bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping Tumor-Specific Expression QTLs in Impure Tumor Samples
Authors: Wilson Douglas R. , Sun Wei , Ibrahim Joseph G.
Published: May 2017

The study of gene expression quantitative trait loci (eQTL) is an effective approach to illuminate the functional roles of genetic variants. Computational methods have been developed for eQTL mapping using gene expression data from microarray or RNA-seq technology. Application of these methods for eQTL mapping in tumor tissues is problematic because tumor tissues are composed of both tumor and infiltrating normal cells (e.g. immune cells) and eQTL effects may vary between tumor and infiltrating normal cells. To address this challenge, we have developed a new method for eQTL mapping using RNA-seq data from tumor samples. Our method separately estimates the eQTL effects in tumor and infiltrating normal cells using both total expression and allele-specific expression (ASE). We demonstrate that our method controls type I error rate and has higher power than some alternative approaches. We applied our method to study RNA-seq data from The Cancer Genome Atlas and illustrated the similarities and differences of eQTL effects in tumor and normal cells.
ELEMENT-FREE MULTISCALE MODELING OF LARGE DEFORMATION BEHAVIOR OF RED BLOOD CELL MEMBRANE WITH MALARIA INFECTION
Authors: Ademiloye A.S. , Zhang L.W. , Liew K.M.
Published: May 2017

In normal physiological and healthy conditions, red blood cells (RBCs) deform readily as they pass through the microcapillaries and the spleen. In this paper, we examine the effects ofPlasmodium falciparuminfection and maturation on the large deformation behavior of malaria-infected red blood cells (iRBCs) by means of a three-dimensional (3D) multiscale meshfree method. We numerically simulated the optical tweezers experiment and observed the force-displacement response of the iRBC membrane as malaria infection progresses. Our simulation results agree well with experimental data and confirm that the deformability of malaria-infected cells decreases significantly as malaria infection progresses.
Eyeballs on science: Impact is not just citations, but how big is readership?
Authors: Winker Kevin
Published: May 2017

A full evaluation of the impact of scientific publications needs to count readers who don’t generate citations. But this is very difficult to do. I set up a scholarly foraging experiment to try to estimate readership for my own body of work: a personal web site with ‘reprint’ pdf files available for downloading and a web statistics program engaged to count these downloads. (I made the site topically rather than author-oriented to increase potential audience size.) Despite this, human users are difficult to count. There are a lot of bots, spiders, and other web programs that increasingly mimic human behavior (e.g., with IP- and chrono-camouflage), and humans’ own behaviors are changing (e.g., reading papers online many times). From four years of data, after culling both automated activity (a fascinating ecosystem) and humans reading repeatedly online, my papers receive ∼4000-8000 downloads per year, about an order of magnitude higher than the number of citations they receive annually. This is a conservative minimum, because these publications can be obtained from other sources as well. On average, this body of work may be being read at an approximately 10:1 download-to-citation ratio. At a more granular scale, downloads do not correlate with citations; there are some papers being downloaded at about a 100:1 ratio, and it turns out these are exactly how they were meant to be used (e.g., an instruction manual). How intensively someone reads a paper is of course highly variable, but this exercise gives us an idea of how broad our publications’ impacts actually are. Citations alone don’t come close to measuring it.
Genome-wide characterization of differential transcript usage inArabidopsis thaliana
Authors: Vaneechoutte Dries , Estrada April R. , Lin Ying-Chen , Loraine Ann E. , Vandepoele Klaas
Published: May 2017

Alternative splicing and the usage of alternate transcription start- or stop sites allows a single gene to produce multiple transcript isoforms. Most plant genes express certain isoforms at a significantly higher level than others, but under specific conditions this expression dominance can change, resulting in a different set of dominant isoforms. These events of Differential Transcript Usage (DTU) have been observed for thousands ofArabidopsis thaliana,Zea maysandVitis viniferagenes and have been linked to development and stress response. However, the characteristics of these genes, nor the implications of DTU on their protein coding sequences or functions, are currently well understood. Here we present a dataset of isoform dominance and DTU for all genes in the AtRTD2 reference transcriptome based on a protocol that was benchmarked on simulated data and validated through comparison with a published RT-PCR panel. We report DTU events for 8,148 genes across 206 public RNA-Seq samples and find that protein sequences are affected in 22% of the cases. The observed DTU events show high consistency across replicates and reveal reproducible patterns in response to treatment and development. We also demonstrate that genes with different evolutionary ages, expression breadths, and functions show large differences in the frequency at which they undergo DTU and in the effect that these events have on their protein sequences. Finally, we showcase how the generated dataset can be used to explore DTU events for genes of interest or to find genes with specific DTU in samples of interest.

SIGNIFICANCE STATEMENT

Differential transcript usage through alternative splicing has been reported for thousands of genes in plants, yet genome-wide datasets to study the implications for gene functions are thus far not available. Here we present the first reference dataset of isoform dominance and differential transcript usage forArabidopsis thalianabased on 206 public RNA-Seq samples and provide insights in the occurrence and functional consequences of alternative splicing.
Crosstalk between diverse synthetic protein degradation tags inEscherichia coli
Authors: Butzin Nicholas C. , Mather William H.
Published: May 2017

Recently, a synthetic circuit inE. colidemonstrated that two proteins engineered with LAA tags targeted to the native protease ClpXP are susceptible to crosstalk due to competition for degradation between proteins. To understand proteolytic crosstalk beyond the single protease regime, we investigated inE. colia set of synthetic circuits designed to probe the dynamics of existing and novel degradation tags fused to fluorescent proteins. These circuits were tested using both microplate reader and single-cell assays. We first quantified the degradation rates of each tag in isolation. We then tested if there was crosstalk between two distinguishable fluorescent proteins engineered with identical or different degradation tags. We demonstrated that proteolytic crosstalk was indeed not limited to the LAA degradation tag, but was also apparent between other diverse tags, supporting the complexity of theE. coliprotein degradation system.
Sensorimotor processing in the basal ganglia leads to transient beta oscillations during behavior
Authors: Mirzaei Amin , Kumar Arvind , Leventhal Daniel , Mallet Nicolas , Aertsen Ad , Berke Joshua , Schmidt Robert
Published: May 2017

Brief epochs of beta oscillations have been implicated in sensorimotor control in the basal ganglia of task-performing healthy animals. However, which neural processes underlie their generation and how they are affected by sensorimotor processing remains unclear. To determine the mechanisms underlying transient beta oscillations in the local field potential (LFP), we combined computational modeling of the subthalamo-pallidal network for the generation of beta oscillations with realistic stimulation patterns derived from single unit data. The single unit data were recorded from different basal ganglia subregions in rats performing a cued choice task. In the recordings we found distinct firing patterns in the striatum, globus pallidus and subthalamic nucleus related to sensory and motor events during the behavioral task. Using these firing patterns to generate realistic inputs to our network model lead to transient beta oscillations with the same time course as the rat LFP data. In addition, our model can account for further non-intuitive aspects of beta modulation, including beta phase resets following sensory cues and correlations with reaction time. Overall, our model can explain how the combination of temporally regulated sensory responses of the subthalamic nucleus, ramping activity of the subthalamic nucleus, and movement-related activity of the globus pallidus, leads to transient beta oscillations during behavior.

Significance Statement

Transient beta oscillations emerge in the normal functioning cortico-basal ganglia loop during behavior. In this work we employ a unique approach connecting a computational model closely with experimental data. In this way we achieve a simulation environment for our model that mimics natural input patterns in awake behaving animals. Using this approach we demonstrate that a computational model for beta oscillations in Parkinson’s disease can also account for complex patterns of transient beta oscillations in healthy animals. Therefore, we propose that transient beta oscillations in healthy animals share the same mechanism with pathological beta oscillations in Parkinson’s disease. This important result connects functional and pathological roles of beta oscillations in the basal ganglia.
A confidence-based reinforcement learning model for perceptual learning
Authors: Guggenmos Matthias , Sterzer Philipp
Published: May 2017

It is well established that learning can occur without external feedback, yet normative reinforcement learning theories have difficulties explaining such instances of learning. Recently, we reported on a confidence-based reinforcement learn-ing model for the model case of perceptual learning (Guggenmos, Wilbertz, Hebart, & Sterzer, 2016), according to which the brain capitalizes on internal monitoring processes when no external feedback is available. In the model, internal confidence prediction errors – the difference between current confidence and expected confidence – serve as teaching signals to guide learning. In the present paper, we explore an extension to this idea. The main idea is that the neural information processing pathways activated for a given sensory stimulus are subject to fluctuations, where some pathway configurations lead to higher confidence than others. Confidence prediction errors strengthen pathway configurations for which fluctuations lead to above-average confidence and weaken those that are associated with below-average con-fidence. We show through simulation that the model is capable of self-reinforced perceptual learning and can benefit from exploratory network fluctuations. In addition, by simulating different model parameters, we show that the ideal confidence-based learner should (i) exhibit high degrees of network fluctuation in the initial phase of learning, but re-duced fluctuations as learning progresses, (ii) have a high learning rate for network updates for immediate performance gains, but a low learning rate for long-term maximum performance, and (iii) be neither too under-nor too overconfident. In sum, we present a model in which confidence prediction errors strengthen favorable network fluctuations and enable learning in the absence of external feedback. The model can be readily applied to data of real-world perceptual tasks in which observers provided both choice and confidence reports.
Quantitative Protein Topography Measurements by High Resolution Hydroxyl Radical Protein Footprinting Enable Accurate Molecular Model Selection
Authors: Xie Boer , Sood Amika , Woods Robert J. , Sharp Joshua S.
Published: May 2017

We report an integrated workflow that allows mass spectrometry-based high-resolution hydroxyl radical protein footprinting (HR-HRPF) measurements to accurately measure the absolute average solvent accessible surface area () of amino acid side chains. This approach is based on application of multi-point HR-HRPF, electron-transfer dissociation (ETD) tandem MS (MS/MS) acquisition, measurement of effective radical doses by radical dosimetry, and proper normalization of the inherent reactivity of the amino acids. The accuracy of the resulting  measurements was tested by using well-characterized protein models. Moreover, we demonstrated the ability to use  measurements from HR-HRPF to differentiate molecular models of high accuracy (< 3Å backbone RMSD) from models of lower accuracy (> 4Å backbone RMSD). The ability of  data from HR-HRPF to differentiate molecular model quality was found to be comparable to that of  data obtained from X-ray crystal structures, indicating the accuracy and utility of HR-HRPF for evaluating the accuracy of computational models.
Identifying core biological processes distinguishing human eye tissues with precise systems-level gene expression analyses and weighted correlation networks
Authors: Bryan John M , Fufa Temesgen D , Bharti Kapil , Brooks Brian P , Hufnagel Robert B , McGaughey David M
Published: May 2017

The human eye is built from several specialized tissues which direct, capture, and pre-process information to provide vision. The gene expression of the different eye tissues has been extensively profiled with RNA-seq across numerous studies. Large consortium projects have also used RNA-seq to study gene expression patterning across many different human tissues, minus the eye. There has not been an integrated study of expression patterns from multiple eye tissues compared to other human body tissues. We have collated all publicly available healthy human eye RNA-seq datasets as well as dozens of other tissues. We use this fully integrated dataset to probe the biological processes and pan expression relationships between the cornea, retina, RPE-choroid complex, and the rest of the human tissues with differential expression, clustering, and GO term enrichment tools. We also leverage our large collection of retina and RPE-choroid tissues to build the first human weighted gene correlation networks and use them to highlight known biological pathways and eye gene disease enrichment. We also have integrated publicly available single cell RNA-seq data from mouse retina into our framework for validation and discovery. Finally, we make all these data, analyses, and visualizations available via a powerful interactive web application (https://eyeintegration.nei.nih.gov/).
Priming in a permissive type I-C CRISPR-Cas system reveals distinct dynamics of spacer acquisition and loss
Authors: Rao Chitong , Chin Denny , Ensminger Alexander W.
Published: May 2017

CRISPR-Cas is a bacterial and archaeal adaptive immune system that uses short, invader-derived sequences termed spacers to target invasive nucleic acids. Upon recognition of previously encountered invaders, the system can stimulate secondary spacer acquisitions, a process known as primed adaptation. Previous studies of primed adaptation have been complicated by intrinsically high interference efficiency of most systems againstbona fidetargets. As such, most primed adaptation to date has been studied within the context of imperfect sequence complementarity between spacers and targets. Here, we take advantage of a native type I-C CRISPR-Cas system inLegionella pneumophilathat displays robust primed adaptation even within the context of a perfectly matched target. Using next-generation sequencing to survey acquired spacers, we observe strand bias and positional preference that are consistent with a 3′ to 5′ translocation of the adaptation machinery. We show that spacer acquisition happens in a wide range of frequencies across the plasmid, including a remarkable hotspot that predominates irrespective of the priming strand. We systematically characterize protospacer sequence constraints in both adaptation and interference and reveal extensive flexibilities regarding the protospacer adjacent motif in both processes. Lastly, in a strain with a genetically truncated CRISPR array, we observe greatly increased interference efficiency coupled with a dramatic shift away from spacer acquisition towards spacer loss. Based on these observations, we propose that theLegionellatype I-C system represents a powerful model to study primed adaptation and the interplay between CRISPR interference and adaptation.
Gaussian curvature directs the distribution of spontaneous curvature on bilayer membrane necks
Authors: Chabanon Morgan , Rangamani Padmini
Published: May 2017

Formation of membrane necks is crucial for fission and fusion in lipid bilayers. In this work, we seek to answer the following fundamental question: what is the relationship between protein-induced spontaneous mean curvature and the Gaussian curvature at a membrane neck? Using an augmented Helfrich model for lipid bilayers to include membrane-protein interaction, we solve the shape equation on catenoids to find the field of spontaneous curvature that satisfies mechanical equilibrium of membrane necks. In this case, the shape equation reduces to a variable coefficient Helmholtz equation for spontaneous curvature, where the source term is proportional to the Gaussian curvature. We show how this latter quantity is responsible for non-uniform distribution of spontaneous curvature in minimal surfaces. We then explore the energetics of catenoids with different spontaneous curvature boundary conditions and geometric asymmetries to show how heterogeneities in spontaneous curvature distribution can couple with Gaussian curvature to result in membrane necks of different geometries.
Visualization and label-free quantification of microfluidic mixing using quantitative phase imaging
Authors: Park GwangSik , Han Dongsik , Kim GwangSu , Shin Seungwoo , Kim Kyoohyun , Park Je-Kyun , Park YongKeun
Published: May 2017

Microfluidic mixing plays a key role in various fields, including biomedicine and chemical engineering. To date, although various approaches for imaging microfluidic mixing have been proposed, they provide only quantitative imaging capability and require for exogenous labeling agents. Quantitative phase imaging techniques, however, circumvent these problems and offer label-free quantitative information about concentration maps of microfluidic mixing. We present the quantitative phase imaging of microfluidic mixing in various types of PDMS microfluidic channels with different geometries; the feasibility of the present method was validated by comparing it with the results obtained by theoretical calculation based on Fick’s law.
A theory for ecological survey methods to map individual distributions
Authors: Takashina Nao , Beger Maria , Kusumoto Buntarou , Rathnayake Suren , Possingham Hugh P.
Published: May 2017

Spatially-explicit approaches are widely recommended for ecosystem management. The quality of the data, such as presence/absence or habitat maps, affects the management actions recommended, and is, therefore, key to management success. However, available data are often biased and incomplete. Previous studies have advanced ways to resolve data bias and missing data, but questions remain about how we design ecological surveys to develop a dataset through field surveys. Ecological surveys may have multiple spatial scales, including the spatial extent of the target ecosystem (observation window), the resolution for mapping individual distributions (mapping unit), and the survey area within each mapping unit (sampling unit). We developed an ecological survey method for mapping individual distributions by applying spatially-explicit stochastic models. We used spatial point processes to describe individual spatial placements using either random or clustering processes. We then designed ecological surveys with different spatial scales and individual detectability. We found that the choice of mapping unit affected the presence mapped fraction, and the fraction of the total individuals covered by the presence mapped patches. Tradeoffs were found between these quantities and the map resolution, associated with equivalent asymptotic behaviors for both metrics at sufficiently small and large mapping unit scales. Our approach enabled consideration of the effect of multiple spatial scales in surveys, and estimation of the survey outcomes such as the presence mapped fraction and the number of individuals situated in the presence detected units. The developed theory may facilitate management decision-making and inform the design of monitoring and data gathering.
Deciphering the developmental program in the ascidianCiona intestinalisjust prior to gastrulation
Authors: Harada Yoshito
Published: May 2017

The embryo of the ascidianCiona intestinalisdisplays striking anatomical simplicity, with an invariant cleavage pattern during development. It has a monoploid genome like the model organismsDrosophila melanogasterandCaenorhabditis elegans, whereas vertebrates generally exhibit tetraploidy. In this study, I took advantage of these characteristics to investigate the development of the organism as one reverse-engineers an industrial product. First, the spatial expression of 211 genes was digitalized. Some genes showed variable expression patterns, which might reflect multiple snapshots of a single temporally dynamic expression at different times. Several developmental territories of the embryo were considered to be very similar to each other; however, this digitalization of gene expression patterns showed that differences occurred between individual blastomeres even within a single developmental territory. Furthermore,Ciona Brachyury(Ci-Bra) was expressed in those blastomeres in which bothFox (forkhead-box) A-aandZic (zinc-finger) Lwere expressed, these proteins being upstream regulators ofCi-Bra.The approach described enables the developmental program to be studiedin silico.

SUMMARY STATEMENT

A detailed expansion of our knowledge on an animal developmental program by using already published gene expression data with the aid of computers
Inheritance of OCT4 predetermines fate choice in human embryonic stem cells
Authors: Wolff Samuel C. , Dumitru Raluca , Kedziora Katarzyna M. , Dungee Cierra D. , Zikry Tarek M. , Haggerty Rachel A. , Cheng JrGang , Beltran Adriana S. , Purvis Jeremy E.
Published: May 2017

Clonal cells can make different fate decisions, but it is often unclear to what extent these decisions are autonomous or predetermined. Here, we introduce a live-cell reporter for the pluripotency factor OCT4 into human embryonic stem cells to understand how they choose between self-renewal and differentiation. By tracing the histories of individual cells over multiple generations, we found that cells whose offspring were destined to differentiate showed decreased expression of OCT4 long before exposure to the differentiation stimulus. OCT4 levels were lineage-dependent; however, during cell division, mother cells distributed OCT4 asymmetrically to daughters. The resulting ratio of OCT4 between sister cells—established within minutes of mitosis—was predictive of downstream fates: cells receiving a greater ratio of maternal OCT4 showed sustained OCT4 levels and a reduced capacity to differentiate. Our observations imply that the choice between two developmental fates is almost entirely predetermined at the time of cell birth through inheritance of a pluripotency factor.
Rearrangement Scenarios Guided by Chromatin Structure
Authors: Pulicani Sylvain , Simonaitis Pijus , Swenson Krister M.
Published: May 2017

Genome architecture can be drastically modified through a succession of large-scale rearrangements. In the quest to infer accurate ancestral rearrangement scenarios, it is often the case that parsimony principal alone does not impose enough constraints. Thus, the current challenge is to consider more biological information in the inference process. In previous work, we introduced a model for such a task, based on a partition into equivalence classes of the adjacencies between genes. Such a partition is amenable to the representation of spacial constraints as given by Hi-C data. A major open question is the validity of such a model. In this note, we show that the quality of a clustering of the adjacencies based on Hi-C data is directly correlated to the quality of a rearrangement scenario that we compute betweenDrosophila melanogasterandD. yakuba.
The CRISPR spacer space is dominated by sequences from the species-specific mobilome
Authors: Shmakov Sergey A. , Sitnik Vassilii , Makarova Kira S. , Wolf Yuri I. , Severinov Konstantin V. , Koonin Eugene V.
Published: May 2017

The CRISPR-Cas is the prokaryotic adaptive immunity system that stores memory of past encounters with foreign DNA in spacers that are inserted between direct repeats in CRISPR arrays 1,2. Only for a small fraction of the spacers, homologous sequences, termed protospacers, are detectable in viral, plasmid or microbial genomes 3,4. The rest of the spacers remain the CRISPR “dark matter”. We performed a comprehensive analysis of the spacers from all CRISPR-cas loci identified in bacterial and archaeal genomes, and found that, depending on the CRISPR-Cas subtype and the prokaryotic phylum, protospacers were detectable for 1 to about 19% of the spacers (∼7% global average). Among the detected protospacers, the majority, typically, 80 to 90%, originate from viral genomes, and among the rest, the most common source are genes integrated in microbial chromosomes but involved in plasmid conjugation or replication. Thus, almost all spacers with identifiable protospacers target mobile genetic elements (MGE). The GC-content, as well as dinucleotide and tetranucleotide compositions, of microbial genomes, their spacer complements, and the cognate viral genomes show a nearly perfect correlation and are almost identical. Given the near absence of self-targeting spacers, these findings are best compatible with the possibility that the spacers, including the dark matter, are derived almost completely from the species-specific microbial mobilomes.
Modules of co-occurrence in the cyanobacterial pan-genome
Authors: Beck Christian , Knoop Henning , Steuer Ralf
Published: May 2017

The increasing availability of fully sequenced cyanobacterial genomes opens unprecedented opportunities to investigate the manifold adaptations and functional relationships that determine the genetic content of individual bacterial species. Here, we use comparative genome analysis to investigate the cyanobacterial pan-genome based on 77 strains whose complete genome sequence is available. Our focus is the co-occurrence of likely ortholog genes, denoted as CLOGs. We conjecture that co-occurrence CLOGs is indicative of functional relationships between the respective genes. Going beyond the analysis of pair-wise co-occurrences, we introduce a novel network approach to identify modules of co-occurring ortholog genes. Our results demonstrate that these modules exhibit a high degree of functional coherence and reveal known as well as previously unknown functional relationships. We argue that the high functional coherence observed for the extracted modules is a consequence of the similar-yet-diverse nature of the cyanobacterial phylum. We provide a simple toolbox that facilitates further analysis of our results with respect to specific cyanobacterial genes of interest.
Conserving Phylogenetic Diversity can be a Poor Strategy for Conserving Functional Diversity
Authors: Mazel Florent , Mooers Arne , Dalla Riva Giulio Valentino , Pennell Matthew W.
Published: May 2017

For decades, academic biologists have advocated for making conservation decisions in light of evolutionary history. Specifically, they suggest that policymakers should prioritize conserving phylogenetically diverse assemblages. The most prominent argument is that conserving phylogenetic diversity (PD) will also conserve diversity in traits and features (functional diversity; FD), which may be valuable for a number of reasons. The claim that PD-maximized (‘maxPD’) sets of taxa will also have high FD is often taken at face value and in cases where researchers have actually tested it, they have done so by measuring the phylogenetic signal in ecologically important functional traits. The rationale is that if traits closely mirror phylogeny, then saving the maxPD set of taxa will tend to maximize FD and if traits do not have phylogenetic structure, then saving the maxPD set of taxa will be no better at capturing FD than criteria that ignore PD. Here, we suggest that measuring the phylogenetic signal in traits is uninformative for evaluating the effectiveness of using PD in conservation. We evolve traits under several different models and, for the first time, directly compare the FD of a set of taxa that maximize PD to the FD of a random set of the same size. Under many common models of trait evolution and tree shapes, conserving the maxPD set of taxa will conserve more FD than conserving a random set of the same size. However, this result cannot be generalized to other classes of models. We find that under biologically plausible scenarios, using PD to select species can actually lead to less FD compared to a random set. Critically, this can occur even when there is phylogenetic signal in the traits. Predicting exactly when we expect using PD to be a good strategy for conserving FD is challenging, as it depends on complex interactions between tree shape and the assumptions of the evolutionary model. Nonetheless, if our goal is to maintain trait diversity, the fact that conserving taxa based on PD will not reliably conserve at least as much FD as choosing randomly raises serious concerns about the general utility of PD in conservation.
Arginase 1 is negatively regulated by β-catenin signaling in the lung
Authors: Sennello Joseph A. , Flozak Annette S. , Misharin Alexander V. , Gottardi Cara J. , Lam Anna P.
Published: May 2017

We previously demonstrated that mice lacking the Wnt co-receptor, Lrp5, had attenuated pulmonary fibrosis in the bleomycin model. We found that Arginase 1 (Arg1), an enzyme that converts L-arginine to urea and ornithine, was markedly elevated inLrp5-/-lungs compared with wild-type mice after bleomycin injury. We show that this induction is not apparently due to the expression of Th2 cytokines, IL-4 and IL-13, but instead is due to Wnt/β-catenin signaling, which negatively regulates Arg1 expression in lung macrophages. Although Arg1 expression in macrophages has been used to define an alternatively activated phenotype, flow cytometry analysis of alveolar and interstitial macrophage sub-populations inLrp5-/-lungs 14 days after bleomycin injury revealed no clear evidence of skewing from a classical to an alternatively activated phenotype. Upregulation ofArg1expression and arginase activity might diminish lung arginine levels with consequent alterations in collagen or cytokine production. However, dietary supplementation of bleomycin-treatedLrp5-/-mice with the Arg1 substrate, L-arginine, failed to alter lung collagen content or cytokine levels 21 days after bleomycin injury. These findings demonstrate that Arg1 is negatively regulated by β-catenin signaling in macrophages, raising the possibility that Wnt signaling directs alterations in immune cell metabolism that may be relevant to lung repair after injury.
Deep learning of the regulatory grammar of yeast 5’ untranslated regions from 500,000 random sequences
Authors: Cuperus Josh , Groves Benjamin , Kuchina Anna , Rosenberg Alexander B. , Jojic Nebojsa , Fields Stanley , Seelig Georg
Published: May 2017

Our ability to predict protein expression from DNA sequence alone remains poor, reflecting our limited understanding ofcis-regulatory grammar and hampering the design of engineered genes for synthetic biology applications. Here, we generate a model that predicts the translational efficiency of the 5’ untranslated region (UTR) of mRNAs in the yeastSaccharomyces cerevisiae.We constructed a library of half a million 50-nucleotide-long random 5’ UTRs and assayed their activity in a massively parallel growth selection experiment. The resulting data allow us to quantify the impact on translation of Kozak sequence composition, upstream open reading frames (uORFs) and secondary structure. We trained a convolutional neural network (CNN) on the random library and showed that it performs well at predicting the translational efficiency of both a held-out set of the random 5’ UTRs as well as nativeS. cerevisiae5’ UTRs. The model additionally was used to computationally evolve highly translating 5’ UTRs. We confirmed experimentally that the great majority of the evolved sequences lead to higher translation rates than the starting sequences, demonstrating the predictive power of this model.
The core transcriptome of mammalian placentas and the divergence of expression with placental shape
Authors: Armstrong Don L. , McGowen Michael R. , Weckle Amy , Pantham Priyadarshini , Caravas Jason , Agnew Dalen , Benirschke Kurt , Savage-Rumbaugh Sue , Nevo Eviatar , Kim Chong J. , Wagner Günter P. , Romero Roberto , Wildman Derek E.
Published: May 2017

Introduction

The placenta is arguably the most anatomically variable organ in mammals even though its primary function is conserved.

Method

Using RNA-Seq, we measured the expression profiles of 55 term placentas of 14 species of mammals representing all major eutherian superordinal clades and marsupials, and compared the evolution of expression across clades.

Results

We identified a set of 115 core genes which is expressed (FPKM≥10) in all eutherian placentas, including genes with immune-modulating properties (ANXA2,ANXA1,S100A11,S100A10, andLGALS1), cell-cell interactions (LAMC1,LUM, andLGALS1), invasion (GRB2andRALB) and syncytialization (ANXA5andANXA1). We also identified multiple pre-eclampsia associated genes which are differentially expressed inHomo sapienswhen compared to the other 13 species. Multiple genes are significantly associated with placenta morphology, includingEREGandWNT5Awhich are both associated with placental shape.

Discussion

115 genes are important for the core functions of the placenta in all eutherian species analyzed. The molecular functions and pathways enriched in the core placenta align with the evolutionarily conserved functionality of the placenta.
Prominent lateral spread of imaged evoked activity beyond cortical columns in barrel cortex provides foundation for coding whisker identity
Authors: Jacobs Nathan S. , Frostig Ron D.
Published: May 2017

The posterior medial barrel subfield (PMBSF) of rat primary somatosensory cortex exquisitely demonstrates topography and columnar organization, defining features of sensory cortices in the mammalian brain. Optical imaging and neuronal recordings in rat PMBSF demonstrates how evoked cortical activity following single whisker stimulation also rapidly spreads laterally into surrounding cortices, disregarding columnar and modality boundaries. The current study quantifies the spatial prominence of such lateral activity spreads by demonstrating that functional connectivity between laterally spaced cortical locations is actually stronger than between vertically spaced cortical locations. Further, the total amount of evoked activity within and beyond single column boundaries was quantified based on intrinsic signal optical imaging, single units and local field potentials (LFPs) recordings, revealing that the vast majority of whisker evoked activity in PMBSF occurs beyond columnar boundaries. Finally, a simple two layer artificial neural network model of PMBSF demonstrates the capacity of extra-columnar evoked activity spread to provide a foundation for accurate whisker stimulus classification that is robust to random scaling of inputs and local noise. Indeed, classification performance improved when more of the lateral spread was included in the model, providing further evidence for the relevance of the lateral spread.
Metformin for high‐altitude performance?
Authors: Burtscher Martin
Published: May 2017

Metformin has been introduced for treatment of type 2 diabetes but may also have ergogenic properties at high altitude by improving muscle glycogen repletion. However, very little information is available on potential risks associated with the (mis)use of metformin by healthy people.
Family or Money? The False Dilemma in Property Dispossession in Shanghai
Authors: Zhang Yunpeng
Published: May 2017

This article examines the lived experiences of property dispossession caused by the World Expo 2010 in Shanghai. Specifically, it examines the category of the family, which is overlooked in the existing literature, and probes into the political production of family conflicts and breakdowns. It characterizes the prevailing regime of dispossession in contemporary China as decentralized legal authoritarianism and argues that the organization of the Expo‐induced dispossession deviated from this because of the distinctive state structures involved. For this reason, tensions within the state apparatus were temporarily suspended, leading to reduced opportunity for resistance. The state's monopoly of symbolic production rendered contesting claims to property ownership illegitimate and made monetary compensation the only option. This turned confrontation with the state into domestic disputes. Organized as a state‐led project, dispossession also exploited displacees' past experiences of a ‘caring' state or state terror, giving rise to different attitudes towards displacement and thus causing more family disputes. Moreover, mobilization of the entire state apparatus also permitted the use of coercive and violent means without legal and moral concerns. Tactics that manipulated, and in some cases completely severed, relations within and beyond the displaced families are explored in depth. The article concludes with a call to change the ways that dispossession has been conceived and conducted in practice.
Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib
Authors: Lankheet Nienke A. G. , Desar Ingrid M. E. , Mulder Sasja F. , Burger David M. , Kweekel Dinemarie M. , van Herpen Carla M. L. , van der Graaf Winette T. A. , van Erp Nielka P.
Published: May 2017

Aim

Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring‐based dose optimization in daily practice.

Methods

A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow‐up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high‐performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels.

Results

In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels.

Conclusions

Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.
Principles of pharmacological research of nutraceuticals
Authors: Andrew Ruth , Izzo Angelo A
Published: May 2017

Linked Articles

This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc
Modulation of Kv11.1 (hERG) channels by 5‐(((1H–indazol‐5‐yl)oxy)methyl)‐N‐(4‐(trifluoromethoxy)phenyl)pyrimidin‐2‐amine (ITP‐2), a novel small molecule activator
Authors: Sale Harinath , Roy Samrat , Warrier Jayakumar , Thangathirupathy Srinivasan , Vadari Yoganand , Gopal Shruthi K , Krishnamurthy Prasad , Ramarao Manjunath
Published: May 2017

Background and Purpose

Activators of Kv11.1 (hERG) channels have potential utility in the treatment of acquired and congenital long QT (LQT) syndrome. Here, we describe a new hERG channel activator, 5‐(((1H–indazol‐5‐yl)oxy)methyl)‐N‐(4‐(trifluoromethoxy)phenyl)pyrimidin‐2‐amine (ITP‐2), with a chemical structure distinct from previously reported compounds.

Experimental Approach

Conventional electrophysiological methods were used to assess the effects of ITP‐2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK‐293 cells.

Key Results

ITP‐2 selectively increased test pulse currents (EC50 1.0 μM) and decreased tail currents. ITP‐2 activated hERG1a homomeric channels primarily by causing large depolarizing shifts in the midpoint of voltage‐dependent inactivation and hyperpolarizing shifts in the voltage‐dependence of activation. In addition, ITP‐2 slowed rates of inactivation and made recovery from inactivation faster. hERG1a/1b heteromeric channels showed reduced sensitivity to ITP‐2 and their inactivation properties were differentially modulated. Effects on midpoint of voltage‐dependent inactivation and rates of inactivation were less pronounced for hERG1a/1b channels. Effects on voltage‐dependent activation and activation kinetics were not different from hERG1a channels. Interestingly, hERG1b channels were inhibited by ITP‐2. Inactivation‐impairing mutations abolished activation by ITP‐2 and led to inhibition of hERG channels. ITP‐2 exerted agonistic effect from extracellular side of the membrane and could activate one of the arrhythmia‐associated trafficking‐deficient LQT2 mutants.

Conclusions and Implications

ITP‐2 may serve as another novel lead molecule for designing robust activators of hERG channels. hERG1a/1b gating kinetics were differentially modulated by ITP‐2 leading to altered sensitivity. ITP‐2 is capable of activating an LQT2 mutant and may be potentially useful in the development of LQT2 therapeutics.
T and B cell clonal expansion in Ras-associated lymphoproliferative disease (RALD) as revealed by next-generation sequencing
Authors: Levy-Mendelovich S , Lev A , Rechavi E , Barel O , Golan H , Bielorai B , Neumann Y , Simon A J , Somech R
Published: May 2017

Ras-associated lymphoproliferative disease (RALD) is an autoimmune lymphoproliferative syndrome (ALPS)-like disease caused by mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) or neuroblastoma RAS viral (V-Ras) oncogene homologue (NRAS). The immunological phenotype and pathogenesis of RALD have yet to be studied extensively. Here we report a thorough immunological investigation of a RALD patient with a somatic KRAS mutation. Patient lymphocytes were analysed for phenotype, immunoglobulin levels and T cell proliferation capacity. T and B cell receptor excision circles (TREC and KREC, respectively), markers of naive T and B cell production, were measured serially for 3 years. T and B cell receptor repertoires were studied using both traditional assays as well as next-generation sequencing (NGS). TREC and KREC declined dramatically with time, as did T cell receptor diversity. NGS analysis demonstrated T and B clonal expansions and marked restriction of T and B cell receptor repertoires compared to healthy controls. Our results demonstrate, at least for our reported RALD patient, how peripheral T and B clonal expansions reciprocally limit lymphocyte production and restrict the lymphocyte receptor repertoire in this disease. Decreased naive lymphocyte production correlated with a clinical deterioration in our patient's immune status, suggesting that TREC and KREC may be used as an aid in monitoring disease progression. Both the methodologies used here and the conclusions regarding immune homeostasis may be applicable to the research of ALPS and other immune dysregulation syndromes.
Measuring long‐term trends in policy coherence for development
Authors: Koch Dirk‐Jan
Published: May 2017

This article measures long term trends in policy coherence for development. Based on result chains, it develops a counterfactual methodology, and then applies it to assess changes in inputs, outputs and outcomes over time. While the literature does not indicate any significant change in policy coherence for development over the last decade, this research finds that, if the time scale is lengthened to 50 years, an overall increase in policy coherence for development of the Dutch government, vis‐à‐vis the DR Congo, in the domains of finance and security, can be detected. These changes in policy coherence for development inputs seem to have contributed, in conjunction with similar policies from other countries, in some instances, to positive outcomes in the DRC.
‘Because family and friends got easily weary of taking care’: a new perspective on the specialization in the elderly care sector in early modern Holland
Authors: Boele Anita , de Moor Tine
Published: May 2017

This article investigates the causes of the remarkable growth in and specialization of elderly care institutions in the Netherlands during the early modern period, and relates these developments to a number of major changes in the household formation process, which had both a direct and an indirect impact on the need for elderly care in general and on the relationships between the elderly and next of kin (partners, children, and other family members). Some specific features of the specialization in care, such as the care provisions for couples, point towards an underlying change in these relationships, which may have resulted from a combination of factors such as neolocality, high marriage ages for both men and women, and, related to this, the small spousal age gap and large numbers of singles. In the typical nuclear household society of early modern Holland, even when children lived close enough and were financially capable to provide help, parents often still relied on extra‐familial elderly care provisions. This article also argues that this practice was embedded in a persistent moral culture accentuating independence, agency, self‐help, investment in the younger generation, and community, instead of putting family responsibilities first.