inadvertently, support neoliberal discourse. Through an example of local community campaign for increased access to public space and services, I highlight options to enhance counter-hegemonic potential of community development as a critical practice aimed at advancing the commons.
Interactive online brain shape visualization
Authors: Keshavan Anisha , Klein Arno , Cipollini Ben
Published: August 2016

Urbanization presents unique environmental challenges to human commensal species. The Afrotropical Anopheles gambiae complex contains a number of synanthropic mosquito species that are major vectors of malaria. To examine ongoing cryptic diversification within the complex, we performed reduced representation sequencing on 941 mosquitoes collected across four ecogeographic zones in Cameroon. We find evidence for clear subdivision within An. coluzzii and An. gambiae s.s. - the two most significant malaria vectors in the region. Importantly, in both species rural and urban populations of mosquitoes were genetically differentiated. Genome scans of cryptic subgroups reveal pervasive signatures of selection centered on genes involved in xenobiotic resistance. Notably, a selective sweep containing eight detoxification enzymes is unique to urban mosquitoes that exploit polluted breeding sites. Overall, our study reveals that anthropogenic environmental modification is driving population differentiation and local adaptation in African malaria mosquitoes with potentially significant consequences for malaria epidemiology.
Optimized implementations of voxel-wise degree centrality and local functional connectivity density mapping in AFNI
Authors: Craddock R. Cameron , Clark Daniel J.
Published: August 2016

Degree centrality (DC) and local functional connectivity density (lFCD) are statistics calculated from brain connectivity graphs that measure how important a brain region is to the graph. DC (a.k.a. global functional connectivity density) is calculated as the number of connections a region has with the rest of the brain (binary DC), or the sum of weights for those connections (weighted DC). lFCD was developed to be a surrogate measure of DC that is faster to calculate by restricting its computation to regions that are spatially adjacent. Although both of these measures are popular for investigating inter-individual variation in brain connectivity, efficient neuroimaging tools for computing them are scarce. The goal of this Brainhack project was to contribute optimized implementations of these algorithms to the widely used, open source, AFNI software package.
Overcoming the dichotomy: new insights into the genomic diversity of open and isolated European populations
Authors: Anagnostou Paolo , Dominici Valentina , Battaggia Cinzia , Pagani Luca , Vilar Miguel , Wells Spencer , Pettener Davide , Sarno Stefania , Boattini Alessio , Francalacci Paolo , Colonna Vincenza , Vona Giuseppe , Calò Carla , Destro Bisol Giovanni , Tofanelli Sergio
Published: August 2016

Human populations are often dichotomized into “isolated” and “open” using cultural and/or geographical barriers to gene flow as differential criteria. Although widespread, the use of these alternative categories could obscure further heterogeneity due to inter-population differences in effective size, growth rate, and timing or amount of gene flow. We compared intra and interpopulation variation measures combining novel and literature data relative to 87,818 autosomal SNPs in 14 open populations and 10 geographic and/or linguistic European isolates. Patterns of intra-population diversity were found to vary significantly more among isolates, probably due to differential levels of drift and inbreeding. The relatively large effective size estimated for some population isolates challenges the generalized view that they originate from small founding groups. Principal component scores based on measures of intra-population variation of isolated and open populations turned out to be distributed along a sort of continuum, with an area of intersection between the two groups. Patterns of inter-population diversity were even closer, as we were able to detect some differences between population groups only for a few multidimensional scaling dimensions. Therefore, different lines of evidence suggest that dichotomizing human populations into open and isolated fails to capture the actual relations among their genomic features.
Evolution of simple multicellularity increases environmental complexity
Authors: Rebolleda-Gómez María , Ratcliff William C. , Fankhauser Jonathon , Travisano Michael
Published: August 2016

Multicellularity—the integration of previously autonomous cells into a new, more complex organism—is one of the major transitions in evolution. Multicellularity changed evolutionary possibilities and facilitated the evolution of increased complexity. Transitions to multicellularity are associated with rapid diversification and increased ecological opportunity but the potential mechanisms are not well understood. In this paper we explore the ecological mechanisms of multicellular diversification during experimental evolution of the brewer’s yeast,Saccharomyces cerevisiae. The evolution from single cells into multicellular clusters modifies the structure of the environment, changing the fluid dynamics and creating novel ecological opportunities. This study demonstrates that even in simple conditions, incipient multicellularity readily changes the environment, facilitating the origin and maintenance of diversity.
Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue
Authors: Bhalala Oneil G. , Nath Artika P. ,   UK Brain Expression Consortium, Inouye Michael , Sibley Christopher R.
Published: August 2016

Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from six Psychiatric Genomics Consortium and CONVERGE Consortium studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). We identified 6 188 and 16 720 cis-acting SNPs exceeding genome-wide significance (p<5x10−8) in the UKBEC and GTEx datasets, respectively. 1 288 cis-eQTLs were significant in a metaanalysis leveraging overlapping brain regions and were associated with expression of 15 genes, including three non-coding RNAs. One cis-eQTL, rs 16969968, results in a functionally disruptive missense mutation inCHRNA5, a schizophrenia-implicated gene. Meta-analysis identified 297trans-eQTLs associated with 24 genes that were significant in a region-specific manner. Importantly, comparing across tissues, we find that blood eQTLs largely do not capture brain cis-eQTLs. This study identifies putatively causal genes whose expression in region-specific brain tissue may contribute to the risk of schizophrenia and affective disorders.
On the estimation errors ofKMandVfrom time-course experiments using the Michaelis–Menten equation
Authors: Stroberg Wylie , Schnell Santiago
Published: August 2016

The conditions under which the Michaelis–Menten equation accurately captures the steady-state kinetics of a simple enzyme-catalyzed reaction is contrasted with the conditions under which the same equation can be used to estimate parameters,KMandV, from progress curve data. Validity of the underlying assumptions leading to the Michaelis–Menten equation are shown to be necessary, but not sufficient to guarantee accurate estimation ofKMandV. Detailed error analysis and numerical “experiments” show the required experimental conditions for the independent estimation of bothKMandVfrom progress curves. A timescale,tQ, measuring the portion of the time course over which the progress curve exhibits substantial curvature provides a novel criterion for accurate estimation ofKMandVfrom a progress curve experiment. It is found that, if the initial substrate concentration is of the same order of magnitude asKM, the estimated values of theKMandVwill correspond to their true values calculated from the microscopic rate constants of the corresponding mass-action system, only so long as the initial enzyme concentration is less thanKM.
An autonomous meiosis-specific region of yeast Nup2 (hNup50) promotes normal meiotic chromosome dynamics inSaccharomyces cerevisiae
Authors: Chu Daniel B. , Burgess Sean M.
Published: August 2016

Meiosis is a specialized cellular program required to create haploid gametes from diploid parent cells. Prior to the first meiotic division, homologous chromosomes pair, synapse, and recombine to ensure their proper disjunction at anaphase I. Additionally, telomeres tethered at the nuclear envelope cluster in the bouquet configuration where they are subjected to dramatic pulling forces acting from outside of the nucleus. InSaccharomyces cerevisiae, the telomere-associated protein Ndj1 is required for bouquet formation. When Ndj1 is absent, these dramatic motions cease and multiple steps of meiosis I prophase progression are delayed. Here we identified Nup2 in a pool of enriched proteins that co-purify with tagged Ndj1 from meiotic cell extracts. Nup2 is a nonessential nucleoporin that functions in nuclear transport, boundary activity, and telomere silencing in mitotically dividing cells. We found that deletion ofNUP2delayed pairing and synapsis during meiosis, and led to decreased spore viability, similar to thendj1Δmutant phenotype. Surprisingly, thenup2Δ ndj1Δdouble mutant failed to segregate chromosomes, even though the meiotic program continued. These results suggest that a physical impediment to nuclear division is created in the absence of Nup2 and Ndj1. Our deletion analysis ofNUP2identified a previously uncharacterized 125-amino acid region that is both necessary and sufficient to complement all ofnup2Δ’s meiotic phenotypes, which we call themeioticautonomousregion (MAR). We propose that Ndj1 and Nup2 function in parallel pathways to promote the dynamic chromosome events of meiotic chromosome dynamics, perhaps through the establishment or maintenance of higher-order chromosome organization.
A damped oscillator imposes temporal order on posterior gap gene expression inDrosophila
Authors: Verd Berta , Clark Erik , Wotton Karl R. , Janssens Hilde , Jiménez-Guri Eva , Crombach Anton , Jaeger Johannes
Published: August 2016

Insects determine their body segments in two different ways. Short-germband insects, such as the flour beetleTribolium castaneum, use a molecular clock to establish segments sequentially. In contrast, long-germband insects, such as the vinegar flyDrosophila melanogaster, determine all segments simultaneously through a hierarchical cascade of gene regulation. Gap genes constitute the first layer of theDrosophilasegmentation gene hierarchy, downstream of maternal gradients such as that of Caudal (Cad). We use data-driven mathematical modelling and phase space analysis to show that shifting gap domains in the posterior half of theDrosophilaembryo are an emergent property of a robust damped oscillator mechanism, suggesting that the regulatory dynamics underlying long- and short-germband segmentation are much more similar than previously thought. InTribolium, Cad has been proposed to modulate the frequency of the segmentation oscillator. Surprisingly, our simulations and experiments show that the shift rate of posterior gap domains is independent of maternal Cad levels inDrosophila. Our results suggest a novel evolutionary scenario for the short- to long-germband transition, and help explain why this transition occurred convergently multiple times during the radiation of the holometabolan insects.

Author summary

Different insect species exhibit one of two distinct modes of determining their body segments during development: they either use a molecular oscillator to position segments sequentially, or they generate segments simultaneously through a hierarchical gene-regulatory cascade. The sequential mode is ancestral, while the simultaneous mode has been derived from it independently several times during evolution. In this paper, we present evidence which suggests that simultaneous segmentation also involves an oscillator in the posterior of the embryo of the vinegar fly,Drosophila melanogaster. This surprising result indicates that both modes of segment determination are much more similar than previously thought. Such similarity provides an important step towards explaining the frequent evolutionary transitions between sequential and simultaneous segmentation.
AN ISOCHORE FRAMEWORK UNDERLIES CHROMATIN ARCHITECTURE
Authors: Jabbari Kamel , Bernardi Giorgio
Published: August 2016

A recent investigation showed the existence of correlations between the architectural features of mammalian interphase chromosomes and the compositional properties of isochores. This result prompted us to compare maps of the Topologically Associating Domains (TADs) and of the Lamina Associated Domains (LADs) with the corresponding isochore maps of mouse and human chromosomes. This approach revealed that: 1) TADs and LADs correspond to isochores,i.e.,isochores are the genomic units that underlie chromatin domains; 2) the conservation of TADs and LADs in mammalian genomes is explained by the evolutionary conservation of isochores; 3) chromatin domains corresponding to GC-poor isochores (e.g.,LADs) interact with other domains also corresponding to GC-poor isochores even if located far away on the chromosomes; in contrast, chromatin domains corresponding to GC-rich isochores (e.g.,TADs) show more localized chromosomal interactions, many of which are inter-chromosomal. In conclusion, this investigation establishes a link between DNA sequences and chromatin architecture, explains the evolutionary conservation of TADs and LADs and provides new information on the spatial distribution of GC-poor/gene-poor and GC-rich/gene-rich chromosomal regions in the interphase nucleus.
Fast and accuratede novogenome assembly from long uncorrected reads
Authors: Vaser Robert , Sović Ivan , Nagarajan Niranjan , Šikić Mile
Published: August 2016

The assembly of long reads from Pacific Biosciences and Oxford Nanopore Technologies typically requires resource intensive error correction and consensus generation steps to obtain high quality assemblies. We show that the error correction step can be omitted and high quality consensus sequences can be generated efficiently with a SIMD accelerated, partial order alignment based stand-alone consensus module called Racon. Based on tests with PacBio and Oxford Nanopore datasets we show that Racon coupled with Miniasm enables consensus genomes with similar or better quality than state-of-the-art methods while being an order of magnitude faster.

Racon is available open source under the MIT license athttps://github.com/isovic/racon.git.
Long-time analytic approximation of large stochastic oscillators: simulation, analysis and inference
Authors: Minas Giorgos , Rand David A
Published: August 2016

In order to analyse large complex stochastic dynamical models such as those studied in systems biology there is currently a great need for both analytical tools and also algorithms for accurate and fast simulation and estimation. We present a new stochastic approximation of biological oscillators that addresses these needs. Our method, called phase-corrected LNA (pcLNA) overcomes the main limitations of the standard Linear Noise Approximation (LNA) to remain uniformly accurate for long times, still maintaining the speed and analytically tractability of the LNA. As part of this, we develop analytical expressions for key probability distributions and associated quantities, such as the Fisher Information Matrix and Kullback-Leibler divergence and we introduce a new approach to system-global sensitivity analysis. We also present algorithms for statistical inference and for long-term simulation of oscillating systems that are shown to be as accurate but much faster than leaping algorithms and algorithms for integration of diffusion equations. Stochastic versions of published models of the circadian clock and NF-κB system are used to illustrate our results.
Sympatry with the devil? Niche-based approach explains the mechanisms allowing coexistence of native and non-native salmonids
Authors: Musseau Camille , Vincenzi Simone , Jesenšek Dušan , Boulêtreau Stéphanie , Santoul Frédéric , Crivelli Alain J
Published: August 2016

Niche-based hypotheses have been proposed to explain processes and mechanisms of success in the establishment of non-native species into native communities. Competition due to niche overlap may lead to native species niche shift and to native species replacement. To understand the ecological consequences of trophic interactions between non-native rainbow trout and native and endangered marble trout, we used as model system the Idrijca river (Western Slovenia) in which marble trout occurs either in allopatry (MTa) or in sympatry (MTs) with rainbow trout (RTs). We focused on different metrics of niche change such as centroid shift, niche overlap and trophic niche breadth using stable isotope analysis (δ15N and δ13C). Our results showed plasticity in niche overlap between MTs and RTs and niche shift of marble trout when occurring in sympatry with RTs, but not due to a niche replacement of MTs by RTs. Niche breadth of marble trout increases in sympatry and the trophic position during the growth period was higher for MTs than MTa.
Chromosome arm specific patterns of polymorphism associated with chromosomal inversions in the major African malaria vector, Anopheles funestus
Authors: Kamdem Colince , Fouet Caroline , White Bradley J.
Published: August 2016

Chromosomal inversions facilitate local adaptation of beneficial mutations and modulate genetic polymorphism, but the extent of their effects within the genome is still insufficiently understood. The genome ofAnopheles funestus, a malaria mosquito endemic to sub-Saharan Africa, contains an impressive number of paracentric polymorphic inversions, which are unevenly distributed among chromosomes and provide an excellent framework for investigating the genomic impacts of chromosomal rearrangements. Here we present results of a fine-scale analysis of genetic variation within the genome of two weakly differentiated populations ofAnopheles funestusinhabiting contrasting moisture conditions in Cameroon. Using population genomic analyses, we found that genetic divergence between the two populations is centered on regions of the genome corresponding to three inversions, which are characterized by high values ofFST, absolute sequence divergence and fixed differences. Importantly, in contrast to the 2L chromosome arm, which is collinear, nucleotide diversity is significantly reduced along the entire length of three autosome arms bearing multiple overlapping chromosomal rearrangements. These findings support the idea that interactions between reduced recombination and natural selection within inversions contribute to sculpt nucleotide polymorphism across chromosomes inAn. funestus.
Task-related multivariate activation states during task-free rest
Authors: Chen Richard H. , Ito Takuya , Kulkarni Kaustubh R. , Cole Michael W.
Published: August 2016

Much of our lives are spent in unconstrained rest states, yet cognitive brain processes are primarily investigated using task-constrained states. It may be possible to utilize the insights gained from experimental control of task processes as reference points for investigating unconstrained rest. To facilitate comparison of rest and task functional MRI (fMRI) data we focused on activation amplitude patterns, commonly used for task but not rest analyses. During rest, we identified spontaneous changes in temporally extended whole-brain activation pattern states. This revealed a hierarchical organization of rest states. The top consisted of two competing states consistent with previously identified “task-positive” and “task-negative” activation patterns. These states were composed of more specific states that repeated over time and across individuals. Contrasting with the view that rest consists of only task-negative states, task-positive states occurred 40% of the time while individuals “rested,” suggesting task-focused activity occurs during rest. Further, analysis of task data revealed a similar hierarchical structure of brain states. Together these results suggest brain activation dynamics form a general hierarchy across task and rest, with a small number of dominant general states reflecting basic functional modes and a variety of specific states likely reflecting a rich variety of cognitive processes.
How the AFF1/4 scaffold recruits the elongation factor ELL2 to promote HIV-1 proviral transcription
Authors: Qi Shiqian , Li Zichong , Schulze-Gahmen Ursula , Stjepanovic Goran , Zhou Qiang , Hurley James H.
Published: August 2016

The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the superelongation complex required for HIV-1 proviral transcription. We determined the 2.0-Å resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. The AFF4-ELL2 interface is imperfectly packed, leaving a cavity suggestive of a potential binding site for transcription-promoting small molecules.
Interspecific interference competition at the resource patch scale: do large herbivores spatially avoid elephants while accessing water?
Authors: Ferry Nicolas , Dray Stéphane , Fritz Hervé , Valeix Marion
Published: August 2016

Animals may anticipate and try to avoid, at some costs, physical encounters with other competitors. This may ultimately impact their foraging distribution and intake rates. Such cryptic interference competition is difficult to measure in the field, and extremely little is known at the interspecific level.

We tested the hypothesis that smaller species avoid larger ones because of potential costs of interference competition and hence expected them to segregate from larger competitors at the scale of a resource patch. We assessed fine‐scale spatial segregation patterns between three African herbivore species (zebra Equus quagga, kudu Tragelaphus strepsiceros and giraffe Giraffa camelopardalis) and a megaherbivore, the African elephant Loxodonta africana, at the scale of water resource patches in the semi‐arid ecosystem of Hwange National Park, Zimbabwe.

Nine waterholes were monitored every two weeks during the dry season of a drought year, and observational scans of the spatial distribution of all herbivores were performed every 15 min. We developed a methodological approach to analyse such fine‐scale spatial data.

Elephants increasingly used waterholes as the dry season progressed, as did the probability of co‐occurrence and agonistic interaction with elephants for the three study species. All three species segregated from elephants at the beginning of the dry season, suggesting a spatial avoidance of elephants and the existence of costs of being close to them. However, contrarily to our expectations, herbivores did not segregate from elephants the rest of the dry season but tended to increasingly aggregate with elephants as the dry season progressed.

We discuss these surprising results and the existence of a trade‐off between avoidance of interspecific interference competition and other potential factors such as access to quality water, which may have relative associated costs that change with the time of the year.
Semi‐natural habitats mitigate the effects of temperature rise on wild bees
Authors: Papanikolaou Alexandra D. , Kühn Ingolf , Frenzel Mark , Schweiger Oliver
Published: August 2016

The effect of climate change on wild bee communities is of major concern since the decline of bee species could imperil the provision of pollination services. Additionally, habitat loss and fragmentation are major threats to wild bee populations, but improvements to the landscape structure could also improve the general conditions for wild bees. However, potential interactive effects of climate change and landscape structure on wild bee communities remain unknown.

In this study, we assessed the potential of semi‐natural areas to maintain robust communities under changing weather conditions. We used bee monitoring data from six 4 × 4 km field sites across Germany. Almost 30 000 bee specimens were collected from 2010 to 2012 in 16 local communities per site at six sampling occasions per year. Following a multimodel inference approach, we identified the most important weather and landscape variables as well as interaction terms that affect wild bee species richness and total abundance.

Correcting for overall phenology, we found a strong negative relationship between bee species richness and temperature, indicating that future increasing temperatures will lead to a decrease in species richness. However, a high proportion of semi‐natural habitats can considerably decrease the detrimental effect of warmer temperatures on bee species richness and abundance.

Synthesis and applications. Semi‐natural areas and green infrastructure elements within agricultural landscapes become even more important under changing temperature conditions to mitigate the negative effects of increasing temperatures on wild bee species richness and total abundance. This has important implications for conservation decision making, suggesting that maintaining or restoring a fair amount of semi‐natural areas could serve as a countermeasure against climate change for wild bees.
The cost of local, multi‐professional obstetric emergencies training
Authors: Yau Christopher W.H. , Pizzo Elena , Morris Steve , Odd David E. , Winter Cathy , Draycott Timothy J.
Published: August 2016

Introduction

We aim to outline the annual cost of setting up and running a standard, local, multi‐professional obstetric emergencies training course, PROMPT (PRactical Obstetric Multi‐Professional Training), at Southmead Hospital, Bristol, UK – a unit caring for approximately 6500 births per year.

Material and methods

A retrospective, micro‐costing analysis was performed. Start‐up costs included purchasing training mannequins and teaching props, printing of training materials and assembly of emergency boxes (real and training). The variable costs included administration time, room hire, additional printing and the cost of releasing all maternity staff in the unit, either as attendees or trainers. Potential, extra start‐up costs for maternity units without established training were also included.

Results

The start‐up costs were €5574 and the variable costs for 1 year were €143 232. The total cost of establishing and running training at Southmead for 1 year was €148 806. Releasing staff as attendees or trainers accounted for 89% of the total first year costs, and 92% of the variable costs. The cost of running training in a maternity unit with around 6500 births per year was approximately €23 000 per 1000 births for the first year and around €22 000 per 1000 births in subsequent years.

Conclusions

The cost of local, multi‐professional obstetric emergencies training is not cheap, with staff costs potentially representing over 90% of the total expenditure. It is therefore vital that organizations consider the clinical effectiveness of local training packages before implementing them, to ensure the optimal allocation of finite healthcare budgets.
Corneal endothelial cell loss after Baerveldt glaucoma drainage device implantation in the anterior chamber
Authors: Tan Annelie N. , Webers Carroll A. B. , Berendschot Tos T. J. M. , de Brabander John , de Witte Pauline M. , Nuijts Rudy M. M. A. , Schouten Johannes S. A. G. , Beckers Henny J. M.
Published: August 2016

Purpose

To investigate central and peripheral corneal endothelial cell density (ECD) in relation to Baerveldt (BV) glaucoma drainage device (GDD) tube corneal (TC) distance.

Methods

Prospective study of all patients scheduled for glaucoma tube surgery with 36 months follow‐up. A BV GDD was inserted into the anterior chamber (AC). Anterior segment optical coherence tomography (AS‐OCT) scans were made to determine the TC distance. Central and peripheral ECD was measured, preoperatively and at 3, 6, 12, 24 and 36 months postoperatively.

Results

Fifty‐three eyes were included [primary open‐angle glaucoma, (n = 13); secondary glaucoma, (n = 30); and primary angle‐closure glaucoma, (n = 10)]. Central ECD significantly decreased during follow‐up, with a mean decrease of 4.54% per year (p < 0.001), and 6.57% in the peripheral quadrant closest to the BV GDD tube (PQC, p < 0.001). In the PQC, a yearly decrease of 1.57% was shown after transiridial tube placement versus 7.43% after placement ‘free’ into the AC (p = 0.006). Endothelial cell (EC) loss was related to TC distance (mean 1.69 mm), with a central loss of 6.20% and 7.25% in the PQC per year with shorter TC distances, versus a central loss of 4.11% and 5.77% in the PQC per year with longer TC distances (outside mean ± 2SD, p < 0.001). A difference in EC loss by glaucoma subtype was not identified.

Conclusion

The TC distance is of significant influence on corneal ECD, a shorter TC distance causing more severe EC loss, especially in the PQC. Transiridial placement of the BV GDD tube seems safer than placement ‘free’ into the AC.
Eccentric small‐zone ray tracing wavefront aberrometry for refraction in keratoconus
Authors: Fredriksson Anneli , Behndig Anders
Published: August 2016

Purpose

To compare objective refraction using small‐zone eccentric laser ray tracing (LRT) wavefront aberrometry to standard autorefraction in keratoconus (KC), and whether the visual acuities achieved with these refractions differ from corresponding values in healthy eyes.

Methods

Twenty‐nine eyes of 29 patients with KC and 29 eyes of 29 healthy controls were included in this prospective unmasked case–control study. The uncorrected (UCVA) and spectacle‐corrected (SCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuities based on refractions derived from LRT in central and four eccentric zones were compared to those achieved with standard autorefraction. The spherical equivalent (M) and two astigmatic power vectors (C0 and C45) were calculated for all refractions. Pentacam HR® was used to generate keratometry readings of the corresponding zones.

Results

In KC, the refraction from the upper nasal zone rendered a higher SCVA than the standard autorefraction more often than in the controls (p < 0.001). There were no significant variation in M between the different LRT measurement points in the control group, but central data provided the best SCVA. The UCVA:s and SCVA:s were worse in KC, and the KC eyes showed inferior myopia and superior hyperopia. Multiple refractions rendered similar SCVA:s in KC. Pentacam HR® showed higher keratometry readings infero‐temporally, but also lower readings supero‐nasally, compared to controls.

Conclusion

In KC, eccentric LRT measurements gave better SCVA than standard autorefraction more often than in healthy eyes. Eccentric LRT may become a valuable tool in the demanding task of subjective refraction in KC.
Vitreous and subretinal fluid concentrations of orally administered dabigatran in patients with rhegmatogenous retinal detachment
Authors: Mulder Verena C. , Kluft Cornelis , van Meurs Jan C.
Published: August 2016

Purpose

One of the factors that was shown to contribute to the development of proliferative vitreoretinopathy (PVR) is the coagulation factor thrombin. Therefore, a specific oral thrombin inhibitor such as dabigatran might be a possible therapeutic option. An oral drug has the advantage of patient‐friendly prolonged administration in contrast to drugs that can only be applied during vitrectomy, on condition that the drug reaches the target site. We tested whether dabigatran reaches the vitreous and subretinal fluid (SRF) after a single oral dose of dabigatran.

Methods

Twenty‐eight patients with a retinal detachment received a single dose of 220 mg dabigatran etexilate 2–8 hr prior to surgery. During surgery, we took a blood sample and a vitreous or subretinal fluid sample. The concentration of dabigatran was measured using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).

Results

The dabigatran concentration between 2 and 9 hr after administration was higher in SRF than in vitreous (max 8.5 and 3.8 ng/ml). Corresponding plasma concentrations ranged from 15 to 225 ng/ml. There was a significant relationship between SRF levels and plasma levels (rs = 0.68, p = 0.014); the levels in vitreous fluid showed no such relationship (rs = 0.20, p = 0.48). In addition, we measured the vitreous concentration of a non‐study patient using 150 mg dabigatran twice daily. The concentration was approximately 10 times higher than after a single dosage (25.8 ng/ml).

Conclusion

We demonstrate that oral intake of dabigatran, a candidate drug to modulate PVR, results in potentially relevant intraocular concentrations. We suggest that repeated dosing may lead to higher concentrations, but this should be further explored.
Neuropsychiatric disorders in patients with neurocysticercosis
Authors: Ramirez‐Bermudez Jesus , Higuera‐Calleja Jesus , Espinola‐Nadurille Mariana , Corona Teresa
Published: August 2016

Introduction:

The purpose of this study was to explore the presence of neuropsychiatric disorders in patients with neurocysticercosis (NCC).

Method:

Patients with untreated NCC (n = 45) and healthy controls (n = 45) underwent psychiatric and neuropsychological assessments.

Results:

The majority of patients in the NCC group (64.4%) had at least 1 psychiatric diagnosis, compared with a minority in the control group (31.1%). The frequency of neurocognitive disorders, and particularly dementia (major neurocognitive disorder), was significantly higher in the group of patients with NCC.

Discussion:

This study confirms the relationship between NCC and cognitive disorders.
Effect of fermented red ginseng on cytochrome P450 and P‐glycoprotein activity in healthy subjects, as evaluated using the cocktail approach
Authors: Kim Min‐Gul , Kim Yunjeong , Jeon Ji‐Young , Kim Dal‐Sik
Published: August 2016

Aims

We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P‐glycoprotein (P‐gp), in healthy volunteers.

Methods

This study was an open‐label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova).

Results

Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least‐square mean metabolic ratio (90% CI) was 0.901 (0.830–0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720–0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925–1.197) for omeprazole (CYP2C19) to 5‐hydroxyomeprazole, 1.150 (0.860–1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673–0.990) for midazolam (CYP3A4) to 1‐hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast) for fexofenadine (P‐gp) was 1.322 (1.112–1.571).

Conclusion

No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two‐week administration of concentrated fermented red ginseng. However, the inhibition of P‐gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P‐gp substrate drugs.