bluuebunny/crossref_metadata_2025 huggingface dataset:
How do red-eyed treefrog embryos sense motion in predator attacks? Assessing the role of vestibular mechanoreception
Authors: Jung Julie , Kim Su J. , Pérez Arias Sonia M. , McDaniel James G. , Warkentin Karen M.
Published: May 2019

The widespread ability to alter hatching timing in response to environmental cues can serve as a defense against threats to eggs. Arboreal embryos of red-eyed treefrogs, Agalychnis callidryas, hatch up to 30% prematurely to escape predation. This escape-hatching response is cued by physical disturbance of eggs during attacks, including vibrations or motion, and thus depends critically on mechanosensory ability. Predator-induced hatching appears later in development than flooding-induced, hypoxia-cued hatching; thus, its onset is not constrained by the development of hatching ability. It may, instead, reflect the development of mechanosensor function. We hypothesize that vestibular mechanoreception mediates escape-hatching in snake attacks, and that the developmental period when hatching-competent embryos fail to flee from snakes reflects a sensory constraint. We assessed the ontogenetic congruence of escape-hatching responses and an indicator of vestibular function, the vestibulo-ocular reflex (VOR), in three ways. First, we measured VOR in two developmental series of embryos 3–7 days old to compare with the published ontogeny of escape success in attacks. Second, during the period of greatest variation in VOR and escape success, we compared hatching responses and VOR across sibships. Finally, in developmental series, we compared the response of individual embryos to a simulated attack cue with their VOR. The onset of VOR and hatching responses were largely concurrent at all three scales. Moreover, latency to hatch in simulated attacks decreased with increasing VOR. These results are consistent with a key role of the vestibular system in the escape-hatching response of A. callidryas embryos to attacks.

Red-eyed treefrogs’ hatching responses to predator attacks, vibration playbacks, and egg-jiggling appear when vestibular function develops. Ear development may be a key limiting factor in the onset of mechanosensory-cued hatching.
CLASP2 lattice-binding near microtubule plus ends stabilizes kinetochore attachments
Authors: Girão Hugo , Okada Naoyuki , Figueiredo Ana C. , Garcia Zaira , Moutinho-Santos Tatiana , Azevedo Jorge , Macedo-Ribeiro Sandra , Hayashi Ikuko , Maiato Helder
Published: May 2019

The fine regulation of kinetochore microtubule dynamics during mitosis ensures proper chromosome segregation by promoting error correction and spindle assembly checkpoint (SAC) satisfaction. CLASPs are widely conserved microtubule plus-end-tracking proteins that regulate microtubule dynamics throughout the cell cycle and independently localize to kinetochores during mitosis. Thus, CLASPs are ideally positioned to regulate kinetochore microtubule dynamics, but the underlying molecular mechanism remains unknown. Here we found that human CLASP2 can dimerize through its C-terminal kinetochore-targeting domain, but kinetochore localization was independent of dimerization. CLASP2 kinetochore localization, microtubule plus-end-tracking and microtubule lattice binding through TOG2 and TOG3 (but not TOG1) domains, independently sustained normal spindle length, timely SAC satisfaction, chromosome congression and faithful segregation. Measurements of kinetochore microtubule half-life in living cells expressing RNAi-resistant mutants revealed that CLASP2 kinetochore localization, microtubule plus-end-tracking and lattice binding cooperatively modulate kinetochore microtubule stability during mitosis. Thus, CLASP2 regulates kinetochore microtubule dynamics by integrating distinctive microtubule-binding properties at the kinetochore-microtubule interface to ensure chromosome segregation fidelity.
CLN3 regulates endosomal function by modulating Rab7A activity
Authors: Yasa Seda , Modica Graziana , Sauvageau Etienne , Kaleem Abuzar , Hermey Guido , Lefrancois Stephane
Published: May 2019

Mutations in CLN3 are a cause of juvenile NCL (JNCL), also known as Batten Disease. Clinical manifestations includes cognitive regression, progressive loss of vision and motor function, epileptic seizures, and a significantly reduced lifespan. CLN3 localizes to endosomes and lysosomes, and has been implicated in intracellular trafficking and autophagy. However, the precise molecular function of CLN3 remains to be elucidated. We show that CLN3 interacts with Rab7A, a small GTPase that regulates several functions at late endosomes. We found that CLN3 is required for the efficient endosome-to-TGN trafficking of the lysosomal sorting receptors by regulating the Rab7A/retromer interaction. In cells lacking CLN3 or expressing CLN3 harbouring a disease-causing mutation, the lysosomal sorting receptors were degraded. We also demonstrated that CLN3 is required for the Rab7A/PLEKHM1 interaction, which is required for autophagosome/lysosome fusion. Overall, our data provides a molecular explanation behind phenotypes observed in JNCL.
Context-dependent requirement of H3K9 methyltransferase activity during cellular reprogramming to iPSCs
Authors: Vidal Simon , Polyzos Alexander , Valencia Jorge Morales , Wang Hongsu , Swanzey Emily , Ee Ly-sha , Amlani Bhishma , Tu Shengjiang , Gong Yixiao , Snetkova Valentina , Skok Jane A. , Tsirigos Aristotelis , Kim Sangyong , Apostolou Effie , Stadtfeld Matthias
Published: May 2019

Methylation of histone 3 at lysine 9 (H3K9) is widely regarded as a major roadblock for cellular reprogramming and interference with associated methyltransferases such as EHMT1 and EHMT2 (also known as GLP and G9A, respectively) increases the efficiencies at which induced pluripotent stem cells (iPSCs) can be derived. Activation of histone and DNA demethylases by ascorbic acid (AA) has become a common approach to facilitate the extensive epigenetic remodeling required for iPSC formation, but possible functional interactions between the H3K9 methylation machinery and AA-stimulated enzymes remain insufficiently explored. Here we show that reduction of EHMT1/2 activity counteracts iPSC formation in an optimized reprogramming system in the presence of AA. Mechanistically, EHMT1/2 activity under these conditions is required for efficient downregulation of somatic genes and transition into an epithelial state. Of note, transient inhibition of EHMT1/2 during reprogramming yields iPSCs that fail to efficiently give rise to viable mice, suggesting persistent molecular defects in these cells. Genetic interference with the H3K9 demethylase KDM3B ameliorated the adverse effect of EHMT1/2 inhibition on iPSC formation. Together, our observations document novel functions of H3K9 methyltransferases during iPSC formation and suggest that the balancing of AA-stimulated enzymes by EHMT1/2 supports efficient and error-free iPSC reprogramming to pluripotency.
Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes
Authors: Laghmach Rabia , Di Pierro Michele , Potoyan Davit A
Published: May 2019

The nuclear envelope segregates the genome of Eukaryota from the cytoplasm. Within the nucleus, chromatin is further compartmentalized into architectures that change throughout the lifetime of the cell. Epigenetic patterns along the chromatin polymer strongly correlate with chromatin compartmentalization and, accordingly, also change during the cell life cycle and at differentiation. Recently, it has been suggested that sub-nuclear chromatin compartmentalization might result from a process of liquid-liquid phase separation orchestrated by the epigenetic marking and operated by proteins that bind to chromatin. Here, we translate these observations into a diffuse interface model of chromatin, which we named MEsoscale Liquid mOdel of Nucleus (MELON). Using this streamlined continuum model of the genome, we study the large-scale rearrangements of chromatin that happen at different stages of the growth and senescence of the cell, and during nuclear inversion events. Particularly, we investigate the role of droplet diffusion, fluctuations, and heterochromatin-lamina interactions during nuclear remodeling. Our results indicate that the physical process of liquid-liquid phase separation, together with surface effects is sufficient to recapitulate much of the large-scale morphology and dynamics of chromatin along the life cycle of cells.

SIGNIFICANCE STATEMENT

Eukaryotic chromatin occupies a few micrometers of nuclear space while remaining dynamic and accessible for gene regulation. The physical state of nuclear chromatin is shaped by the juxtaposition of complex, out of equilibrium processes on one hand and intrinsic polymeric aspect of the genome on the other. Recent experiments have revealed a remarkable ability of disordered nuclear proteins to drive liquid-liquid phase separation of chromatin domains. We have built a mesoscale liquid model of nuclear chromatin which allows dissecting the contribution of liquid behavior of chromatin to nuclear order of eukaryotes. Our results show that liquid-liquid phase separation, together with surface effects is sufficient for recapitulating large-scale morphology and dynamics of chromatin at many stages of the nuclear cycle.
Paragraph: A graph-based structural variant genotyper for short-read sequence data
Authors: Chen Sai , Krusche Peter , Dolzhenko Egor , Sherman Rachel M. , Petrovski Roman , Schlesinger Felix , Kirsche Melanie , Bentley David R. , Schatz Michael C. , Sedlazeck Fritz J. , Eberle Michael A.
Published: May 2019

Accurate detection and genotyping of structural variations (SVs) from short-read data is a long-standing area of development in genomics research and clinical sequencing pipelines. We introduce Paragraph, an accurate genotyper that models SVs using sequence graphs and SV annotations. We demonstrate the accuracy of Paragraph on whole-genome sequence data from three samples using long read SV calls as the truth set, and then apply Paragraph at scale to a cohort of 100 short-read sequenced samples of diverse ancestry. Our analysis shows that Paragraph has better accuracy than other existing genotypers and can be applied to population-scale studies.
Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads
Authors: Vollger Mitchell R. , Logsdon Glennis A. , Audano Peter A. , Sulovari Arvis , Porubsky David , Peluso Paul , Wenger Aaron M. , Concepcion Gregory T. , Kronenberg Zev N. , Munson Katherine M. , Baker Carl , Sanders Ashley D. , Spierings Diana C.J. , Lansdorp Peter M. , Surti Urvashi , Hunkapiller Michael W. , Eichler Evan E.
Published: May 2019

The sequence and assembly of human genomes using long-read sequencing technologies has revolutionized our understanding of structural variation and genome organization. We compared the accuracy, continuity, and gene annotation of genome assemblies generated from either high-fidelity (HiFi) or continuous long-read (CLR) datasets from the same complete hydatidiform mole human genome. We find that the HiFi sequence data assemble an additional 10% of duplicated regions and more accurately represent the structure of tandem repeats, as validated with orthogonal analyses. As a result, an additional 5 Mbp of pericentromeric sequences are recovered in the HiFi assembly, resulting in a 2.5-fold increase in the NG50 within 1 Mbp of the centromere (HiFi 480.6 kbp, CLR 191.5 kbp). Additionally, the HiFi genome assembly was generated in significantly less time with fewer computational resources than the CLR assembly. Although the HiFi assembly has significantly improved continuity and accuracy in many complex regions of the genome, it still falls short of the assembly of centromeric DNA and the largest regions of segmental duplication using existing assemblers. Despite these shortcomings, our results suggest that HiFi may be the most effective stand-alone technology for de novo assembly of human genomes.
Pan cancer patterns of allelic imbalance from chromosomal aberrations in 33 tumor types
Authors: Sivakumar Smruthy , San Lucas F Anthony , Jakubek Yasminka A , Fowler Jerry , Scheet Paul
Published: May 2019

Somatic copy number alterations (SCNAs), including deletions and duplications, serve as hallmarks of tumorigenesis. SCNAs may span entire chromosomes and typically result in deviations from an expected one-to-one ratio of alleles at heterozygous loci, leading to allelic imbalance (AI). The Cancer Genome Atlas (TCGA) reports SCNAs identified using a circular binary segmentation (CBS) algorithm, providing segment mean copy number estimates from Affymetrix single-nucleotide polymorphism DNA microarray total (log R ratio) intensities, but not allele-specific (“B allele”) intensities that inform of AI. Here we seek to provide a TCGA-wide description of AI in tumor genomes, including AI induced by SCNAs and copy-neutral loss-of-heterozygosity (cnLOH), using a powerful haplotype-based method applied to allele-specific intensities. We present AI summaries for all 33 tumor sites and propose an automated adjustment procedure to improve calibration of existing SCNA calls in TCGA for tumors with high levels of aneuploidy where baseline intensities were difficult to establish without annotation of AI. Overall, 94% of tumor samples exhibited AI. Recurrent events included deletions of 17p, 9q, 3p, amplifications of 8q, 1q, 7p as well as mixed event types on 8p and 13q. The AI-based approach identified frequent cnLOH on 17p across multiple tumor sites, with additional site-specific cnLOH patterns. Our findings support the exploration of additional methods for robust automated inference procedures and to aid empirical discoveries across TCGA.
Cell numbers, distribution, shape, and regional variation throughout the murine hippocampal formation from the adult brain Allen Reference Atlas
Authors: Attili Sarojini M. , Silva Marcos F.M. , Nguyen Thuy-vi , Ascoli Giorgio A.
Published: May 2019

Quantifying the distribution of cells in every brain region is fundamental to attaining a comprehensive census of distinct neuronal and glial types. Until recently, estimating neuron numbers involved time-consuming procedures that were practically limited to stereological sampling. Progress in open-source image recognition software, growth in computing power, and unprecedented neuroinformatics developments now offer the potentially paradigm-shifting alternative of comprehensive cell-by-cell analysis in an entire brain region. The Allen Brain Atlas provides free digital access to complete series of raw Nissl-stained histological section images along with regional delineations. Automated cell segmentation of these data enables reliable and reproducible high-throughput quantification of regional variations in cell count, density, size, and shape at whole-system scale. While this strategy is directly applicable to any regions of the mouse brain, we first deploy it here on the closed-loop circuit of the hippocampal formation: the medial and lateral entorhinal cortices; dentate gyrus (DG); areas Cornu Ammonis 3 (CA3), CA2, and CA1; and dorsal and ventral subiculum. Using two independent image processing pipelines and the adult mouse reference atlas, we report the first cellular-level soma segmentation in every sub-region and layer of the left hippocampal formation through the full rostral-caudal extent, except for the (already well characterized) principal layers of CA and DG. The overall numbers (∼600k cells in entorhinal cortex, ∼200k in DG, ∼430k in CA1-3, and ∼290k in subiculum) are corroborated by traditional stereological sampling on a data subset and well match sparse published reports.
Fast and accurate bacterial species identification in biological samples using LC-MS/MS mass spectrometry and machine learning
Authors: Roux-Dalvai Florence , Gotti Clarisse , Leclercq Mickaël , Hélie Marie-Claude , Boissinot Maurice , Arrey Tabiwang N. , Dauly Claire , Fournier Frédéric , Kelly Isabelle , Marcoux Judith , Bestman-Smith Julie , Bergeron Michel G. , Droit Arnaud
Published: May 2019

The identification of microbial species in biological samples is essential to many applications in health, food safety and environment. MALDI-TOF MS technology has become a tool of choice for microbial identification but it has several drawbacks including: it requires a long step of bacterial culture prior to analysis (24h), it has a low specificity and is not quantitative. We have developed a new strategy for identifying bacterial species in biological samples using specific LC-MS/MS peptidic signatures. In the first training step, deep proteome coverage of bacteria of interest is obtained in Data Independent Acquisition (DIA) mode, followed by the use of machine learning to define the peptides the most susceptible to distinguish each bacterial species from the others. Then, in the second step, this peptidic signature is monitored in biological samples using targeted proteomics. This method, which allows the bacterial identification from clinical specimens in less than 4h, has been applied to fifteen species representing 84% of all Urinary Tract Infections (UTI). More than 31000 peptides in 200 samples have been quantified by DIA and analyzed by machine learning to determine an 82 peptides signature and build prediction models able to classify the fifteen bacterial species. This peptidic signature was validated for its use in routine conditions using Parallel Reaction Monitoring on a capillary flow chromatography coupled to a Thermo Scientific™ Q Exactive HF-X instrument. Linearity and reproducibility of the method were demonstrated as well as its accuracy on donor specimens. Within 4h and without bacterial culture, our method was able to predict the predominant bacteria infecting a sample in 97% of cases and 100% above the 1×105 CFU/mL threshold commonly used by clinical laboratories. This work demonstrates the efficiency of our method for the rapid and specific identification of the bacterial species causing UTI and could be extended in the future to other biological specimens and to bacteria having specific virulence or resistance factors.
Mouse IgG2a antibodies specific for the commensalStreptococcus mitisshow stronger cross-reactivity withStreptococcus pneumoniaethan IgG1 antibodies
Authors: Shekhar Sudhanshu , Khan Rabia , Khan Ata Ul Razzaq , Petersen Fernanda Cristina
Published: May 2019

Here we show that mouse IgG2a and IgG1 antibodies specific for the commensalStreptococcus mitiscross-react with the pathogenStreptococcus pneumoniae, although the cross-reactivity conferred by IgG2a is stronger than IgG1 antibodies. These findings may have implications for designingS. mitis-based vaccines against pneumococcal infections.
Development of an innovative in vitro method for mass production of Verticillium dahliae microsclerotia
Authors: Sayago P. , Juncosa F , Albarracín Orio A. , Paccioretti M. , Gonzalez V. , Otero M.L. , Ducasse D.A
Published: May 2019

The soil-borne fungal plant pathogen Verticillium dahliae can infect more than 300 plant species including important economic crops, causing great economic loses. V. dahliae can persist and survive more than 14 years in the soil by resistance structures, known as microsclerotia, which constitute the primary inoculum in the field. In vitro mass production of microsclerotia is essential for performing many pathological assays. Nevertheless to harvest the microsclerotia is not an easy task and several protocols have been described although none of them is completely satisfying for different reasons. here we present a new protocol that is reproducible, robust, simple and fast allows to overcome the difficulties for obtaining massive amounts of microsclerotia. In summary, we developed a new culture medium that we called Pluronic Potato Medium (PPM) because it is essentially potato dextrose media with the hydrogel, Pluronic F127 as a solidifying agent. The microsclerotia collected in form PPM were infectious in tomato plants were they were able to reproduce the disease and we recovered and quantitated V. dahliae in infected plants.
Recurrent interactions can explain the variance in single trial responses
Authors: Kotekal Subhodh , MacLean Jason N.
Published: May 2019

1.

To develop a complete description of sensory encoding, it is necessary to account for trial-to-trial variability in cortical neurons. Using a generalized linear model with terms corresponding to the visual stimulus, mouse running speed, and experimentally measured neuronal correlations, we modeled short term dynamics of L2/3 murine visual cortical neurons to evaluate the relative importance of each factor to neuronal variability within single trials. We find single trial predictions improve most when conditioning on the experimentally measured local correlations in comparison to predictions based on the stimulus or running speed. Specifically, accurate predictions are driven by positively co-varying and synchronously active functional groups of neurons. Including functional groups in the model enhances decoding accuracy of sensory information compared to a model that assumes neuronal independence. Functional groups, in encoding and decoding frameworks, provide an operational definition of Hebbian assemblies in which local correlations largely explain neuronal responses on individual trials.
Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts
Authors: Rashkin Sara R. , Graff Rebecca E. , Kachuri Linda , Thai Khanh K. , Alexeeff Stacey E. , Blatchins Maruta A. , Cavazos Taylor B. , Corley Douglas A. , Emami Nima C. , Hoffman Joshua D. , Jorgenson Eric , Kushi Lawrence H. , Meyers Travis J. , Van Den Eeden Stephen K. , Ziv Elad , Habel Laurel A. , Hoffmann Thomas J. , Sakoda Lori C. , Witte John S.
Published: May 2019

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction
Authors: Marzo Matthew G. , Griswold Jacqueline M. , Ruff Kristina M. , Buchmeier Rachel E. , Fees Colby P. , Markus Steven M.
Published: May 2019

Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These “dyneinopathies” define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To overcome complications associated with studying dynein function in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we have determined the molecular basis for several broad classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we have alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein complexes. In addition to revealing molecular insight into dynein regulation, our data reveal an unexpected correlation between the degree of dynein dysfunction and disease type.
Population selection and sequencing ofC. eleganswild isolates identifies a region on chromosome III affecting starvation resistance
Authors: Webster Amy K. , Hung Anthony , Moore Brad T. , Guzman Ryan , Jordan James M. , Kaplan Rebecca E. W. , Hibshman Jonathan D. , Tanny Robyn E. , Cook Daniel E. , Andersen Erik , Ryan Baugh L.
Published: May 2019

To understand the genetic basis of complex traits, it is important to be able to efficiently phenotype many genetically distinct individuals. In the nematodeCaenorhabditis elegans, individuals have been isolated from diverse populations around the globe and whole-genome sequenced. As a result, hundreds of wild strains with known genome sequences can be used for genome-wide association studies (GWAS). However, phenotypic analysis of these strains can be laborious, particularly for quantitative traits requiring multiple measurements per strain. Starvation resistance is likely a fitness-proximal trait for nematodes, and it is related to metabolic disease risk in humans. However, natural variation inC. elegansstarvation resistance has not been characterized, and precise measurement of the trait is time-intensive. Here, we developed a population selection and sequencing-based approach to phenotype starvation resistance in a pool of 96 wild strains. We used restriction site-associated DNA sequencing (RAD-seq) to infer the frequency of each strain among survivors in a mixed culture over time during starvation. We used manual starvation survival assays to validate the trait data, confirming that strains that increased in frequency over time are starvation-resistant relative to strains that decreased in frequency. These results document natural variation in starvation resistance. Further, we found that variation in starvation resistance is significantly associated with variation at a region on chromosome III. Using a near-isogenic line (NIL), we showed the importance of this genomic interval for starvation resistance. This study demonstrates the feasibility of using population selection and sequencing in an animal model for phenotypic analyses of quantitative traits, reveals natural variation of starvation resistance inC. elegans, and identifies a genomic region that contributes to such variation.
Atomistic modeling towards predictive cardiotoxicity
Authors: DeMarco Kevin R. , Dawson John R. D. , Yang Pei-Chi , Bekker Slava , Ngo Van A. , Noskov Sergei Y. , Yarov-Yarovoy Vladimir , Clancy Colleen E. , Vorobyov Igor
Published: May 2019

Current methods for assessing safety pharmacology in the context of cardiac arrhythmia risk are unable to distinguish between drugs that cause cardiac rhythm disturbances and benign drugs. Drugs deemed likely to be unsafe share the common property of blocking the human Ether-à-go-go-Related Gene (hERG) encoded cardiac potassium channel and consequent prolongation of QT interval on the ECG. However, hERG block and QT prolongation alone are not selective indicators for cardiac arrhythmia. Here we present a prototype computational framework to distinguish between safe and unsafe hERG blockers. We used recent cryo-EM hERG structure to build and validate an atomistic structural model of the channel open conducting state. We also developed structural atomistic models of dofetilide, a hERG blocking drug with high pro-arrhythmia risk, in both charged and neutral ionization states. Next, we employed unbiased and enhanced sampling all-atom molecular dynamics (MD) simulations to probe atomic-scale mechanisms of dofetilide interaction with open-state hERG. Multi-microsecond drug “flooding” simulations revealed spontaneous dofetilide binding to the channel pore through the intracellular gate. Umbrella sampling MD was used to compute dofetilide affinity to hERG, in good agreement with experiment, as well as ingress and egress rates, which in a novel linkage between the atomistic and functional scale are utilized in our companion paper (Yang P-Cet al.2019bioRxiv:635433) to parameterize functional kinetic models of dofetilide - hERG interactions used to predict emergent drug effects on the cardiac rhythm. This study represents the first necessary components of a computational framework for virtual cardiac safety pharmacology screening from the atom to the rhythm.
Geometric coupling of helicoidal ramps and curvature-inducing proteins in organelle membranes
Authors: Chabanon Morgan , Rangamani Padmini
Published: May 2019

Cellular membranes display an incredibly diverse range of shapes, both in the plasma membrane and at membrane bound organelles. These morphologies are intricately related to cellular functions, enabling and regulating fundamental membrane processes. However, the biophysical mechanisms at the origin of these complex geometries are not fully understood from the standpoint of membrane-protein coupling. In this work, we focused on a minimal model of helicoidal ramps representative of specialized endoplasmic reticulum compartments. Given a helicoidal membrane geometry, we asked what is the distribution of spontaneous curvature required to maintain this shape at mechanical equilibrium? Based on the Helfrich energy of elastic membranes with spontaneous curvature, we derived the shape equation for minimal surfaces, and applied it to helicoids. We showed the existence of switches in the sign of the spontaneous curvature associated with geometric variations of the membrane structures. Furthermore, for a prescribed gradient of spontaneous curvature along the exterior boundaries, we identified configurations of the helicoidal ramps that are confined between two infinitely large energy barriers. Overall our results suggest possible mechanisms for geometric control of helicoidal ramps in membrane organelles based on curvature-inducing proteins.
A Four Electrode Method to Study Dynamics of Ion Activity and Transport in Skeletal Muscle Fibers
Authors: Heiny Judith A. , Cannon Stephen C. , DiFranco Marino
Published: May 2019

Ion movements across biological membranes, driven by electrochemical gradients or active transport mechanisms, control essential cell functions. Membrane ion movements can manifest as electrogenic currents or electroneutral fluxes, and either process can alter the extracellular and/or intracellular concentration of the transported ion(s). Classical electrophysiological methods allow accurate measurement of membrane ion movements when the transport mechanism produces a net ionic current; however, they cannot directly measure electroneutral fluxes and do not detect any accompanying change in intracellular ion concentrations.

Here, we developed a method for simultaneously measuring ion movements and the accompanying dynamic changes in intracellular ion concentration(s) in intact skeletal muscle fibers under voltage– or current clamp in real time. The method combines a two-microelectrode voltage-clamp with ion-selective and reference microelectrodes (4 electrode system). We validate the electrical stability of the system and the viability of the preparation for periods of approximately 1 h. We demonstrate the power of this method with measurements of intracellular Cl-, H+, and Na+ to show: 1) voltage-dependent redistribution of Cl- ions; 2) intracellular pH changes induced by changes in extracellular pCO2; and 3) electroneutral and electrogenic Na+ movements controlled by the Na,K-ATPase. The method is useful for studying a range of transport mechanisms in many cell types, particularly when the transmembrane ion movements are electrically silent and/or when the transport activity measurably changes the intracellular activity of a transported ion.
Foraging rates of ram‐filtering North Atlantic right whales
Authors: van der Hoop Julie Marie , Nousek‐McGregor Anna E. , Nowacek Douglas P. , Parks Susan E. , Tyack Peter , Madsen Peter Teglberg
Published: May 2019

North Atlantic right whales spend their summer months foraging primarily in American and Canadian Atlantic waters on high‐energy‐density prey. Here, they rapidly accumulate and store energy obtained within a few months to support future migrations and reproduction while fasting. High drag from their ram‐filter foraging strategy places a limit on what prey densities will be energetically efficient to target.

Our understanding of the volume of prey‐laden water filtered by right whales during a dive or foraging bout, and what information they use to decide to forage or not, has been limited by the difficulties of measuring when they feed at depth, how fast they swim during continuous ram filtration and how often they might swallow accumulated prey.

We used 10 DTAG deployments from right whales in the Bay of Fundy, Canada, to quantify swimming speeds and estimate the volume of prey‐laden water filtered per dive. We used the tag's inertial sensors to evaluate the timing of frequent biomechanical changes that likely indicate the truncation of continuous filtration, and whether the number or timing of these fluking bouts relates to longer feeding dives or other foraging decisions.

During foraging dives, right whales descended at 1.4 (±0.2 SD) m/s and slowed to swim at 1.1 (±0.3) m/s while filtering. We found consistent pauses in the fluking behaviour of foraging right whales, every 56 (±22) s. Whales filtered on average 78 (±30) m3 of water per fluking bout and on average 673 (±201) m3 per dive.

Right whales filter large volumes of water at low speeds with a high duty cycle, but require sufficiently high prey energy densities to compensate for a high‐drag foraging strategy. Closely related bowhead whales have a larger gape but swim more slowly, filtering greater volumes with lower drag. Our findings highlight that right whales acquire their energy in a relatively short period of intense foraging; even moderate changes in their feeding behaviour or their prey energy density are likely to negatively impact their yearly energy budgets and therefore reduce fitness substantially.

A plain language summary is available for this article.
Evidence for locally adaptive metabolic rates among ant populations along an elevational gradient
Authors: Shik Jonathan Zvi , Arnan Xavier , Oms Cristela Sanchez , Cerdá Xim , Boulay Raphaël
Published: May 2019

As global temperatures rise, the mechanistic links between temperature, physiology and behaviour will increasingly define predictions of ecological change. However, for many taxa, we currently lack consensus about how thermal performance traits vary within and across populations, and whether and how locally adaptive trait plasticity can buffer warming effects.

The metabolic cold adaptation hypothesis posits that cold environments (e.g. high elevations and latitudes) select for high metabolic rates (MR), even after controlling for body size differences, and that this enables high activity levels when an organism is near its cold lower thermal limits. Steep MR reaction norms are further predicted at cold temperatures to enable rapid behavioural activation with rising temperatures needed to exploit brief thermal windows suitable for performing eco‐evolutionary tasks.

We tested these predictions by performing common garden experiments comparing thermal reaction norms of MR (from 15 to 32°C) and behaviour (from 10 to 40°C) across populations of the antAphaenogaster ibericasampled from a 2 km elevation gradient in the Sierra Nevada Mountains of southern Spain.

As predicted, high‐elevation ants had higher MR and steeper MR‐temperature reaction norms. However, higher rates of energy use did not yield the predicted benefits of steeper activity‐level reaction norms.

The evidence for locally adaptive metabolic physiology only became apparent at intermediate temperatures, highlighting the importance of testing thermal performance hypotheses across thermal gradients, rather than focusing only on performance at thermal limits (i.e.critical thermal values).

The partial support for the metabolic cold adaptation hypothesis highlights that while organisms likely show a wealth of unexplored metabolic temperature plasticity, the physiological mechanisms and eco‐evolutionary trade‐offs underlying such local adaptation remain obscure.
Scaling up the effects of inbreeding depression from individuals to metapopulations
Authors: Nonaka Etsuko , Sirén Jukka , Somervuo Panu , Ruokolainen Lasse , Ovaskainen Otso , Hanski Ilkka
Published: May 2019

Inbreeding is common in nature, and many laboratory studies have documented that inbreeding depression can reduce the fitness of individuals. Demonstrating the consequences of inbreeding depression on the growth and persistence of populations is more challenging because populations are often regulated by density‐ or frequency‐dependent selection and influenced by demographic and environmental stochasticity. A few empirical studies have shown that inbreeding depression can increase extinction risk of local populations. The importance of inbreeding depression at the metapopulation level has been conjectured based on population‐level studies but has not been evaluated.

We quantified the impact of inbreeding depression affecting the fitness of individuals on metapopulation persistence in heterogeneous habitat networks of different sizes and habitat configuration in a context of natural butterfly metapopulations.

We developed a spatial individual‐based simulation model of metapopulations with explicit genetics. We used Approximate Bayesian Computation to fit the model to extensive demographic, genetic and life‐history data available for the well‐studied Glanville fritillary butterfly (Melitaea cinxia) metapopulations in the Åland islands in SW Finland. We compared 18 semi‐independent habitat networks differing in size and fragmentation.

The results show that inbreeding is more frequent in small habitat networks, and consequently, inbreeding depression elevates extinction risks in small metapopulations. Metapopulation persistence and neutral genetic diversity maintained in the metapopulations increase with the total habitat amount in and mean patch size of habitat networks. Dispersal and mating behaviour interact with landscape structure to determine how likely it is to encounter kin while looking for mates.

Inbreeding depression can decrease the viability of small metapopulations even when they are strongly influenced by stochastic extinction–colonization dynamics and density‐dependent selection. The findings from this study support that genetic factors, in addition to demographic factors, can contribute to extinctions of small local populations and also of metapopulations.
Species diversification and phylogenetically constrained symbiont switching generated high modularity in the lichen genus Peltigera
Authors: Chagnon Pierre‐Luc , Magain Nicolas , Miadlikowska Jolanta , Lutzoni Francois
Published: May 2019

Ecological interactions range from purely specialized to extremely generalized in nature. Recent research has showed very high levels of specialization in the cyanolichens involving Peltigera (mycobionts) and their Nostoc photosynthetic partners (cyanobionts). Yet, little is known about the mechanisms contributing to the establishment and maintenance of such high specialization levels.

Here, we characterized interactions between Peltigera and Nostoc partners at a global scale, using more than one thousand thalli. We used tools from network theory, community phylogenetics and biogeographical history reconstruction to evaluate how these symbiotic interactions may have evolved.

After splitting the interaction matrix into modules of preferentially interacting partners, we evaluated how module membership might have evolved along the mycobionts’ phylogeny. We also teased apart the contributions of geographical overlap vs phylogeny in driving interaction establishment between Peltigera and Nostoc taxa.

Module affiliation rarely evolves through the splitting of large ancestral modules. Instead, new modules appear to emerge independently, which is often associated with a fungal speciation event. We also found strong phylogenetic signal in these interactions, which suggests that partner switching is constrained by conserved traits. Therefore, it seems that a high rate of fungal diversification following a switch to a new cyanobiont can lead to the formation of large modules, with cyanobionts associating with multiple closely retated Peltigera species.

Finally, when restricting our analyses to Peltigera sister species, the latter differed more through partner acquisition/loss than replacement (i.e., switching). This pattern vanishes as we look at sister species that have diverged longer ago. This suggests that fungal speciation may be accompanied by a stepwise process of (a) novel partner acquisition and (b) loss of the ancestral partner. This could explain the maintenance of high specialization levels in this symbiotic system where the transmission of the cyanobiont to the next generation is assumed to be predominantly horizontal.

Synthesis. Overall, our study suggests that oscillation between generalization and ancestral partner loss may maintain high specialization within the lichen genus Peltigera, and that partner selection is not only driven by partners’ geographical overlap, but also by their phylogenetically conserved traits.
Land acquisition induced conflicts in suburban China: a procedural perspective
Authors: Wang Mark Y.L. , Song Yanan , Li Chen
Published: May 2019

Protests and opposition to land acquisition from displaced peasants for fair compensation occur on a daily basis in China and have become the most prominent social problem in rural parts of the country. Employing a procedural perspective on conflict, this paper aims to uncover the complexities and tensions that are triggered in the process by drawing on a case of a land confiscation in Jining City, a medium‐size city in Shandong Province, China. Our research shows that conflicts exist at various scales: both between the local governments and rural households and between the village officials and villagers. The paper argues that ambiguity in de jure and de facto land acquisition procedures has resulted in both an escalation of conflict and increasing inequality in the outcomes and benefits of the process. We discuss and conclude that the differences between de jure and de facto procedures in the process of land acquisition are a significant institutional barrier in the resolution of conflict in this important issue for rural China.
Managerial Discretion and Task Interdependence in Teams
Authors: Arnold Markus C. , Tafkov Ivo D.
Published: May 2019

This study investigates whether task interdependence in teams alters the effectiveness of managerial discretion in motivating team performance. Teams are particularly useful when employees' tasks are interdependent—that is, when the degree to which the increase in team performance resulting from a team member's effort depends on the effort and skills of the other team members. The reason is that the more interdependent tasks are, the more employees need to coordinate their actions and help one another to achieve their objectives. Prior research analyzing settings where task interdependence is absent suggests that providing managers with discretion over team bonus allocation can improve team performance relative to equal team bonus allocations because it strengthens the link between contributions to team output and rewards. Economic theory suggests that managerial discretion will also improve team performance when task interdependence is present and information is efficiently used. However, we use behavioral theory to predict that managerial discretion is less effective in the presence of task interdependence, because managers do not fully incorporate all relevant information into bonus decisions and because managerial discretion hurts coordination and helping, which is particularly problematic under task interdependence. We find that while discretion over compensation has a positive effect on team performance relative to equal bonus allocation when task interdependence is absent, it has a negative effect when task interdependence is present. Additional analyses provide support for our underlying theory. Results of our study contribute to both theory and practice by suggesting that, ironically, managerial discretion may be most useful when the potential benefits of employing teams are lowest and least useful when the potential benefits are highest. Our results help explain why firms often grant managers only partial or no discretion over team members' compensation.
Unexpected SEC Resource Constraints and Comment Letter Quality
Authors: Ege Matthew , Glenn Jennifer L. , Robinson John R.
Published: May 2019

We investigate whether reviews of transactional filings by the SEC unexpectedly constrain SEC resources, leading to lower quality comment letters for periodic reports. The Sarbanes‐Oxley Act requires the SEC to review periodic reports (e.g., 10‐Ks) at least once every three years. However, the SEC also reviews transactional filings (e.g., initial public offerings and acquisitions), which are unpredictable and often occur in waves. We find comment letters for periodic reports are of lower quality (in terms of outputs, inputs, and firm responses) during periods of abnormally high transactional filings. We also find that comment letters issued during periods of abnormally high versus low transactional filings are associated with increased information asymmetry and lower earnings response coefficients in the quarter after the resolution of the comment letter. Overall, our results suggest that unexpected resource constraints affect the quality of SEC oversight of periodic reports.
Auditors, Specialists, and Professional Jurisdiction in Audits of Fair Values
Authors: Griffith Emily E.
Published: May 2019

Auditors frequently use valuation specialists to help them evaluate fair values, but researchers and regulators know little about how auditors use these specialists. Based on interviews with 28 auditors and 14 valuation specialists, I develop a theoretical framework informed by expert systems and professional competition theories. The interviews suggest that institutional pressures in the fair value environment unevenly impact auditors and specialists, causing tension between auditors' needs for ontological security and jurisdictional claims. This tension leads to one‐sided competition between auditors and specialists and incomplete acceptance of specialists' work. Auditors' competitive behaviors coupled with this incomplete acceptance result in a tendency to make specialists' work conform to auditors' views. Collectively, these findings suggest that auditors use specialists as an institutional mechanism to create comfort, but not insight. This study links expert systems and professional competition theories, and it provides critical insight into some assumptions underlying tenets of each theory. It also informs researchers, regulators, and practitioners interested in understanding and addressing problems related to the use of specialists.