bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractCurrent 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

AbstractCellular 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

ABSTRACTIon 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

Abstract

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.

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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

AbstractAs 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

AbstractInbreeding 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

Abstract

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

AbstractProtests 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

ABSTRACTThis 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

ABSTRACTWe 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

ABSTRACTAuditors 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.
Capitalization of In‐Process Research and Development under SFAS 141R and Information Asymmetry
Authors: Chung Hyeesoo (Sally) H. , Hillegeist Stephen A. , Park You‐Il (Chris) , Wynn Jinyoung P. 
Published: May 2019

ABSTRACTThis study examines the effect of capitalizing acquired in‐process research and development (IPR&D) on information asymmetry under Statement of Financial Accounting Standards No. 141 (R) (SFAS 141R). SFAS 141R requires acquirers to fully recognize IPR&D at fair value as an indefinite‐lived intangible asset until completion or discontinuation of the project. Prior research suggests IPR&D capitalization will result in an improvement in the information environment. In contrast, we find no evidence that capitalizing IPR&D improved the information environment for IPR&D acquirers. Instead, most of our results suggest no significant change in information asymmetry for IPR&D acquirers during the post‐SFAS 141R period, relative to the concurrent changes for non‐IPR&D acquirers. In cases in which the results suggest a statistically significant increase, the economic magnitudes are relatively small. In addition, we find no evidence that IPR&D acquirers engaged in increased classification shifting between IPR&D and goodwill during the post‐SFAS 141R period, as critics of capitalization had feared.
The Benefit of Mean Auditors: The Influence of Social Interaction and the Dark Triad on Unjustified Auditor Trust
Authors: Hobson Jessen L. , Stern Matthew T. , Zimbelman Aaron F. 
Published: May 2019

ABSTRACTRegulators and researchers have expressed concerns that social interaction leads auditors to unjustifiably trust managers, constituting a lack of sufficient professional skepticism. Using both an abstract laboratory experiment and a contextually rich experiment with practicing auditors we predict and find that higher Dark Triad auditors (those with higher levels of the shared core between psychopathy, narcissism, and Machiavellianism) are relatively more resistant to lapses in professional skepticism due to the effects of social interaction. This is likely driven by higher Dark Triad auditors' callousness, lack of empathy, and lack of response to social stimuli. In contrast, while higher social interaction initially increases lower Dark Triad auditors' unjustified trust in managers, this effect reverses in subsequent interactions when lower Dark Triad auditors observe evidence suggesting managers have reported aggressively. These findings add to research on the effect of auditor personality traits, audit‐client social interaction, and the interaction of these two variables, and suggest that practitioners and researchers account for the interplay of Dark Triad traits and social interaction and their effect on professional skepticism.