bluuebunny/crossref_metadata_2025 huggingface dataset:
Transportation and Production Lot-size for Sugarcane under Uncertainty of Machine Capacity
Authors: Sudtachat Kanchala
Published: April 2018

The integrated transportation and production lot size problems is important effect to total cost of operation system for sugar factories. In this research, we formulate a mathematic model that combines these two problems as two stage stochastic programming model. In the first stage, we determine the lot size of transportation problem and allocate a fixed number of vehicles to transport sugarcane to the mill factory. Moreover, we consider an uncertainty of machine (mill) capacities. After machine (mill) capacities realized, in the second stage we determine the production lot size and make decision to hold units of sugarcane in front of mills based on discrete random variables of machine (mill) capacities. We investigate the model using a small size problem. The results show that the optimal solutions try to choose closest fields and lower holding cost per unit (at fields) to transport sugarcane to mill factory. We show the results of comparison of our model and the worst case model (full capacity). The results show that our model provides better efficiency than the results of the worst case model.
Research on the Dimensional Accuracy Measurement Method of Cylindrical Spun Parts Based on Machine Vision
Authors: Gangfeng Xiao , Xingwei Zhong , Weixian Shen , Qinxiang Xia , Weiping Chen
Published: April 2018

A new method for measuring the dimensional accuracy of the cylindrical spun parts based on machine vision was proposed to overcome the artificial deviation and low efficiency of manual measurement. The image acquisition system of machine vision was built up. The methods of image processing and edge extraction of cylindrical spun parts were studied. The straightness and ovality of the cylindrical spun parts were obtained by the proposed new method. The results showed that the edge contour of the cylindrical spun parts extracted by Canny edge detector is better than Sobel and Prewitt edge detector. The dimensional accuracy of the cylindrical spun parts can be obtained accurately by the proposed measurement method based on machine vision. The relative errors of the straightness and ovality between the machine vision and the manual measurement are less than 10%.
Lighting: a driver of the sustainable revolution
Authors: Verhaar Harry
Published: April 2018

Some of the most important things in life are taken for granted, and nowhere is this truer than with light. In this article, we will look at some important milestones marking light’s path from human evolution to sustainable revolution, challenges facing the modern lighting industry as well as the world we live in, and what the future promises. In a sense, a new revolution is at hand. It would be hard to overestimate the fundamental importance of light as it shapes virtually everything we sense and experience.
Saliva versus Plasma Therapeutic Drug Monitoring of Pregabalin in Jordanian Patients
Authors: Idkaidek Nasir , Hamadi Salim , El-Assi Manal , Al-Shalalfeh Ahmad , Al-Ghazawi Ahmad
Published: April 2018

The objective is using saliva instead of plasma for pregabalin therapeutic drug monitoring (TDM) since saliva reflects the free non–protein bound drug concentration, simple and noninvasive sampling, cheaper and does not require the expertise of drawing blood. Forty four patients participated in this study, two samples of saliva and another two of blood were taken from each patient; first sample of both saliva and blood is the trough sample and was taken just before the first dose of the day and second sample is the peak sample and was taken 1 h after taking the first dose of the day. Descriptive statistics and t-testing after log transformation were done using Excel, p-value=0.05 was adopted for significant difference. Optimized effective intestinal permeability of pregabalin was estimated by PK-Sim program version 7. This study for the first time revealed that pregabalin is excreted in saliva and classified as class 1 based on Salivary Excretion Classification System (SECS). A good correlation of 0.71-0.83 between Cmin and Cmax of plasma and saliva pregabalin was observed respectively which indicate that saliva sampling is a good alternative matrix for pregabalin TDM. C/D-ratios were calculated to demonstrate pharmacokinetic variability of Pregabalin; the results showed that C/D-ratio was higher in women, elderly and in those patients who had Scr.≥0.9 mg/dl. Proposed pregabalin therapeutic ranges are 0.7 to 1.84 µg/ml in plasma and 0.055 to 0.145 µg/ml in saliva, for neuropathic pain, diabetic neuropathy and disc prolapse patients.
Socially mediated populism: the communicative strategies of political leaders on Facebook
Authors: Mazzoleni Gianpietro , Bracciale Roberta
Published: April 2018

Populism has been defined in many different ways, mostly in regard to political ideology and political dynamics, but only in recent years in relation to communication variables. The aim of this paper is to contribute to the identification of a socially mediated type of populist communication profoundly affected by the specific nature of social media. It presents and discusses empirical evidence on Italy’s populist and non-populist leaders that use Facebook regularly, and highlights the extent of the overflow of populist communication patterns and ideological features into mainstream political communication. Populist ideology fragments emerged in Italian leaders’ Facebook posts, thus leading to two main conclusions: first, populism appears to be ‘endemic’ in the Italian online facebooksphere; second, political actors—even non-populist ones—do not disdain the adoption of typical populist rhetorics.
A simulation study of CS2 solutions in two related ionic liquids with dications and monocations
Authors: Lynden-Bell R. M. , Quitevis E. L.
Published: April 2018

Atomistic simulations of solutions of CS2 in an ionic liquid, [C8(C1im)2][NTf2]2, with a divalent cation and in the corresponding ionic liquid with a monovalent cation, [C4C1im][NTf2], were carried out. The low-frequency librational density of states of the CS2 was of particular interest in view of recent optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES). Compared to the monocation ionic liquid, the maximum shifts to higher frequencies in the dication ionic liquid under ambient conditions, but was found to be significantly pressure-dependent. CS2 molecules lie above and below the plane of the imidazolium rings and found to be close to the butyl tails of the monocation. The diffusion rates and embedding energies of solvent ions and CS2 in the two ionic liquids were measured.
Solving the integration problem of one transistor one memristor architecture with a Bi-layer IGZO film through synchronous process
Authors: Chang Che-Chia , Liu Po-Tsun , Chien Chen-Yu , Fan Yang-Shun
Published: April 2018

This study demonstrates the integration of a thin film transistor (TFT) and resistive random-access memory (RRAM) to form a one-transistor-one-resistor (1T1R) configuration. With the concept of the current conducting direction in RRAM and TFT, a triple-layer stack design of Pt/InGaZnO/Al2O3 is proposed for both the switching layer of RRAM and the channel layer of TFT. This proposal decreases the complexity of fabrication and the numbers of photomasks required. Also, the robust endurance and stable retention characteristics are exhibited by the 1T1R architecture for promising applications in memory-embedded flat panel displays.
Abnormal growth kinetics of h-BN epitaxial monolayer on Ru(0001) enhanced by subsurface Ar species
Authors: Wei Wei , Meng Jie , Meng Caixia , Ning Yanxiao , Li Qunxiang , Fu Qiang , Bao Xinhe
Published: April 2018

Growth kinetics of epitaxial films often follows the diffusion-limited aggregation mechanism, which shows a “fractal-to-compact” morphological transition with increasing growth temperature or decreasing deposition flux. Here, we observe an abnormal “compact-to-fractal” morphological transition with increasing growth temperature for hexagonal boron nitride growth on the Ru(0001) surface. The unusual growth process can be explained by a reaction-limited aggregation (RLA) mechanism. Moreover, introduction of the subsurface Ar atoms has enhanced this RLA growth behavior by decreasing both reaction and diffusion barriers. Our work may shed light on the epitaxial growth of two-dimensional atomic crystals and help to control their morphology.
Space-charge limited current in CdTe thin film solar cell
Authors: Li Qiang , Shen Kai , Li Xun , Yang Ruilong , Deng Yi , Wang Deliang
Published: April 2018

In this study, we demonstrate that space-charge limited current (SCLC) is an intrinsic current shunting leakage in CdTe thin film solar cells. The SCLC leakage channel, which is formed by contact between the front electrode, CdTe, and the back electrode, acts as a metal-semiconductor-metal (MSM) like transport path. The presence of SCLC leaking microchannels in CdTe leads to a band bending at the MSM structure, which enhances minority carrier recombination and thus decreases the minority carrier lifetime in CdTe thin film solar cells. SCLC was found to be a limiting factor both for the fill factor and the open-circuit voltage of CdTe thin film solar cells.
Multi-object investigation using two-wavelength phase-shift interferometry guided by an optical frequency comb
Authors: Ibrahim Dahi Ghareab Abdelsalam , Yasui Takeshi
Published: April 2018

Two-wavelength phase-shift interferometry guided by optical frequency combs is presented. We demonstrate the operation of the setup with a large step sample simultaneously with a resolution test target with a negative pattern. The technique can investigate multi-objects simultaneously with high precision. Using this technique, several important applications in metrology that require high speed and precision are demonstrated.
Generating structured light with phase helix and intensity helix using reflection-enhanced plasmonic metasurface at 2 μm
Authors: Zhao Yifan , Du Jing , Zhang Jinrun , Shen Li , Wang Jian
Published: April 2018

Mid-infrared (2–20 μm) light has been attracting great attention in many areas of science and technology. Beyond the extended wavelength range from visible and near-infrared to mid-infrared, shaping spatial structures may add opportunities to grooming applications of mid-infrared photonics. Here, we design and fabricate a reflection-enhanced plasmonic metasurface and demonstrate efficient generation of structured light with the phase helix and intensity helix at 2 μm. This work includes two distinct aspects. First, structured light (phase helix, intensity helix) generation at 2 μm, which is far beyond the ability of conventional spatial light modulators, is enabled by the metasurface with sub-wavelength engineered structures. Second, the self-referenced intensity helix against environmental noise is generated without using a spatially separated light. The demonstrations may open up advanced perspectives to structured light applications at 2 μm, such as phase helix for communications and non-communications (imaging, sensing) and intensity helix for enhanced microscopy and advanced metrology.
Nonlinear frequency doubling characteristics of asymmetric vortices of tunable, broad orbital angular momentum spectrum
Authors: Alam Sabir Ul , Rao A. Srinivasa , Ghosh Anirban , Vaity Pravin , Samanta G. K.
Published: April 2018

We report on a simple experimental scheme to generate and control the orbital angular momentum (OAM) spectrum of the asymmetric vortex beams in a nonlinear frequency conversion process. Using a spiral phase plate (SPP) and adjusting the transverse shift of the SPP with respect to the incident Gaussian beam axis, we have transformed the symmetric (intensity distribution) optical vortex of order l into an asymmetric vortex beam of measured broad spectrum of OAM modes of orders l, l − 1, l − 2, …, 0 (Gaussian mode). While the position of the SPP determines the distribution of the OAM modes, we have also observed that the modal distribution of the vortex beam changes with the shift of the SPP of all orders and finally results in a Gaussian beam (l = 0). Using single-pass frequency doubling of the asymmetric vortices, we have transferred the pump OAM spectra, l, l − 1, l − 2, …, 0, into the broad spectra of higher order OAM modes, 2l, 2l − 1, 2l − 2, …, 0 at green wavelength, owing to OAM conservation in nonlinear processes. We also observed an increase in single-pass conversion efficiency with the increase in asymmetry of the pump vortices producing a higher power vortex beam of mixed OAM modes at a new wavelength than that of the pure OAM mode.
Electric-field effect on the easy cone angle of the easy-cone state in CoFeB/MgO investigated by ferromagnetic resonance
Authors: Okada Atsushi , Kanai Shun , Fukami Shunsuke , Sato Hideo , Ohno Hideo
Published: April 2018

We investigate the effect of an electric field on the cone angle of the easy-cone state in a CoFeB/MgO stack by ferromagnetic resonance as a function of temperature. We find that the easy cone state appears in the CoFeB/MgO system below 200 K. The application of electric field E modulates the effective first-order magnetic anisotropy energy constant, whereas the second-order magnetic anisotropy energy constant is almost independent of E, resulting in the variation of the cone angle by E. The present observation reveals the importance of the modulation of the magnetic anisotropy by E in magnetic tunnel junctions exhibiting an easy-cone state under spin-transfer-torque-induced switching.
Glassy dynamics of landscape evolution
Authors: Ferdowsi Behrooz , Ortiz Carlos P. , Jerolmack Douglas J.
Published: April 2018

Significance

Soil is apparently solid as it moves downhill at glacial speeds, but can also liquefy from rain or earthquakes. This behavior is actually similar to that of glass, which creeps very slowly at low temperatures but becomes a liquid at higher temperatures. We develop a discrete granular-physics hillslope model, which shows that the similarities between soil and glass are more than skin deep. Despite the geologic and climatic complexity of natural environments, the shapes and erosion rates of hillsides over geologic timescales appear to be governed by generic dynamics characteristic of disordered and amorphous materials.
Interaction between cardiac myosin-binding protein C and formin Fhod3
Authors: Matsuyama Sho , Kage Yohko , Fujimoto Noriko , Ushijima Tomoki , Tsuruda Toshihiro , Kitamura Kazuo , Shiose Akira , Asada Yujiro , Sumimoto Hideki , Takeya Ryu
Published: April 2018

Significance

The actin cytoskeleton in living cells is not static but undergoes dynamic reorganization. Actin-containing thin filaments in cardiac sarcomeres are no exception; they exhibit exchange of actin subunits at the ends within actively contracting cardiomyocytes. Fhod3, an actin organizer in cardiac sarcomeres, is implicated in regulation of actin assembly in cardiomyocytes, although the mechanism is largely unknown. We discovered a direct molecular link between Fhod3 and cMyBP-C, a thick myosin filament-associated protein that modulates myocardial contraction via cross-bridge arrangement. Because Fhod3 adversely affected cardiac function in the absence of cMyBP-C, the interaction may serve to control the Fhod3-mediated actin reorganization at the cross-bridge region. Our results provide insight into actin reorganization in cardiac sarcomeres with implications for cardiac function.
Reduction in adaptor amounts establishes degradation hierarchy among protease substrates
Authors: Yeom Jinki , Gao Xiaohui , Groisman Eduardo A.
Published: April 2018

Significance

A given protease typically degrades multiple substrates that serve different functions and may be required in variable amounts under specific cellular conditions. Some substrates require adaptor proteins to be delivered to the protease. We find that changes in the abundance of an adaptor can lead to differential degradation of substrates that have different affinities for the adaptor. Thus, adaptor amounts can have a broad impact, as illustrated by the increase in antibiotic persister bacteria when the abundance of the ClpS adaptor is decreased. Specific growth conditions decrease ClpS abundance decreasing proteolysis of a subset of ClpSAP substrates.
MYB72-dependent coumarin exudation shapes root microbiome assembly to promote plant health
Authors: Stringlis Ioannis A. , Yu Ke , Feussner Kirstin , de Jonge Ronnie , Van Bentum Sietske , Van Verk Marcel C. , Berendsen Roeland L. , Bakker Peter A. H. M. , Feussner Ivo , Pieterse Corné M. J.
Published: April 2018

Significance

Plant roots nurture a large diversity of soil microbes via exudation of chemical compounds into the rhizosphere. In turn, beneficial root microbiota promote plant growth and immunity. The root-specific transcription factor MYB72 has emerged as a central regulator in this process. Here, we show that MYB72 regulates the excretion of the coumarin scopoletin, an iron-mobilizing phenolic compound with selective antimicrobial activity that shapes the root-associated microbial community. Selected soil-borne fungal pathogens appeared to be highly sensitive to the antimicrobial activity of scopoletin, while twoMYB72-inducing beneficial rhizobacteria were tolerant. Our results suggest that probiotic root-associated microbes that activate the iron-deficiency response during colonization stimulate MYB72-dependent excretion of scopoletin, thereby potentially improving their niche establishment and enhancing plant growth and protection.
Coupling MALDI-TOF mass spectrometry protein and specialized metabolite analyses to rapidly discriminate bacterial function
Authors: Clark Chase M. , Costa Maria S. , Sanchez Laura M. , Murphy Brian T.
Published: April 2018

Significance

Mass spectrometry is a powerful technique that has been used to identify bacteria by their protein content and to assess bacterial functional traits through analysis of their specialized metabolites. However, until now these analyses have operated independently, which has resulted in the inability to rapidly connect bacterial phylogenetic identity with potential environmental function. To bridge this gap, we designed a MALDI-TOF mass spectrometry data acquisition and bioinformatics pipeline (IDBac) to integrate data from both intact protein and specialized metabolite spectra directly from bacterial cells grown on agar. This technique organizes bacteria into highly similar phylogenetic groups and allows for comparison of metabolic differences of hundreds of isolates in just a few hours.
Complementary charge-based interaction between the ribosomal-stalk protein L7/12 and IF2 is the key to rapid subunit association
Authors: Ge Xueliang , Mandava Chandra Sekhar , Lind Christoffer , Åqvist Johan , Sanyal Suparna
Published: April 2018

Significance

The main constituent of the ribosomal stalk is L12, a multicopy protein of the ribosomal 50S subunit that interacts with the translational GTPases in different stages of translation. Using mutagenesis, fast kinetics, and molecular dynamics simulations, we show that charge complementarity between a conserved region on the C-terminal domain of L12 and a conserved region on the G domain of initiation factor 2 (IF2) forms the basis of L12–IF2 interaction, which is crucial for fast association of the ribosomal subunits. Our analysis also suggests that L12 possibly interacts with other G factors by a similar mechanism. This study provides significant mechanistic insights into the interaction of L12 and the translational GTPases at the molecular level.
The Lives and Afterlives ofVis and Rāmin
Authors: Cross Cameron
Published: April 2018

This article is a review of the afterlife, or Nachleben, of the romanceVis and Rāmin, one of the first representatives of its genre in New Persian literature. In addition to providing readers with an extensive bibliography of sources and research concerning the poem, it also analyzes these materials to put forward two basic arguments: one, that moral or religious antipathy to the poem’s contents may not have played as great a role in its fortunes as did aesthetic taste; and two, that V&R proved to be a more widely circulated and durable work than is commonly supposed, but on the level of fragments, not the entire text. In light of these arguments, it is proposed that studies structured around the comparison of fragments—themes, ideas, ethics, and motifs, rather than whole texts—may offer more purchase in constructing models of analysis that situate V&R, and Persian literature more broadly, within a literary oikumene in which it connects and interacts with neighboring traditions.
Educating Australian musicians: are we playing it safe?
Authors: Wijsman Suzanne , Ackermann Bronwen J
Published: April 2018

The effectiveness of health promotion through arts engagement, and the health benefits and social importance of music in particular, are becoming increasingly recognized. However, like sport, music-making is an athletic endeavour, one that often involves high physiological and psychological loadings on the bodies and minds of musicians. Research over the past 30 years has revealed alarming rates of injury among musicians, and has identified health risk factors associated with music performance faced by professional and student musicians. Australia lacks consistent provision of essential health education for musicians, and research shows an unacceptably high prevalence of performance-related health problems among musicians of all ages. This article advocates for effective health promotion to be embraced in the policies and practices of Australian music performance organizations and educational bodies. It argues that a cultural shift is required, recognizing that a settings-based approach to health literacy is as fundamentally important for musicians as it is for any other occupation or athletic activity. Embedding health education into the delivery of music education will not only help to prevent injury over the lifespan of Australian musicians, it will support and sustain their capacity to contribute towards societal wellbeing and public health outcomes.
Why Am I Seeing This Ad? The Effect of Ad Transparency on Ad Effectiveness
Authors: Kim Tami , Barasz Kate , John Leslie K
Published: April 2018

Given the increasingly specific ways marketers can target ads, consumers and regulators are demanding ad transparency: disclosure of how consumers’ personal information was used to generate ads. We investigate how and why ad transparency impacts ad effectiveness. Drawing on literature about offline norms of information sharing, we posit that ad transparency backfires when it exposes marketing practices that violate norms about “information flows”—consumers’ beliefs about how their information should move between parties. Study 1 inductively shows that consumers deem information flows acceptable (or not) based on whether their personal information was: 1) obtained within versus outside of the website on which the ad appears, and 2) stated by the consumer versus inferred by the firm (the latter of each pair being less acceptable). Studies 2 and 3 show that revealing unacceptable information flows reduces ad effectiveness, which is driven by increasing consumers’ relative concern for their privacy over desire for the personalization that such targeting affords. Study 4 shows the moderating role of platform trust: when consumers trust a platform, revealing acceptable information flows increases ad effectiveness. Studies 5a and 5b, conducted in the field with a loyalty program website (i.e., a trusted platform), demonstrate this benefit of transparency.
Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center
Authors: Nakajima Madoka , Miyajima Masakazu , Akiba Chihiro , Ogino Ikuko , Kawamura Kaito , Sugano Hidenori , Hara Takeshi , Tange Yuichi , Fusegi Keiko , Karagiozov Kostadin , Arai Hajime
Published: April 2018

BACKGROUND

Treating idiopathic normal pressure hydrocephalus (iNPH) with lumboperitoneal shunts (LPSs) may cause cerebrospinal fluid (CSF) overdrainage.

OBJECTIVE

To investigate whether LPSs, including gravitational “add-on” and programmable pressure valves (PPVs/+GVs), reduce complications and improve outcomes.

METHODS

We compared PPVs/+small lumen abdominal catheters (SLs) to PPVs/+GVs using different opening pressures for supine and standing positions. We analyzed 115 patients with iNPH in 2 consequent cohorts: 48 patients receiving LPSs with PPVs/+SLs and 67 patients receiving LPSs with PPVs/+GVs. The modified Rankin Scale (mRS), Japan iNPH grading scale, Mini Mental State Examination, Frontal Assessment Battery, and CSF biomarkers were evaluated.

RESULTS

Comparisons of postoperative clinical factors in 64 patients in the PPV/+SL and PPV/+GV groups using 1:1 propensity score matching revealed differences in the mean (±standard deviation) postoperative mRS (2.65 ± 1.07 vs 2.16 ± 1.02, P = .049) and gait disturbance scores (1.97 ± 1.03 vs 1.39 ± 0.92, P = .011). Thus, outcomes improved in the LPS group with the GV. Serious and nonserious adverse event rates for the PPV/+SL and PPV/+GV groups were 22.9% and 19.4% (P = .647) and 38% and 17.9% (P = .018), respectively, indicating higher rates of subdural collections for the PPV/+SL group.

CONCLUSION

This is the first study to examine LPS treatment for iNPH using a GV in tandem with a PPV. Our results suggest that the CSF shunt flow volume is restricted in the standing position and maintained in the supine position, thus improving iNPH symptoms. This may reduce intracranial CSF hypotension-related complications.
Further Mathematics, student choice and transition to university: part 1 - Mathematics degrees
Authors: Lyakhova Sofya , Neate Andrew
Published: April 2018

The transition from studying mathematics at school to university is known to be challenging for students. Given the desire to increase participation in science, technology, engineering and mathematics subjects at degree level, it is important to ensure that the school mathematics curriculum is providing suitable preparation for the challenges ahead, and yet remains both accessible and popular. This two-part study investigates student choices of studying the post-16 A-level Mathematics and Further Mathematics qualifications in the UK and their impact on the transition from school to university mathematics. Student opinions were accessed via a survey of undergraduate students and also individual interviews. This first part of the study considers the responses of mathematics undergraduate students and finds that both those who studied Further Mathematics and those who did not perceive studying Further Mathematics as advantageous for their degree courses. However, the advantages identified mostly relate to the familiarity with topics, while students still feel unprepared for studying more abstract and proof-based mathematics. The study found that some factors which may be beneficial for transition currently lie outside the mainstream school mathematics syllabus and include studying through blended learning provided by the Further Mathematics Support Programme, practicing more advanced extension exam papers and attending university outreach events. The choice of Further Mathematics is found to be influenced by the attitudes of the students, their teachers and their parents, to both mathematics as a subject and to Further Mathematics as a qualification as well as student perceptions of Further Mathematics and their plans in terms of degree and university choice.
Communication Among Team Members Within the Patient-centered Medical Home and Patient Satisfaction With Providers
Authors: Stockdale Susan E. , Rose Danielle , Darling Jill E. , Meredith Lisa S. , Helfrich Christian D. , Dresselhaus Timothy R. , Roos Philip , Rubenstein Lisa V.
Published: April 2018

Background:

The Patient-centered Medical Home (PCMH) uses team-based care to improve patient outcomes, including satisfaction. The quality of patients’ communication with their primary care providers (PCPs) is a key determinant of patient satisfaction. A shift to team-based care could disrupt the therapeutic relationship between patients and their PCPs and reduce patient satisfaction if communication and coordination among primary care team members is poor. Little is known about the relationship between intrateam communication within a PCMH and patient satisfaction with PCPs, and whether patient-provider communication might mediate this relationship.

Objectives:

To examine the relationship between intrateam communication in a PCMH and patients’ satisfaction with assigned PCPs, and whether patient-provider communication mediates this relationship.

Research Design:

Cross-sectional surveys of Veterans Health Administration PCPs (2011–2012, n=149) matched with their assigned patients’ surveys (n=3329). Mediation analyses using a nested data structure, controlling for patient and provider characteristics.

Measures:

Patient satisfaction with PCPs, patient-reported patient-provider communication, and PCP-reported intrateam communication within the PCMH.

Results:

Intrateam communication and patient-provider communication were independently associated with patients’ satisfaction with their PCPs. Patient-provider communication mediated 56% of the association between intrateam communication and patient satisfaction. Better intrateam communication combined with better patient-provider communication predicted high satisfaction (81%), compared with poor intrateam communication and poor patient-provider communication (22%).

Conclusions:

PCMH environments with better communication among team members are likely to experience better patient-provider communication and high patient satisfaction. PCMH practices with low ratings of patient satisfaction may need to look beyond individual PCPs to communication within and across teams.
Epigenetic drug discovery: a success story for cofactor interference
Authors: Ganesan A.
Published: April 2018

Within the past two decades, seven epigenetic drugs have received regulatory approval and numerous other candidates are currently in clinical trials. Among the epigenetic targets are the writer and eraser enzymes that are, respectively, responsible for the reversible introduction and removal of structural modifications in the nucleosome. This review discusses the progress achieved in the design and development of inhibitors against the key writer and eraser pairs: DNA methyltransferases and Tet demethylases; lysine/arginine methyltransferases and lysine demethylases; and histone acetyltransferases and histone deacetylases. A common theme for the successful inhibition of these enzymes in a potent and selective manner is the targeting of the cofactors present in the active site, namely zinc and iron cations,
S
-adenosylmethione, nicotinamide adenine dinucleotide, flavin adenine dinucleotide and acetyl Coenzyme A.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors
Authors: Halby Ludovic , Marechal Nils , Pechalrieu Dany , Cura Vincent , Franchini Don-Marc , Faux Céline , Alby Fréderic , Troffer-Charlier Nathalie , Kudithipudi Srikanth , Jeltsch Albert , Aouadi Wahiba , Decroly Etienne , Guillemot Jean-Claude , Page Patrick , Ferroud Clotilde , Bonnefond Luc , Guianvarc'h Dominique , Cavarelli Jean , Arimondo Paola B.
Published: April 2018

DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound
4
and its derivative
2
showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound
4
binds to the PRMT4 active site, displacing strongly the
S
-adenosyl-
l
-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Interplay between long non-coding RNAs and epigenetic machinery: emerging targets in cancer?
Authors: Hanly David J. , Esteller Manel , Berdasco María
Published: April 2018

Of the diverse array of putative molecular and biological functions assigned to long non-coding RNAs (lncRNAs), one attractive perspective in epigenetic research has been the hypothesis that lncRNAs directly interact with the proteins involved in the modulation of chromatin conformation. Indeed, epigenetic modifiers are among the most frequent protein partners of lncRNAs that have been identified to date, of which histone methyltransferases and protein members of the Polycomb Repressive Complex PRC2 have received considerable attention. This review is focused on how lncRNAs interface with epigenetic factors to shape the outcomes of crucial biological processes such as regulation of gene transcription, modulation of nuclear architecture, X inactivation in females and pre-mRNA splicing. Because of our increasing knowledge of their role in development and cellular differentiation, more research is beginning to be done into the deregulation of lncRNAs in human disorders. Focusing on cancer, we describe some key examples of disease-focused lncRNA studies. This knowledge has significantly contributed to our ever-improving understanding of how lncRNAs interact with epigenetic factors of human disease, and has also provided a plethora of much-needed novel prognostic biomarker candidates or potential therapeutic targets. Finally, current limitations and perspectives on lncRNA research are discussed here.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Protein methyltransferase inhibitors as precision cancer therapeutics: a decade of discovery
Authors: Copeland Robert A.
Published: April 2018

The protein methyltransferases (PMTs) represent a large class of enzymes that catalyse the methylation of side chain nitrogen atoms of the amino acids lysine or arginine at specific locations along the primary sequence of target proteins. These enzymes play a key role in the spatio-temporal control of gene transcription by performing site-specific methylation of lysine or arginine residues within the histone proteins of chromatin, thus effecting chromatin conformational changes that activate or repress gene transcription. Over the past decade, it has become clear that the dysregulated activity of some PMTs plays an oncogenic role in a number of human cancers. Here we review research of the past decade that has identified specific PMTs as oncogenic drivers of cancers and progress toward the discovery and development of selective, small molecule inhibitors of these enzymes as precision cancer therapeutics.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells
Authors: Mellini Paolo , Marrocco Biagina , Borovika Diana , Polletta Lucia , Carnevale Ilaria , Saladini Serena , Stazi Giulia , Zwergel Clemens , Trapencieris Peteris , Ferretti Elisabetta , Tafani Marco , Valente Sergio , Mai Antonello
Published: April 2018

Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound
1o
(
N
-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1
H
-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover,
1o
displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Excision of the doubly methylated base
N
4
,5-dimethylcytosine from DNA by
Escherichia coli
Nei and Fpg proteins
Authors: Alexeeva Marina , Guragain Prashanna , Tesfahun Almaz N. , Tomkuvienė Miglė , Arshad Aysha , Gerasimaitė Rūta , Rukšėnaitė Audronė , Urbanavičiūtė Giedrė , Bjørås Magnar , Laerdahl Jon K. , Klungland Arne , Klimašauskas Saulius , Bjelland Svein
Published: April 2018

Cytosine (C) in DNA is often modified to 5-methylcytosine (m
5
C) to execute important cellular functions. Despite the significance of m
5
C for epigenetic regulation in mammals, damage to m
5
C has received little attention. For instance, almost no studies exist on erroneous methylation of m
5
C by alkylating agents to doubly or triply methylated bases. Owing to chemical evidence, and because many prokaryotes express methyltransferases able to convert m
5
C into
N
4
,5-dimethylcytosine (m

N

4,5
C) in DNA, m

N

4,5
C is probably present
in vivo
. We screened a series of glycosylases from prokaryotic to human and found significant DNA incision activity of the
Escherichia coli
Nei and Fpg proteins at m

N

4,5
C residues
in vitro
. The activity of Nei was highest opposite cognate guanine followed by adenine, thymine (T) and C. Fpg-complemented Nei by exhibiting the highest activity opposite C followed by lower activity opposite T. To our knowledge, this is the first description of a repair enzyme activity at a further methylated m
5
C in DNA, as well as the first alkylated base allocated as a Nei or Fpg substrate. Based on our observed high sensitivity to nuclease S1 digestion, we suggest that m

N

4,5
C occurs as a disturbing lesion in DNA and that Nei may serve as a major DNA glycosylase in
E. coli
to initiate its repair.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Germ cell tumour subtypes display differential expression of microRNA371a-3p
Authors: Vilela-Salgueiro Bárbara , Barros-Silva Daniela , Lobo João , Costa Ana Laura , Guimarães Rita , Cantante Mariana , Lopes Paula , Braga Isaac , Oliveira Jorge , Henrique Rui , Jerónimo Carmen
Published: April 2018

Testicular germ cell tumours (TGCTs) are a heterogeneous group of neoplasms, mostly affecting young men. Curability rates are high and adequate treatment relies on careful and accurate pathological and clinical assessment. Indeed, TGCTs' histopathological subtyping is critical for adequate therapeutic decision. Considering the limitation of currently available serum biomarkers, novel candidates have been proposed, most notably miR-371a-3p, which outperformed classical serum markers, but no detailed information concerning TGCT subtype was available. Thus, we carried out evaluation of miR-371a-3p expression levels among TGCT subtypes using a consecutive cohort of tissue samples. MiR-371a-3p discriminated TGCTs from control tissues with high sensitivity and specificity (AUC = 0.99). Furthermore, seminomas displayed higher miR-371a-3p expression levels compared to non-seminomatous TGCTs, which also showed significant differences among them. Nonetheless, prepubertal TGCTs depicted lower miR-371a-3p expression levels than postpubertal TGCTs. Globally, miR-371a-3p expression levels decreased in parallel with progressive cell differentiation. We concluded that miR-371a-3p is TGCTs-specific and it might be clinically useful for early detection and disease monitoring.

This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Genetic patterning in Central Eurasia: population history and pigmentation
Authors: Røyrvik Ellen C. , Yuldasheva Nadira , Tonks Susan , Winney Bruce , Ruzibakiev Ruslan , Wells R. Spencer , Bodmer Walter F.
Published: April 2018

Central-western Asia has often been underrepresented in population genetic studies, but it is important for the clarification of the peopling of Eurasia and the relationship between its western and eastern extremities. We genotyped individuals from over 40 population groups, mostly central Eurasian, for mitochondrial HVR1,CCR5del32and five functionalMC1Rvariants (p.Val60Leu, p.Val92Met, p.Arg151Cys, p.Arg160Trp, p.Arg163Gln), and collected published genotype data for comparison. Mitochondrial profiles confirm both the higher heterozygosity in Central Asia than in surrounding areas, and the broadly northern European distribution ofCCR5del32. TheMC1Rvariants profile alone is a good determinant of the longitudinal position of a population group, and combined FSTvalues divide Eurasia into seven broad geographic divisions. We can conclude that Central Asia shares genetic features with both eastern and western Eurasia, compatible with both a scenario where the former acted as a source for the latter two’s genetic diversity, or one where Central Asia is a ‘hybrid zone’ where eastern and western peoples met. Furthermore, the overall high FSTvalues for functionalMC1Rvariants combined with presumed selection pressures on skin pigmentation in low-UV areas lead us to conclude that different variants were selected for in east and west Eurasia, an example of convergent evolution.
Diversity of feature selectivity in macaque visual cortex arising from limited number of broadly-tuned input channels
Authors: Mohan Yamni S. , Jayakumar Jaikishan , Lloyd Errol K.J. , Levichkina Ekaterina , Vidyasagar Trichur R.
Published: April 2018

Spikes (action potential) responses of most primary visual cortical cells in the macaque are sharply tuned for the orientation of a line or an edge and neurons preferring similar orientations are clustered together in cortical columns. The preferred stimulus orientation of these columns span the full range of orientations, as observed in recordings of spikes, which represent the outputs of cortical neurons. However, when we imaged also the thalamic input to these cells that occur on a larger spatial scale, we found that the orientation domain map of the primary visual cortex did not show the diversity of orientations exhibited by signals representing outputs of the cells. This map was dominated by just the one orientation that is most commonly represented in subcortical responses. This supports cortical feature selectivity and columnar architecture being built upon feed-forward signals transmitted from the thalamus in a very limited number of broadly-tuned input channels.
Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
Authors: Doyle Stephen R. , Illingworth Christopher J. R. , Laing Roz , Bartley David J. , Redman Elizabeth , Martinelli Axel , Holroyd Nancy , Morrison Alison A. , Rezansoff Andrew , Tracey Alan , Devaney Eileen , Berriman Matthew , Sargison Neil , Cotton James A. , Gilleard John S.
Published: April 2018

Background

Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved.

Results

Here, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this Q.TL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection.

Conclusions

We have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high quality reference genome in interpreting the signals of selection so identified.
Complementary chromosome folding by transcription factors and cohesin
Authors: Pereira M. C. F. , Brackley C. A. , Michieletto D. , Annunziatella C. , Bianco S. , Chiariello A. M. , Nicodemi M. , Marenduzzo D.
Published: April 2018

The spatial organisation of interphase chromosomes is known to affect genomic function, yet the principles behind such organisation remain elusive. Here, we first compare and then combine two well-known biophysical models, the transcription factor (TF) and loop extrusion (LE) models, and dissect their respective roles in organising the genome. Our results suggest that extrusion and transcription factors play complementary roles in folding the genome: the former are necessary to compact gene deserts or “inert chromatin” regions, the latter are sufficient to explain most of the structure found in transcriptionally active or repressed domains. Finally, we find that to reproduce interaction patterns found in HiC experiments we do not need to postulate an explicit motor activity of cohesin (or other extruding factors): a model where co-hesin molecules behave as molecular slip-links sliding diffusively along chromatin works equally well.
Angiodysplasia Detection and Localization Using Deep Convolutional Neural Networks
Authors: Shvets Alexey , Iglovikov Vladimir , Rakhlin Alexander , Kalinin Alexandr A.
Published: April 2018

Accurate detection and localization for angiodysplasia lesions is an important problem in early stage diagnostics of gastrointestinal bleeding and anemia. Gold-standard for angiodysplasia detection and localization is performed using wireless capsule endoscopy. This pill-like device is able to produce thousand of high enough resolution images during one passage through gastrointestinal tract. In this paper we present our winning solution for MICCAI 2017 Endoscopic Vision SubChallenge: Angiodysplasia Detection and Localization its further improvements over the state-of-the-art results using several novel deep neural network architectures. It address the binary segmentation problem, where every pixel in an image is labeled as an angiodysplasia lesions or background. Then, we analyze connected component of each predicted mask. Based on the analysis we developed a classifier that predict angiodysplasia lesions (binary variable) and a detector for their localization (center of a component). In this setting, our approach outperforms other methods in every task subcategory for angiodysplasia detection and localization thereby providing state-of-the-art results for these problems. The source code for our solution is made publicly available at https://github.com/ternaus/angiodysplasia-segmentation