bluuebunny/crossref_metadata_2025_split huggingface dataset:
Site‐directed spin label electron paramagnetic resonance spectroscopy as a probe of conformational dynamics in the Fe(III) “locked‐off” state of the CO‐sensing transcription factor CooA
Authors: Hines Judy P. , Dent Matthew R. , Stevens Daniel J. , Burstyn Judith N. 
Published: August 2018

AbstractThe transcriptional activator CooA belongs to the CRP/FNR (cAMP receptor protein/fumarate and nitrate reductase) superfamily of transcriptional regulators and uses heme to sense carbon monoxide (CO). Effector‐driven allosteric activation is well understood in CRP, a CooA homologue. A structural allosteric activation model for CooA exists which parallels that of CRP; however, the role of protein dynamics, which is crucial in CRP, is not well understood in CooA. We employed site‐directed spin labeling electron paramagnetic resonance spectroscopy to probe CooA motions on the μs‐ms timescale. We created a series of Cys substitution variants, each with a cysteine residue introduced into a key functional region of the protein: K26C, E60C, F132C, D134C, and S175C. The heme environment and DNA binding affinity of each variant were comparable to those of wild‐type CooA, with the exception of F132C, which displayed reduced DNA binding affinity. This observation confirms a previously hypothesized role for Phe132 in transmitting the allosteric CO binding signal. Osmolyte perturbation studies of Fe(III) “locked‐off” CooA variants labeled with either MTSL or MAL‐6 nitroxide spin labels revealed that multicomponent EPR spectra report on conformational flexibility on the μs‐ms timescale. Multiple dynamic populations exist at every site examined in the structurally uncharacterized Fe(III) “locked‐off” CooA. This observation suggests that, in direct contrast to effector‐free CRP, Fe(III) “locked‐off” CooA undergoes conformational exchange on the μs‐ms timescale. Importantly, we establish MAL‐6 as a spin label with a redox‐stable linkage that may be utilized to compare conformational dynamics between functional states of CooA.
AggScore: Prediction of aggregation‐prone regions in proteins based on the distribution of surface patches
Authors: Sankar Kannan , Krystek Stanley R. , Carl Stephen M. , Day Tyler , Maier Johannes K. X. 
Published: August 2018

AbstractProtein aggregation is a phenomenon that has attracted considerable attention within the pharmaceutical industry from both a developability standpoint (to ensure stability of protein formulations) and from a research perspective for neurodegenerative diseases. Experimental identification of aggregation behavior in proteins can be expensive; and hence, the development of accurate computational approaches is crucial. The existing methods for predicting protein aggregation rely mostly on the primary sequence and are typically trained on amyloid‐like proteins. However, the training bias toward beta amyloid peptides may worsen prediction accuracy of such models when applied to larger protein systems. Here, we present a novel algorithm to identify aggregation‐prone regions in proteins termed “AggScore” that is based entirely on three‐dimensional structure input. The method uses the distribution of hydrophobic and electrostatic patches on the surface of the protein, factoring in the intensity and relative orientation of the respective surface patches into an aggregation propensity function that has been trained on a benchmark set of 31 adnectin proteins. AggScore can accurately identify aggregation‐prone regions in several well‐studied proteins and also reliably predict changes in aggregation behavior upon residue mutation. The method is agnostic to an amyloid‐specific aggregation context and thus may be applied to globular proteins, small peptides and antibodies.
The GluN2B‐Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand‐unbinding and domain opening
Authors: Wells Gordon , Yuan Hongjie , McDaniel Miranda J. , Kusumoto Hirofumi , Snyder James P. , Liotta Dennis C. , Traynelis Stephen F. 
Published: August 2018

Abstract
N‐methyl‐D‐aspartate (NMDA) receptors are transmembrane glutamate‐binding ion channels that mediate neurotransmission in mammals. NMDA receptor subunits are tetrameric complexes of GluN1 and GluN2A‐D subunits, encoded by the GRIN gene family. Of these subunits, GluN2B is suggested to be required for normal development of the central nervous system. A mutation identified in a patient with developmental delay, E413G, resides in the GluN2B ligand‐binding domain and substantially reduces glutamate potency by an unknown mechanism. GluN2B Gly413, though near the agonist, is not in van der Waals contact with glutamate. Visual analysis of the GluN2B structure with the E413G mutation modeled suggests that replacement of Glu with Gly at this position increases solvent access to the ligand‐binding domain. This was confirmed by molecular modeling, which showed that the ligand is more mobile in GluN2B‐E413G than WT GluN2B. Evaluation of agonist occupancy using random accelerated molecular dynamics (RAMD) simulations predicts that the glutamate exits the binding‐site more rapidly for GluN2B‐E413G than WT receptors. This analysis was extended to other binding‐site mutations, which produced qualitative agreement between experimentally determined EC50 values, deactivation time constants, and ligand motion within the binding‐site. Furthermore, long sub‐microsecond molecular dynamics simulations of the bi‐lobed ligand‐binding domain revealed that it adopted a cleft‐open ligand‐free state more often for GluN2B‐E413G than wild‐type GluN2B. This is consistent with the idea that L‐glutamate binding is altered such that the ligand‐binding domain occupies the open‐cleft conformation associated with the closed channel.
Bayesian detection of potential risk using inference on blinded safety data
Authors: Mukhopadhyay Saurabh , Waterhouse Brian , Hartford Alan 
Published: August 2018

SUMMARYSafety surveillance is a critical issue for ongoing clinical trials to actively identify and evaluate important safety information. With the new regulatory emphasis on aggregate review of safety, sponsors are faced with the challenge to develop systematic and sound quantitative methods to assess risk from blinded safety data during the pre‐approval period of a new therapy. To address this challenge, a novel statistical method is proposed to monitor and detect safety signals with data from blinded ongoing clinical trials, specifically for adverse events of special interest (AESI) when historical data are available to provide background rates. This new method is a two‐step Bayesian evaluation of safety signals composed of a screening analysis followed by a sensitivity analysis. This Bayesian modeling framework allows making inference on the relative risk in blinded ongoing clinical trials to detect any safety signal for AESI. The blinded safety teams can use this method to assess the signal and decide if any safety signals should be escalated for unblinded review.
Reasonable two‐stage adaptive designs for single‐arm phase II clinical trials
Authors: Kashiwabara Kosuke , Matsuyama Yutaka 
Published: August 2018

SUMMARYIn cancer phase II trials, determining the sample size of a single‐arm two‐stage design remains a challenge. To overcome this problem, Simon's two‐stage design was extended to an adaptive design: at the interim analysis, the total sample size can be set to either of the two preplanned values. However, without any restriction on design construction, an optimal or suboptimal design derived may have counter‐intuitive or unreasonable design features, which make the chosen design less persuasive and inefficient. Thus, we thoroughly examined how the expected, total, and maximum sample sizes of the optimal or suboptimal designs are affected by excluding the counter‐intuitive or unreasonable designs. We adopted the four optimality criteria: minimizing the expected sample size at the null hypothesis (O1), minimizing the maximum expected sample size over the hypotheses (O2), and minimizing the maximum sample sizes with additional adaption of either of the former two (O3 or O4, respectively). We found that focusing on reasonable design may drastically reduce the maximum sample size when the first optimality criterion is applied. Under the other optimality criteria, although the impact on optimality brought by our proposed strategy may be slight, exclusion of unreasonable design is still useful to reduce the candidate designs, which will considerably reduce the computational time for design search and can facilitate the design choice among optimal and suboptimal designs. We further discuss the utility of our proposal in an example of a real clinical trial and conclude the paper with general recommendations.
Perovskite/Organic Bulk‐Heterojunction Integrated Ultrasensitive Broadband Photodetectors with High Near‐Infrared External Quantum Efficiency over 70%
Authors: Wu Gang , Fu Ruilin , Chen Jiehuan , Yang Weitao , Ren Jie , Guo Xuankun , Ni Zhenyi , Pi Xiaodong , Li Chang‐Zhi , Li Hanying , Chen Hongzheng 
Published: August 2018

AbstractUltraviolet‐visible‐near infrared (UV‐Vis‐NIR) broadband detection is important for image sensing, communication, and environmental monitoring, yet remains as a challenge in achieving high external quantum efficiency (EQE) in the broad spectrum range. Herein, sensitive broadband integrated photodetectors (PDs) with high EQE levels are reported. The organic bulk‐heterojunction (OBHJ) layer, based on a NIR sensitive organic acceptor, is employed to extend the response spectrum of the perovskite PDs. A key strategy of introducing dual electron transport materials respectively for Vis and NIR regions into the active layer of integrated PDs is applied. Further combined with the proper energy level alignment and reasonable distribution of PC61BM in the active layer, the extraction and transport of photo induced charges in between perovskite and OBHJ is promoted efficiently. The integrated PD with the optimized structure exhibits an EQE mostly beyond 70% in the Vis–NIR region, which is the highest value among the ever reported solution‐processable broadband PDs. The highest responsivity is 0.444 and 0.518 A W−1 in the Vis and NIR region, respectively. The specific detectivity is beyond 1010 Jones in the range from 340 to 940 nm, enabling the device to detect weak signals in the UV to NIR broad region.
PARC: A novel OS cache manager
Authors: Chang Hsung‐Pin , Chiang Cheng‐Pang 
Published: August 2018

SummaryTo boost input‐output performance, operating systems employ a kernel‐managed caching space called the buffer cache or page cache. Given the limited size of a buffer cache, an effective cache manager is required to decide which blocks should be evicted from the cache. Previous cache managers use historical information to make replacement decisions. However, existing approaches are unable to maximize performance since they rely on limited historical information. Motivated by the limitations of existing solutions, this paper proposes a novel manager called the Pattern‐assisted Adaptive Recency Caching (PARC) manager. PARC simultaneously uses the historical information of recency, frequency, and access patterns to estimate the locality strengths of blocks and, upon a cache miss, evicts the block with the least strength. Specifically, PARC exploits the reference regularities exhibited in past input‐output behaviors to actively and rapidly adapt the recency and frequency information of blocks so as to precisely distinguish blocks with long‐ and short‐term utility. Through comprehensive simulations on a variety of traces of different access patterns, we show that PARC is robust since, except for random workloads where the performance of each cache manager is similar, PARC always outperforms existing solutions.
Toward a methodology for the system integration of adaptive resilience in armor
Authors: Cannon Joseph , Paulo Eugene 
Published: August 2018

AbstractThis article introduces a novel augmentation to systems engineering methodology based on the integration of adaptive capacity, which produces enhanced resilience in technological systems that operate in complex operating environments. The implementation of this methodology enhances system resistance to top‐level function failure or accelerates the system's functional recovery in the event of a top‐level function failure due to functional requirement shift, evolutions, or perturbations. The research expands system engineering, design, and integration methodologies, which currently do not explicitly address system adaptation and resilience, through the definition and demonstration of a methodology to integrate adaptive resilience and demonstrates its implementation in a relevant armor system case study. The methodology accomplishes this objective by defining adaptive design considerations, identifying controllable adaptive performance factors, characterizing adaptive performance factors and configurations, mapping and integrating adaptive components, and verifying and validating the adaptive components and configurations that achieve system requirements and adaptive design considerations. The utility of this research is demonstrated through development of an adaptive resilient armor system called the mechanically adaptive armor linkage (MAAL), which was designed, developed, and validated using the methodology for the system integration of adaptive resilience (MSIAR). The conceptual validity of the methodology is proven through a physical comparative test and evaluation of the system described in the case study. The research and resulting methodology supplements and enhances traditional systems engineering processes by offering systems designers the opportunity to integrate adaptive capacity into systems, enhancing their resilient resistance, or recovery to top‐level function failure in complex operating environments.
Acoustic Telemetry and Benthic Habitat Mapping Inform the Spatial Ecology of Shortnose Sturgeon in the Hudson River, New York, USA
Authors: Pendleton Richard M. , Standley Christopher R. , Higgs Amanda L. , Kenney Gregg H. , Sullivan Patrick J. , Sethi Suresh A. , Harris Bradley P. 
Published: August 2018

AbstractA history of overexploitation and industrialization of riverine habitats has impacted the Shortnose Sturgeon Acipenser brevirostrum, leading this species to become one of the earliest listed under the U.S. Endangered Species Act. The present understanding of Shortnose Sturgeon spatial ecology is based on observations from a limited number of Atlantic coastal rivers. To better understand Shortnose Sturgeon in the Hudson River, New York, we used acoustic telemetry to characterize seasonal habitat use and to identify regions of the river where seasonal sturgeon activity occurred. From 2012 to 2016, 101 adult fish were tagged and tracked, and sturgeon detections per unit effort (a metric of fish observation standardized by search effort) were evaluated against benthic habitat variables by using generalized additive regression models. Models indicated strong habitat associations in the spring season defined by gravel‐dominated substrates and specific depth ranges, presumably associated with spawning activity. During summer, Shortnose Sturgeon were more dispersed, associating with muddy habitats, whereas in fall/winter, sturgeon congregated in specific regions of the river. These data demonstrate that river use and habitat associations vary seasonally and identify important areas for managing overlap between seasonal habitat use by Shortnose Sturgeon and human activity on the river.
Hamiltonian formulation of general relativity and post-Newtonian dynamics of compact binaries
Authors: Schäfer Gerhard , Jaranowski Piotr 
Published: August 2018

AbstractHamiltonian formalisms provide powerful tools for the computation of approximate analytic solutions of the Einstein field equations. The post-Newtonian computations of the explicit analytic dynamics and motion of compact binaries are discussed within the most often applied Arnowitt–Deser–Misner formalism. The obtention of autonomous Hamiltonians is achieved by the transition to Routhians. Order reduction of higher derivative Hamiltonians results in standard Hamiltonians. Tetrad representation of general relativity is introduced for the tackling of compact binaries with spinning components. Configurations are treated where the absolute values of the spin vectors can be considered constant. Compact objects are modeled by use of Dirac delta functions and their derivatives. Consistency is achieved through transition to d-dimensional space and application of dimensional regularization. At the fourth post-Newtonian level, tail contributions to the binding energy show up. The conservative spin-dependent dynamics finds explicit presentation in Hamiltonian form through next-to-next-to-leading-order spin–orbit and spin1–spin2 couplings and to leading-order in the cubic and quartic in spin interactions. The radiation reaction dynamics is presented explicitly through the third-and-half post-Newtonian order for spinless objects, and, for spinning bodies, to leading-order in the spin–orbit and spin1–spin2 couplings. The most important historical issues get pointed out.
A flow on the verge of turbulent breakdown
Authors: Chomaz J.-M. 
Published: August 2018

Stably stratified sheared flows are ubiquitous in geophysical flows from the ocean to the stars, and the route to turbulence in these flows remains an open question. The article by Lefauve et al. (J. Fluid Mech., vol. 848, 2018, pp. 508–544) is an invitation to this journey. With impressive experimental precision mastered by few teams in the world, the nature of the coherent structure that dominates the flow on the verge of turbulent breakdown is revealed and analysed through one- or two-dimensional modern stability analysis of an experimentally obtained base flow. The effect of confinement is surprisingly strong, advocating for leaving the textbook flows, inhomogeneous in only one direction, for the more complex shores of real flows, now accessible to analysis of multidimensional stability problems. The route explored by Lefauve et al. (2018) renews with the long tradition of the supercritical bifurcation scenario, it revisits the linear stability theory with possibility of resonances, critical layers and more to be imagined, since complex base flows are now available to explore both experimentally and analytically.
The electoral costs of policy commitments
Authors: Betz Timm 
Published: August 2018

AbstractExisting arguments across political science posit that parties in government use domestic and international institutions to lock in their own policy preferences by tying the hands of successors. I demonstrate that these arguments contrast with the assumption of office-seeking parties and therefore portray an incomplete picture of the incentives of governments. The paper emphasizes the trade-off between implementing policy preferences, on the one hand, and exploiting partisan differences for electoral success, on the other hand: locking in a policy takes an issue off the table, but it also undermines a party’s ability to leverage differences to the opposition in elections. Because office-seeking parties need to take into account these electoral consequences, they have a disincentive to tie their successors’ hands. I advance this argument in the context of the establishment of independent central banks, provide empirical evidence, and suggest implications for the literature on international institutions.
Personalised fish intake recommendations: the effect of background exposure on optimisation
Authors: Persson Maria , Fagt Sisse , Nauta Maarten J. 
Published: August 2018

AbstractNational dietary guidelines are directed at the general population. However, these guidelines may be perceived as unrealistic by a substantial part of the population, as they differ considerably from individual consumption patterns and preferences. Personalised dietary recommendations will probably improve adherence, and it has been shown that these recommendations can be derived by mathematical optimisation methods. However, to better account for risks and benefits of specific foods, the background exposure to nutrients and contaminants needs to be considered as well. This background exposure may come from other foods and supplements, and also from environmental sources like the air and the sun. The objective of this study was therefore to analyse the effect of including individual variation in background exposure when modelling personalised dietary recommendations for fish. We used a quadratic programming model to generate recommended fish intake accounting for personal preference by deviating as little as possible from observed individual intake. Model constraints ensure that the modelled intake meets recommendations for EPA, DHA and vitamin D without violating tolerable exposure to methyl mercury, dioxins and dioxin-like polychlorinated biphenyls. Several background exposures were analysed for 3016 Danish adults, whose food intakes and body weights were reported in a national dietary survey. We found that the lower nutrient constraints were critical for the largest part of the study population, and that a total of 55% should be advised to increase their fish intake. The modelled fish intake recommendations were particularly sensitive to the vitamin D background exposure.
Temporal measurements of extreme ultraviolet (EUV) emission, from low temperature, EUV-induced plasmas
Authors: Bartnik A. , Fiedorowicz H. , Wachulak P. , Fok T. 
Published: August 2018

AbstractIn this work, extreme ultraviolet (EUV) emission, from EUV induced, low-temperature microplasmas, were investigated. To perform temporal measurements of the EUV pulses of low intensity, in a medium vacuum, under the pressure of the order of 0.1–0.01 mbar a special detection system was prepared. The system was based on an EUV collector and a semiconductor detector, sensitive for the EUV photons. The collector consisted of two identical grazing incidence, paraboloidal mirrors, and allowed to focus a part of the radiation emitted from the microplasma onto the detector surface. An absorption filter, mounted between the collector and the detector, allowed for selection of an interesting wavelength range. Plasmas were created by irradiation of small portions of gases, injected into the vacuum chamber, using a laser produced plasma EUV source. Three gases were used for the EUV induced plasma formation: neon, krypton, and xenon. Low-temperature plasmas, created in these gases, contained multiply charged ions, emitting radiation in similar wavelength ranges. Two detectors, AXUV20HS1 and AXUVHS5, were used for the measurements. It was shown that differences between the corresponding signal profiles, obtained using both detectors, were not very significant. Moreover, it was demonstrated that the duration of the EUV emission from plasmas, created in different gases, were comparable with the duration of the driving EUV pulse. The longest EUV emission was observed for Kr plasmas, approximately 1.5 times the full width half maximum of the driving EUV pulse.
The Ideological Boundary Condition on Great Society Employment Policy
Authors: Bowring Anaïs Miodek 
Published: August 2018

Abstract:The 1960s was a period of political opening for employment policy, when important questions about unemployment and economic insecurity were debated and a number of ambitious policies were enacted. Yet the Great Society’s employment policy agenda was also fundamentally limited in scope; it comprised interventions that reinforced rather than altered existing labor market mechanisms. Previous work suggests that primarily institutional factors were responsible for this constraint. By contrast, I contend that in addition to institutional factors, there was an ideological boundary condition on the era’s employment policy. The Johnson administration’s policymakers conformed to aspects of the liberal tradition in America, which limited policy options as well as the efficiency and efficacy of implemented policy.