bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel equivalent definition of Caputo fractional derivative without singular kernel and superconvergent analysis
Authors: Liu Zhengguang , Li Xiaoli
Published: May 2018

In this article, we present a new second-order finite difference discrete scheme for a fractal mobile/immobile transport model based on equivalent transformative Caputo formulation. The new transformative formulation takes the singular kernel away to make the integral calculation more efficient. Furthermore, this definition is also effective where α is a positive integer. Besides, the T-Caputo derivative also helps us to increase the convergence rate of the discretization of the α-order(0 < α < 1) Caputo derivative from O(τ2−α) to O(τ3−α), where τ is the time step. For numerical analysis, a Crank-Nicolson finite difference scheme to solve the fractal mobile/immobile transport model is introduced and analyzed. The unconditional stability and a priori estimates of the scheme are given rigorously. Moreover, the applicability and accuracy of the scheme are demonstrated by numerical experiments to support our theoretical analysis.
Design and fabrication of plasmonic cavities for magneto-optical sensing
Authors: Loughran T. H. J. , Roth J. , Keatley P. S. , Hendry E. , Barnes W. L. , Hicken R. J. , Einsle J. F. , Amy A. , Hendren W. , Bowman R. M. , Dawson P.
Published: May 2018

The design and fabrication of a novel plasmonic cavity, intended to allow far-field recovery of signals arising from near field magneto-optical interactions, is presented. Finite element modeling is used to describe the interaction between a gold film, containing cross-shaped cavities, with a nearby magnetic under-layer. The modeling revealed strong electric field confinement near the center of the cross structure for certain optical wavelengths, which may be tuned by varying the length of the cross through a range that is compatible with available fabrication techniques. Furthermore, the magneto optical Kerr effect (MOKE) response of the composite structure can be enhanced with respect to that of the bare magnetic film. To confirm these findings, cavities were milled within gold films deposited upon a soluble film, allowing relocation to a ferromagnetic film using a float transfer technique. Cross cavity arrays were fabricated and characterized by optical transmission spectroscopy prior to floating, revealing resonances at optical wavelengths in good agreement with the finite element modeling. Following transfer to the magnetic film, circular test apertures within the gold film yielded clear magneto-optical signals even for diameters within the sub-wavelength regime. However, no magneto-optical signal was observed for the cross cavity arrays, since the FIB milling process was found to produce nanotube structures within the soluble under-layer that adhered to the gold. Further optimization of the fabrication process should allow recovery of magneto-optical signal from cross cavity structures.
Nanostructured porous carbons with high rate cycling and floating performance for supercapacitor application
Authors: Ochai-Ejeh F. O. , Momodu D. Y. , Madito M. J. , Khaleed A. A. , Oyedotun K. O. , Ray S. C. , Manyala N.
Published: May 2018

Biomass-derived activated carbon from cork (Quercus Suber) (ACQS) was prepared via a two-step environment-friendly route using mild KHCO3 as the activating agent. This synthesis route makes the material produced less toxic for usage as electrode material for energy storage application. The ACQS has well-defined microporous and mesoporous structures and a specific surface area of 1056.52 m2 g-1 and pore volume of 0.64 cm3 g-1. Three-electrode tests were performed in 6 M KOH, 1 M H2SO4 and 3 M KNO3 aqueous electrolytes, to analyse the material performance in acidic, basic, and neutral media. Specific capacitance values (Cs) of 133 F g-1/167 F g-1 at 1.0 A g-1 was obtained in 3 M KNO3 in the positive/negative potential windows. Due to the observed best performance in neutral 3 M KNO3, further electrochemical analysis of the symmetric device was carried out using the same electrolyte. The device displayed a Cs value of 122 F g-1, energy and power densities of ∼14 W h kg-1 and 450 W kg-1 respectively; at 0.5 A g-1. The device also displayed an excellent stability after potentiostatic floating at a maximum voltage of 1.8 V for 120 h and ∼100% capacitance retention after 10,000 charge-discharge cycles. The excellent stability makes the cork-derived material a potential excellent, cost-effective material for supercapacitor application.
High performance hybrid silicon micropillar solar cell based on light trapping characteristics of Cu nanoparticles
Authors: Zhang Yulong , Fan Zhiqiang , Zhang Weijia , Ma Qiang , Jiang Zhaoyi , Ma Denghao
Published: May 2018

High performance silicon combined structure (micropillar with Cu nanoparticles) solar cell has been synthesized from N-type silicon substrates based on the micropillar array. The combined structure solar cell exhibited higher short circuit current rather than the silicon miropillar solar cell, which the parameters of micropillar array are the same. Due to the Cu nanoparticles were decorated on the surface of silicon micropillar array, the photovoltaic properties of cells have been improved. In addition, the optimal efficiency of 11.5% was measured for the combined structure solar cell, which is better than the silicon micropillar cell.
Perspective: The role of mechanobiology in the etiology of brain
metastasis
Authors: Tanner Kandice
Published: May 2018

Tumor latency and dormancy are obstacles to effective cancer treatment. In brain metastases, emergence of a lesion can occur at varying intervals from diagnosis and in some cases following successful treatment of the primary tumor. Genetic factors that drive brain metastases have been identified, such as those involved in cell adhesion, signaling, extravasation, and metabolism. From this wealth of knowledge, vexing questions still remain; why is there a difference in strategy to facilitate outgrowth and why is there a difference in latency? One missing link may be the role of tissue biophysics of the brain microenvironment in infiltrating cells. Here, I discuss the mechanical cues that may influence disseminated tumor cells in the brain, as a function of age and disease. I further discuss in vitro and in vivo preclinical models such as 3D culture systems and zebrafish to study the role of the mechanical environment in brain metastasis in an effort of providing novel targeted therapeutics.
High p-type doping, mobility, and photocarrier lifetime in arsenic-doped CdTe single crystals
Authors: Nagaoka Akira , Kuciauskas Darius , McCoy Jedidiah , Scarpulla Michael A.
Published: May 2018

Group-V element doping is promising for simultaneously maximizing the hole concentration and minority carrier lifetime in CdTe for thin film solar cells, but there are roadblocks concerning point defects including the possibility of self-compensation by AX metastability. Herein, we report on doping, lifetime, and mobility of CdTe single crystals doped with As between 1016 and 1020 cm−3 grown from the Cd solvent by the travelling heater method. Evidence consistent with AX instability as a major contributor to compensation in samples doped below 1017 cm−3 is presented, while for higher-doped samples, precipitation of a second phase on planar structural defects is also observed and may explain spatial variation in properties such as lifetime. Rapid cooling after crystal growth increases doping efficiency and mobility for times up to 20–30 days at room temperature with the highest efficiencies observed close to 45% and a hole mobility of 70 cm2/Vs at room temperature. A doping limit in the low 1017/cm3 range is observed for samples quenched at 200–300 °C/h. Bulk minority carrier lifetimes exceeding 20 ns are observed for samples doped near 1016 cm−3 relaxed in the dark and for unintentionally doped samples, while a lifetime of nearly 5 ns is observed for 1018 cm−3 As doping. These results help us to establish limits on properties expected for group-V doped CdTe polycrystalline thin films for use in photovoltaics.
A full-dimensional potential energy surface and quantum dynamics of inelastic collision process for H2–HF
Authors: Yang Dongzheng , Huang Jing , Zuo Junxiang , Hu Xixi , Xie Daiqian
Published: May 2018

A full-dimensional ab initio potential energy surface for the H2–HF van der Waals complex was constructed by employing the coupled-cluster singles and doubles with noniterative inclusion of connected triples with augmented correlation-consistent polarised valence quadruple-zeta basis set plus bond functions. Using the improved coupled-states approximation including the nearest neighbor Coriolis couplings, we calculated the state-to-state scattering dynamics for pure rotational and ro-vibrational energy transfer processes. For pure rotational energy transfer, our results showed a different dynamical behavior for para-H2 and ortho-H2 in collision with hydrogen fluoride (HF), which is consistent with the previous study. Interestingly, some strong resonant peaks were presented in the cross sections for ro-vibrational energy transfer. In addition, the calculated vibrational-resolved rate constant is in agreement with the experimental results reported by Bott et al. These dynamics data can be further applied to the numerical simulation of HF chemical lasers.
Real-time heat input monitoring towards robust GMA brazing
Authors: Makwana Pinaac , Goecke Sven-F , De Amitava
Published: May 2018

Gas metal arc (GMA) brazing of thin sheets requires active control of heat input, filler alloy deposition and temperature field on sheet surface. A novel attempt is presented here for a rapid synchronous real-time monitoring of current and voltage transients, filler alloy depositions and temperature field using, respectively, a high-frequency recorder, high-speed videography and two thermal infrared cameras during GMA brazing of galvanized steel sheets. For heat inputs from 100 to 200 J mm−1, the peak temperature varied from 1500 to 1700 K. The high-speed videography showed consistent filler deposition and bead profile. The methodology and results presented here depict a promising resource for real-time monitoring and feedback control of GMA brazing.
Self‐rated wellbeing and physical activity associations in European older adults
Authors: Peralta Miguel , Martins João , Gómez Chávez Francisco , Cortés Almanzar Paola , Marques Adilson
Published: May 2018

Background: Physical activity and self‐rated wellbeing have important benefits to health. However, scientific knowledge regarding their relationship among older adults is scarce. Thus, the aim of this study was to examine the associations between physical activity frequency and several dimensions of self‐rated wellbeing, in a representative sample of European older adults from 28 countries. Methods: This study is based on the European Social Survey round 6, 2012. It had a total sample size of 12,341 older adults (5100 men, 7241 women) with mean age 73.8 ± 6.6 years. Information was collected through a questionnaire, filled‐in during an hour‐long face‐to‐face interview. Physical activity was accessed using the question “On how many of the last 7 days you were physically active continuously for 20 minutes or longer?” and six dimensions of self‐rated wellbeing were used. Results: Physical activity in the last 7 days was linearly related with all dimension of the self‐rated wellbeing and with wellbeing total score for both sexes (men, β = 0.09, 95% CI: 0.07 to 0.10, p < .001; women, β = 0.10, 95% CI: 0.09 to 0.11, p < .001). Conclusions: Physical activity promotion should be stressed as a meaningful strategy to improve people's wellbeing overall. This strategy has special importance when considering the older adult population.
Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes
Authors: Du Ying , Zhao Yingjun , Li Chuan , Zheng Qiuyang , Tian Jing , Li Zhuyi , Huang Timothy Y. , Zhang Wei , Xu Huaxi
Published: May 2018

β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.
Half Wing N219 Aircraft Model Clean Configuration for Flutter Test On Low Speed Wind Tunnel
Authors: Syamsuar Sayuti , Sampurno Budi , Mahasti Katia Mayang , Sakti Pratama Muchamad Bayu , Sasongko Triyono Widi , Kartika Nina , Suksmono Adityo , Aji Saputro Mohamad Ivan , Eskayudha Dimas Bahtera
Published: May 2018

Flutter is a rapid self-feeding motion which is caused by the interaction of aerodynamic, structural and inertial forces. Flutter can cause major damage on aircraft structure which can lead to fatal accident in aviation. Several methods have been evolved to avoid the flutter phenomena occur during the flight envelope of aircraft design. On this study, method was developed by Indonesian Aerospace which consist of Finite Element Method (FEM) analysis, Ground Vibration Test (GVT), and Wind Tunnel Flutter Test (WTT). Based on the study, FEM have similar results toward to Wind Tunnel Flutter Test conjunction the clean configuration of N219 aircraft half wing model.
Trial production of fuel pellet from Acacia mangium bark waste biomass
Authors: Amirta R , Anwar T , Sudrajat  , Yuliansyah  , Suwinarti W
Published: May 2018

Fuel pellet is one of the innovation products that can be produced from various sources of biomass such as agricultural residues, forestry and also wood industries including wood bark. Herein this paper, the potential fuel pellet production using Acacia mangium bark that abundant wasted from chip mill industry was studied. Fuel pellet was produced using a modified animal feed pellet press machine equipped with rotating roller-cylinders. The international standards quality of fuel pellet such as ONORM (Austria), SS (Sweden), DIN (Germany), EN (European) and ITEBE (Italy) were used to evaluate the optimum composition of feedstock and additive used. Theresults showed the quality offuel pellet produced were good compared to commercial sawdust pellet. Mixed of Acacia bark (dust) with 10% of tapioca and 20% of glycerol (w/w) was increased the stable form of pellet and the highest heating value to reached 4,383 Kcal/kg (calorific value). Blending of Acacia bark with tapioca and glycerol was positively improved its physical, chemical and combustion properties to met the international standards requirement for export market. Based on this finding, production of fuel pellet from Acacia bark waste biomass was promising to be developed as an alternative substitution of fossil energy in the future.
Correcting mistakes in predicting distributions
Authors: Marot-Lassauzaie Valérie , Bernhofer Michael , Rost Burkhard
Published: May 2018

Motivation

Many applications monitor predictions of a whole range of features for biological datasets, e.g. the fraction of secreted human proteins in the human proteome. Results and error estimates are typically derived from publications.

Results

Here, we present a simple, alternative approximation that uses performance estimates of methods to error-correct the predicted distributions. This approximation uses the confusion matrix (TP true positives, TN true negatives, FP false positives and FN false negatives) describing the performance of the prediction tool for correction. As proof-of-principle, the correction was applied to a two-class (membrane/not) and to a seven-class (localization) prediction.

Availability and implementation

Datasets and a simple JavaScript tool available freely for all users at http://www.rostlab.org/services/distributions.

Supplementary information

Supplementary data are available at Bioinformatics online.
Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents
Authors: Kadri Sameer S , Adjemian Jennifer , Lai Yi Ling , Spaulding Alicen B , Ricotta Emily , Prevots D Rebecca , Palmore Tara N , Rhee Chanu , Klompas Michael , Dekker John P , Powers John H , Suffredini Anthony F , Hooper David C , Fridkin Scott , Danner Robert L ,   National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH–ARORI)
Published: May 2018

Background

Resistance to all first-line antibiotics necessitates the use of less effective or more toxic “reserve” agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for ≥1 active first-line antibiotic.

Methods

The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ß-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to ≥1 first-line agent, and graded loss of active categories.

Results

Between 2009–2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0–1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1–1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0–1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3–5 to 1–2 to 0.

Conclusion

Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance.
High Risk of Plasmodium vivax Malaria Following Splenectomy in Papua, Indonesia
Authors: Kho Steven , Andries Benediktus , Poespoprodjo Jeanne R , Commons Robert J , Shanti Putu A I , Kenangalem Enny , Douglas Nicholas M , Simpson Julie A , Sugiarto Paulus , Anstey Nicholas M , Price Ric N
Published: May 2018

In Papua, splenectomized individuals have greater risk of malaria in the 12 months following splenectomy but not of mortality. Malaria risk was higher for Plasmodium vivax than P. falciparum. Early radical cure and prophylaxis are warranted in malaria endemic areas.
Sunspot drawings by Japanese official astronomers in 1749–1750
Authors: Hayakawa Hisashi , Iwahashi Kiyomi , Fujiyama Masashi , Kawai Toshiki , Toriumi Shin , Hotta Hideyuki , Iijima Haruhisa , Imada Shinsuke , Tamazawa Harufumi , Shibata Kazunari
Published: May 2018

Sunspot observations with telescopes in the 18th century were carried out in Japan as well as elsewhere. One of these sunspot observations is recorded in an account called Sansaizusetsu narabini Kansei irai Jissoku Zusetsu (Charts of Three Worlds and Diagrams of Actual Observations since Kansei Era). We have analyzed manuscripts of this account to show a total of 15 sunspot drawings during 1749–1750. These observations are considered to be carried out by contemporary official astronomers in Japan, with telescopes covered by zongurasus (< zonglas in Dutch, corresponding to “sunglass” in English). We counted their group number of sunspots to locate them in long-term solar activity and show that their observations were situated near the solar maximum in 1750. We also computed their locations and areas, while we have to admit differences of the variant manuscripts with one another. These observational records show the spread of sunspot observations not only in Europe, but also in Japan, and hence may contribute to crosscheck, or possibly to improve the known sunspot indices.
Antisense transcription in Pseudomonas aeruginosa
Authors: Eckweiler Denitsa , Häussler Susanne
Published: May 2018

A large number of antisense transcripts have been detected in diverse microbial genomes and considerable effort has been devoted to elucidating the functional role of antisense transcription. In this study, we reanalysed extensive RNA sequencing data from the opportunistic pathogen Pseudomonas aeruginosa and found that the majority of genes have a propensity for antisense transcription. Although antisense transcripts were found in more than 80 % of the genes of the P. aeruginosa genome, the majority of sequencing reads were mapping sense and only a minority (<2 %) were mapping antisense to genes. Similarly to the sense expression levels, the antisense expression levels varied under different environmental conditions, with the sense and antisense expression levels often being inversely regulated and modulated by the activity of alternative sigma factors. Environment-modulated antisense transcription showed a bias towards being antisense to genes within regions of genomic plasticity and to those encoding small regulatory RNAs. In the future, the validation and functional characterization of antisense transcripts, and novel transcripts that are antisense to small regulatory RNAs in particular, have the potential to contribute to our understanding of the various levels of transcriptional regulation and its dynamics in the bacterial pathogen P. aeruginosa.
Sun navigation requires compass neurons inDrosophila
Authors: Giraldo Ysabel Milton , Leitch Katherine J. , Ros Ivo K. , Warren Timothy L. , Weir Peter T. , Dickinson Michael H.
Published: May 2018

To follow a straight course, animals must maintain a constant heading relative to a fixed, distant landmark, a strategy termed menotaxis. In experiments using a flight simulator, we found thatDrosophilaadopt arbitrary headings with respect to a simulated sun, and individuals remember their heading preference between successive flights—even over gaps lasting several hours. Imaging experiments revealed that a class of neurons within the central complex, which have been previously shown to act as an internal compass, track the azimuthal motion of a sun stimulus. When these neurons are silenced, flies no longer adopt and maintain arbitrary headings, but instead exhibit frontal phototaxis. Thus, without the compass system, flies lose the ability to execute menotaxis and revert to a simpler, reflexive behavior.

One sentence summary

Silencing the compass neurons in the central complex ofDrosophilaeliminates sun navigation but leaves phototaxis intact.
Walking Drosophila aim to maintain a neural heading estimate at an internal goal angle
Authors: Green Jonathan , Vijayan Vikram , Mussells Pires Peter , Adachi Atsuko , Maimon Gaby
Published: May 2018

While navigating their environment, many animals track their angular heading via the activity of heading-sensitive neurons. How internal heading estimates are used to guide navigational behavior, however, remains largely unclear in any species. We found that normal synaptic output from heading neurons in Drosophila is required for flies to stably maintain their trajectory along an arbitrary direction while navigating a simple virtual environment. We further found that if the heading estimate carried by these neurons is experimentally redirected by focal stimulation, the fly typically turns so as to rotate this internal heading estimate back towards the initial angle, while also slowing down until this correction has been made. These experiments argue that flies compare an internal heading estimate with an internal goal angle to guide navigational decisions, highlighting an important computation underlying how a spatial variable in the brain is translated into navigational action.

One Sentence Summary

Flies compare an internal heading estimate with an internal goal angle to guide navigation.
Combinations of DIPs and Dprs control organization of olfactory receptor neuron terminals in Drosophila
Authors: Barish Scott , Nuss Sarah , Strunilin Ilya , Bao Suyang , Mukherjee Sayan , Jones Corbin , Volkan Pelin C.
Published: May 2018

In Drosophila, 50 classes of olfactory receptor neurons (ORNs) connect to 50 class-specific and uniquely positioned glomeruli in the antennal lobe. Despite the identification of cell surface receptors regulating axon guidance, how ORN axons sort to form 50 stereotypical glomeruli remains unclear. Here we show that the heterophilic cell adhesion proteins, DIPs and Dprs, are expressed in ORNs during glomerular formation. Each ORN class expresses a unique combination of DIPs/dprs, with neurons of the same class expressing interacting partners, suggesting a role in class-specific self-adhesion ORN axons. Analysis of DIP/Dpr expression revealed that ORNS that target neighboring glomeruli have different combinations, and ORNs with very similar DIP/Dpr combinations can project to distant glomeruli in the antennal lobe. Perturbations of DIP/dpr gene function result in local projection defects of ORN axons and glomerular positioning, without altering correct matching of ORNs with their target neurons. Our results suggest that context-dependent differential adhesion through DIP/Dpr combinations regulate self-adhesion and sort ORN axons into uniquely positioned glomeruli.
Polymer brush bilayer at thermal equilibrium: A density functional theory approach
Authors: Edwards Mike John
Published: May 2018

By means of the density functional theory (DFT) framework, the longstanding problem of the polymer brush bilayers at thermal equilibrium is studied. The calculated density profiles reveal that the brushes balance compression and interpenetration when they come into contact. The equation of state of the polymer brush bilayers is obtained and it represents scaling of the pressure with molecular parameters and distance between substrates. The results of this study may shed light in our understanding of some severe Musculoskeletal diseases which degrade the synovium. The significance of this study lays on the fact that the molecular structure is investigated through fundamental physical laws. So, this study bridges between theoretical biological physics and medicine.
Molecular mechanism of depolarization-dependent inactivation in W366F mutant of Kv1.2
Authors: Kondo H. X. , Yoshida N. , Shirota M. , Kinoshita K.
Published: May 2018

Voltage-gated potassium channels play crucial roles in regulating membrane potential. They are activated by membrane depolarization, allowing the selective permeation of potassium ions across the plasma membrane, and enter a nonconducting state after lasting depolarization of membrane potential, a process known as inactivation. Inactivation in voltage-activated potassium channels occurs through two distinct mechanisms, N-type inactivation and C-type inactivation. C-type inactivation is caused by conformational changes in the extracellular mouth of the channel, while N-type inactivation is elicited by changes in the cytoplasmic mouth of the protein. The W434F-mutated Shaker channel is known as a nonconducting mutant and is in a C-type inactivation state at a depolarizing membrane potential. To clarify the structural properties of C-type inactivated protein, we performed molecular dynamics simulations of the wild-type and W366F (corresponding to W434F in Shaker) mutant of the Kv1.2-2.1 chimera channel. The W366F mutant was in a nearly nonconducting state with a depolarizing voltage and recovered from inactivation with a reverse voltage. Our simulations and 3D-RISM analysis suggested that structural changes in the selective filter upon membrane depolarization trap potassium ions around the entrance of the selectivity filter and prevent ion permeation. This pore restriction is involved in the molecular mechanism of C-type inactivation.
Voltage-sensitive dye delivery through the blood brain barrier using adenosine receptor agonist Regadenoson
Authors: Pak Rebecca W. , Kang Jeeun , Valentine Heather , Loew Leslie M. , Thorek Daniel L.J. , Boctor Emad M. , Wong Dean F. , Kang Jin U.
Published: May 2018

Optical imaging of brain activity has mostly employed genetically manipulated mice, which cannot be translated to clinical human usage. Observation of brain activity directly is challenging due to difficulty in delivering dyes and other agents through the blood brain barrier (BBB). Using fluorescence imaging, we have demonstrated the feasibility of delivering the near-infrared voltage-sensitive dye (VSD) IR-780 perchlorate to the brain tissue through pharmacological techniques, via an adenosine agonist (Regadenoson). Comparison of VSD fluorescence of mouse brains without and with Regadenoson showed significantly increased residence time of the fluorescence signal in the latter case, indicative of VSD diffusion into the brain tissue. Dose and timing of Regadenoson were varied to optimize BBB permeability for VSD delivery.
Genome assembly and gene expression in the American black bear provides new insights into the renal response to hibernation
Authors: Srivastava Anuj , Sarsani Vishal Kumar , Fiddes Ian , Sheehan Susan M. , Seger Rita L. , Barter Mary E. , Neptune-Bear Selena , Lindqvist Charlotte , Korstanje Ron
Published: May 2018

The prevalence of chronic kidney disease (CKD) is rising worldwide and 10-15% of the global population currently suffers from CKD and its complications. Given the increasing prevalence of CKD there is an urgent need to find novel treatment options. The American black bear (Ursus americanus) copes with months of lowered kidney function and metabolism during hibernation without the devastating effects on metabolism and other consequences observed in humans. In a biomimetic approach to better understand kidney adaptations and physiology in hibernating black bears, we established a high-quality genome assembly. Subsequent RNA-Seq analysis of kidneys comparing gene expression profiles in black bears entering (late fall) and emerging (early spring) from hibernation identified 169 protein-coding genes that were differentially expressed. Of these, 101 genes were downregulated and 68 genes were upregulated after hibernation. Fold changes ranged from 1.8-fold downregulation (RTN4RL2) to 2.4-fold upregulation (CISH). Most notable was the upregulation of cytokine suppression genes (SOCS2, CISH, and SERPINC1) and the lack of increased expression of cytokines and genes involved in inflammation. The identification of these differences in gene expression in the black bear kidney may provide new insights in the prevention and treatment of CKD.
Trans-ethnic polygenic analysis supports genetic overlaps of lumbar disc degeneration with height, body mass index, and bone mineral density
Authors: Zhou Xueya , Cheung Ching-Lung , Karasugi Tatsuki , Karppinen Jaro , Samartzis Dino , Hsu Yi-Hsiang , Mak Timothy Shin-Heng , Song You-Qiang , Chiba Kazuhiro , Kawaguchi Yoshiharu , Li Yan , Chan Danny , Cheung Kenneth Man-Chee , Ikegawa Shiro , Cheah Kathryn Song-Eng , Sham Pak Chung
Published: May 2018

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, although phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.
MiRNA expression profiles of serum exosomes derived from individuals with latent and active tuberculosis
Authors: Lyu Lingna , Wang Jinghui , Jia Hongyan , Pan Liping , Li Zihui , Du Fengjiao , Du Boping , Sun Qi , Zhang Zongde
Published: May 2018

Tuberculosis (TB) has become a leading cause of death worldwide, which is largely attributed to the difficulties in diagnosis and treatment of TB patients. Exosomes carrying RNA, particularly miRNA, have been indicated their functional and diagnostic potential in diseases, including tuberculosis (TB). In the present study, we performed RNA-seq based analysis on exosomal miRNA profiles for clinical specimens of healthy controls (HC), active tuberculosis (TB) and latent tuberculosis infection (LTBI). We identified many distinct up-regulated and down-regulated differentially expressed miRNA and further screened top 20 in each compared groups which might provide a potential panel for differentiation of HC, LTBI, and TB. We classified all the differentially expressed miRNAs into six expression patterns and identified three persistently up-regulated miRNA (hsa-miR-140-3p, hsa-miR-3184-5p and hsa-miR-423-3p) as potential markers during TB progression. Combined with our previously detected exsomal mRNA, we screened the genes overlapped with predicted mRNA targets of differentially expressed miRNA and analyzed their involvement in Biological Process, indicating a decreased signaling transduction and increased cell death in LTBI and TB. Our results indicate the selective packaging of RNA cargoes into exosomes under different stages of Mycobacterium tuberculosis infection and facilitate further study of TB pathogenesis and development.

IMPORTANCE

The main reason for failure to eliminate TB is lack of understanding molecular mechanism of TB pathogenesis and difficulties in TB diagnosis and treatment. Exosomes provide a promising research tool because they are released from various cells containing valuable biochemical information related to diseases. We reveale distinct miRNA expression profile of the exosomes, which indicates selective packaging of RNA cargoes into exosomes under different stages of Mycobacterium tuberculosis infection. Further, we also provide evidence of related miRNA candidates potentially involving in TB progression and facilitating discovery of TB biomarkers.
The Effects of Vancomycin on the Viability and Osteogenic Potential of Bone-derived Mesenchymal Stem Cells
Authors: Booysen Elzaan , Sadie-Van Gijsen Hanél , Deane Shelly M. , Ferris William , Dicks Leon M.T.
Published: May 2018

Periprosthetic joint infections (PJI), caused by methicillin-resistant Staphylococcus aureus (MRSA), is the major cause of total hip arthroplasty (THA) failures. Traditionally, MRSA is treated with vancomycin, administrated intravenously or applied directly onto infected tissue. The effect of direct (as opposed to systemic) vancomycin treatment on bone formation and remodelling is largely unknown. The minimal inhibitory concentration (MIC) of vancomycin was determined by adding 200 μl of different concentrations (1 – 20 μg/ml) to actively growing cultures of S. aureus Xen 31 (methicillin-resistant) and S. aureus Xen 36 (methicillin-sensitive), respectively, and recording changes in optical density over 24 h. Bone marrow-derived and proximal femur-derived mesenchymal stem cells (bmMSCs and pfMSCs) from rat femora were exposed to 1 x MIC (5 μg/ml) and 4 x MIC (20 μg/ml) of vancomycin for 7 days. Cell viability was determined by staining with crystal violet and MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), respectively, and osteogenic differentiation by staining with Alizarin Red S. Vancomycin had no effect on the viability of bmMSCs and pfMSCs, even at high levels (20 μg/ml). The osteogenic differentiation of pfMSCs was partially inhibited, while osteogenesis in bmMSCs was not severely affected. The direct application of vancomycin to infected bone tissue, even at excessive levels, may preserve the viability of resident MSC populations. Short-term demineralization may thus be reversed after cessation of vancomycin treatment, improving the outcome of THA surgery.
Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes
Authors: Wangchuk Phurpa , Constantinoiu Constantin , Kouremenos Konstantinos A. , Becker Luke , Jones Linda , Shepherd Catherine , Buitrago Geraldine , Giacomin Paul , Daly Norelle , McConville Malcolm J. , Ryan Rachael Y. M. , Miles John J. , Loukas Alex
Published: May 2018

Iatrogenic hookworm therapy shows promise for treating disorders that result from a dysregulated immune system, including inflammatory bowel disease (IBD). Here we use a metabolomics approach to characterize the non-protein small molecule complement of hookworms. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of somatic tissue extracts revealed the presence of 52 polar metabolites and 22 non-polar components including short chain fatty acids (SCFA). Several of these small metabolites, notably the SCFA, have been shown to have anti-inflammatory properties in various diseases, including IBD. Using a murine model of colitis and human peripheral blood mononuclear cells, we demonstrate that somatic tissue extracts of the hookwormAncylostoma caninumcontain small molecules with anti-inflammatory activities. Of the five extracts tested, two of them significantly protected mice against T cell-mediated immunopathology and weight loss in a chemically-induced colitis model. Moreover, one of the anti-colitic extracts suppressedex vivoproduction of inflammatory cytokines from primary human leukocytes. While the origin of the SCFA (parasite or host microbiota-derived) present in the hookworm somatic tissue extracts cannot be ascertained from this study, it is possible thatA. caninummay be actively promoting an anti-inflammatory host microbiome by facilitating immune crosstalk through SCFA production.
On the Development of Sesamoid Bones
Authors: Eyal Shai , Rubin Sarah , Krief Sharon , Levin Lihi , Zelzer Elazar
Published: May 2018

Sesamoid bones are a special group of small auxiliary bones that form in proximity to joints and contribute to their stability and function. Sesamoid bones display high degree of variability in size, location, penetrance and anatomical connection to the main skeleton across vertebrate species. Therefore, providing a comprehensive developmental model or classification system for sesamoid bones is challenging. Here, we examine the developmental mechanisms of three anatomically different sesamoid bones, namely patella, lateral fabella and digit sesamoids. Through a comprehensive comparative analysis at the cellular, molecular and mechanical levels, we demonstrate that all three types of sesamoid bones originated fromSox9+/Scx+progenitors under the regulation of TGFβ and independent of mechanical stimuli from muscles. We show that BMP4 was necessary specifically for differentiation of patella but not of lateral fabella or digit sesamoids, whereas BMP2 regulated the growth of all examined sesamoids. Next, we show that whereas patella and digit sesamoids initially formed in juxtaposition to long bones, the lateral fabella formed independently at a distance. Finally, we provide evidence suggesting that while patella detached from the femur by formation of a synovial joint, digit sesamoids detached from the phalanx by a fibrocartilage joint. Collectively, these findings highlight both common and divergent molecular and mechanical features of sesamoid bone development, thereby advancing our understanding of their evolutionary plasticity.
CRISPR screen reveals that EHEC’s T3SS and Shiga toxin rely on shared host factors for infection
Authors: Pacheco Alline R. , Lazarus Jacob E. , Sit Brandon , Schmieder Stefanie , Lencer Wayne I. , Blondel Carlos J. , Doench John G. , Davis Brigid M. , Waldor Matthew K.
Published: May 2018

EnterohemorrhagicEscherichia coli(EHEC) has two critical virulence factors – a type III secretion system (T3SS) and Shiga toxins (Stx) – that are required for the pathogen to colonize the intestine and cause diarrheal disease. Here, we carried out a genome-wide CRISPR/Cas9 loss-of-function screen to identify host loci that facilitate EHEC infection of intestinal epithelial cells. Many of the guide RNAs identified targeted loci known to be associated with sphingolipid biosynthesis, particularly for production of globotriaosylceramide (Gb3), the Stx receptor. Two loci (TM9SF2 and LAPTM4A) with largely unknown functions were also targeted. Mutations in these loci not only rescued cells from Stx-mediated cell death, but also prevented cytotoxicity associated with the EHEC T3SS. These mutations interfered with early events associated with T3SS and Stx pathogenicity, markedly reducing entry of T3SS effectors into host cells and binding of Stx. The convergence of Stx and T3SS onto overlapping host targets provides guidance for design of new host-directed therapeutic agents to counter EHEC infection.

Importance

EnterohemorrhagicEscherichia coli(EHEC) has two critical virulence factors – a type III secretion system (T3SS) and Shiga toxins (Stx) – that are required for colonizing the intestine and causing diarrheal disease. We screened a genome-wide collection of CRISPR mutants derived from intestinal epithelial cells and identified mutants with enhanced survival following EHEC infection. Many had mutations that disrupted synthesis of a subset of lipids (sphingolipids) that includes the Stx receptor globotriaosylceramide (Gb3), and hence protect against Stx intoxication. Unexpectedly, we found that sphingolipids also mediate early events associated with T3SS pathogenicity. Since antibiotics are contraindicated for the treatment of EHEC, therapeutics targeting sphingolipid biosynthesis are a promising alternative, as they could provide protection against both of the pathogen’s key virulence factors.
Knowledge, attitudes and awareness of the human papillomavirus among health professionals in New Zealand
Authors: Sherman Susan M. , Bartholomew Karen , Denison Hayley J. , Patel Hersha , Moss Esther L. , Douwes Jeroen , Bromhead Collette
Published: May 2018

Background

Human papillomavirus (HPV) is a common sexually transmitted infection that is implicated in 99.7% of cervical cancers and several other cancers that affect both men and women. Despite the role that HPV plays in an estimated 5% of all cancers and the evolving role of HPV vaccination and testing in protecting the public against these cancers, preliminary research in New Zealand health care professionals suggest knowledge about HPV may not be sufficient.

Methods

A total of 230 practice nurses, smear takers and other clinical and laboratory staff who attended a range of training events completed a cross-sectional survey between April 2016 and July 2017. The survey explored four broad areas: demographics and level of experience, HPV knowledge (general HPV knowledge, HPV triage and test of cure (TOC) knowledge and HPV vaccine knowledge), attitudes towards the HPV vaccine and self-perceived adequacy of HPV knowledge.

Results

The mean score on the general HPV knowledge questions was 13.2 out of 15, with only 25.2% of respondents scoring 100%. In response to an additional question, 14.0% thought (or were unsure) that HPV causes HIV/AIDS. The mean score on the HPV Triage and TOC knowledge questions was 7.4 out of 10, with only 9.1% scoring 100%. The mean score on the HPV vaccine knowledge questions was 6.0 out of 7 and 44.3% scored 100%. Only 62.6% of respondents agreed or strongly agreed that they were adequately informed about HPV, although 71.8% agreed or strongly agreed that they could confidently answer HPV-related questions asked by patients. Multivariate analyses revealed that knowledge in each domain predicted confidence in responding to patient questions. Furthermore, the number of years since training predicted both HPV knowledge and Triage and TOC knowledge.

Discussion

Although overall level of knowledge was adequate, there were significant gaps in knowledge, particularly about the role of HPV testing in the New Zealand National Cervical Screening Programme. More education is required to ensure that misinformation and stigma do not inadvertently result from interactions between health practitioners and the public.