bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlinearity in parametric instabilities during the injection of lower hybrid waves into tokamak plasmas
Authors: Liu Zhiyuan , Gao Zhe , Zhao Aihui
Published: April 2019

Nonlinear kinetic theory of parametric instabilities is developed and applied to study the parametric process during the injection of lower hybrid waves into tokamak plasmas. Four approaches containing different nonlinear terms are numerically solved and compared. For the resonant mode decay, the quasi-linear treatment is enough for the daughter branches. However, for the quasi-mode decay, the contribution from the nonlinear response of quasi-mode should be included in the governing equations of the sidebands. The results with correct nonlinear terms can recover those from the usually used fluid-kinetic hybrid approach in the electrostatic limit, but the kinetic theory and its simplification method developed here could be more generally applied to study parametric instabilities within the full electromagnetic framework.
Plasmon-exciton coupling in nanostructured metal-semiconductor composite films
Authors: Savchuk Viktoriia V. , Gamernyk Roman V. , Virt Ihor S. , Malynych Serhiy Z. , Pinchuk Anatoliy O.
Published: April 2019

Nonlinear optical response of metal-semiconductor Zn0.8Co0.2O/Au nanocomposite films was studied experimentally and theoretically. Z-scan measurements revealed a positive nonlinear index of refraction of the composite film. Fluorescent spectroscopy measurements exhibited a narrow sharp peak that might be attributed to exciton peak of semiconductor nanostructured thin film enhanced by nearby gold nanoparticles. Classical electrodynamic calculations of a quantum dot in close proximity to a gold nanoparticle agree well with the experimentally observed normalized quantum efficiency.
Large-scale and contact-free fabrication of microwell arrays based on electro-pressure of depositing ions
Authors: Li Cao , Zou Jinglong , Wu Jiading , Zhu Tingting , Fei Peng , Liu Sheng , Zheng Huai
Published: April 2019

Microwell arrays are showing great potentials for various optoelectronic and biological applications. However, large-scale fabrication of microwell arrays remains a big challenge to modern micro- and nanotechnology. Here, we report a novel fabrication method that can produce massive aligned microwells in a cost-effective way. With using ionic wind, the hole arrays of pre-fabricated masks can be projected on polymer films and form microwell arrays in a contact-free way, and at high efficiency. Thousands of microwells can be rapidly fabricated in several minutes with their parameters, such as shape, size, and density, being widely tunable, through adjusting the mask’s design and its location in the ionic wind. The fabricated circle and square holes in microwells perfectly replicate the features from the mask, thus being successfully used to trap suspension cells and culture them sustainably till significant cell patterns are formed.
Physically principled reflection models applied to filtered camera imaging inversions in metal walled fusion machines
Authors: Carr M. , Meakins A. , Silburn S. A. , Karhunen J. , Bernert M. , Bowman C. , Callarelli A. , Carvalho P. , Giroud C. , Harrison J. R. , Henderson S. S. , Huber A. , Lipschultz B. , Lunt T. , Moulton D. , Reimold F. ,   ASDEX Upgrade Team,   JET Contributors,   MAST-Upgrade Team,   EUROfusion MST1 Team
Published: April 2019

Ray-tracing techniques are applied to filtered divertor imaging, a diagnostic that has long suffered from artifacts due to the polluting effect of reflected light in metal walled fusion machines. Physically realistic surface reflections were modeled using a Cook-Torrance micro-facet bi-directional reflection distribution function applied to a high resolution mesh of the vessel geometry. In the absence of gonioreflectometer measurements, a technique was developed to fit the free parameters of the Cook-Torrance model against images of the JET in-vessel light sources. By coupling this model with high fidelity plasma fluid simulations, photo-realistic renderings of a number of tokamak plasma emission scenarios were generated. Finally, a sensitivity matrix describing the optical coupling of a JET divertor camera and the emission profile of the plasma was obtained, including full reflection effects. These matrices are used to perform inversions on measured data and shown to reduce the level of artifacts in inverted emission profiles.
Boundary layer turbulence and freestream turbulence interface, turbulent spot and freestream turbulence interface, laminar boundary layer and freestream turbulence interface
Authors: Wu Xiaohua , Wallace James M. , Hickey Jean-Pierre
Published: April 2019

We study the boundary-layer turbulence and freestream turbulence interface (BTFTI), the turbulent spot and freestream turbulence interface (TSFTI), and the laminar boundary-layer and freestream turbulence interface (LBFTI) using direct simulation. Grid spacings in the freestream are less than 1 Kolmogorov length scale during transition. Probability density functions of temperature and its derivatives are used to select the interface identification threshold, corroborated by a vorticity-based method. The interfaces so detected are confirmed to be physical a posteriori by the distinctive quasi-step-jump behavior in the swirling strength and temperature statistics along traverses normal to the BTFTI and TSFTI. No interface-normal inflection is detected across the LBFTI for either swirling strength, temperature, vorticity magnitude, Reynolds shear stress, streamwise velocity, normal velocity, or turbulence kinetic energy. The present direct numerical simulation data thus cast serious doubts on the shear-sheltering hypothesis/theory, which asserts that a subset of freestream fluctuations is blocked by the LBFTI. In the early stage of transition, quasi-spanwise structures exist on the LBFTI. The TSFTI shape is dominated by head prints of concentrated hairpin vortices. Further downstream, the BTFTI geometry is strongly modulated by groves of hairpin vortices (the boundary layer large-scale motions) with a distinct streamwise preferential orientation. Streamwise velocity and turbulence kinetic energy only exhibit minor plateaus (rather than quasi-step-jump) across the BTFTI and the TSFTI. We emphasize that it is more meaningful and important to acquire reproducible and reliable interface-normal statistics prior to considering any plausible substructures and elusive transient dynamics of the BTFTI, TSFTI, and LBFTI.
Metal-organic framework structures: adsorbents for natural gas storage
Authors: Tsivadze Aslan Yu. , Aksyutin Oleg E. , Ishkov Alexander G. , Knyazeva Marina K. , Solovtsova Olga V. , Men’shchikov Ilya E. , Fomkin Anatoly A. , Shkolin Andrey V. , Khozina Elena V. , Grachev Vladimir A.
Published: April 2019

Natural gas (methane) forms an essential part of modern power supply. However, natural gas storage and transportation are associated with fire and explosion hazard, which restricts extensive application of natural gas as a fuel. The adsorption technique is among the most promising and safe ways for natural gas storage and transportation, which allows a significant increase in the methane density up to values characteristic of liquids as a result of physical adsorption in microporous adsorbents at moderate pressures. The review considers adsorption systems for natural gas (methane) storage based on metal-organic frameworks, which possess high characteristic energy of adsorption and a regular nanoporous structure with high pore volumes and specific surface areas. The possibility of controlling the porous structure and physicochemical behaviour of metal-organic frameworks during their synthesis and functionalization is analyzed, including the fabrication of composites and shaping, which may enhance their performance in the adsorption storage and transportation of natural gas.

The bibliography includes 315 references.
Reproductive biology of Macrobrachium amazonicum (Heller, 1862) populations with distinct phenotypes in Neotropical reservoirs during the 'El Niño' event
Authors: Paschoal Lucas R. P. , de Oliveira Leo J. F. , Andrioli Guilherme C. , Zara Fernando J.
Published: April 2019

Here, we investigated the reproductive biology (frequency and distribution patterns of ovigerous females, fecundity, reproductive output and egg size and volume) of Macrobrachium amazonicum in four populations living in Neotropical reservoirs, so as to verify whether this process was affected by the 2014–2016 ‘El Niño’ event. The following two phenotypes were identified: in two populations, small-size (SS) females (CL: 9.05 and 10.06mm) carried few eggs (X: 141 and 219) with a larger volume (X: 0.188 and 0.212mm3), whereas, in the other two populations, large-size (LS) females (CL: 15.89 and 14.51mm) carried many eggs (X: 814 and 846) with a smaller volume (X: 0.130 and 0.143mm3). All populations showed continuous reproduction and similar reproductive output. ‘El Niño’ did not directly affect both phenotypes, which is a reflection of the reproductive plasticity observed in this species. This phenomenon acted as a stressing factor, modifying the reproductive patterns of the species in a space–temporal scale. Ovigerous females showed specificity in habitat use, with SS females being associated with macrophytes in deeper environments (refuges), and LS females being associated with shallow sandy areas (shelter and nursery). The high variability of reproductive aspects is better explained by intrinsic factors and could be implying an incipient speciation.
Novel multimarker comparisons address the genetic population structure of silvertip sharks (Carcharhinus albimarginatus)
Authors: Green M. E. , Appleyard S. A. , White W. , Tracey S. , Devloo-Delva F. , Ovenden J. R.
Published: April 2019

The silvertip shark (Carcharhinus albimarginatus) is a reef-associated shark, with an intermittent distribution across the Indo-Pacific Ocean. Owing to global declines, the species is listed as Vulnerable under the International Union of Conservation for Nature Red List. Samples from 152C. albimarginatus were collected from three locations: Papua New Guinea (PNG), east Australia and Seychelles. Samples were analysed using mitochondrial, microsatellite and double-digest restriction-associated DNA (ddRAD) generated single nucleotide polymorphism markers. As expected across a vast oceanic expanse, no gene flow was identified between south-west Pacific locations and Seychelles for any marker (population differentiation measured using ΦST values 0.92–0.98, FST values 0.036–0.059). Mitochondrial DNA indicated significant population structuring between PNG and east Australia (ΦST=0.102), but nuclear markers suggested connectivity between these geographically close regions (FST=0.000–0.001). In combination with known telemetry movements for C. albimarginatus, our results suggest stepping-stone patterns of movement between regions is likely driven by reproductive requirements. The use of three distinct marker types in this study has facilitated a powerful genetic description of the population connectivity of C. albimarginatus between the three sampled regions. Importantly, the connectivity described between PNG and east Australia should be used as a guide for managing the south-west Pacific stock of C. albimarginatus.
Comparing signals of natural selection between three Indigenous North American populations
Authors: Reynolds Austin W. , Mata-Míguez Jaime , Miró-Herrans Aida , Briggs-Cloud Marcus , Sylestine Ana , Barajas-Olmos Francisco , Garcia-Ortiz Humberto , Rzhetskaya Margarita , Orozco Lorena , Raff Jennifer A. , Hayes M. Geoffrey , Bolnick Deborah A.
Published: April 2019

Significance

Recent studies have shown that humans have adapted to many different environments around the world. However, few studies have centered on Indigenous groups in the Americas. We present a comparative analysis of genetic adaptations in humans across North America using genome-wide scans for signals of natural selection in three populations inhabiting vastly different environments. We find evidence for adaptation to cold and high latitudes in an Alaskan population, whereas infectious disease was a strong selective pressure in the southeastern United States and central Mexico. Because there are few shared signals of selection between populations, these sweeps likely occurred after population differentiation in the Americas. This study fills an important gap in our knowledge of genetic adaptations in humans.
Effectiveness of homologous Thai letterforms presented in parafoveal vision
Authors: Punsongserm Rachapoom , Sunaga Shoji , Ihara Hisayasu
Published: April 2019

Design approaches to improve Thai font legibility by clarifying idealistic key features using a blur simulation
method have been proposed. Specifically, the jutting out of the tail of characters and inclusion of a loop-with-serrated-line,
together with sufficient character width, have been found to improve legibility. In the current study, a set of four homologous
characters was presented to the parafoveal region with a short-exposure methodology to display the characters with low visual
acuity. Overall, the results revealed that most of the chosen idealistic key features enhanced the legibility of characters
presented in parafoveal vision. However, the detailed results revealed variation in the amount of confusion between letter pairs
for each tested character. These findings suggest the need for several practical improvements by modifying the specific features
of each letter. Although the results of the short-exposure and blur simulation approaches differed at times, the findings of both
studies suggest possibilities for developing optimal letterforms using a combination of both methodologies.
Developing tools to support patients and healthcare providers when in conversation about obesity
Authors: Noël Guillermina , Luig Thea , Heatherington Melanie , Campbell-Scherer Denise
Published: April 2019

People living with obesity suffer from multiple health issues, including diabetes and mental health problems.
Misinformation about the complex nature of this condition greatly affects the way one manages obesity. This results in unrealistic
expectations by both healthcare providers and patients. Effective obesity management must be individually tailored for each
patient. The objective of this project was to improve four communication tools by co-designing them with patients. A co-design
approach was used to improve the efficacy and applicability of the tools through a working collaboration between patients, care
providers, and researchers. While most articles describe processes to create shared-decision making (SDM) tools which compare
alternative diagnosis and treatment options, few papers describe models to create SDM tools which go beyond showing benefits and
risks. In this paper, we describe our process and approach to the re-design of four of the 5As obesity tools. We hope this study
provides a valuable model for other teams.
Microstructure and mechanical property of high strength Mg–Sn–Zn–Al alloys
Authors: Li Yun , Wang Fang , Hu Tong , Zheng Ruixiao , Xiao Wenlong , Lyu Shaoyuan , Ma Chaoli
Published: April 2019

This paper aims to reveal the microstructure and mechanical properties of as-cast and hot-rolled Mg–Sn–Zn–Al based alloys. Three alloys, Mg–5Sn–2Zn (TZ52), Mg–5Sn–2Zn–2Al (TAZ522) and Mg–5Sn–5Al–1Zn–0.2Mn (TAZM5510) alloys were studied. The results revealed that the as-cast alloys showed fine dendritic structures. The TAZM5510 alloys exhibited moderate yield strength of 98 MPa with good elongation of ∼15%, which was comparable to several commercially used Mg die-castings. Mechanical properties were significantly improved after multi-pass rolling. The TZ52 sheet showed a high yield strength of 277 MPa with excellent ductility exceeding 30%, and the TAZM5510 sheet exhibited the highest tensile strength of 386 MPa while keeping desirable elongation of 16.6%. These sheets are termed as strong and ductile Mg–Sn–Zn–Al wrought alloys.
Fermented product of rice with Lactobacillus kefiranofaciens induces anti-aging effects and heat stress tolerance in nematodes via DAF-16
Authors: Sugawara Takaya , Furuhashi Tsubasa , Shibata Kenji , Abe Masayuki , Kikuchi Keita , Arai Masato , Sakamoto Kazuichi
Published: April 2019

Rice kefiran is superior in functionality, has high concentration of mucilaginous polysaccharide, and low lipid content, compared to conventional kefiran. However, reports on its physiological functionality, especially studies on life expectancy and aging, in model organisms are rare. In this study, nematodes were used as model organisms that were fed rice kefiran, along with Escherichia coli OP50, as a result of which, the lifespan of nematodes was extended and age-related retardation of mobility was suppressed. It also increased the heat stress resistance in nematodes. Experiments using daf-16 deletion mutant revealed that rice kefiran functions via DAF-16. Thus, this study revealed the longevity, anti-aging and heat stress tolerance effects of rice kefiran in nematodes.
ATG9 raises the BAR for PI4P in autophagy
Authors: Shatz Oren , Elazar Zvulun
Published: April 2019

ATG9 vesicles are crucial for autophagy, yet the role of ATG9 remains unclear. In this issue, Judith et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201901115) implicate the BAR protein Arfaptin2 in the loading of PI4-kinase IIIβ onto ATG9 vesicles for recruitment of ATG13 to the site of autophagosome biogenesis.
Fluid surface coatings for solid-state nanopores: comparison of phospholipid bilayers and archaea-inspired lipid monolayers
Authors: Eggenberger Olivia M , Leriche Geoffray , Koyanagi Takaoki , Ying Cuifeng , Houghtaling Jared , Schroeder Thomas B H , Yang Jerry , Li Jiali , Hall Adam , Mayer Michael
Published: April 2019

In the context of sensing and characterizing single proteins with synthetic nanopores, lipid bilayer coatings provide at least four benefits: first, they minimize unwanted protein adhesion to the pore walls by exposing a zwitterionic, fluid surface. Second, they can slow down protein translocation and rotation by the opportunity to tether proteins with a lipid anchor to the fluid bilayer coating. Third, they provide the possibility to impart analyte specificity by including lipid anchors with a specific receptor or ligand in the coating. Fourth, they offer a method for tuning nanopore diameters by choice of the length of the lipid’s acyl chains. The work presented here compares four properties of various lipid compositions with regard to their suitability as nanopore coatings for protein sensing experiments: (1) electrical noise during current recordings through solid-state nanopores before and after lipid coating, (2) long-term stability of the recorded current baseline and, by inference, of the coating, (3) viscosity of the coating as quantified by the lateral diffusion coefficient of lipids in the coating, and (4) the success rate of generating a suitable coating for quantitative nanopore-based resistive pulse recordings. We surveyed lipid coatings prepared from bolaamphiphilic, monolayer-forming lipids inspired by extremophile archaea and compared them to typical bilayer-forming phosphatidylcholine lipids containing various fractions of curvature-inducing lipids or cholesterol. We found that coatings from archaea-inspired lipids provide several advantages compared to conventional phospholipids; the stable, low noise baseline qualities and high viscosity make these membranes especially suitable for analysis that estimates physical protein parameters such as the net charge of proteins as they enable translocation events with sufficiently long duration to time-resolve dwell time distributions completely. The work presented here reveals that the ease or difficulty of coating a nanopore with lipid membranes did not depend significantly on the composition of the lipid mixture, but rather on the geometry and surface chemistry of the nanopore in the solid state substrate. In particular, annealing substrates containing the nanopore increased the success rate of generating stable lipid coatings.
ClinOmicsTrailbc: a visual analytics tool for breast cancer treatment stratification
Authors: Schneider Lara , Kehl Tim , Thedinga Kristina , Grammes Nadja Liddy , Backes Christina , Mohr Christopher , Schubert Benjamin , Lenhof Kerstin , Gerstner Nico , Hartkopf Andreas Daniel , Wallwiener Markus , Kohlbacher Oliver , Keller Andreas , Meese Eckart , Graf Norbert , Lenhof Hans-Peter
Published: April 2019

Motivation

Breast cancer is the second leading cause of cancer death among women. Tumors, even of the same histopathological subtype, exhibit a high genotypic diversity that impedes therapy stratification and that hence must be accounted for in the treatment decision-making process.

Results

Here, we present ClinOmicsTrailbc, a comprehensive visual analytics tool for breast cancer decision support that provides a holistic assessment of standard-of-care targeted drugs, candidates for drug repositioning and immunotherapeutic approaches. To this end, our tool analyzes and visualizes clinical markers and (epi-)genomics and transcriptomics datasets to identify and evaluate the tumor’s main driver mutations, the tumor mutational burden, activity patterns of core cancer-relevant pathways, drug-specific biomarkers, the status of molecular drug targets and pharmacogenomic influences. In order to demonstrate ClinOmicsTrailbc’s rich functionality, we present three case studies highlighting various ways in which ClinOmicsTrailbc can support breast cancer precision medicine. ClinOmicsTrailbc is a powerful integrated visual analytics tool for breast cancer research in general and for therapy stratification in particular, assisting oncologists to find the best possible treatment options for their breast cancer patients based on actionable, evidence-based results.

Availability and implementation

ClinOmicsTrailbc can be freely accessed at https://clinomicstrail.bioinf.uni-sb.de.

Supplementary information

Supplementary data are available at Bioinformatics online.
Evidence for Similar Prefrontal Structural and Functional Alterations in Male and Female Rats Following Chronic Stress or Glucocorticoid Exposure
Authors: Anderson Rachel M , Johnson Shane B , Lingg Ryan T , Hinz Dalton C , Romig-Martin Sara A , Radley Jason J
Published: April 2019

Previous work of ours and others has documented regressive changes in neuronal architecture and function in the medial prefrontal cortex (mPFC) of male rats following chronic stress. As recent focus has shifted toward understanding whether chronic stress effects on mPFC are sexually dimorphic, here we undertake a comprehensive analysis to address this issue. First, we show that chronic variable stress (14-day daily exposure to different challenges) resulted in a comparable degree of adrenocortical hyperactivity, working memory impairment, and dendritic spine loss in mPFC pyramidal neurons in both sexes. Next, exposure of female rats to 21-day regimen of corticosterone resulted in a similar pattern of mPFC dendritic spine attrition and increase in spine volume. Finally, we examined the effects of another widely used regimen, chronic restraint stress (CRS, 21-day of daily 6-h restraint), on dendritic spine changes in mPFC in both sexes. CRS resulted in response decrements in adrenocortical output (habituation), and induced a pattern of consistent, but less widespread, dendritic spine loss similar to the foregoing challenges. Our data suggest that chronic stress or glucocorticoid exposure induces a relatively undifferentiated pattern of structural and functional alterations in mPFC in both males and females.
Mosaic Tetrasomy 9p Associated With Inflammatory Bowel Disease
Authors: Sifuentes-Dominguez Luis , Starokadomskyy Petro , Welch Jacob , Gurram Bhaskar , Park Jason Y , Koduru Prasad , Burstein Ezra
Published: April 2019

The genetic basis of inflammatory bowel disease remains to be elucidated completely. Here we report on a patient with inflammatory bowel disease who has mosaic tetrasomy of the short arm of chromosome 9, a genomic region that harbours the type I interferon gene cluster. We show that increased interferon activation is present in peripheral blood and intestinal tissue from this patient, similar to previous reports of autoinflammatory organ damage driven by interferon activation in other patients with this chromosomal abnormality. To our knowledge, this is the first case of tetrasomy 9p-associated interferonopathy driving intestinal inflammation and highlights the role that type-I interferon pathways can play in the pathogenesis of intestinal inflammation.
In silicoprediction and characterisation of secondary metabolite clusters in the plant pathogenic fungusVerticillium dahliae
Authors: Shi-Kunne Xiaoqian , Jové Roger de Pedro , Depotter Jasper R L , Ebert Malaika K , Seidl Michael F , Thomma Bart P H J
Published: April 2019

Fungi are renowned producers of natural compounds, also known as secondary metabolites (SMs) that display a wide array of biological activities. Typically, the genes that are involved in the biosynthesis of SMs are located in close proximity to each other in so-called secondary metabolite clusters. Many plant-pathogenic fungi secrete SMs during infection in order to promote disease establishment, for instance as cytocoxic compounds. Verticillium dahliae is a notorious plant pathogen that can infect over 200 host plants worldwide. However, the SM repertoire of this vascular pathogen remains mostly uncharted. To unravel the potential of V. dahliae to produce SMs, we performed in silico predictions and in-depth analyses of its secondary metabolite clusters. Using distinctive traits of gene clusters and the conserved signatures of core genes 25 potential SM gene clusters were identified. Subsequently, phylogenetic and comparative genomics analyses were performed, revealing that two putative siderophores, ferricrocin and TAFC, DHN-melanin and fujikurin may belong to the SM repertoire of V. dahliae.
A cost-effectiveness analysis of maternal and neonatal health interventions in Ethiopia
Authors: Memirie Solomon Tessema , Tolla Mieraf Taddesse , Desalegn Dawit , Hailemariam Mengistu , Norheim Ole Frithjof , Verguet Stéphane , Johansson Kjell Arne
Published: April 2019

Ethiopia is one of the sub-Saharan African countries contributing to the highest number of maternal and neonatal deaths. Coverage of maternal and neonatal health (MNH) interventions has remained very low in Ethiopia. We examined the cost-effectiveness of selected MNH interventions in an Ethiopian setting. We analysed 13 case management and preventive MNH interventions. For all interventions, we used an ingredients-based approach for cost estimation. We employed a static life table model to estimate the health impact of a 20% increase in intervention coverage relative to the baseline. We used disability-adjusted life years (DALYs) as the health outcome measure while costs were expressed in 2018 US$. Analyses were based on local epidemiological, demographic and cost data when available. Our finding shows that 12 out of the 13 interventions included in our analysis were highly cost-effective. Interventions targeting newborns such as neonatal resuscitation (institutional), kangaroo mother care and management of newborn sepsis with injectable antibiotics were the most cost-effective interventions with incremental cost-effectiveness ratios of US$7, US$8 and US$17 per DALY averted, respectively. Obstetric interventions (induction of labour, active management of third stage of labour, management of pre-eclampsia/eclampsia and maternal sepsis, syphilis treatment and tetanus toxoid during pregnancy) and safe abortion cost between US$100 and US$300 per DALY averted. Calcium supplementation for pre-eclampsia and eclampsia prevention was the least cost-effective, with a cost per DALY of about US$3100. Many of the MNH interventions analysed were highly cost-effective, and this evidence can inform the ongoing essential health services package revision in Ethiopia. Our analysis also shows that calcium supplementation does not appear to be cost-effective in our setting.
The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson’s disease
Authors: Yi Wei , MacDougall Emma J , Tang Matthew Y , Krahn Andrea I , Gan-Or Ziv , Trempe Jean-François , Fon Edward A
Published: April 2019

Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early-onset Parkinson’s disease (EOPD). Hundreds of naturally occurring Parkin variants have been reported, both in Parkinson's disease (PD) patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remain unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence—including measures of mitophagy and protein stability and predictive structural modeling—and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.
Precise genome editing using a CRISPR-Cas9 method highlights the role of CoERG11 amino acid substitutions in azole resistance in Candida orthopsilosis
Authors: Morio Florent , Lombardi Lisa , Binder Ulrike , Loge Cédric , Robert Estelle , Graessle Denise , Bodin Marine , Lass-Flörl Cornelia , Butler Geraldine , Le Pape Patrice
Published: April 2019

Background

Azoles are one of the main antifungal classes for the treatment of candidiasis. In the current context of emerging drug resistance, most studies have focused on Candida albicans, Candida glabrata or Candida auris but, so far, less is known about the underlying mechanisms of resistance in other species, including Candida orthopsilosis.

Objectives

We investigated azole resistance in a C. orthopsilosis clinical isolate recovered from a patient with haematological malignancy receiving fluconazole prophylaxis.

Methods

Antifungal susceptibility to fluconazole was determined in vitro (CLSI M27-A3) and in vivo (in a Galleria mellonella model of invasive candidiasis). The CoERG11 gene was then sequenced and amino acid substitutions identified were mapped on the predicted 3D structure of CoErg11p. A clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) genome-editing strategy was used to introduce relevant mutations into a fluconazole-susceptible C. orthopsilosis isolate.

Results

Compared with unrelated C. orthopsilosis isolates, the clinical isolate exhibited both in vitro and in vivo fluconazole resistance. Sequencing of the CoERG11 gene identified several amino acid substitutions, including two possibly involved in fluconazole resistance (L376I and G458S). Both mutations mapped close to the active site of CoErg11p. Engineering these mutations in a different genetic background using CRISPR-Cas9 demonstrated that G458S, but not L376I, confers resistance to fluconazole and voriconazole.

Conclusions

Our data show that the G458S amino acid substitution in CoERG11p, but not L376I, contributes to azole resistance in C. orthopsilosis. In addition to highlighting the potential of CRISPR-Cas9 technology for precise genome editing in the field of antifungal resistance, we discuss some points that are critical to improving its efficiency.
Research-grade data in the real world: challenges and opportunities in data quality from a pragmatic trial in community-based practices
Authors: Divney Anna A , Lopez Priscilla M , Huang Terry T , Thorpe Lorna E , Trinh-Shevrin Chau , Islam Nadia S
Published: April 2019

Randomized controlled trials face cost, logistic, and generalizability limitations, including difficulty engaging racial/ethnic minorities. Real-world data (RWD) from pragmatic trials, including electronic health record (EHR) data, may produce intervention evaluation findings generalizable to diverse populations. This case study of Project IMPACT describes unique barriers and facilitators of optimizing RWD to improve health outcomes and advance health equity in small immigrant-serving community-based practices. Project IMPACT tested the effect of an EHR-based health information technology intervention on hypertension control among small urban practices serving South Asian patients. Challenges in acquiring accurate RWD included EHR field availability and registry capabilities, cross-sector communication, and financial, personnel, and space resources. Although using RWD from community-based practices can inform health equity initiatives, it requires multidisciplinary collaborations, clinic support, procedures for data input (including social determinants), and standardized field logic/rules across EHR platforms.
The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer
Authors: Watanabe Hiromi , Kubo Toshio , Ninomiya Kiichiro , Kudo Kenichiro , Minami Daisuke , Murakami Etsuko , Ochi Nobuaki , Ninomiya Takashi , Harada Daijiro , Yasugi Masayuki , Ichihara Eiki , Ohashi Kadoaki , Fujiwara Keiichi , Hotta Katsuyuki , Tabata Masahiro , Maeda Yoshinobu , Kiura Katsuyuki
Published: April 2019

Introduction

Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients.

Methods

We defined ‘rechallenge’ as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers.

Results

A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8–2.6] and 6.5 months [95% CI: 1.4–19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs.

Conclusions

In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.
Elevating H3K27me3 level sensitizes colorectal cancer to oxaliplatin
Authors: Wang Qi , Chen Xi , Jiang Yuhang , Liu Sanhong , Liu Hanshao , Sun Xiaohua , Zhang Haohao , Liu Zhi , Tao Yu , Li Cuifeng , Hu Yiming , Liu Dandan , Ye Deji , Liu Yongzhong , Wang Mingliang , Zhang Xiaoren
Published: April 2019

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
The effects of 50 Hz magnetic field–exposed cell culture medium on cellular functions in FL cells
Authors: Fei Yue , Su Liling , Lou Haifeng , Zhao Chuning , Wang Yiqin , Chen Guangdi
Published: April 2019

Although extremely low frequency magnetic fields (ELF-MFs) have been classified as a possible carcinogen for humans by the International Agency for Research on Cancer (IARC), their biological effects and underlying mechanisms are still unclear. Our previous study indicated that ELF-MF exposure influenced the relative permittivity of the saline solution, suggesting that the MF exposure altered physical properties of the solution. To explore the biophysical mechanism of ELF-MF–induced biological effects, this study examined the effects of 50 Hz sinusoidal MF at 0–4.0 mT on the permittivity of culture medium with phase-interrogation surface plasmon resonance (SPR) sensing. Then, the biological effects of MF pre-exposed culture medium on cell viability, the mitogen-activated protein kinase (MAPK) signaling pathways, oxidative stress, and genetic stabilities were analyzed using Cell Counting Kit-8, western blot, flow cytometry, γH2AX foci formation, and comet assay. The results showed that SPR signals were decreased under MF exposure in a time- and dose-dependent manner, and the decreased SPR signals were reversible when the exposure was drawn off. However, MF pre-exposed culture medium did not significantly change cell viability, intracellular reactive oxygen species level, activation of the MARK signaling pathways, or genetic stabilities in human amniotic epithelial cells (FL cells). In conclusion, our data suggest that the relative permittivity of culture medium was influenced by 50 Hz MF exposure, but this change did not affect the biological processes in FL cells.
PhyloToL: A Taxon/Gene-Rich Phylogenomic Pipeline to Explore Genome Evolution of Diverse Eukaryotes
Authors: Cerón-Romero Mario A , Maurer-Alcalá Xyrus X , Grattepanche Jean-David , Yan Ying , Fonseca Miguel M , Katz L A
Published: April 2019

Estimating multiple sequence alignments (MSAs) and inferring phylogenies are essential for many aspects of comparative biology. Yet, many bioinformatics tools for such analyses have focused on specific clades, with greatest attention paid to plants, animals, and fungi. The rapid increase in high-throughput sequencing (HTS) data from diverse lineages now provides opportunities to estimate evolutionary relationships and gene family evolution across the eukaryotic tree of life. At the same time, these types of data are known to be error-prone (e.g., substitutions, contamination). To address these opportunities and challenges, we have refined a phylogenomic pipeline, now named PhyloToL, to allow easy incorporation of data from HTS studies, to automate production of both MSAs and gene trees, and to identify and remove contaminants. PhyloToL is designed for phylogenomic analyses of diverse lineages across the tree of life (i.e., at scales of >100 My). We demonstrate the power of PhyloToL by assessing stop codon usage in Ciliophora, identifying contamination in a taxon- and gene-rich database and exploring the evolutionary history of chromosomes in the kinetoplastid parasite Trypanosoma brucei, the causative agent of African sleeping sickness. Benchmarking PhyloToL’s homology assessment against that of OrthoMCL and a published paper on superfamilies of bacterial and eukaryotic organellar outer membrane pore-forming proteins demonstrates the power of our approach for determining gene family membership and inferring gene trees. PhyloToL is highly flexible and allows users to easily explore HTS data, test hypotheses about phylogeny and gene family evolution and combine outputs with third-party tools (e.g., PhyloChromoMap, iGTP).
Responsive self-assembly of tectoRNAs with loop–receptor interactions from the tetrahydrofolate (THF) riboswitch
Authors: Mitchell Charles , Polanco Julio A , DeWald Laura , Kress Dustin , Jaeger Luc , Grabow Wade W
Published: April 2019

Naturally occurring RNAs are known to exhibit a high degree of modularity, whereby specific structural modules (or motifs) can be mixed and matched to create new molecular architectures. The modular nature of RNA also affords researchers the ability to characterize individual structural elements in controlled synthetic contexts in order to gain new and critical insights into their particular structural features and overall performance. Here, we characterized the binding affinity of a unique loop–receptor interaction found in the tetrahydrofolate (THF) riboswitch using rationally designed self-assembling tectoRNAs. Our work suggests that the THF loop–receptor interaction has been fine-tuned for its particular role as a riboswitch component. We also demonstrate that the thermodynamic stability of this interaction can be modulated by the presence of folinic acid, which induces a local structural change at the level of the loop–receptor. This corroborates the existence of a THF binding site within this tertiary module and paves the way for its potential use as a THF responsive module for RNA nanotechnology and synthetic biology.
MRPrimerW2: an enhanced tool for rapid design of valid high-quality primers with multiple search modes for qPCR experiments
Authors: Jeon Hajin , Bae Jeongmin , Hwang Sang-Hyun , Whang Kyu-Young , Lee Hyun-Seob , Kim Hyerin , Kim Min-Soo
Published: April 2019

For the best results in quantitative polymerase chain reaction (qPCR) experiments, it is essential to design high-quality primers considering a multitude of constraints and the purpose of experiments. The constraints include many filtering constraints, homology test on a huge number of off-target sequences, the same constraints for batch design of primers, exon spanning, and avoiding single nucleotide polymorphism (SNP) sites. The target sequences are either in database or given as FASTA sequences, and the experiment is for amplifying either each target sequence with each corresponding primer pairs designed under the same constraints or all target sequences with a single pair of primers. Many websites have been proposed, but none of them including our previous MRPrimerW fulfilled all the above features. Here, we describe the MRPrimerW2, the update version of MRPrimerW, which fulfils all the features by maintaining the advantages of MRPrimerW in terms of the kinds and sizes of databases for valid primers and the number of search modes. To achieve it, we exploited GPU computation and a disk-based key-value store using PCIe SSD. The complete set of 3 509 244 680 valid primers of MRPrimerW2 covers 99% of nine important organisms in an exhaustive manner. Free access: http://MRPrimerW2.com
Reporting Methodology of Neurosurgical Studies Utilizing the American College of Surgeons-National Surgical Quality Improvement Program Database: A Systematic Review and Critical Appraisal
Authors: Yolcu Yagiz , Wahood Waseem , Alvi Mohammed Ali , Kerezoudis Panagiotis , Habermann Elizabeth B , Bydon Mohamad
Published: April 2019

BACKGROUND

Use of large databases such as the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) has become increasingly common in neurosurgical research.

OBJECTIVE

To perform a critical appraisal and evaluation of the methodological reporting for studies in neurosurgical literature that utilize the ACS-NSQIP database.

METHODS

We queried Ovid MEDLINE, EMBASE, and PubMed databases for all neurosurgical studies utilizing the ACS-NSQIP. We assessed each study according to number of criteria fulfilled with respect to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement, REporting of studies Conducted using Observational Routinely-collected Health Data (RECORD) Statement, and Journal of American Medical Association–Surgical Section (JAMA-Surgery) Checklist. A separate analysis was conducted among papers published in core and noncore journals in neurosurgery according to Bradford's law.

RESULTS

A total of 117 studies were included. Median (interquartile range [IQR]) scores for number of fulfilled criteria for STROBE Statement, RECORD Statement, and JAMA-Surgery Checklist were 20 (IQR:19-21), 9 (IQR:8-9), and 6 (IQR:5-6), respectively. For STROBE Statement, RECORD Statement, and JAMA-Surgery Checklist, item 9 (potential sources of bias), item 13 (supplemental information), and item 9 (missing data/sensitivity analysis) had the highest number of studies with no fulfillment among all studies (56, 68, 50%), respectively. When comparing core journals vs noncore journals, no significant difference was found (STROBE, P = .94; RECORD, P = .24; JAMA-Surgery checklist, P = .60).

CONCLUSION

While we observed an overall satisfactory reporting of methodology, most studies lacked mention of potential sources of bias, data cleaning methods, supplemental information, and external validity. Given the pervasive role of national databases and registries for research and health care policy, the surgical community needs to ensure the credibility and quality of such studies that ultimately aim to improve the value of surgical care delivery to patients.