bluuebunny/crossref_metadata_2025 huggingface dataset:
Software architectures for health care cyber‐physical systems: A systematic literature review
Authors: Plaza Andrea M. , Díaz Jessica , Pérez Jennifer
Published: January 2018

Cyber‐physical systems (CPS) refer to the next generation of Information and Communication Technology systems that mainly integrate sensing, computing, and communication to monitor, control, and interact with a physical process to provide citizens and businesses with smart applications and services: health care, smart homes, smart cities, and so on. In recent years, health care has become one of the most important services due to the continuous increases in its costs. This has motivated extensive research on health care CPS, and some of that research has focused on describing the software architecture behind these systems. However, there is no secondary study to consolidate the research. This paper aims to identify and compare existing research on software architectures for health care CPS in order to determine successful solutions that could guide other architects and practitioners in their health care projects. We conducted a systematic literature review and compared the selected studies based on a characterization schema. The research synthesis results in a knowledge base of software architectures for health care CPS, describing their stakeholders, functional and non‐functional features, quality attributes architectural views and styles, components, and implementation technologies. This systematic literature review also identifies research gaps, such as the lack of open common platforms, as well as directions for future research.
Roaring bitmaps: Implementation of an optimized software library
Authors: Lemire Daniel , Kaser Owen , Kurz Nathan , Deri Luca , O'Hara Chris , Saint‐Jacques François , Ssi‐Yan‐Kai Gregory
Published: January 2018

Compressed bitmap indexes are used in systems such as Git or Oracle to accelerate queries. They represent sets and often support operations such as unions, intersections, differences, and symmetric differences. Several important systems such as Elasticsearch, Apache Spark, Netflix's Atlas, LinkedIn's Pivot, Metamarkets' Druid, Pilosa, Apache Hive, Apache Tez, Microsoft Visual Studio Team Services, and Apache Kylin rely on a specific type of compressed bitmap index called Roaring. We present an optimized software library written in C implementing Roaring bitmaps: CRoaring. It benefits from several algorithms designed for the single‐instruction–multiple‐data instructions available on commodity processors. In particular, we present vectorized algorithms to compute the intersection, union, difference, and symmetric difference between arrays. We benchmark the library against a wide range of competitive alternatives, identifying weaknesses and strengths in our software. Our work is available under a liberal open‐source license.
Overall design optimization of dedicated outboard airfoils for horizontal axis wind turbine blades
Authors: Li Xingxing , Yang Ke , Liao Caicai , Bai Jingyan , Zhang Lei , Xu Jianzhong
Published: January 2018

Designing the primary airfoils for the outboard part of wind turbine blades is a complicated problem of balancing structural, aerodynamic, and acoustic requirements. This paper presents an optimization method for the overall performance of outboard wind turbine airfoils. Based on the complex flow characteristics of the rotor blades and the varying requirements along the span of a blade, the design principles of outboard airfoils were investigated. The requirements for improving the structural performance and reducing the aerodynamic noise were combined with the following aerodynamic design considerations: high efficiency, low extreme loads, stability, and a wide operating region. Thus, this paper proposes a new mathematical model for overall airfoil optimization using the airfoil performance evaluation indicators. Then, an integrated optimization design platform is established for outboard airfoils. Through 2 design cases, new airfoils with desirable aerodynamic characteristics and improved overall performance were obtained. Comparisons between the new airfoils and reference airfoils based on numerical predictions indicate that the proposed method with the newly established mathematical model can effectively balance the complex requirements of the airfoil and improve its overall performance. More notably, the design cases also indicate that the established optimization design method can be used to address special designs of outboard airfoils for different blade requirements.
Surveying the landscape of optogenetic methods for detection of protein–protein interactions
Authors: Wiens Matthew D. , Campbell Robert E.
Published: January 2018

Mapping the protein–protein interaction (PPi) landscape is of critical importance to furthering our understanding how cells and organisms function. Optogenetic methods, that is, approaches that utilize genetically encoded fluorophores or fluorogenic enzyme reactions, uniquely enable the visualization of biochemical phenomena in live cells with high spatial and temporal accuracy. Applying optogenetic methods to the detection of PPis requires the engineering of protein‐based systems in which an optical signal undergoes a substantial change when the two proteins of interest interact. In recent years, researchers have developed a number of creative and effective optogenetic methods that achieve this goal, and used them to further elaborate our map of the PPi landscape. In this review, we provide an introduction to the general principles of optogenetic PPi detection, and then provide a number of representative examples of how these principles have been applied. We have organized this review by categorizing methods based on whether the signal generated is reversible or irreversible in nature, and whether the signal is localized or nonlocalized at the subcellular site of the PPi. We discuss these techniques giving both their benefits and drawbacks to enable rational choices about their potential use.

This article is categorized under:

Laboratory Methods and Technologies > Imaging

Laboratory Methods and Technologies > Macromolecular Interactions, Methods

Analytical and Computational Methods > Analytical Methods
Organic acidurias in adults: late complications and management
Authors: Tuncel Ali Tunç , Boy Nikolas , Morath Marina A. , Hörster Friederike , Mütze Ulrike , Kölker Stefan
Published: January 2018

Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono‐, di‐ and/or tricarboxylic acids (“organic acids”) and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however #Affected individuals may already present during the newborn period with life‐threatening acute metabolic crises and acute multi‐organ failure. Tandem mass spectrometry‐based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be “metabolically stable”. This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long‐term care.
Regional geothermal aquifer architecture of the fluvial Lower Cretaceous Nieuwerkerk Formation – a palynological analysis
Authors: Willems Cees J.L. , Vondrak Andrea , Munsterman Dirk K. , Donselaar Marinus E. , Mijnlieff Harmen F.
Published: January 2018

The primary challenge for efficient geothermal doublet design and deployment is the adequate prediction of the size, shape, lateral extent and thickness (or aquifer architecture) of aquifers. In the West Netherlands Basin, fluvial Lower Cretaceous sandstone-rich successions form the main aquifers for geothermal heat exploitation. Large variations in the thickness of these successions are recognised in currently active doublet systems that cannot be explained. This creates an uncertainty in aquifer thickness prediction, which increases the uncertainty in doublet lifetime prediction as it has an impact on net aquifer volume. The goal of this study was to improve our understanding of the thickness variations and regional aquifer architecture of the Nieuwerkerk Formation geothermal aquifers. For this purpose, new palynological data were evaluated to correlate aquifers in currently active doublet systems based on their chronostratigraphic position and regional Maximum Flooding Surfaces. Based on the palynological cuttings analysis, the fluvial interval of the Nieuwerkerk Formation was subdivided into two successions: a Late Ryazanian to Early Valanginian succession and a Valanginian succession. Within these successions trends were identified in sandstone content. In combination with seismic interpretation, maps were constructed that predict aquifer thickness and their lateral extent in the basin. The study emphasises the value of palynological analyses to reduce the uncertainty of fluvial hot sedimentary aquifer exploitation.
Kant’s ‘Five Ways’: Transcendental Idealism in Context
Authors: MILES MURRAY
Published: January 2018

In 1772, Kant outlined the new problem of his critical period in terms of four possible “ways” of understanding the agreement of knowledge with its object. This study expands Kant’s terse descriptions of these ways, examining why he rejected them. Apart from clarifying the historical context in which Kant saw his own achievement (the Fifth Way), the chief benefits of exploring the historical background of Way Two, in particular, are that it (1) explains the puzzlingintuitus originarius/intellectus archetypusdichotomy, and (2) casts doubt on the received idea that Kant broke with the traditional theocentric model of cognition.
Crash Risk in Currency Returns
Authors: Chernov Mikhail , Graveline Jeremy , Zviadadze Irina
Published: January 2018

We develop an empirical model of bilateral exchange rates. It includes normal shocks with stochastic variance and jumps in an exchange rate and in its variance. The probability of a jump in an exchange rate corresponding to depreciation (appreciation) of the U.S. dollar is increasing in the domestic (foreign) interest rate. The probability of a jump in variance is increasing in the variance only. Jumps in exchange rates are associated with announcements; jumps in variance are not. On average, jumps account for 25% of currency risk. The dollar carry index retains these features. Options suggest that jump risk is priced.
Neural correlates of ostracism in transgender persons living according to their gender identity: a potential risk marker for psychopathology?
Authors: Mueller Sven C. , Wierckx Katrien , Boccadoro Sara , T'Sjoen Guy
Published: January 2018

Background

Stigmatization in society carries a high risk for development of psychopathology. Transgender persons are at particularly high risk for such stigmatization and social rejection by others. However, the neural correlates of ostracism in this group have not been captured.

Method

Twenty transgender men (TM, female-to-male) and 19 transgender women (TW, male-to-female) already living in their gender identity and 20 cisgender men (CM) and 20 cisgender women (CW) completed a cyberball task assessing both exclusion and re-inclusion during functional magnetic resonance imaging (fMRI).

Results

During psychosocial stress between-group differences were found in the dorsal and ventral anterior cingulate cortex (ACC) and the inferior frontal gyrus (IFG). Patterns were consistent with sex assigned at birth, i.e. CW showed greater activation in dorsal ACC and IFG relative to CM and TW. During re-inclusion, transgender persons showed greater ventral ACC activity relative to CW, possibly indicating persistent feelings of exclusion. Functional connectivity analyses supported these findings but showed a particularly altered functional connectivity between ACC and lateral prefrontal cortex in TM, which may suggest reduced emotional regulation to the ostracism experience in this group. Depressive symptoms or hormonal levels were not associated with these findings.

Conclusion

The results bear implications for the role of social exclusion in development of mental health problems in socially marginalized groups.
Gravitational Waves: Physics at the Extreme
Authors: van den Brand Jo
Published: January 2018

Last year, the LIGO Scientific Collaboration and the Virgo Collaboration announced the first detection of a gravitational wave. A century after the fundamental predictions of Einstein, the first direct observation of a binary black hole system merging to form a single black hole was made. The observations provide unique access to the properties of spacetime at extreme curvatures: the strong-field and high-velocity regime. It allows unprecedented tests of general relativity for the nonlinear dynamics of highly disturbed black holes. LIGO and Virgo realized a global interferometer network, and more detections were made, including a signal from a binary neutron star merger. The scientific impact of the various detections will be explained. In addition, key technological aspects will be addressed, such as the interferometric detection principle, optics, as well as sensors and actuators. Attention is paid to Advanced Virgo, the European detector near Pisa, which came online in 2017. We end with a discussion of the largest challenges in the field, including plans for the Einstein Telescope, a large underground observatory for gravitational-wave science.
Development of a patient experience questionnaire to improve lifestyle services in primary care
Authors: Brauer Paula , Royall Dawna , Kaethler Anneli , Mayhew Alexandra , Israeloff-Smith Maya
Published: January 2018

Aim

We developed a self-report tool to assess patients’ experiences with lifestyle services in team-based primary care and pilot tested the questionnaire as part of a lifestyle intervention study to reverse metabolic syndrome.

Background

Older client satisfaction questionnaires have been generally inadequate for quality improvement purposes, as they have been focused mainly on interpersonal skills of providers and/or in the context of one disease. New approaches to assessing the patient experience of lifestyle programs in primary care are needed and could inform quality improvement efforts over time.

Methods

The first phase in developing the questionnaire involved a group-administered questionnaire distributed to 38 healthcare providers in five groups to prioritize variables to include in the survey. Concepts were taken from a previous review of available questionnaires assessing primary care services. The draft questionnaire was reviewed by 11 participants from a lifestyle program using think-aloud cognitive interviewing techniques. The modified self-administered questionnaire (paper and online versions) was then pilot tested with 164 recipients of a nutrition and physical activity intervention program.

Findings

Providers ranked the top variables to include in the questionnaire as: ‘trust,’ ‘general communication,’ ‘first-contact accessibility,’ ‘whole-person care,’ and ‘respectfulness.’ After cognitive interviewing and revisions, 21 multiple choice and two open-ended questions were used for pilot testing. Pilot testing identified additional minor wording changes that were needed for clarity, a decreased number of questions for redundant concepts, and decreased options for ceiling effects, resulting in 20 multiple choice and one open-ended question.

Conclusions

The modified self-administered patient experience questionnaire to assess lifestyle services in primary care has undergone rigorous development. Further validation is needed. The assessment of patient experience of lifestyle programs can be used to supplement other data to assess the overall effectiveness of such programs.
Have You Voted? Teaching OSCOLA with Mentimeter
Authors: Skoyles Alison , Bloxsidge Erin
Published: January 2018

This article details a small project undertaken by Information Skills Advisers at London South Bank University to increase student engagement in lecture theatre settings through the use of a web-based audience response system (ARS), Mentimeter. Supporting the School of Law, librarians delivered an interactive OSCOLA referencing session to a large capacity lecture theatre. A previous session was redesigned to increase student engagement and active learning utilising interactive quiz questions which students answered using mobile devices. The majority of feedback from students and staff who participated in this pilot project was positive and showed an increase in student engagement. This article is based on the presentation, ‘Have You Voted?: Teaching OSCOLA with Mentimeter’ delivered at the BIALL Annual Conference 2017. It will examine the process of adapting a lecture to include interactive content using an ARS, and will discuss the outcomes of the pilot session and explore benefits and challenges inherent in using technology of this type in a large classroom.
SLS/BIALL Academic Law Library Survey 2015/2016
Authors: Gee David
Published: January 2018

This is the latest report analysing the results of the Society of Legal Scholars and BIALL Survey. It has been written by David Gee, Deputy Librarian at the Institute of Advanced Legal Studies, School of Advanced Study, University of London.
Biting midges (Diptera: Ceratopogonidae) as indicators of biostratigraphy, ecological reconstructions and identification of amber deposits
Authors: Szadziewski Ryszard
Published: January 2018

Biting midges (Diptera: Ceratopogonidae) are a large family of flies that commononly appear in Lower Cretaceous to Miocene strata, with over 280 fossil species (4.3 % of the family), belonging to 49 genera (26 extant; 23 extinct). Morphological characters used in the identification of fossil genera and species are identical to those used in studies of extant Ceratopogonidae and, as a result, their potential indicative value is reliable. Two relictual extant genera,Leptoconopsand Austroconops, reported from Lower Cretaceous Lebanese amber, are at least 125 million years old. Certain ceratopogonid genera are indicative for the Lower Cretaceous, Upper Cretaceous, Eocene or Miocene. A morphological character indicative for the Upper Cretaceous and Cenozoic is macrotrichia on the wing membrane of adults. Indicator species and genera are reviewed for all amber deposits. Eocene Baltic amber contains the best known fauna of biting midges, with 109 named species. Some genera are indicative of aquatic and semiaquatic habitats (predaceous genera, subfamily Ceratopogoninae), forests with rotting trees (Forcipomyia), sandy sea shore habitats (Leptoconops), a cold boreal climate (Ceratopogon) or warm climates (Nannohelea,Austroconops,Leptoconops,Meunierohelea,Metahelea). Females require a protein-rich meal and are well known for feeding on the blood of vertebrates, but many feed on other things, so this information can help with the interpretation of palaeoenvironments.Washingtonhelea taimyricaSzadziewski, 1996, described from Siberian amber, is transferred to the fossil genusPalaeobrachypogon:P.taimyricus(Szadziewski, 1996), comb. nov. ForSerromyia alphea,mistakenly redescribed and illustrated from Eocene Bitterfeld amber (= Baltic amber) by Szadziewski (1993), a new name –SerromyiaerrataSzadziewski, nom. nov. – is proposed.
New palaeodictyopterans from the Late Carboniferous of the UK (Insecta: Palaeodictyopterida)
Authors: Prokop Jakub , Pecharová Martina , Jarzembowski Edmund A. , Ross Andrew J.
Published: January 2018

New palaeodictyopterans,Vernooijia sassoonaegen.etsp. nov. (Breyeriidae) andMazonopterumcooperisp. nov. (Homoiopteridae) are described from the Middle Pennsylvanian (Westphalian D/Late Asturian) of Writhlington, near Radstock (UK). Based on the re-examination of venation inBreyeriaharlemensis, we propose the transfer of this species to the genusVernooijiaasV.harlemensis(Brauckmann & Gröning, 1996) comb. nov. We report the first record ofHomaloneurasp. (Spilapteridae) from the Langsettian to Duckmantian of Coseley, Staffordshire. Additionally, we report a fragmentary wing from the Middle Pennsylvanian (late Westphalian D/early Cantabrian) of the Forest of Dean, Gloucestershire, tentatively belonging to the Lycocercidae. Our re-examination of a putative blattodean nymph described by Rolfe (1967) allows re-assignment to Palaeodictyoptera, as it has well-developed wing pads with a corrugated pattern of probably original tracheation and lacunal channels, identified as presumably nymphal exuvia ofIdoptilussp. Surprisingly, our study reveals the presence of three triangular caudal appendages bearing prominent lateral lamellae emerging from the terminal abdominal segment, previously unknown in other nymphs of Palaeodictyoptera. We assume that these lamellae were originally covered with dense setae and possibly represent modified caudal appendages in the form of tracheal gills, as known in the nymphs of damselflies (Odonata: Zygoptera). Thus, the scenario of a possible aquatic lifestyle for nymphs of at least some members of Palaeodictyoptera, as considered by Brongniart (1885, 1893) and Handlirsch (1906), cannot be definitely excluded.
Development of Coping Strategies From Childhood to	Adolescence
Authors: Eschenbeck Heike , Schmid Steffen , Schröder Ines , Wasserfall Nicola , Kohlmann Carl-Walter
Published: January 2018

Abstract. Extensive research exists on coping in children and adolescents. However, developmental issues have only recently started to receive more attention. The present study examined age differences and developmental changes in six coping strategies (social support seeking, problem solving, avoidant coping, palliative emotion regulation, anger-related emotion regulation, and media use) assessed by a coping questionnaire (German Stress and Coping Questionnaire for Children and Adolescents, SSKJ 3–8; Lohaus, Eschenbeck, Kohlmann, & Klein-Heßling, 2006 ) in middle/late childhood and early adolescence. At the initial assessment, 917 children from grades 3 to 7 (age range 8–15 years) were included (cross-sectional sample). Three cohorts (grades 3–5 at baseline) were traced longitudinally over 1½ years with four assessments (longitudinal sample: n = 388). The cross-sectional coping data showed significant effects for grade level in four coping strategies. Older children scored higher in problem solving and media use, and lower in avoidant coping. Seventh graders scored lower than fourth and fifth graders in social support seeking. Longitudinal data confirmed time effects and cohort effects indicating developmental changes. Increases over time were found for problem solving and media use; decreases were found for avoidant coping and anger-related emotion regulation. For social support seeking, an increase within the youngest cohort (grades 3–5) was found. Developmental trends (in cross-sectional and longitudinal data), with especially strong increases for problem solving or declines in avoidant coping in the youngest cohort, differed for the two studied stressful situations (social, academic) but were independent of the child’s gender. To conclude, particularly in the age range of 9–11 years relevant developmental changes toward a more active coping seem to appear.
Low-cost and cleanroom-free fabrication of microneedles
Authors: Nejad Hojatollah Rezaei , Sadeqi Aydin , Kiaee Gita , Sonkusale Sameer
Published: January 2018

We present a facile, low-cost and cleanroom-free technique for the fabrication of microneedles using molds created by laser ablation. Microneedle mold with high aspect ratios is achieved on acrylic sheet by engraving a specific pattern of crossover lines (COL) using CO2 laser cutter. Ablating COL pattern on the acrylic sheet creates a sharp conical shape in the center of the design. We have shown that a variety of microneedle shapes with different heights and tip angles can be easily achieved by changing the number and the length of the COL. Polydimethylsiloxane (PDMS) microneedles were fabricated by casting the PDMS on the mold. The resulted PDMS microneedles are oxygen plasma treated and then silanized. Another PDMS layer is casted on PDMS microneedles and detached after curing. The silanization prevents those two layers of PDMS from bonding to each other and makes them easily detachable. After detachment of the PDMS mold of microneedles, the mold is used to fabricate degradable polyvinyl alcohol microneedle patch suitable for transdermal drug delivery. The release kinetics of the needles are also shown and discussed in order to prove the applicability of the needles.
Direct cell–cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo
Authors: Furuya Masayuki , Kikuta Junichi , Fujimori Sayumi , Seno Shigeto , Maeda Hiroki , Shirazaki Mai , Uenaka Maki , Mizuno Hiroki , Iwamoto Yoriko , Morimoto Akito , Hashimoto Kunihiko , Ito Takeshi , Isogai Yukihiro , Kashii Masafumi , Kaito Takashi , Ohba Shinsuke , Chung Ung-il , Lichtler Alexander C. , Kikuchi Kazuya , Matsuda Hideo , Yoshikawa Hideki , Ishii Masaru
Published: January 2018

Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial–temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell–cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell–cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell–cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo.
Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA
Authors: Rehage Nina , Davydova Elena , Conrad Christine , Behrens Gesine , Maiser Andreas , Stehklein Jenny E. , Brenner Sven , Klein Juliane , Jeridi Aicha , Hoffmann Anne , Lee Eunhae , Dianzani Umberto , Willemsen Rob , Feederle Regina , Reiche Kristin , Hackermüller Jörg , Leonhardt Heinrich , Sharma Sonia , Niessing Dierk , Heissmeyer Vigo
Published: January 2018

The ubiquitously expressed RNA-binding proteins Roquin-1 and Roquin-2 are essential for appropriate immune cell function and postnatal survival of mice. Roquin proteins repress target mRNAs by recognizing secondary structures in their 3′-UTRs and by inducing mRNA decay. However, it is unknown if other cellular proteins contribute to target control. To identify cofactors of Roquin, we used RNA interference to screen ~1500 genes involved in RNA-binding or mRNA degradation, and identified NUFIP2 as a cofactor of Roquin-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, which stabilizes NUFIP2 in cells. Post-transcriptional repression of human ICOS by endogenous Roquin proteins requires two neighboring non-canonical stem-loops in the ICOS 3′-UTR. This unconventional cis-element as well as another tandem loop known to confer Roquin-mediated regulation of the Ox40 3′-UTR, are bound cooperatively by Roquin and NUFIP2. NUFIP2 therefore emerges as a cofactor that contributes to mRNA target recognition by Roquin.
Publisher Correction: Fusion guide RNAs for orthogonal gene manipulation with Cas9 and Cpf1
Authors: Kweon Jiyeon , Jang An-Hee , Kim Da-eun , Yang Jin Wook , Yoon Mijung , Rim Shin Ha , Kim Jin-Soo , Kim Yongsub
Published: January 2018

The originally published version of this Article contained an error in the spelling of the author Da-eun Kim, which was incorrectly given as Da-Eun Kim. Furthermore, in Figure 1a, the Cas9 protein was positioned incorrectly during typesetting. These errors have now been corrected in both the PDF and HTML versions of the Article.
The Chemical Fluctuation Theorem governing gene expression
Authors: Park Seong Jun , Song Sanggeun , Yang Gil-Suk , Kim Philip M. , Yoon Sangwoon , Kim Ji-Hyun , Sung Jaeyoung
Published: January 2018

Gene expression is a complex stochastic process composed of numerous enzymatic reactions with rates coupled to hidden cell-state variables. Despite advances in single-cell technologies, the lack of a theory accurately describing the gene expression process has restricted a robust, quantitative understanding of gene expression variability among cells. Here we present the Chemical Fluctuation Theorem (CFT), providing an accurate relationship between the environment-coupled chemical dynamics of gene expression and gene expression variability. Combined with a general, accurate model of environment-coupled transcription processes, the CFT provides a unified explanation of mRNA variability for various experimental systems. From this analysis, we construct a quantitative model of transcription dynamics enabling analytic predictions for the dependence of mRNA noise on the mRNA lifetime distribution, confirmed against stochastic simulation. This work suggests promising new directions for quantitative investigation into cellular control over biological functions by making complex dynamics of intracellular reactions accessible to rigorous mathematical deductions.
Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus
Authors: Zhang Tie-Yuan , Keown Christopher L. , Wen Xianglan , Li Junhao , Vousden Dulcie A. , Anacker Christoph , Bhattacharyya Urvashi , Ryan Richard , Diorio Josie , O’Toole Nicholas , Lerch Jason P. , Mukamel Eran A. , Meaney Michael J.
Published: January 2018

Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG. We find genome-wide transcriptional and methylation differences between dorsal and ventral DG, including at key developmental transcriptional factors. Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Enrichment also enhances dorsal-ventral differences in DNA methylation, including at binding sites of the transcription factor NeuroD1, a regulator of adult neurogenesis. These results indicate a dorsal-ventral asymmetry in transcription and methylation that parallels well-known functional and anatomical differences, and that may be enhanced by environmental enrichment.
Adaptive design of an X-ray magnetic circular dichroism spectroscopy experiment with Gaussian process modelling
Authors: Ueno Tetsuro , Hino Hideitsu , Hashimoto Ai , Takeichi Yasuo , Sawada Masahiro , Ono Kanta
Published: January 2018

Spectroscopy is a widely used experimental technique, and enhancing its efficiency can have a strong impact on materials research. We propose an adaptive design for spectroscopy experiments that uses a machine learning technique to improve efficiency. We examined X-ray magnetic circular dichroism (XMCD) spectroscopy for the applicability of a machine learning technique to spectroscopy. An XMCD spectrum was predicted by Gaussian process modelling with learning of an experimental spectrum using a limited number of observed data points. Adaptive sampling of data points with maximum variance of the predicted spectrum successfully reduced the total data points for the evaluation of magnetic moments while providing the required accuracy. The present method reduces the time and cost for XMCD spectroscopy and has potential applicability to various spectroscopies.
Effects of genetic variants on platelet reactivity and one-year clinical outcomes after percutaneous coronary intervention: A prospective multicentre registry study
Authors: Joo Hyung Joon , Ahn Sung Gyun , Park Jae Hyoung , Park Ji Young , Hong Soon Jun , Kim Seok-Yeon , Choi WoongGil , Gwon HyeonCheol , Lim Young-Hyo , Kim Weon , Kang Woong Chol , Cho Yun-Hyeong , Kim Yong Hoon , Yoon JungHan , Shin WonYong , Hong Myeong-Ki , Garg Scot , Jang Yangsoo , Lim Do-Sun
Published: January 2018

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI). The relationship of platelet reactivity and genetic polymorphism with clinical outcomes with newer-generation drug-eluting stents is unclear. We analysed 4,587 patients for the most powerful single-nucleotide polymorphisms (CYP2C19, CYP2C9, ABCB1, PON1, and P2Y12) related to on-treatment platelet reactivity (OPR). The optimal cut-off value of high OPR for major adverse thrombotic events was 266. CYP2C19 was significantly associated with high OPR and the number of CYP2C19*R (*2 or *3) alleles was proportional to the increased risk of high OPR. Death, myocardial infarction (MI), stroke, stent thrombosis, and bleeding events were assessed during a 1-year follow-up period. Primary endpoints were death and non-fatal MI. The cumulative 1-year incidence of death and stent thrombosis was significantly higher in patients with CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3 (Group 3) than in patients with CYP2C19*1/*1 (Group 1). Multivariate Cox proportional hazard model showed that cardiac death risk was significantly higher in Group 3 than in Group 1 (hazard ratio 2.69, 95% confidence interval 1.154–6.263, p = 0.022). No association was reported between bleeding and OPR. Thus, CYP2C19 may exert a significant impact on the prognosis of PCI patients even in the era of newer-generation drug-eluting stents.
Tumor Tissue Detection using Blood-Oxygen-Level-Dependent Functional MRI based on Independent Component Analysis
Authors: Huang Huiyuan , Lu Junfeng , Wu Jinsong , Ding Zhongxiang , Chen Shuda , Duan Lisha , Cui Jianling , Chen Fuyong , Kang Dezhi , Qi Le , Qiu Wusi , Lee Seong-Whan , Qiu ShiJun , Shen Dinggang , Zang Yu-Feng , Zhang Han
Published: January 2018

Accurate delineation of gliomas from the surrounding normal brain areas helps maximize tumor resection and improves outcome. Blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) has been routinely adopted for presurgical mapping of the surrounding functional areas. For completely utilizing such imaging data, here we show the feasibility of using presurgical fMRI for tumor delineation. In particular, we introduce a novel method dedicated to tumor detection based on independent component analysis (ICA) of resting-state fMRI (rs-fMRI) with automatic tumor component identification. Multi-center rs-fMRI data of 32 glioma patients from three centers, plus the additional proof-of-concept data of 28 patients from the fourth center with non-brain musculoskeletal tumors, are fed into individual ICA with different total number of components (TNCs). The best-fitted tumor-related components derived from the optimized TNCs setting are automatically determined based on a new template-matching algorithm. The success rates are 100%, 100% and 93.75% for glioma tissue detection for the three centers, respectively, and 85.19% for musculoskeletal tumor detection. We propose that the high success rate could come from the previously overlooked ability of BOLD rs-fMRI in characterizing the abnormal vascularization, vasomotion and perfusion caused by tumors. Our findings suggest an additional usage of the rs-fMRI for comprehensive presurgical assessment.
Efficient differentiation of human pluripotent stem cells into skeletal muscle cells by combining RNA-based MYOD1-expression and POU5F1-silencing
Authors: Akiyama Tomohiko , Sato Saeko , Chikazawa-Nohtomi Nana , Soma Atsumi , Kimura Hiromi , Wakabayashi Shunichi , Ko Shigeru B. H. , Ko Minoru S. H.
Published: January 2018

Direct generation of skeletal muscle cells from human pluripotent stem cells (hPSCs) would be beneficial for drug testing, drug discovery, and disease modelling in vitro. Here we show a rapid and robust method to induce myogenic differentiation of hPSCs by introducing mRNA encoding MYOD1 together with siRNA-mediated knockdown of POU5F1 (also known as OCT4 or OCT3/4). This integration-free approach generates functional skeletal myotubes with sarcomere-like structure and a fusion capacity in several days. The POU5F1 silencing facilitates MYOD1 recruitment to the target promoters, which results in the significant activation of myogenic genes in hPSCs. Furthermore, deep sequencing transcriptome analyses demonstrated that POU5F1-knockdown upregulates the genes associated with IGF- and FGF-signaling and extracellular matrix that may also support myogenic differentiation. This rapid and direct differentiation method may have potential applications in regenerative medicine and disease therapeutics for muscle disorders such as muscular dystrophy.
Parturition in baboons (PAPIO SPP.)
Authors: Schlabritz-Loutsevitch N. , Maher J. , Sullivan R. , Mari G. , Schenone M. , Cohen H. L. , Word R. A. , Hubbard G. B. , Dick E. J.
Published: January 2018

The Old World non-human primates (NHP) - baboons (Papio spp.) share similarities with humans regarding fetal and placental development and some pregnancy-related complications. Information about the mechanism of birth and complications arising during parturition in these species is relatively sparse. In this manuscript, we add information from a series of pathological and observational cases to highlight insights and selected complications of birth in Papio spp, based on video-recording of the delivery process, X-ray, MRI, and ultrasound evaluations in pregnant baboons. Additionally, we abstracted pathology records obtained from perinatal loss in a large baboon colony during a 17 year period. The presented cases provide important information for the management of pregnancy and delivery in Papio spp.
Association between modified CHA2DS2-VASc Score with Ankle-Brachial index < 0.9
Authors: Hsu Po-Chao , Lee Wen-Hsien , Lee Hsiang-Chun , Tsai Wei-Chung , Chu Chun-Yuan , Chen Ying-Chih , Lee Chee-Siong , Lin Tsung-Hsien , Voon Wen-Chol , Sheu Sheng-Hsiung , Su Ho-Ming
Published: January 2018

The ankle-brachial index (ABI) is a reliable diagnostic examination for peripheral arterial occlusive disease (PAOD). We previously reported CHADS2 score was significantly correlated with PAOD. However, the association between CHA2DS2-VASc score and ABI < 0.9 is not evaluated in the literature. The aim of the present study was to investigate whether CHA2DS2-VASc score has a strong association with PAOD. We enrolled 1482 patients in this study. PAOD was defined as ABI < 0.9 in either leg. Vascular disease in CHA2DS2-VASc score was modified as vascular disease except PAOD. Of the 1482 subjects, the prevalence of ABI < 0.9 was 5.6%. Multivariate analysis showed that the increased age, decreased estimated glomerular filtration rate and increased modified CHA2DS2-VASc score (OR, 1.764; p < 0.001) were independent associated with ABI < 0.9. In addition, the percentage of ABI < 0.9 in patients with modified CHA2DS2-VASc score of 0, 1, and <2 were 0%, 0.9%, and 0.7%, respectively (All < 1%). Our study demonstrated modified CHA2DS2-VASc score was significantly associated with ABI < 0.9. Calculation of modified CHA2DS2-VASc score might be useful in identifying patients with PAOD and in stratifying the risk of PAOD in non-AF patients.
Structural Covariance of Gray Matter Volume in HIV Vertically Infected Adolescents
Authors: Li Jielan , Gao Lei , Wen Zhi , Zhang Jing , Wang Panying , Tu Ning , Lei Hao , Lin Fuchun , Gui Xi’en , Wu Guangyao
Published: January 2018

Human immunodeficiency virus (HIV) infection significantly affect neurodevelopmental and behavioral outcomes. We investigated whether alterations of gray matter organization and structural covariance networks with vertical HIV infection adolescents exist, by using the GAT toolbox. MRI data were analysed from 25 HIV vertically infected adolescents and 33 HIV-exposed-uninfected control participants. The gray matter volume (GMV) was calculated, and structural brain networks were reconstructed from gray matter co-variance. Gray matter losses were pronounced in anterior cingulate cortex (ACC), right pallidum, right occipital lobe, inferior parietal lobe, and bilateral cerebellum crus. The global brain network measures were not significantly different between the groups; however, the nodal alterations were most pronounced in frontal, temporal, basal ganglia, cerebellum, and temporal lobes. Brain hubs in the HIV-infected subjects increased in number and tended to shift to sensorimotor and temporal areas. In the HIV-infected subjects, decreased GMVs in ACC and bilateral cerebellum were related to lower Mini-Mental State Examination scores; the CD4 counts were positively related to the GMVs in ACC and sensorimotor areas. These findings suggest that focally reduced gray matter, disrupted nodal profiles of structural wirings, and a shift in hub distribution may represent neuroanatomical biomarkers of HIV infection on the developing brain.
Ultra-high Photoresponsivity in Suspended Metal-Semiconductor-Metal Mesoscopic Multilayer MoS2 Broadband Detector from UV-to-IR with Low Schottky Barrier Contacts
Authors: Saenz Gustavo A. , Karapetrov Goran , Curtis James , Kaul Anupama B.
Published: January 2018

The design, fabrication, and characterization of ultra-high responsivity photodetectors based on mesoscopic multilayer MoS2 is presented, which is a less explored system compared to direct band gap monolayer MoS2 that has received increasing attention in recent years. The device architecture is comprised of a metal-semiconductor-metal (MSM) photodetector, where Mo was used as the contact metal to suspended MoS2 membranes. The photoresponsivity $${\boldsymbol{R}}$$
R
was measured to be ~1.4 × 104 A/W, which is > 104 times higher compared to prior reports, while the detectivity D* was computed to be ~2.3 × 1011 Jones at 300 K at an optical power P of ~14.5 pW and wavelength λ of ~700 nm. In addition, the dominant photocurrent mechanism was determined to be the photoconductive effect (PCE), while a contribution from the photogating effect was also noted from trap-states that yielded a wide spectral photoresponse from UV-to-IR (400 nm to 1100 nm) with an external quantum efficiency (EQE) ~104. From time-resolved photocurrent measurements, a decay time τ
d
~ 2.5 ms at 300 K was measured from the falling edge of the photogenerated waveform after irradiating the device with a stream of incoming ON/OFF white light pulses.
Combined use of EpCAM and FRα enables the high-efficiency capture of circulating tumor cells in non-small cell lung cancer
Authors: Chen Luojun , Peng Min , Li Na , Song Qibin , Yao Yi , Xu Bin , Liu Huali , Ruan Peng
Published: January 2018

Circulating tumor cells (CTCs) provide a new approach for auxiliary diagnosis, therapeutic effect evaluation, and prognosis prediction for cancer patients. The epithelial cell adhesion molecule (EpCAM)-based separation method (CellSearch) showed good clinical use in multiple types of cancer. Nevertheless, some non-small cell lung cancer (NSCLC) tumor cells have a lower expression of EpCAM and are less frequently detected by CellSearch. Here, we present a highly sensitive immunomagnetic separation method to capture CTCs based on two cell surface markers for NSCLC, EpCAM and Folate receptor alpha (FRα). Our method has been demonstrated to be more efficient in capturing NSCLC cells (P < 0.01) by enriching three types of CTCs: EpCAM+/FRα−/low, EpCAM−/low/FRα+, and EPCAM+/FRα+. In 41 NSCLC patients, a significantly higher CTC capture rate (48.78% vs. 73.17%) was obtained, and by using a cutoff value of 0 CTC per 2 ml of blood, the sensitivities were 53.66% and 75.61% and the specificities were 100% and 90% for anti-EpCAM-MNs or a combination of anti-EpCAM-MNs and anti-FRα-MNs, respectively. Compared with the tumor-specific LT-PCR based on FRα, our method can isolate intact FRα+ CTCs, and it is advantageous for additional CTC-related downstream analysis. Our results provide a new method to increase the CTC capture efficiency of NSCLC.
The Direction of Tumour Growth in Glioblastoma Patients
Authors: Esmaeili Morteza , Stensjøen Anne Line , Berntsen Erik Magnus , Solheim Ole , Reinertsen Ingerid
Published: January 2018

Generating MR-derived growth pattern models for glioblastoma multiforme (GBM) has been an attractive approach in neuro-oncology, suggesting a distinct pattern of lesion spread with a tendency in growing along the white matter (WM) fibre direction for the invasive component. However, the direction of growth is not much studied in vivo. In this study, we sought to study the dominant directions of tumour expansion/shrinkage pre-treatment. We examined fifty-six GBMs at two time-points: at radiological diagnosis and as part of the pre-operative planning, both with contrast-enhanced T1-weighted MRIs. The tumour volumes were semi-automatically segmented. A non-linear registration resulting in a deformation field characterizing the changes between the two time points was used together with the segmented tumours to determine the dominant directions of tumour change. To compute the degree of alignment between tumour growth vectors and WM fibres, an angle map was calculated. Our results demonstrate that tumours tend to grow predominantly along the WM, as evidenced by the dominant vector population with the maximum alignments. Our findings represent a step forward in investigating the hypothesis that tumour cells tend to migrate preferentially along the WM.
Determinants of breast size in Asian women
Authors: Lim Li Yan , Ho Peh Joo , Liu Jenny , Chay Wen Yee , Tan Min-Han , Hartman Mikael , Li Jingmei
Published: January 2018

Breast size as a risk factor of breast cancer has been studied extensively with inconclusive results. Here we examined the associations between breast size and breast cancer risk factors in 24,353 Asian women aged 50 to 64 years old enrolled in a nationwide mammography screening project conducted between October 1994 and February 1997. Information on demographic and reproductive factors was obtained via a questionnaire. Breast size was ascertained as bust line measured at study recruitment and total breast area measured from a mammogram. The average bust line and total breast area was 91.2 cm and 102.3 cm2, respectively. The two breast measurements were moderately correlated (Spearman correlation coefficient = 0.65). Age, BMI, marital and working status were independently associated with bust line and total breast area. In the multivariable analyses, the most pronounced effects were observed for BMI (24.2 cm difference in bust line and 39.4 cm2 in breast area comparing women with BMI ≥30 kg/m2 to BMI <20 kg/m2). Ethnicity was a positive predictor for total breast area, but not bust line.