bluuebunny/crossref_metadata_2025 huggingface dataset:
UPLC‐Q‐TOF‐MS/MS‐guided dereplication of Pulsatilla chinensis to identify triterpenoid saponins
Authors: Jin Miao‐miao , Zhang Wen‐dan , Jiang Hong‐hong , Du Ying‐feng , Guo Wei , Cao Liang , Xu Hui‐jun
Published: April 2018

Introduction

Triterpenoid saponins are the major bioactive constituents of Pulsatilla chinensis, playing an important role in various biological activities such as anti‐tumour, cognition‐enhancing, anti‐biosis, anti‐inflammatory, hypoglycemic and immunological adjuvant.

Objective

To establish a systematic strategy based on ultra‐high‐performance liquid chromatography‐quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐Q‐TOF‐MS/MS) for the efficient characterisation and identification of triterpenoid saponins in crude extracts from Pulsatilla chinensis.

Methodology

In this work, the strategy includes two aspects: (1) positive mode: by target screening, we can deduce the aglycone type and the composition of sugar moiety according to the fragment ions; untargeted screening includes four steps, find unknown, formula finder, ChemSpider search and MS/MS identification; (2) negative mode: according to the MS/MS spectra, the composition of sugar chain bonded to C‐28 is inferred reasonably. The extract of Pulsatilla chinensis was separated within 60 min on a C18 column and eluted with methanol and water both containing 0.1% formic acid.

Results

As a result, a total of 22 triterpenoid saponins (11 pairs of isomers) with four aglycone skeletons were tentatively identified or elucidated in crude extracts from Pulsatilla chinensis based on their retention times, the mass spectrometric fragmentation patterns, and MS and MS/MS data.

Conclusion

This study provides an efficient analysis strategy to rapidly identify the triterpenoid saponins in Pulsatilla species even in traditional Chinese medicines.
Upregulation of DWARF27 is associated with increased strigolactone levels under sulfur deficiency in rice
Authors: Shindo Masato , Shimomura Koichiro , Yamaguchi Shinjiro , Umehara Mikihisa
Published: April 2018

Plants produce strigolactones (SLs) in roots in response to nitrogen or phosphate deficiency. To evaluate SL levels under other mineral deficiencies in rice, we cultivated rice seedlings in hydroponic media without nitrogen, phosphorus, potassium, sulfur, calcium, magnesium, and iron. Tiller bud outgrowth was stimulated under calcium deficiency because of low SL levels. SL levels increased under sulfur deficiency, in addition to phosphate, and nitrogen deficiencies. To explore which genes are key regulators of SL production under sulfur deficiency, we analyzed the expression of SL‐related genes in sulfur‐sufficient and sulfur‐deficient conditions. An SL biosynthesis gene, DWARF27 (D27), was strongly expressed under sulfur deficiency, and its expression was decreased by sulfur supply. The levels of D10, D17, and OsMAX1 transcripts did not differ between sulfur‐sufficient and sulfur‐deficient conditions. These results suggest that the increased SL levels under sulfur deficiency are due to a high expression of D27. A combination of nitrogen, phosphorus, and sulfur deficiencies had no additive synergistic effect on SL production. Under combined phosphorus and sulfur deficiency, the expression levels of most SL biosynthesis genes were elevated. The number of tiller buds in the d27 mutant was higher than in the wild type, but lower than in other d mutants. Under sulfur deficiency, the chlorophyll content of d27 was lower than those of other d mutants. These results indicate that D27 plays an important role in adaptation to sulfur deficiency in rice.
Olanzapine‐associated hyperammonemia
Authors: Lam Y. W. Francis
Published: April 2018

Hyperammonemia is a metabolic disorder that can occur secondary to a variety of medical conditions and also can be associated with use of medications, especially valproic acid. The following case described episodes of hyperammonemia associated with olanzapine use.
Warning signs on stimulants
Authors: Price Lawrence H.
Published: April 2018

I think I am safe in suggesting that the Morbidity and Mortality Weekly Report (MMWR), published by the Centers for Disease Control and Prevention (CDC), is regularly read by few of our readers. While it has broadened its scope considerably over time, it retains much of its historical focus on infectious diseases and environmental exposures, with limited coverage of topics that might be of compelling interest to those of us in psychiatric medicine. However, my criteria for “compelling” were met by the MMWR paper by Anderson et al.1 that we cover as one of our lead articles in this month's issue.
Electrochemical Reduction of CO2 in Water‐Based Electrolytes KHCO3 and K2SO4 Using Boron Doped Diamond Electrodes
Authors: Romero Cuellar Nayra Sofia , Wiesner‐Fleischer Kerstin , Hinrichsen Olaf , Fleischer Maximilian
Published: April 2018

The performance of Boron Doped Diamond (BDD) electrodes for the electrochemical reduction of CO2 at room temperature and in water‐based electrolytes was investigated. Techniques such as linear sweep voltammetry, chronoamperometry, and chronopotentiometry were used to confirm the activity of BDD for the CO2 reduction. Besides H2, CO and HCOOH were found as major products with CH3OH as a minor product. The effect of anionic species with and without buffer capacity was investigated using KHCO3 and K2SO4 as electrolytes. BDD did not show any degradation after using it in several experiments. The Faradaic efficiency (FE) for CO in the gas phase and the concentration of HCOOH in the liquid phase were higher in K2SO4 than in KHCO3. However, the total FE for C1 products was lower than 20%. Then BDD electrodes were modified with silver, which improved the FE for CO to 68% in K2SO4 at −1.8 V vs. Ag/AgCl. Galvanostatic experiments were also performed for 10 hours at −10 mA cm−2 producing 30% FE for CO in the gas phase and 43,9 mM HCOOH in the liquid phase.
The Syntheses and Vibrational Spectra of 16O‐ and 18O‐Enriched cis‐MO2 (M=Mo, W) Complexes
Authors: Peuronen Anssi , Sillanpää Reijo , Lehtonen Ari
Published: April 2018

In this contribution, we report convenient synthetic approaches for obtaining 16O/18O‐enriched dioxidometalVI complexes, MO2(L) (W, Mo), with a linear, tetradentate amine phenolate ligand N,N′‐dimethyl‐N,N′‐bis(2‐hydroxy‐3,5‐dimethylbenzyl)ethylenediamine (H2L) and describe their characterization by IR and Raman spectroscopy complemented by DFT computational analysis. The isotopologues of WO2(L) were made of tungstenVI trisglycolate W(eg)3 (eg=1,2‐ethanediolate dianion) and ligand H2L in the presence of either H2[16O] or H2[18O], whereas Mo16O2(L) was made using Na2MoO4⋅2H2O which was converted to Mo18O2(L) by oxido substitution using H2[18O]. The complementary IR and Raman analyses show the ν(MO2)s and ν(MO2)a at 934 and 899 cm–1 for W16O2(L) and at 914 and 898 cm–1 for Mo16O2(L), respectively. In the vibrational spectra of the 18O substituted derivatives, the ν(MO2)s were shifted to lower energy by 43 cm–1 for W18O2(L) and by 41 cm–1 for Mo18O2(L) whereas asymmetric MO2 stretches in the IR were partially overlapped by an organic ligand related stretch. However, Raman spectroscopy, accompanied by DFT calculations, allowed the deciphering the ν(MO2)a shifts of 47 cm–1 for W18O2(L) and 31 cm–1 for Mo18O2(L).
Bio‐inspired network on chip having both guaranteed throughput and best effort services using fault‐tolerant algorithm
Authors: Sethi Muhammad Athar Javed , Hussin Fawnizu Azmadi , Hamid Nor Hisham
Published: April 2018

Network‐on‐chip (NoC) is a communication framework for multiple cores connected together in a system‐on‐chip (SoC). Different NoC architectures have provided quality of service (QoS) parameters of best effort (BE) and guaranteed throughput (GT). GT services are provided by having a dedicated connection using circuit switching or connection‐oriented mechanism of packet switching. GT traffic is usually preferred for real‐time traffic such as video processing and multimedia applications. BE services are provided using packet switching. Cache updates is an example of BE noncritical traffic. In this paper, we implement a novel biologically inspired fault‐tolerant algorithm that provides both GT and BE QoS. In order to provide fault tolerance, the router architectures is also updated. The bio‐inspired, fault‐tolerant techniques are a novel way to provide fault tolerance in NoC. Faults in the NoC arise as the size of the devices are shrinking on the NoC, which include the router, links, and processing elements (PEs), to accommodate the complex communication requirements of applications. The proposed NoC's fault‐tolerant methods (synaptogenesis and sprouting) are adapted from the biological brain's robust fault‐tolerant mechanisms. From the experimental results, the throughput and bandwidth utilization are dropped by 3.55 and 4.87%, respectively, during the recovery from faults. The interflit arrival time and packet network latency are increased by only 7.03 and 22.60%, respectively, during the recovery from faults. The algorithm also performs as efficiently as the traditional fault‐tolerant techniques. © 2018 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
A Hamiltonian‐based analytical method for fracture analysis of linear thermo‐viscoelastic media
Authors: Tong Zhenzhen , Cheng Xianhe , Rong Dalun , Xu Chenghui , Zhou Zhenhuan , Xu Xinsheng
Published: April 2018

A Hamiltonian‐based methodology is presented to study the fracture behaviors of the thermo‐viscoelastic materials based on the Laplace transform. The governing equations and associated boundary conditions are rebuilt in a Hamiltonian form by using the symplectic mathematics in the frequency domain (s‐domain). The fundamental unknown vector composed of both displacements and stresses variables is expanded in terms of the symplectic eigensolutions. The corresponding unknown coefficients of the symplectic series are determined from the outer boundary conditions. Thus, the main unknowns are obtained and transformed into the time domain (t‐domain). The fracture parameters including stress intensity factors (SIFs) and J‐integrals are derived simultaneously. Numerical examples as well as convergence studies are given and are found to be in good agreement with the ANSYS results. A parametric study of thermo‐viscoelastic parameters is included also.
From visco to perfect plasticity in thermoviscoelastic materials
Authors: Rossi Riccarda
Published: April 2018

We consider a thermodynamically consistent model for thermoviscoplasticity. For the related PDE system, coupling the heat equation for the absolute temperature, the momentum balance with viscosity and inertia for the displacement variable, and the flow rule for the plastic strain, we propose two weak solvability concepts, ‘entropic’ and ‘weak energy’ solutions, where the highly nonlinear heat equation is suitably formulated. Accordingly, we prove two existence results by passing to the limit in a carefully devised time discretization scheme. Furthermore, we study the asymptotic behavior of weak energy solutions as the rate of the external data becomes slower and slower, which amounts to taking the vanishing‐viscosity and inertia limit of the system. We prove their convergence to a global energetic solution to the Prandtl‐Reuss model for perfect plasticity, whose evolution is ‘energetically’ coupled to that of the (spatially constant) limiting temperature.
How to Teach and Assess Whole Number Arithmetic: A Commentary on Chapter 11
Authors: Margolinas Claire
Published: April 2018

Chapter 11 and the different contributions in the proceedings of working group 4 have explored different aspects of the teaching and assessing of whole number arithmetic. We often underestimate teacher’s required knowledge, not only for selecting challenging and dense tasks but also, within a determined task, for assessing the diverse needs of individuals and respect to these needs. It is certainly not a little challenge for mathematics education research to describe the knowledge at stake: even within the field of WNA and even if we take a single lesson. In this chapter, I will focus on the difficulty to make coherent choices in teaching and assessing whole number arithmetic and the various pieces of knowledge that are necessary to do so. Whole number arithmetic is not a homogeneous domain in this chapter, so I will discuss some aspects: memorizing numerical facts, writing numbers and numerical sentences and additive structure’s field. These considerations will lead to a commentary about Macao’s lesson.
Tradition in Whole Number Arithmetic
Authors: Arzarello Ferdinando , Azrou Nadia , Bartolini Bussi Maria G. , de Lora Sued Sarah Inés González , Sun Xu Hua , Siu Man Keung
Published: April 2018

The main topics discussed by the panel and the resulting questions to be answered are introduced along with some bibliographic references. The main topics of discussion concern the relationships between tradition and the verbal and non-verbal representations of numbers, numbers and artefacts of arithmetic and the role of technological devices in emulating traditional abaci and allowing direct interaction with the screens of multitouch devices in counting activities. Another crucial issue concerns the different languages that can be present in a classroom for historical and cultural reasons. This represents a challenge for teachers, who must cope with the ways in which words can shape the specific connotations of the meanings of numbers. Although all of these facets of numbers need to be coordinated with the standard mathematical concepts, they also appear in the multimodal representations that are used to teach them, such as words, textbooks, notes and teachers’ and students’ gestures. All of these factors intertwine and sometimes conflict with the richness of the representations and practices that children encounter outside school in their everyday lives.
Special Needs in Research and Instruction in Whole Number Arithmetic
Authors: Verschaffel Lieven , Baccaglini-Frank Anna , Mulligan Joanne , van den Heuvel-Panhuizen Marja , Xin Yan Ping , Butterworth Brian
Published: April 2018

This chapter provides an overview of the ICME 23 Study panel on special needs in research and instruction in whole number arithmetic. It starts with a general introduction by Verschaffel about the state of affairs in and the major issues and challenges for research and educational practice in the field of mathematical learning difficulties (MLD). Afterwards these issues and challenges are explored and discussed from four different angles by four scholars with complementary specializations in the domain of children with MLD and/or other special needs in the curricular domain of whole number arithmetic, namely, Anna Baccaglini-Frank, Joanne Mulligan, Marja van den Heuvel-Panhuizen and Yan Ping Xin. Finally, Brian Butterworth discusses these four contributions, particularly with respect to the questions ‘what constitutes the “mathematics” that MLD research and practice should address’ and ‘what can be considered as appropriate interventions for children with special needs’
Quantities, Numbers, Number Names and the Real Number Line
Authors: Bass Hyman
Published: April 2018

This paper describes an approach to developing concepts of number using general notions of quantity and their measurement. This approach, most prominently articulated by Davydov and his colleagues, is discussed, and some arguments favouring this approach are offered. First is that it provides a coherent development of both whole numbers and fractions. Second, it makes the geometric number line continuum present from the start of the school curriculum as a useful mathematical object and concept into which real numbers can eventually take up residence. Third, in the Davydov approach, there are some significant opportunities for some early algebraic thinking. I further present an instructional context and approach to place value that simulates a hypothetical invention of a place value system of number representation.
Language and Cultural Issues in the Teaching and Learning of WNA
Authors: Sun Xu Hua , Bartolini Bussi Maria G.
Published: April 2018

Language and culture play a common, key role in conveying concepts in mathematics teaching and learning for mathematical thinking development. Linguistic transparency can foster the construction of mathematical meanings and support the understanding that occurs in learning discourse. A cross-cultural examination of languages should thus allow us to understand linguistic supports or limitations that may interfere with students’ learning and teachers’ teaching of mathematics. This chapter examines number naming and structure across languages and language issues related to whole number structure, arithmetic operations and key concepts of place value and equality from a linguistic perspective. It also specifically considers how the Chinese language has been linked with Chinese arithmetic in ancient and present times.
Some Further Results on the Tempered Multistable Approach
Authors: Le Courtois Olivier
Published: April 2018

This article provides new results on the tempered multistable approach. After a preliminary section recalling the main definitions, we show the correspondence between a series representation and a characteristic function representation for asymmetrical field-based tempered multistable processes and for asymmetrical independent increments tempered multistable processes. We also show that both processes are semimartingales, which is a convenient property in finance. Next, we study the structure of autocorrelations that is conveyed by this approach. Finally, we provide an illustration showing the term structures of Value-at-Risk that can be obtained with this model.
Hybrid binary bat enhanced particle swarm optimization algorithm for solving feature selection problems
Authors: Tawhid Mohamed A. , Dsouza Kevin B.
Published: April 2018

In this paper, we present a new hybrid binary version of bat and enhanced particle swarm optimization algorithm in order to solve feature selection problems. The proposed algorithm is called Hybrid Binary Bat Enhanced Particle Swarm Optimization Algorithm (HBBEPSO). In the proposed HBBEPSO algorithm, we combine the bat algorithm with its capacity for echolocation helping explore the feature space and enhanced version of the particle swarm optimization with its ability to converge to the best global solution in the search space. In order to investigate the general performance of the proposed HBBEPSO algorithm, the proposed algorithm is compared with the original optimizers and other optimizers that have been used for feature selection in the past. A set of assessment indicators are used to evaluate and compare the different optimizers over 20 standard data sets obtained from the UCI repository. Results prove the ability of the proposed HBBEPSO algorithm to search the feature space for optimal feature combinations.
Canadian Association of Radiologists White Paper on Artificial Intelligence in Radiology
Authors: Tang An , Tam Roger , Cadrin-Chênevert Alexandre , Guest Will , Chong Jaron , Barfett Joseph , Chepelev Leonid , Cairns Robyn , Mitchell J. Ross , Cicero Mark D. , Poudrette Manuel Gaudreau , Jaremko Jacob L. , Reinhold Caroline , Gallix Benoit , Gray Bruce , Geis Raym ,   for the Canadian Association of Radiologists (CAR) Artificial Intelligence Working Group, O'Connell Timothy , Babyn Paul , Koff David , Ferguson Darren , Derkatch Sheldon , Bilbily Alexander , Shabana Wael
Published: April 2018

Artificial intelligence (AI) is rapidly moving from an experimental phase to an implementation phase in many fields, including medicine. The combination of improved availability of large datasets, increasing computing power, and advances in learning algorithms has created major performance breakthroughs in the development of AI applications. In the last 5 years, AI techniques known as deep learning have delivered rapidly improving performance in image recognition, caption generation, and speech recognition. Radiology, in particular, is a prime candidate for early adoption of these techniques. It is anticipated that the implementation of AI in radiology over the next decade will significantly improve the quality, value, and depth of radiology's contribution to patient care and population health, and will revolutionize radiologists' workflows. The Canadian Association of Radiologists (CAR) is the national voice of radiology committed to promoting the highest standards in patient-centered imaging, lifelong learning, and research. The CAR has created an AI working group with the mandate to discuss and deliberate on practice, policy, and patient care issues related to the introduction and implementation of AI in imaging. This white paper provides recommendations for the CAR derived from deliberations between members of the AI working group. This white paper on AI in radiology will inform CAR members and policymakers on key terminology, educational needs of members, research and development, partnerships, potential clinical applications, implementation, structure and governance, role of radiologists, and potential impact of AI on radiology in Canada.
Interkulturelle Unterschiede im Erleben und Verhalten nach sozialer Exkludierung
Authors: Pfundmair Michaela , Graupmann Verena , Frey Dieter , Aydin Nilüfer
Published: April 2018

Zusammenfassung. Soziale Exkludierung, von anderen entfernt gehalten zu werden, zieht schwerwiegende psychische und physische Reaktionen nach sich. Wie stark allerdings Menschen von sozialer Exkludierung bedroht sind, hängt von verschiedenen Faktoren ab. Im vorliegenden Forschungsartikel wird der Frage nachgegangen, inwiefern kulturelle Unterschiede das Erleben sozialer Exkludierung beeinflussen. Die aktuelle Forschung zeigt, dass Personen mit kollektivistischem Hintergrund von Exkludierung weniger psychologisch beeinträchtigt sind als Personen mit individualistischem Hintergrund, weil sie als weniger bedrohlich und destabilisierend wahrgenommen wird. Neben der Darstellung empirischer Befunde werden die Grenzen des Effekts diskutiert, sowie theoretische und praktische Implikationen vorgestellt.
Electroencephalographic delta/alpha frequency activity differentiates psychotic disorders: a study of schizophrenia, bipolar disorder and methamphetamine-induced psychotic disorder
Authors: Howells Fleur M , Temmingh Hendrik S , Hsieh Jennifer H , van Dijen Andrea V , Baldwin David S , Stein Dan J
Published: April 2018

Electroencephalography (EEG) has been proposed as a neurophysiological biomarker to delineate psychotic disorders. It is known that increased delta and decreased alpha, which are apparent in psychosis, are indicative of inappropriate arousal state, which leads to reduced ability to attend to relevant information. On this premise, we investigated delta/alpha frequency activity, as this ratio of frequency activity may serve as an effective neurophysiological biomarker. The current study investigated differences in delta/alpha frequency activity, in schizophrenia (SCZ), bipolar I disorder with psychotic features and methamphetamine-induced psychosis. One hundred and nine participants, including individuals with SCZ (n = 28), bipolar I disorder with psychotic features (n = 28), methamphetamine-induced psychotic disorder (MPD) (n = 24) and healthy controls (CON, n = 29). Diagnosis was ascertained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition disorders and current medication was recorded. EEG was undertaken in three testing conditions: resting eyes open, resting eyes closed and during completion of a simple cognitive task (visual continuous performance task). EEG delta/alpha frequency activity was investigated across these conditions. First, delta/alpha frequency activity during resting eyes closed was higher in SCZ and MPD globally, when compared to CON, then lower for bipolar disorder (BPD) than MPD for right hemisphere. Second, delta/alpha frequency activity during resting eyes open was higher in SCZ, BPD and MPD for all electrodes, except left frontal, when compared to CON. Third, delta/alpha frequency activity during the cognitive task was higher in BPD and MPD for all electrodes, except left frontal, when compared to CON. Assessment of EEG delta/alpha frequency activity supports the delineation of underlying neurophysiological mechanisms present in psychotic disorders, which are likely related to dysfunctional thalamo-cortical connectivity. Delta/alpha frequency activity may provide a useful neurophysiological biomarker to delineate psychotic disorders.
Reverse translated and gold standard continuous performance tests predict global cognitive performance in schizophrenia
Authors: Bismark Andrew W. , Thomas Michael L. , Tarasenko Melissa , Shiluk Alexandra L. , Rackelmann Sonia Y. , Young Jared W. , Light Gregory A.
Published: April 2018

Attentional dysfunction contributes to functional impairments in schizophrenia (SZ). Sustained attention is typically assessed via continuous performance tasks (CPTs), though many CPTs have limited cross-species translational validity and place demands on additional cognitive domains. A reverse-translated 5-Choice Continuous Performance Task (5C-CPT) for human testing—originally developed for use in rodents—was designed to minimize demands on perceptual, visual learning, processing speed, or working memory functions. To-date, no studies have validated the 5C-CPT against gold standard attentional measures nor evaluated how 5C-CPT scores relate to cognition in SZ. Here we examined the relationship between the 5C-CPT and the CPT-Identical Pairs (CPT-IP), an established and psychometrically robust measure of vigilance from the MATRICS Consensus Cognitive Battery (MCCB) in a sample of SZ patients (n = 35). Relationships to global and individual subdomains of cognition were also assessed. 5C-CPT and CPT-IP measures of performance (d-prime) were strongly correlated (r = 0.60). In a regression model, the 5C-CPT and CPT-IP collectively accounted for 54% of the total variance in MCCB total scores, and 27.6% of overall cognitive variance was shared between the 5C-CPT and CPT-IP. These results indicate that the reverse translated 5C-CPT and the gold standard CPT-IP index a common attentional construct that also significantly overlaps with variance in general cognitive performance. The use of simple, cross-species validated behavioral indices of attentional/cognitive functioning such as the 5C-CPT could accelerate the development of novel generalized pro-cognitive therapeutics for SZ and related neuropsychiatric disorders.
Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS
Authors: Pan David Z. , Garske Kristina M. , Alvarez Marcus , Bhagat Yash V. , Boocock James , Nikkola Elina , Miao Zong , Raulerson Chelsea K. , Cantor Rita M. , Civelek Mete , Glastonbury Craig A. , Small Kerrin S. , Boehnke Michael , Lusis Aldons J. , Sinsheimer Janet S. , Mohlke Karen L. , Laakso Markku , Pajukanta Päivi , Ko Arthur
Published: April 2018

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi–C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.
Real-time magnetic actuation of DNA nanodevices via modular integration with stiff micro-levers
Authors: Lauback Stephanie , Mattioli Kara R. , Marras Alexander E. , Armstrong Maxim , Rudibaugh Thomas P. , Sooryakumar Ratnasingham , Castro Carlos E.
Published: April 2018

DNA nanotechnology has enabled complex nanodevices, but the ability to directly manipulate systems with fast response times remains a key challenge. Current methods of actuation are relatively slow and only direct devices into one or two target configurations. Here we report an approach to control DNA origami assemblies via externally applied magnetic fields using a low-cost platform that enables actuation into many distinct configurations with sub-second response times. The nanodevices in these assemblies are manipulated via mechanically stiff micron-scale lever arms, which rigidly couple movement of a micron size magnetic bead to reconfiguration of the nanodevice while also enabling direct visualization of the conformation. We demonstrate control of three assemblies—a rod, rotor, and hinge—at frequencies up to several Hz and the ability to actuate into many conformations. This level of spatiotemporal control over DNA devices can serve as a foundation for real-time manipulation of molecular and atomic systems.
A TAD boundary is preserved upon deletion of the CTCF-rich Firre locus
Authors: Barutcu A. Rasim , Maass Philipp G. , Lewandowski Jordan P. , Weiner Catherine L. , Rinn John L.
Published: April 2018

The binding of the transcriptional regulator CTCF to the genome has been implicated in the formation of topologically associated domains (TADs). However, the general mechanisms of folding the genome into TADs are not fully understood. Here we test the effects of deleting a CTCF-rich locus on TAD boundary formation. Using genome-wide chromosome conformation capture (Hi-C), we focus on one TAD boundary on chromosome X harboring ~ 15 CTCF binding sites and located at the long non-coding RNA (lncRNA) locus Firre. Specifically, this TAD boundary is invariant across evolution, tissues, and temporal dynamics of X-chromosome inactivation. We demonstrate that neither the deletion of this locus nor the ectopic insertion of Firre cDNA or its ectopic expression are sufficient to alter TADs in a sex-specific or allele-specific manner. In contrast, Firre’s deletion disrupts the chromatin super-loop formation of the inactive X-chromosome. Collectively, our findings suggest that apart from CTCF binding, additional mechanisms may play roles in establishing TAD boundary formation.
Quantum metrology with quantum-chaotic sensors
Authors: Fiderer Lukas J. , Braun Daniel
Published: April 2018

Quantum metrology promises high-precision measurements of classical parameters with far reaching implications for science and technology. So far, research has concentrated almost exclusively on quantum-enhancements in integrable systems, such as precessing spins or harmonic oscillators prepared in non-classical states. Here we show that large benefits can be drawn from rendering integrable quantum sensors chaotic, both in terms of achievable sensitivity as well as robustness to noise, while avoiding the challenge of preparing and protecting large-scale entanglement. We apply the method to spin-precession magnetometry and show in particular that the sensitivity of state-of-the-art magnetometers can be further enhanced by subjecting the spin-precession to non-linear kicks that renders the dynamics chaotic.
Sign epistasis caused by hierarchy within signalling cascades
Authors: Nghe Philippe , Kogenaru Manjunatha , Tans Sander J.
Published: April 2018

Sign epistasis is a central evolutionary constraint, but its causal factors remain difficult to predict. Here we use the notion of parameterised optima to explain epistasis within a signalling cascade, and test these predictions in Escherichia coli. We show that sign epistasis arises from the benefit of tuning phenotypic parameters of cascade genes with respect to each other, rather than from their complex and incompletely known genetic bases. Specifically, sign epistasis requires only that the optimal phenotypic parameters of one gene depend on the phenotypic parameters of another, independent of other details, such as activating or repressing nature, position within the cascade, intra-genic pleiotropy or genotype. Mutational effects change sign more readily in downstream genes, indicating that optimising downstream genes is more constrained. The findings show that sign epistasis results from the inherent upstream-downstream hierarchy between signalling cascade genes, and can be addressed without exhaustive genotypic mapping.
Towards a new approach to reveal dynamical organization of the brain using topological data analysis
Authors: Saggar Manish , Sporns Olaf , Gonzalez-Castillo Javier , Bandettini Peter A. , Carlsson Gunnar , Glover Gary , Reiss Allan L.
Published: April 2018

Little is known about how our brains dynamically adapt for efficient functioning. Most previous work has focused on analyzing changes in co-fluctuations between a set of brain regions over several temporal segments of the data. We argue that by collapsing data in space or time, we stand to lose useful information about the brain’s dynamical organization. Here we use Topological Data Analysis to reveal the overall organization of whole-brain activity maps at a single-participant level—as an interactive representation—without arbitrarily collapsing data in space or time. Using existing multitask fMRI datasets, with the known ground truth about the timing of transitions from one task-block to next, our approach tracks both within- and between-task transitions at a much faster time scale (~4–9 s) than before. The individual differences in the revealed dynamical organization predict task performance. In summary, our approach distills complex brain dynamics into interactive and behaviorally relevant representations.
How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin
Authors: Doud Michael B. , Lee Juhye M. , Bloom Jesse D.
Published: April 2018

Influenza virus can escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if there was strong pressure to do so. Here, we map all single amino-acid mutations that increase resistance to broad antibodies to H1 hemagglutinin. Our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody to hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies to hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we examine, breadth is an imperfect indicator of the potential for viral escape via single mutations. Antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.
Improved calcium sensor GCaMP-X overcomes the calcium channel perturbations induced by the calmodulin in GCaMP
Authors: Yang Yaxiong , Liu Nan , He Yuanyuan , Liu Yuxia , Ge Lin , Zou Linzhi , Song Sen , Xiong Wei , Liu Xiaodong
Published: April 2018

GCaMP, one popular type of genetically-encoded Ca2+ indicator, has been associated with various side-effects. Here we unveil the intrinsic problem prevailing over different versions and applications, showing that GCaMP containing CaM (calmodulin) interferes with both gating and signaling of L-type calcium channels (CaV1). GCaMP acts as an impaired apoCaM and Ca2+/CaM, both critical to CaV1, which disrupts Ca2+ dynamics and gene expression. We then design and implement GCaMP-X, by incorporating an extra apoCaM-binding motif, effectively protecting CaV1-dependent excitation–transcription coupling from perturbations. GCaMP-X resolves the problems of detrimental nuclear accumulation, acute and chronic Ca2+ dysregulation, and aberrant transcription signaling and cell morphogenesis, while still demonstrating excellent Ca2+-sensing characteristics partly inherited from GCaMP. In summary, CaM/CaV1 gating and signaling mechanisms are elucidated for GCaMP side-effects, while allowing the development of GCaMP-X to appropriately monitor cytosolic, submembrane or nuclear Ca2+, which is also expected to guide the future design of CaM-based molecular tools.
Somatic activating mutations in MAP2K1 cause melorheostosis
Authors: Kang Heeseog , Jha Smita , Deng Zuoming , Fratzl-Zelman Nadja , Cabral Wayne A. , Ivovic Aleksandra , Meylan Françoise , Hanson Eric P. , Lange Eileen , Katz James , Roschger Paul , Klaushofer Klaus , Cowen Edward W. , Siegel Richard M. , Marini Joan C. , Bhattacharyya Timothy
Published: April 2018

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.
Performance of the Trioplex real-time RT-PCR assay for detection of Zika, dengue, and chikungunya viruses
Authors: Santiago Gilberto A. , Vázquez Jesús , Courtney Sean , Matías Katia Y. , Andersen Lauren E. , Colón Candimar , Butler Angela E. , Roulo Rebecca , Bowzard John , Villanueva Julie M. , Muñoz-Jordan Jorge L.
Published: April 2018

The emergence and spread of Zika virus (ZIKV) presented a challenge to the diagnosis of ZIKV infections in areas with transmission of dengue (DENV) and chikungunya (CHIKV) viruses. To facilitate detection of ZIKV infections, and differentiate these infections from DENV and CHIKV, we developed the Trioplex real-time RT-PCR assay (Trioplex assay). Here, we describe the optimization of multiplex and singleplex formats of the assay for a variety of chemistries and instruments to facilitate global standardization and implementation. We evaluated the analytical performance of all Trioplex modalities for detection of these three pathogens in serum and whole blood, and for ZIKV in urine. The limit of detection for the three viruses and in different RNA-extraction modalities is near 103 genome copy equivalents per milliliter (GCE/mL). Simultaneous testing of more than one specimen type from each patient provides a 6.4% additional diagnostic sensitivity. Overall, the high sensitivity of the Trioplex assay demonstrates the utility of this assay ascertaining Zika cases.
STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection
Authors: Ding Siyuan , Diep Jonathan , Feng Ningguo , Ren Lili , Li Bin , Ooi Yaw Shin , Wang Xin , Brulois Kevin F. , Yasukawa Linda L. , Li Xingnan , Kuo Calvin J. , Solomon David A. , Carette Jan E. , Greenberg Harry B.
Published: April 2018

Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Highly frequent somatic mutations in genes encoding core cohesin subunits have been reported in multiple cancer types. Here, using a genome-wide CRISPR-Cas9 screening approach to identify host dependency factors and novel innate immune regulators of rotavirus (RV) infection, we demonstrate that the loss of STAG2, an important component of the cohesin complex, confers resistance to RV replication in cell culture and human intestinal enteroids. Mechanistically, STAG2 deficiency results in spontaneous genomic DNA damage and robust interferon (IFN) expression via the cGAS-STING cytosolic DNA-sensing pathway. The resultant activation of JAK-STAT signaling and IFN-stimulated gene (ISG) expression broadly protects against virus infections, including RVs. Our work highlights a previously undocumented role of the cohesin complex in regulating IFN homeostasis and identifies new therapeutic avenues for manipulating the innate immunity.
Multicomponent reactions provide key molecules for secret communication
Authors: Boukis Andreas C. , Reiter Kevin , Frölich Maximiliane , Hofheinz Dennis , Meier Michael A. R.
Published: April 2018

A convenient and inherently more secure communication channel for encoding messages via specifically designed molecular keys is introduced by combining advanced encryption standard cryptography with molecular steganography. The necessary molecular keys require large structural diversity, thus suggesting the application of multicomponent reactions. Herein, the Ugi four-component reaction of perfluorinated acids is utilized to establish an exemplary database consisting of 130 commercially available components. Considering all permutations, this combinatorial approach can unambiguously provide 500,000 molecular keys in only one synthetic procedure per key. The molecular keys are transferred nondigitally and concealed by either adsorption onto paper, coffee, tea or sugar as well as by dissolution in a perfume or in blood. Re-isolation and purification from these disguises is simplified by the perfluorinated sidechains of the molecular keys. High resolution tandem mass spectrometry can unequivocally determine the molecular structure and thus the identity of the key for a subsequent decryption of an encoded message.
GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease
Authors: Lozovaya N. , Eftekhari S. , Cloarec R. , Gouty-Colomer L. A. , Dufour A. , Riffault B. , Billon-Grand M. , Pons-Bennaceur A. , Oumar N. , Burnashev N. , Ben-Ari Y. , Hammond C.
Published: April 2018

We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl−]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl−]i levels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson’s disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl−]i levels and GABAergic inhibition.
Allosteric regulation alters carrier domain translocation in pyruvate carboxylase
Authors: Liu Yumeng , Budelier Melissa M. , Stine Katelyn , St. Maurice Martin
Published: April 2018

Pyruvate carboxylase (PC) catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate. The reaction occurs in two separate catalytic domains, coupled by the long-range translocation of a biotinylated carrier domain (BCCP). Here, we use a series of hybrid PC enzymes to examine multiple BCCP translocation pathways in PC. These studies reveal that the BCCP domain of PC adopts a wide range of translocation pathways during catalysis. Furthermore, the allosteric activator, acetyl CoA, promotes one specific intermolecular carrier domain translocation pathway. These results provide a basis for the ordered thermodynamic state and the enhanced carboxyl group transfer efficiency in the presence of acetyl CoA, and reveal that the allosteric effector regulates enzyme activity by altering carrier domain movement. Given the similarities with enzymes involved in the modular synthesis of natural products, the allosteric regulation of carrier domain movements in PC is likely to be broadly applicable to multiple important enzyme systems.
Two-dimensional electronic transport and surface electron accumulation in MoS2
Authors: Siao M. D. , Shen W. C. , Chen R. S. , Chang Z. W. , Shih M. C. , Chiu Y. P. , Cheng C.-M.
Published: April 2018

Because the surface-to-volume ratio of quasi-two-dimensional materials is extremely high, understanding their surface characteristics is crucial for practically controlling their intrinsic properties and fabricating p-type and n-type layered semiconductors. Van der Waals crystals are expected to have an inert surface because of the absence of dangling bonds. However, here we show that the surface of high-quality synthesized molybdenum disulfide (MoS2) is a major n-doping source. The surface electron concentration of MoS2is nearly four orders of magnitude higher than that of its inner bulk. Substantial thickness-dependent conductivity in MoS2nanoflakes was observed. The transfer length method suggested the current transport in MoS2following a two-dimensional behavior rather than the conventional three-dimensional mode. Scanning tunneling microscopy and angle-resolved photoemission spectroscopy measurements confirmed the presence of surface electron accumulation in this layered material. Notably, the in situ-cleaved surface exhibited a nearly intrinsic state without electron accumulation.
Arctic sea ice is an important temporal sink and means of transport for microplastic
Authors: Peeken Ilka , Primpke Sebastian , Beyer Birte , Gütermann Julia , Katlein Christian , Krumpen Thomas , Bergmann Melanie , Hehemann Laura , Gerdts Gunnar
Published: April 2018

Microplastics (MP) are recognized as a growing environmental hazard and have been identified as far as the remote Polar Regions, with particularly high concentrations of microplastics in sea ice. Little is known regarding the horizontal variability of MP within sea ice and how the underlying water body affects MP composition during sea ice growth. Here we show that sea ice MP has no uniform polymer composition and that, depending on the growth region and drift paths of the sea ice, unique MP patterns can be observed in different sea ice horizons. Thus even in remote regions such as the Arctic Ocean, certain MP indicate the presence of localized sources. Increasing exploitation of Arctic resources will likely lead to a higher MP load in the Arctic sea ice and will enhance the release of MP in the areas of strong seasonal sea ice melt and the outflow gateways.