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  • 1
    Publication Date: 2018-10-31
    Description: by Erin S. Kelleher, Jaweria Jaweria, Uchechukwu Akoma, Lily Ortega, Wenpei Tang Transposable elements (TEs) are obligate genetic parasites that propagate in host genomes by replicating in germline nuclei, thereby ensuring transmission to offspring. This selfish replication not only produces deleterious mutations—in extreme cases, TE mobilization induces genotoxic stress that prohibits the production of viable gametes. Host genomes could reduce these fitness effects in two ways: resistance and tolerance. Resistance to TE propagation is enacted by germline-specific small-RNA-mediated silencing pathways, such as the Piwi-interacting RNA (piRNA) pathway, and is studied extensively. However, it remains entirely unknown whether host genomes may also evolve tolerance by desensitizing gametogenesis to the harmful effects of TEs. In part, the absence of research on tolerance reflects a lack of opportunity, as small-RNA-mediated silencing evolves rapidly after a new TE invades, thereby masking existing variation in tolerance. We have exploited the recent historical invasion of the Drosophila melanogaster genome by P -element DNA transposons in order to study tolerance of TE activity. In the absence of piRNA-mediated silencing, the genotoxic stress imposed by P -elements disrupts oogenesis and, in extreme cases, leads to atrophied ovaries that completely lack germline cells. By performing quantitative trait locus (QTL) mapping on a panel of recombinant inbred lines (RILs) that lack piRNA-mediated silencing of P -elements, we uncovered multiple QTL that are associated with differences in tolerance of oogenesis to P -element transposition. We localized the most significant QTL to a small 230-kb euchromatic region, with the logarithm of the odds (LOD) peak occurring in the bruno locus, which codes for a critical and well-studied developmental regulator of oogenesis. Genetic, cytological, and expression analyses suggest that bruno dosage modulates germline stem cell (GSC) loss in the presence of P -element activity. Our observations reveal segregating variation in TE tolerance for the first time, and implicate gametogenic regulators as a source of tolerant variants in natural populations.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 2
    Publication Date: 2018-10-31
    Description: by Michael A. Henson, Poonam Phalak The gut microbiota represent a highly complex ecosystem comprised of approximately 1000 species that forms a mutualistic relationship with the human host. A critical attribute of the microbiota is high species diversity, which provides system robustness through overlapping and redundant metabolic capabilities. The gradual loss of bacterial diversity has been associated with a broad array of gut pathologies and diseases including malnutrition, obesity, diabetes and inflammatory bowel disease. We formulated an in silico community model of the gut microbiota by combining genome-scale metabolic reconstructions of 28 representative species to explore the relationship between species diversity and community growth. While the individual species offered a broad range of metabolic capabilities, communities optimized for maximal growth on simulated Western and high-fiber diets had low diversities and imbalances in short-chain fatty acid (SCFA) synthesis characterized by acetate overproduction. Community flux variability analysis performed with the 28-species model and a reduced 20-species model suggested that enhanced species diversity and more balanced SCFA production were achievable at suboptimal growth rates. We developed a simple method for constraining species abundances to sample the growth-diversity tradeoff and used the 20-species model to show that tradeoff curves for Western and high-fiber diets resembled Pareto-optimal surfaces. Compared to maximal growth solutions, suboptimal growth solutions were characterized by higher species diversity, more balanced SCFA synthesis and lower exchange rates of crossfed metabolites between more species. We hypothesized that modulation of crossfeeding relationships through host-microbiota interactions could be an important means for maintaining species diversity and suggest that community metabolic modeling approaches that allow multiobjective optimization of growth and diversity are needed for more realistic simulation of complex communities.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 3
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    Public Library of Science (PLoS)
    Publication Date: 2018-10-31
    Description: by Maike E. Lindemann, Vanessa Stebner, Alexander Tschischka, Julian Kirchner, Lale Umutlu, Harald H. Quick Purpose The trend towards faster acquisition protocols in whole-body positron emission tomography/magnetic resonance (PET/MR) arises the question of whether short PET data acquisition protocols in a whole-body multi-station context allow for reduced PET acquisition times while providing adequate PET image quality and accurate quantification parameters. The study goal is to investigate how reducing PET acquisition times affects PET image quality and quantification in whole-body PET/MR in patients with oncologic findings. Methods Fifty-one patients with different oncologic findings underwent a clinical whole-body 18F-Fluorodeoxyglucose PET/MR examination. PET data was reconstructed with 4, 3, 2, and 1 min/bed time intervals for each patient to simulate the effect of reduced PET acquisition times. The 4-minute PET reconstructions served as reference standard. All whole-body PET data sets were analyzed regarding image quality, lesion detectability, PET quantification and standardized uptake values. Results A total of 91 lesions were detected in the 4-minute PET reconstructions. The same number of congruent lesions was also noticed in the 3 and 2 minutes-per-bed (mpb) reconstructed images. A total of 2 lesions in 2 patients was not detected in the 1 minute PET data reconstructions due to poor image quality. Image noise in the blood pool increased from 22.2% (4 mpb) to 42.1% (1 mpb). Signal-to-noise ratio declined with shorter timeframes from 13.1 (4 mpb) to 9.3 (1 mpb). SUV mean and SUV max showed no significant changes between 4 and 1 mpb reconstructed timeframes. Conclusions Reconstruction of PET data with different time intervals has shown that 2 minutes acquisition time per bed position instead of 4 minutes is sufficient to provide accurate lesion detection and adequate image quality in a clinical setting, despite the trends to lower image quality with shorter PET acquisition times. This provides latitude for potential reduction of PET acquisition times in fast PET/MR whole-body examinations.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2018-10-31
    Description: by Yu Hu, Yongkang Wong, Wentao Wei, Yu Du, Mohan Kankanhalli, Weidong Geng The surface electromyography (sEMG)-based gesture recognition with deep learning approach plays an increasingly important role in human-computer interaction. Existing deep learning architectures are mainly based on Convolutional Neural Network (CNN) architecture which captures spatial information of electromyogram signal. Motivated by the sequential nature of electromyogram signal, we propose an attention-based hybrid CNN and RNN (CNN-RNN) architecture to better capture temporal properties of electromyogram signal for gesture recognition problem. Moreover, we present a new sEMG image representation method based on a traditional feature vector which enables deep learning architectures to extract implicit correlations between different channels for sparse multi-channel electromyogram signal. Extensive experiments on five sEMG benchmark databases show that the proposed method outperforms all reported state-of-the-art methods on both sparse multi-channel and high-density sEMG databases. To compare with the existing works, we set the window length to 200ms for NinaProDB1 and NinaProDB2, and 150ms for BioPatRec sub-database, CapgMyo sub-database, and csl-hdemg databases. The recognition accuracies of the aforementioned benchmark databases are 87.0%, 82.2%, 94.1%, 99.7% and 94.5%, which are 9.2%, 3.5%, 1.2%, 0.2% and 5.2% higher than the state-of-the-art performance, respectively.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
    Publication Date: 2018-10-31
    Description: by Alexandra Richter, Alberto M. Gándara, Francisco Silva, Antonio Brante The slipper limpet Crepipatella dilatata , native to Chile and Argentina, was introduced in Spain in 2005. The species was thought to inhabit the region of Rias Bajas, yet recently, putative C . dilatata populations have been documented on the coast of north-central Spain and in the Ebro Delta of the Spanish Mediterranean. Here we undertook a multidisciplinary approach to study the invasion biology of this species. Specifically, two geographically distant populations, one being a successfully established population from O Grove and the other a declining population from Gijon, were studied over the course of four years. Analyses of morphological and developmental traits as well as genetic information confirmed the presence of C . dilatata in these sites. The results revealed polymorphism in anatomical traits and shell shape. Shell shape polymorphism was unevenly distributed among sites and among sexes. Males were monomorphic, while females were polymorphic. Of the female morphotypes encountered, one was absent in the declining population from Gijón. Size at first female maturation and female size were greater in the declining population than in the established population. Reproductive success varied seasonally but not spatially among populations. In the established population, gregariousness was significantly greater; the size when sex changes was found to be plastic and socially controlled. The sex ratio of the declining population was female biased while in the established population the sex ratio changed during the study period from being balanced to being female biased. This change in sex ratio was probably due to higher male mortality. Molecular analyses pointed to the localities of Corral Bay in southern Chile and Puerto Madryn in southern Argentina as potential population sources. The intercontinental import of fresh mussels cultivated in Chilean farms is a likely source of this mussel in Spain. Comparison with available data of native populations of C . dilatata strongly indicate that ecophenotypic plasticity, socially controlled sex change, high gregariousness, increased nurse egg supply to viable larvae during the encapsulated developmental period, later maturation and larger female sizes altogether enhance establishment success of this non-indigenous species. Human-mediated factors like the intraregional mussel trade and transplantation are also likely secondary dispersal mechanisms favouring the spread of this organism.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-10-31
    Description: by Evaldo Ferezin, Rouverson Pereira da Silva, Adão Felipe dos Santos, Cristiano Zerbato Hydraulic systems are equipment widely used in stationary industrial equipment and in moving agricultural equipment and construction machines. Currently, the rotation of the vibrating conveyor belt of the peanut digger-inverter is triggered by the tractor power take-off. Considering that for the equipment to operate at its optimal, the tractor engine needs to work at low rotation, responsible for the rotation of the power take-off, this work aimed at developing an electro-hydraulic system able to transmit varying work rotations to the vibrating conveyor belt of the digger-inverter, regardless the rotation of the power take-off and the speed used in the tractor. The electro-hydraulic system uses the oil of the auxiliary hydraulic system (remote control) and electric power of the tractor battery. The rotation of the hydraulic motor that drives the vibrating conveyor axis is controlled by a proportional flow control valve while the direction of rotation is determined by an electro-hydraulic directional valve, controlled by a Vcontrol Personal Device Assistant controller installed in the tractor cab. The electro-hydraulic system developed can be used to control the rotation of the vibrating conveyor belt of the peanut digger-inverter since it meets the torque and power requirements necessary to move the vibrating conveyor belt, with the respective rotation control.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
    Publication Date: 2018-11-01
    Description: by Nada Abdel Aziz, Justin Komguep Nono, Thabo Mpotje, Frank Brombacher Forkhead box P3 (Foxp3 + ) regulatory T (Treg)-cell function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, interleukin-4 (IL-4)-mediated signaling via IL-4 receptor alpha (IL-4Rα) mediates Treg cell transdifferentiation into ex-Foxp3 T helper 2 (Th2) or T helper 17 (Th17) cells. However, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. We generated Foxp3-specific IL-4Rα-deficient mice and demonstrated differential efficiency of IL-4Rα deletion in male (approximately 90%) and female (approximately 40%) animals, because of cyclic recombinase (Cre)-mediated X-linked foxp3 inactivation. Irrespective of the degree of IL-4Rα deletion within the Foxp3 + Treg cell population, mice showed exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections ( Schistosoma mansoni or Nippostrongylus brasiliensis ). Mechanistically, IL-4Rα deletion in males and females led to a reduced expression of Foxp3 and subsequently an impaired accumulation of Foxp3 + Treg cells to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4Rα-mediated signaling during helminth infections decreased the ability of central Treg cells to convert into effector Treg (eTreg) cells and caused a significant down-regulation of markers associated with Treg cell migration (C-X-C motif chemokine receptor 3 [CXCR3]) and accumulation in inflamed tissues (GATA binding protein 3 [GATA3]) as well as survival (B cell lymphoma 2 [Bcl-2]). These findings unprecedentedly, to our knowledge, uncover a role for IL-4Rα signaling in the positive regulation of Foxp3 + Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4Rα signaling in the negative regulation and transdifferentiation of Foxp3 + Treg cells in vivo, our present findings reveal the host requirement for an intact, but not reduced or potentiated, IL-4Rα-mediated signaling on Foxp3 + Treg cells to optimally control inflammation during helminth infections.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 8
    Publication Date: 2018-11-01
    Description: by Hanh Nguyen, Sara Labella, Nicola Silva, Verena Jantsch, Monique Zetka Correct segregation of meiotic chromosomes depends on DNA crossovers (COs) between homologs that culminate into visible physical linkages called chiasmata. COs emerge from a larger population of joint molecules (JM), the remainder of which are repaired as noncrossovers (NCOs) to restore genomic integrity. We present evidence that the RNF212-like C . elegans protein ZHP-4 cooperates with its paralog ZHP-3 to enforce crossover formation at distinct steps during meiotic prophase: in the formation of early JMs and in transition of late CO intermediates into chiasmata. ZHP-3/4 localize to the synaptonemal complex (SC) co-dependently followed by their restriction to sites of designated COs. RING domain mutants revealed a critical function for ZHP-4 in localization of both proteins to the SC and for CO formation. While recombination initiates in zhp-4 mutants, they fail to appropriately acquire pro-crossover factors at abundant early JMs, indicating a function for ZHP-4 in an early step of the CO/NCO decision. At late pachytene stages, hypomorphic mutants exhibit significant levels of crossing over that are accompanied by defects in localization of pro-crossover RMH-1, MSH-5 and COSA-1 to designated crossover sites, and by the appearance of bivalents defective in chromosome remodelling required for segregation. These results reveal a ZHP-4 function at designated CO sites where it is required to stabilize pro-crossover factors at the late crossover intermediate, which in turn are required for the transition to a chiasma that is required for bivalent remodelling. Our study reveals an essential requirement for ZHP-4 in negotiating both the formation of COs and their ability to transition to structures capable of directing accurate chromosome segregation. We propose that ZHP-4 acts in concert with ZHP-3 to propel interhomolog JMs along the crossover pathway by stabilizing pro-CO factors that associate with early and late intermediates, thereby protecting designated crossovers as they transition into the chiasmata required for accurate disjunction.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by William M. Vanderheyden, Alan G. Goodman, Rebecca H. Taylor, Marcos G. Frank, Hans P. A. Van Dongen, Jason R. Gerstner Sleep contributes to cognitive functioning and is sufficient to alter brain morphology and function. However, mechanisms underlying sleep regulation remain poorly understood. In mammals, tumor necrosis factor-alpha (TNFα) is known to regulate sleep, and cytokine expression may represent an evolutionarily ancient mechanism in sleep regulation. Here we show that the Drosophila TNFα homologue, Eiger, mediates sleep in flies. We show that knockdown of Eiger in astrocytes, but not in neurons, significantly reduces sleep duration, and total loss-of-function reduces the homeostatic response to sleep loss. In addition, we show that neuronal, but not astrocyte, expression of the TNFα receptor superfamily member, Wengen, is necessary for sleep deprivation-induced homeostatic response and for mediating increases in sleep in response to human TNFα. These data identify a novel astrocyte-to-neuron signaling mechanism in the regulation of sleep homeostasis and show that the Drosophila cytokine, Eiger, represents an evolutionarily conserved mechanism of sleep regulation across phylogeny.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 10
    Publication Date: 2018-11-01
    Description: by Roy Burstein, Haidong Wang, Robert C. Reiner Jr, Simon I. Hay Background The addition of neonatal (NN) mortality targets in the Sustainable Development Goals highlights the increased need for age-specific quantification of mortality trends, detail that is not provided by summary birth histories (SBHs). Several methods exist to indirectly estimate trends in under-5 mortality from SBHs; however, efforts to monitor mortality trends in important age groups such as the first month and first year of life have yet to utilize the vast amount of SBH data available from household surveys and censuses. Methods and findings We analyzed 243 Demographic and Health Surveys (DHS) from 76 countries, which collected both complete and SBHs from 8.5 million children from 2.3 million mothers to develop a new empirically based method to indirectly estimate time trends in age-specific mortality. We used complete birth history (CBH) data to train a discrete hazards generalized additive model in order to predict individual hazard functions for children based on individual-, mother-, and country-year-level covariates. Individual-level predictions were aggregated over time by assigning probability weights to potential birth years from mothers from SBH data. Age-specific estimates were evaluated in three ways: using cross-validation, using an external database of an additional 243 non-DHS census and survey data sources, and comparing overall under-5 mortality to existing indirect methods.Our model was able to closely approximate trends in age-specific child mortality. Depending on age, the model was able to explain between 80% and 95% of the variation in the validation data. Bias was close to zero in every age, with median relative errors spanning from 0.96 to 1.09. For trends in all under-5s, performance was comparable to the methods used for the Global Burden of Disease (GBD) study and significantly better than the standard indirect (Brass) method, especially in the 5 years preceding a survey. For the 15 years preceding surveys, the new method and GBD methods could explain more than 95% of the variation in the validation data for under-5s, whereas the standard indirect variants tested could only explain up to 88%. External validation using census and survey data found close agreement with concurrent direct estimates of mortality in the NN and infant age groups. As a predictive method based on empirical data, one limitation is that potential issues in these training data could be reflected in the resulting application of the method out of sample. Conclusions This new method for estimating child mortality produces results that are comparable to current best methods for indirect estimation of under-5 mortality while additionally producing age-specific estimates. Use of such methods allows researchers to utilize a massive amount of SBH data for estimation of trends in NN and infant mortality. Systematic application of these methods could further improve the evidence base for monitoring of trends and inequalities in age-specific child mortality.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Ji Su Lee, Je-Ho Mun Background Venous lake (VL) is a common vascular tumor occurring on the lips in the elderly. VL is sometimes difficult to distinguish from melanotic lesions such as labial melanotic macule (LMM) or oral malignant melanoma. However, the dermoscopic features of VL have not been sufficiently established in the literature. Objective This study was aimed at investigating the dermoscopic features of VL on the lips, and to compare the dermoscopic features of VL with those of LMM. Methods We retrospectively investigated the dermoscopic findings of histopathologically proven cases of VL and LMM. Results The structureless pattern (78.6%) and globules/clods (42.9%) were the common patterns in VL cases. Purple was the most frequent color (78.6%), followed by red (42.9%) and blue (42.9%). The structureless pattern (p = 0.003) and the colors purple (p = 0.000), red (p = 0.003), and blue (p = 0.018) were significantly more common in VL than in LMM. In contrast, lines (p = 0.000) and dots (p = 0.044) as patterns, and brown (p = 0.000) and gray (p = 0.044) colors were significantly more frequent in LMM. White structures were more common in VL than in LMM (p = 0.001). Conclusion Structureless patterns or globules/clods with purple, red, or blue coloration can be useful findings when differentiating VLs from LMM on dermoscopy. Therefore, dermoscopic evaluation is a helpful noninvasive ancillary tool in the diagnosis of VL.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
    Publication Date: 2018-11-01
    Description: by Claudia P. Cabrera, Joanna Manson, Joanna M. Shepherd, Hew D. Torrance, David Watson, M. Paula Longhi, Mimoza Hoti, Minal B. Patel, Michael O’Dwyer, Sussan Nourshargh, Daniel J. Pennington, Michael R. Barnes, Karim Brohi
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 13
    Publication Date: 2018-11-01
    Description: by Jin-Won Noh, Young-mi Kim, Nabeel Akram, Ki-Bong Yoo, Jumin Park, Jooyoung Cheon, Young Dae Kwon, Jelle Stekelenburg Background Pakistan has a high burden of newborn mortality, which would be significantly preventable through appropriate routine immunization. The purpose of this study was to measure the basic timely childhood immunization coverage and to identify determinants of factors influencing childhood immunization coverage in Sindh, Pakistan. Methods Data from Maternal and Child Health Program Indicator Survey 2013–2014 which was conducted in Sindh province of Pakistan was used. Outcome measure was full coverage of the basic immunization schedule from child’s vaccination card. The association of receiving basic immunization with demographic factors, socioeconomic status, mother and child health information sources, and perinatal care factors were tested by binary logistic regression. Results Among 2,253 children, 1,156 (51.3%) received age-based full basic immunization. The basic immunization rates were 69.1% for under five weeks old, 38.3% for six to nine weeks, 18.8% for 10–13 weeks, 44.0% for 14 weeks-eight months, 60.4% for nine to 11 months, and 59.1% for over one year. Child’s age, number of living children, parents’ education level, wealth, the source of mother and child health information, number of antenatal care, and assistance during delivery were associated with completing basic immunization. Conclusions The overall full basic immunization coverage in Pakistan was still low. Policy makers should identify children at risk of low immunization coverage and obstacles of receiving antenatal care, implement educational interventions targeting on less educated parents, and conduct mass immunization campaigns for timely and complete immunization.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
    Publication Date: 2018-11-01
    Description: by Ellen Priscilla Nunes Gadelha, Rajendranath Ramasawmy, Bruna da Costa Oliveira, Nágila Moraes Rocha, Jorge Augusto de Oliveira Guerra, George Allan Villa Rouco da Silva, Tirza Gabrielle Ramos de Mesquita, Carolina Chrusciak Talhari Cortez, Anette Chrusciak Talhari Background American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil. Objectives The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose. Materials and methods This study was conducted as a controlled, randomized, open–label clinical trial for a total number of 159 patients with CL. Individuals aged 16–64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment. Results From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L . guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 15
    Publication Date: 2018-11-01
    Description: by Juan Carlos Quintero Vélez, Daniel Camilo Aguirre-Acevedo, Juan David Rodas, Margarita Arboleda, Adriana Troyo, Francisco Vega Aguilar, Lisardo Osorio Quintero, Carlos Rojas Arbeláez Introduction Most of the studies related to rickettsial infection in Colombia are cross-sectional because of the challenge in conducting prospective studies on infectious disease that may have a difficult diagnosis. Although cross-sectional studies are essential to detect people exposed to rickettsiae, they are not suited to demonstrate the recent circulation of this pathogen in areas at risk of transmission. Objective To characterize the epidemiology of incident cases of Spotted fever group (SFG) rickettsial infection in humans and equines from rural areas of Urabá region in Colombia where outbreaks of rickettsiae previously occurred. Materials and methods A prospective study was conducted in the Alto de Mulatos and Las Changas in the Urabá region. Serum samples and socio-ecological information were collected from 597 people enrolled in 2015, and a second sample was collected from 273 people a year later. Indirect immune-fluorescence assays for detection of IgG antibody against rickettsiae were done using slides with Rickettsia rickettsii antigens. A titer ≥128 was considered positive. Incident cases were defined as (i) serological conversion of IgG titers from seronegative to seropositive or (ii) at least a four-fold increase in IgG end point titers in the second sample. Results The cumulative incidence of rickettsial infection was 6.23% (95%CI 3.67–9.78) in humans and 32.31% (21/65) of incident cases in equines. Incident cases were mostly females (82.35%), the median age of cases was 41.02 years (IQR 18.62–54.1), and 29.41% reported tick bites during the study period. Results from multivariate analysis showed that removal of ticks after working outdoors is a protective factor for rickettsial infection (RR 0.26, 95%CI 0.08–0.84) and that a higher incidence of infection occurred in people who reported fever in the last year (RR 4.26, 95%CI 1.15–9.31). Conclusions These results showed recent circulation of SFG rickettsiae in areas where previous lethal outbreaks have been reported, supporting the implementation of preventive measures to halt rickettsial transmission in the studied communities.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 16
    Publication Date: 2018-11-01
    Description: by Casandra I. Montoro, Stefan Duschek, Daniel Schuepbach, Miguel A. Gandarillas, Gustavo A. Reyes del Paso
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
    Publication Date: 2018-11-01
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Bhagirath Singh Chauhan, Sudheesh Manalil, Singarayer Florentine, Prashant Jha
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 19
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Ra Ho, Lina D. Song, Jin A. Choi, Donghyun Jee Background Interventions that can facilitate early diagnosis of age-related macular degeneration (AMD) will facilitate early treatment and improve clinical outcomes but there has been concerns about additional medical costs to the health care system. An examination through a retina fundus photography by a non-specialist has been suggested as a potential cost-effective alternative to a direct examination by a specialist, but limited scientific data exists on the cost-effectiveness of screening strategies for AMD. Our objective is to conduct an economic evaluation of various population-wide screening strategies for AMD among the South Korean population. Methods and findings Using a Markov cohort model, we evaluated the cost-effectiveness of four AMD screening strategies (opportunistic examination, opportunistic treatment, systematic photography, and systematic examination) in comparison with status quo (no screening) for South Korean adults. We projected a life time horizon to study a hypothetical cohort of 100,00 persons of age 40 with and without AMD at baseline. The outcome measures were quality-adjusted life-years (QALYs) gained, cost from the societal perspective, and the incremental cost-effectiveness ratio (ICER) of each strategy. Interventions were evaluated at a willingness-to-pay (WTP) threshold of 30,000,000 KRW ($27,538) per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to address the model uncertainty. Opportunistic examination was strongly dominated because it generated fewer expected QALYs but incurred greater expected cost than the other screening strategies. The mean lifetime expected costs were 289,013 KRW, 363,692 KRW, 9,351,964 KRW, and 12,309,783 KRW, and the mean QALYs gained were 37.73, 37.75, 40.47, 40.68, for no screening, opportunistic treatment, systematic photography, and systematic examination, respectively. The results were most sensitive to the utility weight of mild AMD, the probability of complication from treatment, the cost of being in mild AMD, and the probability of recovery from complication. After eliminating the two weakly dominated strategies, systematic photography was cost-effective at the ICER of 3,310,448 KRW per QALY in comparison to status quo. Conclusions Under the WTP threshold of 30,000,000 KRW per QALY, systematic photography is cost-effective for screening AMD in South Korean adults. Systematic examination by ophthalmologists generates more expected QALY and cost compared to systematic photography.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 20
    Publication Date: 2018-11-01
    Description: by Jiang-Hui Zeng, Xu-Zhi Liang, Hui-Hua Lan, Xu Zhu, Xiu-Yun Liang Background MicroRNA is endogenous non-coding small RNA that negative regulate and control gene expression, and increasing evidence links microRNA to oncogenesis and the pathogenesis of cancer. The goal of this study was to explore the potential molecular mechanism of miR-375 in various cancers. Methods MiR-375 overexpression in different tumor cell lines was probed with microarray data from Gene Expression Omnibus (GEO). The common target genes of miR-375 were obtained by Robust Rank Aggregation (RRA), and identified by miRWalk2.0 software for target gene prediction. Additionally, we directed in silico analysis including Protein-Protein Interactions (PPI) analysis, gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways annotations to provide a summary of the function of miR-375 in various carcinomas. Eventually, data was obtained from The Cancer Genome Atlas (TCGA) were utilized for a validation in 7 cancers. Results The nine miR-375 related chips were acquired by the GEO data. The 5 down regulated genes came from 9 available microarray datasets, which overlapped with the potential target genes predicted by miRWalk2.0 software. The target genes were intensely enriched in amino acid biosynthetic and metabolic process from biological process (GO) and Cysteine and methionine metabolism (KEGG analysis). In view of these approaches, VASN, MAT2B, HERPUD1, TPAPPC6B and TAT are probably the most important miR-375 targets. In addition, miR-375 was negatively correlated with MAT2B, which was verified in 5 tumors of TCGA. Conclusion In summary, this study based on common target genes provides an innovative perspective for exploring the molecular mechanism of miR-375 in human tumors.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 21
    Publication Date: 2018-11-01
    Description: by Miloš Radojević, Bojan Janković, Vladimir Jovanović, Dragoslava Stojiljković, Nebojša Manić The pyrolysis process of various types of biomass (agricultural and wood by-products) in non-isothermal conditions using simultaneous thermal analyses (STA) was investigated. Devolatilization kinetics was implemented through combined application of model-free methods and DAEM (distributed activation energy model) using Gaussian distribution functions of activation energies. Results obtained were used in the curve prediction of the rate of mass loss against temperature at various heating rates by numerical optimization. The possible calculation of biomass samples behavior under pyrolytic conditions as the summation of their pseudo-components, hemicelluloses, cellulose, and lignin is also explored. The differences between experimental and calculated data are less than 3.20% offering a quality test of applicability of proposed model on the kinetic studies of a wide range of biomass samples. It seems that the most physically realistic model is the decomposition of biomass in three reactions, depending on the composition of the biomass regarding hemicelluloses, cellulose, and lignin. Kinetic model applied here may serve as a starting point to build more complex models capable of describing the thermal behavior of plant materials during thermochemical processing.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 22
    Publication Date: 2018-11-01
    Description: by Weerayut Wongjampa, Tipaya Ekalaksananan, Peechanika Chopjitt, Jureeporn Chuerduangphui, Pilaiwan Kleebkaow, Natcha Patarapadungkit, Chamsai Pientong MicroRNAs (miRNAs) are small non-coding RNAs that function to down-regulate gene expression involving in various cellular processes related to carcinogenesis. Recently, miR-22 was identified as a tumor-suppressing miRNA in many human cancers. However, the regulatory mechanism and the specific function of this miRNA in cervical cancer remain unclear. In the present study, we carried out gene transfection, western blot and quantitative RT-PCR to explore the regulatory mechanism and the functional role of miR-22 in cervical cancer. We verified that miR-22 was down-regulated in cervical cancer tissues and cervical cancer cell lines relative to matched non-tumor tissues and normal human cervical keratinocyte line (HCK1T). By contrast, histone deacetylase 6 (HDAC6) was inversely correlated with miR-22 in both cervical tissues and cancer cell lines. Mechanically, HDAC6 was down-regulated by miR-22 at the post-transcriptional level, via a specific target site within the 3’UTR, identified by a luciferase reporter assay. Moreover, we also showed that the correlation between miR-22 and HDAC6 expression was regulated by an E6/p53 pathway in HCK1Ts expressing HPV16 E6. For functional study, an ectopic expression of miR-22 could inhibit cell proliferation and migration, and could induce apoptosis of cervical cancer cell lines. These findings demonstrated that miR-22 was down-regulated in cervical cancer and inversely collated with its downstream target HDAC6. MiR-22 acts as tumor suppressor by inhibiting proliferation and migration, and by inducing apoptosis of cervical cancer cell lines by targeting the 3’UTR of HDAC6. This newly identified E6/p53/miR-22/HDAC6 regulatory network might be a candidate therapeutic target for cervical cancer.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
    Publication Date: 2018-11-01
    Description: by Naren Gajenthra Kumar, Daniel Contaifer Jr, Paul RS Baker, Kim Ekroos, Kimberly K. Jefferson, Dayanjan S. Wijesinghe Modification of the host lipidome via secreted enzymes is an integral, but often overlooked aspect of bacterial pathogenesis. In the current era of prevalent antibiotic resistance, knowledge regarding critical host pathogen lipid interactions has the potential for use in developing novel antibacterial agents. While most studies to date on this matter have focused on specific lipids, or select lipid classes, this provides an incomplete picture. Modern methods of untargeted lipidomics have the capacity to overcome these gaps in knowledge and provide a comprehensive understanding of the role of lipid metabolism in the pathogenesis of infections. In an attempt to determine the role of lipid modifying enzymes produced by staphylococci, we exposed bovine heart lipids, a standardized model for the mammalian lipidome, to spent medium from staphylococcal cultures, and analyzed lipid molecular changes by MS/MS ALL shotgun lipidomics. We elucidate distinct effects of different staphylococcal isolates, including 4 clinical isolates of the pathogenic species Staphylococcus aureus , a clinical isolate of the normally commensal species S . epidermidis , and the non-pathogenic species S . carnosus . Two highly virulent strains of S . aureus had a more profound effect on mammalian lipids and modified more lipid classes than the other staphylococcal strains. Our studies demonstrate the utility of the applied untargeted lipidomics methodology to profile lipid changes induced by different bacterial secretomes. Finally, we demonstrate the promise of this lipidomics approach in assessing the specificity of bacterial enzymes for mammalian lipid classes. Our data suggests that there may be a correlation between the bacterial expression of lipid-modifying enzymes and virulence, and could facilitate the guided discovery of lipid pathways required for bacterial infections caused by S . aureus and thereby provide insights into the generation of novel antibacterial agents.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 24
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Leontine Baje, Jonathan J. Smart, Andrew Chin, William T. White, Colin A. Simpfendorfer Coastal sharks with small body sizes may be among the most productive species of chondrichthyans. The Australian sharpnose shark ( Rhizoprionodon taylori ) is one of the most productive members of this group based on work in northern and eastern Australia. However, life history information throughout the remainder of its range is lacking. To address this knowledge gap, the age, growth and maturity of R . taylori caught in the Gulf of Papua prawn trawl fishery in Papua New Guinea, were studied. One hundred and eighty six individuals, comprising 131 females (31–66 cm TL) and 55 males (31–53 cm TL) were aged using vertebral analysis and growth was modelled using a multi-model approach. The lack of small individuals close to the size at birth made fitting of growth curves more difficult, two methods (fixed length at birth and additional zero aged individuals) accounting for this were trialled. The von Bertalanffy growth model provided the best fit to the data when used with a fixed length-at-birth (L 0 = 26 cm TL). Males ( L ∞ = 46 cm TL, k = 3.69 yr -1 , L 50 = 41.7 cm TL and A 50 = 0.5 years) grew at a faster rate and matured at smaller sizes and younger ages than females ( L ∞ = 58 cm TL, k = 1.98 yr -1 , L 5o = 47.0 cm TL and A 50 = 0.93 years). However, none of the methods to account for the lack of small individuals fully accounted for this phenomenon, and hence the results remain uncertain. Despite this, the results reaffirm the rapid growth of this species and suggest that the Gulf of Papua population may grow at a faster rate than Australian populations. Rhizoprionodon taylori is possibly well placed to withstand current fishing pressure despite being a common bycatch species in the Gulf of Papua prawn trawl fishery. However, further research needs to be undertaken to estimate other key life history parameters to fully assess the population status of this exploited shark species and its vulnerability to fishing in the Gulf of Papua.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 25
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Marcela Filipova, Oumsalama K. Elhelu, Silvia H. De Paoli, Zuzana Fremuntova, Tibor Mosko, Dusan Cmarko, Jan Simak, Karel Holada Evaluating nanoparticle (NP) toxicity in human cell systems is a fundamental requirement for future NP biomedical applications. In this study, we have designed a screening assay for assessing different types of cell death induced by NPs in human umbilical vein endothelial cell (HUVEC) culture. This assay consists of WST-8, LDH and Hoechst 33342 staining, all performed in one well, which enables an evaluation of cell viability, necrosis and apoptosis, respectively, in the same cell sample. The 96-well format and automated processing of fluorescent images enhances the assay rapidity and reproducibility. After testing the assay functionality with agents that induced different types of cell death, we investigated the endothelial toxicity of superparamagnetic iron oxide nanoparticles (SPIONs, 8 nm), silica nanoparticles (SiNPs, 7–14 nm) and carboxylated multiwall carbon nanotubes (CNTCOOHs, 60 nm). Our results indicated that all the tested NP types induced decreases in cell viability after 24 hours at a concentration of 100 μg/ml. SPIONs caused the lowest toxicity in HUVECs. By contrast, SiNPs induced pronounced necrosis and apoptosis. A time course experiment showed the gradual toxic effect of all the tested NPs. CNTCOOHs inhibited tetrazolium derivatives at 100 μg/ml, causing false negative results from the WST-8 and LDH assay. In summary, our data demonstrate that the presented “three-in-one” screening assay is capable of evaluating NP toxicity effectively and reliably. Due to its simultaneous utilization of two different methods to assess cell viability, this assay is also capable of revealing, if NPs interfere with tetrazolium salts.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 26
    Publication Date: 2018-11-01
    Description: by Pius G. Horumpende, Sophia H. Said, Festo S. Mazuguni, Magreth L. Antony, Happiness H. Kumburu, Tolbert B. Sonda, Charles E. Mwanziva, Stephen E. Mshana, Blandina T. Mmbaga, Debora C. Kajeguka, Jaffu O. Chilongola Self-medication is very common especially in developing countries and is documented to be associated with many health risks including antibiotic resistance. This study investigated the prevalence, determinants and knowledge of self-medication among residents of Siha District in Tanzania. A cross-sectional study was conducted among 300 residents in a rural District of Kilimanjaro region, North-eastern Tanzania from 1 st to 28 th April 2017. A semi-structured questionnaire was used to collect information regarding drugs used, knowledge, history and reasons for antibiotic self-medication. Log—binomial regression analysis was done using STATA 13 to examine factors associated with self-medication. A slightly majority of the respondents (58%) admitted to self-medication. Antibiotics most commonly utilized were amoxycillin (43%) and an antiprotozoal drug metronidazole (10%). The most common symptoms that led to self-medication were cough (51.17%), headache/ fever/ malaria (25.57%) and diarrhoea (21.59%). The most common reasons for self-medication were emergency illness (24.00%), health facility charges (20.33%), proximity of pharmacy to home (17.00%) and no reason (16.66%). Almost all reported that self-medication is not better than seeking medical consultation, 98% can result into harmful effects and 96% can result to drug resistance. The level of self-medication in this study is comparable with findings from other studies in developing countries. Pharmacies were commonly used as the first point of medical care. There is therefore a need for educative antibiotic legislative intervention to mitigate the adverse effects of antibiotic self-medication in Siha district in Tanzania.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 27
    Publication Date: 2018-11-01
    Description: by Jason Yap, Richard Fox, Natalie Narsia, Sonia Pinheiro-Maia, Rachel Pounds, Ciaran Woodman, David Luesley, Raji Ganesan, Sean Kehoe, Christopher Dawson Objective Dysregulation of the Hedgehog (Hh) pathway has been described in a variety of cancers, including cervical cancer, a disease which shares a common aetiology with vulval squamous cell carcinoma (VSCC). Here, we investigate a large number of primary VSCC cases for evidence of Hedgehog pathway activation and examine the implications of pathway activity on clinical outcomes in a cohort of patients with primary VSCC. Methods Archival histology blocks containing VSCC and histologically normal adjacent epithelium were retrieved from a cohort of 91 patients who underwent treatment for primary VSCC. Immunohistochemistry staining was undertaken to assess for the expression of key Hh pathway components (SHH, PTCH1, GLI1). A competing risks statistical model was used to evaluate the implications of the levels of key Hh pathway components on clinical outcomes. Results We show that 92% of primary VSCC cases over-expressed one or more components of the Hh signalling pathway when compared to the adjacent normal epithelium. While expression of SHH and GLI1 did not correlate with any clinicopathological criteria, over- or under-expression of PTCH1 was associated with a reduced or increased risk of developing a local disease recurrence, respectively. In VSCC arising on a background of Lichen Sclerosus, the risk of local recurrence was potentiated in cases where PTCH1 was under-expressed. Conclusions Our findings reveal, for the first time, that the Hh pathway is activated in VSCC and that PTCH1 expression can be used as a biomarker to stratify patients and inform clinicians of the risk of their local recurrence, particularly in cases of VSCC associated with LS.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 28
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Masami Fujiwara, Jesse D. Backstrom, Richard T. Woodward The effective management of fish populations requires understanding of both the biology of the species being managed and the behavior of the humans who harvest those species. For many marine fisheries, recreational harvests represent a significant portion of the total fishing mortality. For such fisheries, therefore, a model that captures the dynamics of angler choices and the fish population would be a valuable tool for fisheries management. In this study, we provide such a model, focusing on red drum and spotted seatrout, which are the two of the main recreational fishing targets in the Gulf of Mexico. The biological models are in the form of vector autoregressive models. The anglers’ decision model takes the discrete choice approach, in which anglers first decide whether to go fishing and then determine the location to fish based on the distance and expected catch of two species of fish if they decide to go fishing. The coupled model predicts that, under the level of fluctuation in the abundance of the two species experienced in the past 35 years, the number of trips that might be taken by anglers fluctuates moderately. This fluctuation is magnified as the cost of travel decreases because the anglers can travel long distance to seek better fishing conditions. On the other hand, as the cost of travel increases, their preference to fish in nearby areas increases regardless of the expected catch in other locations and variation in the trips taken declines. The model demonstrates the importance of incorporating anglers’ decision processes in understanding the changes in a fishing effort level. Although the model in this study still has a room for further improvement, it can be used for more effective management of fish and potentially other populations.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 29
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Brooke Rhead, Ina S. Brorson, Tone Berge, Cameron Adams, Hong Quach, Stine Marit Moen, Pål Berg-Hansen, Elisabeth Gulowsen Celius, Dipen P. Sangurdekar, Paola G. Bronson, Rodney A. Lea, Sean Burnard, Vicki E. Maltby, Rodney J. Scott, Jeannette Lechner-Scott, Hanne F. Harbo, Steffan D. Bos, Lisa F. Barcellos DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4 + and CD8 + T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter . Differential DNA methylation was observed near four loci: MOG / ZFP57 , HLA-DRB1 , NINJ2/LOC100049716 , and SLFN12 . Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1 , NINJ2 , and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12 , have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 30
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-01
    Description: by Juan Rivero de Aguilar, Fernando Castillo, Andrea Moreno, Nicolás Peñafiel, Luke Browne, Scott T. Walter, Jordan Karubian, Elisa Bonaccorso Habitat loss has the potential to alter vertebrate host populations and their interactions with parasites. Theory predicts a decrease in parasite diversity due to the loss of hosts in such contexts. However, habitat loss could also increase parasite infections as a result of the arrival of new parasites or by decreasing host immune defenses. We investigated the effect of habitat loss and other habitat characteristics on avian haemosporidian infections in a community of birds within a fragmented landscape in northwest Ecuador. We estimated Plasmodium and Haemoproteus parasite infections in 504 individual birds belonging to 8 families and 18 species. We found differences in infection status among bird species, but no relationship between forest fragment characteristics and infection status was observed. We also found a temporal effect, with birds at the end of the five-month study (which ran from the end of the rainy season thru the dry season), being less infected by Plasmodium parasites than individuals sampled at the beginning. Moreover, we found a positive relationship between forest area and Culicoides abundance. Taken as a whole, these findings indicate little effect of fragment characteristics per se on infection, although additional sampling or higher infection rates would have offered more power to detect potential relationships.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 31
    Publication Date: 2018-11-01
    Description: by Nicola Horstmann, Chau Nguyen Tran, Chelcy Brumlow, Sruti DebRoy, Hui Yao, Graciela Nogueras Gonzalez, Nishanth Makthal, Muthiah Kumaraswami, Samuel A. Shelburne The control of virulence regulator/sensor kinase (CovRS) two-component system is critical to the infectivity of group A streptococcus (GAS), and CovRS inactivating mutations are frequently observed in GAS strains causing severe human infections. CovS modulates the phosphorylation status and with it the regulatory effect of its cognate regulator CovR via its kinase and phosphatase activity. However, the contribution of each aspect of CovS function to GAS pathogenesis is unknown. We created isoallelic GAS strains that differ only by defined mutations which either abrogate CovR phosphorylation, CovS kinase or CovS phosphatase activity in order to test the contribution of CovR phosphorylation levels to GAS virulence, emergence of hypervirulent CovS-inactivated strains during infection, and GAS global gene expression. These sets of strains were created in both serotype M1 and M3 backgrounds, two prevalent GAS disease-causing serotypes, to ascertain whether our observations were serotype-specific. In both serotypes, GAS strains lacking CovS phosphatase activity (CovS-T284A) were profoundly impaired in their ability to cause skin infection or colonize the oropharynx in mice and to survive neutrophil killing in human blood. Further, response to the human cathelicidin LL-37 was abrogated. Hypervirulent GAS isolates harboring inactivating CovRS mutations were not recovered from mice infected with M1 strain M1-CovS-T284A and only sparsely recovered from mice infected with M3 strain M3-CovS-T284A late in the infection course. Consistent with our virulence data, transcriptome analyses revealed increased repression of a broad array of virulence genes in the CovS phosphatase deficient strains, including the genes encoding the key anti-phagocytic M protein and its positive regulator Mga, which are not typically part of the CovRS transcriptome. Taken together, these data establish a key role for CovS phosphatase activity in GAS pathogenesis and suggest that CovS phosphatase activity could be a promising therapeutic target in GAS without promoting emergence of hypervirulent CovS-inactivated strains.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 32
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Reshma Basak, Rishikesh Narayanan Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical signaling. We activated synaptic N-Methyl-d-Aspartate receptors through theta-burst stimulation (TBS) or pairing (TBP) and assessed microdomain propagation along a signaling pathway that included calmodulin, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1. We found that the spatiotemporal spread of the TBS-evoked microdomain in phosphorylated CaMKII (pCaMKII) was amplified in comparison to that of the corresponding calcium microdomain. Next, we assessed the role of two dendritically expressed inactivating channels, one restorative ( A -type potassium) and another regenerative ( T -type calcium), by systematically varying their conductances. Whereas A -type potassium channels suppressed the spread of pCaMKII microdomains by altering the voltage response to TBS, T -type calcium channels enhanced this spread by modulating TBS-induced calcium influx without changing the voltage. Finally, we explored cross-dependencies of these channels with other model components, and demonstrated the heavy mutual interdependence of several biophysical and biochemical properties in regulating microdomains and their spread. Our conclusions unveil a pivotal role for dendritic voltage-gated ion channels in actively amplifying or suppressing biochemical signals and their spatiotemporal spread, with critical implications for clustered synaptic plasticity, robust information transfer and efficient neural coding.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 33
    Publication Date: 2018-11-02
    Description: by Qianyan Li, Takamune T. Saito, Marina Martinez-Garcia, Alison J. Deshong, Saravanapriah Nadarajan, Katherine S. Lawrence, Paula M. Checchi, Monica P. Colaiacovo, JoAnne Engebrecht Breast cancer susceptibility gene 1 (BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination. The Caenorhabditis elegans orthologs, BRC-1 and BRD-1, also function in DNA damage repair, homologous recombination, as well as in meiosis. Using functional GFP fusions we show that in mitotically-dividing germ cells BRC-1 and BRD-1 are nucleoplasmic with enrichment at foci that partially overlap with the recombinase RAD-51. Co-localization with RAD-51 is enhanced under replication stress. As cells enter meiosis, BRC-1-BRD-1 remains nucleoplasmic and in foci, and beginning in mid-pachytene the complex co-localizes with the synaptonemal complex. Following establishment of the single asymmetrically positioned crossover on each chromosome pair, BRC-1-BRD-1 concentrates to the short arm of the bivalent. Localization dependencies reveal that BRC-1 and BRD-1 are interdependent and the complex fails to properly localize in both meiotic recombination and chromosome synapsis mutants. Consistent with a role for BRC-1-BRD-1 in meiotic recombination in the context of the synaptonemal complex, inactivation of BRC-1 or BRD-1 enhances the embryonic lethality of mutants defective in chromosome synapsis. Our data suggest that under meiotic dysfunction, BRC-1-BRD-1 stabilizes the RAD-51 filament and alters the recombination landscape; these two functions can be genetically separated from BRC-1-BRD-1’s role in the DNA damage response. Together, we propose that BRC-1-BRD-1 serves a checkpoint function at the synaptonemal complex where it monitors and modulates meiotic recombination.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 34
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Clareci Silva Cardoso, Antonio Luiz P. Ribeiro, Claudia Di Lorenzo Oliveira, Lea Campos Oliveira, Ariela Mota Ferreira, Ana Luiza Bierrenbach, José Luiz Padilha Silva, Enrico Antonio Colosimo, João Eduardo Ferreira, Tzong-Hae Lee, Michael P. Busch, Arthur Lawrence Reingold, Ester Cerdeira Sabino Background The effectiveness of anti-parasite treatment with benznidazole in the chronic Chagas disease (ChD) remains uncertain. We evaluated, using data from the NIH-sponsored SaMi-Trop prospective cohort study, if previous treatment with benznidazole is associated with lower mortality, less advanced cardiac disease and lower parasitemia in patients with chronic ChD. Methods The study enrolled 1,959 ChD patients and abnormal electrocardiogram (ECG) from in 21 remote towns in Brazil. A total of 1,813 patients were evaluated at baseline and after two years of follow-up. Those who received at least one course of benznidazole were classified as treated group (TrG = 493) and those who were never treated as control group (CG = 1,320). The primary outcome was death after two-year follow-up; the secondary outcomes were presence at the baseline of major ChD-associated ECG abnormalities, NT-ProBNP levels suggestive of heart failure, and PCR positivity. Results Mortality after two years was 6.3%; it was lower in the TrG (2.8%) than the CG (7.6%); adjusted OR: 0.37 (95%CI: 0.21;0.63). The ECG abnormalities typical for ChD and high age-adjusted NT-ProBNP levels suggestive of heart failure were lower in the TrG than the CG, OR: 0.35 [CI: 0.23;0.53]. The TrG had significantly lower rates of PCR positivity, OR: 0.35 [CI: 0.27;0.45]. Conclusion Patients previously treated with benznidazole had significantly reduced parasitemia, a lower prevalence of markers of severe cardiomyopathy, and lower mortality after two years of follow-up. If used in the early phases, benznidazole treatment may improve clinical and parasitological outcomes in patients with chronic ChD. Trial registration ClinicalTrials.gov, Trial registration: NCT02646943.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 35
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Peter A. Combs, Hunter B. Fraser Spatial patterning of gene expression is a key process in development, yet how it evolves is still poorly understood. Both cis- and trans-acting changes could participate in complex interactions, so to isolate the cis-regulatory component of patterning evolution, we measured allele-specific spatial gene expression patterns in D. melanogaster × simulans hybrid embryos. RNA-seq of cryo-sectioned slices revealed 66 genes with strong spatially varying allele-specific expression. We found that hunchback , a major regulator of developmental patterning, had reduced expression of the D. simulans allele specifically in the anterior tip of hybrid embryos. Mathematical modeling of hunchback cis-regulation suggested a candidate transcription factor binding site variant, which we verified as causal using CRISPR-Cas9 genome editing. In sum, even comparing morphologically near-identical species we identified surprisingly extensive spatial variation in gene expression, suggesting not only that development is robust to many such changes, but also that natural selection may have ample raw material for evolving new body plans via changes in spatial patterning.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 36
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 37
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Mikkel M. Andersen, David J. Balding Mitochondrial DNA (mtDNA) is useful to assist with identification of the source of a biological sample, or to confirm matrilineal relatedness. Although the autosomal genome is much larger, mtDNA has an advantage for forensic applications of multiple copy number per cell, allowing better recovery of sequence information from degraded samples. In addition, biological samples such as fingernails, old bones, teeth and hair have mtDNA but little or no autosomal DNA. The relatively low mutation rate of the mitochondrial genome (mitogenome) means that there can be large sets of matrilineal-related individuals sharing a common mitogenome. Here we present the mitolina simulation software that we use to describe the distribution of the number of mitogenomes in a population that match a given mitogenome, and investigate its dependence on population size and growth rate, and on a database count of the mitogenome. Further, we report on the distribution of the number of meioses separating pairs of individuals with matching mitogenome. Our results have important implications for assessing the weight of mtDNA profile evidence in forensic science, but mtDNA analysis has many non-human applications, for example in tracking the source of ivory. Our methods and software can also be used for simulations to help validate models of population history in human or non-human populations.
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    Electronic ISSN: 1553-7404
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  • 38
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Andrés Navarro, Luisa Rubiano, Juan David Arango, Carlos A. Rojas, Neal Alexander, Nancy Gore Saravia, Eliah Aronoff-Spencer Mobile applications (apps) can bring health research and its potential downstream benefits closer to underserved populations. Drawing on experience developing an app for detecting and referring cases of cutaneous leishmaniasis in Colombia, called Guaral/app, we review key steps in creating such mobile health (mHealth) tools. These require consideration of the sociotechnical context using methods such as systems analysis and human-centered design (HCD), predicated on engagement and iteration with all stakeholders. We emphasize usability and technical concerns and describe the interdependency of technical and human considerations for mHealth systems in rural communities.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 39
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Kahsay Huruy, Andargachew Mulu, Uwe Gerd Liebert, Melanie Maier
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 40
    Publication Date: 2018-11-02
    Description: by Mona El Khatib, Przemyslaw Bozko, Vindhya Palagani, Nisar P. Malek, Ludwig Wilkens, Ruben R. Plentz
    Electronic ISSN: 1932-6203
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  • 41
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Akihiro Nishio, Ryo Horita, Toshiyuki Marutani, Mayumi Yamamoto Background The WHO reported the gap between the need for treatment and its provision is huge in low- and middle-income countries. It is estimated there are lots of burden to obtain treatment in these countries. This survey intended to show the delay of their first visit to a psychiatric department and the factors that influence the delay. To elucidate the factors affecting medical accessibility for people with mental illness, we propose the concept of duration of untreated mental illness (DUM), which is the duration between the onset or first symptom of mental illness and the first visit to a psychiatric department or clinic. Methods Participants were 109 Cambodian adults (18 years old and up) who had a psychiatric consultation in one of the following hospitals. We analyzed the relationships between DUM and patients’ background; age, gender, economic status, education level, occupation, hospital access, and diagnosis. Results The average DUM of all participants was 34.8 ± 42.4 months, ranging from 0 to 240 There was no significant difference in DUM by difference in hospital, gender, age, hospital access, education level, occupation, or economic status. Only patient diagnosis was related to DUM. The DUM for patients with schizophrenia and epilepsy was long, while the DUM for patients with neurosis and substance use were short. Conclusion To compare DUM with that of other low- and middle-income countries, DUM of our survey is extremely long. However, those reports were from urban areas within the low- and middle-income countries. We considered our report to include a very important sample showing the condition of psychiatric services in rural areas of low-income countries.
    Electronic ISSN: 1932-6203
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  • 42
    Publication Date: 2018-11-02
    Description: by Burcu Şahin, Joaquín Gomis-Cebolla, Hatice Güneş, Juan Ferré Bacillus thuringiensis ( Bt ) constitutes the active ingredient of many successful bioinsecticides used in agriculture. In the present study, the genetic diversity and toxicity of Bt isolates was investigated by characterization of native isolates originating from soil, fig leaves and fruits from a Turkish collection. Among a total of 80 Bt isolates, 18 of them were found carrying a vip3 gene (in 23% of total), which were further selected. Insecticidal activity of spore/crystal mixtures and their supernatants showed that some of the Bt isolates had significantly more toxicity against some lepidopteran species than the HD1 reference strain. Five isolates were analyzed by LC-MS/MS to determine the Cry protein composition of their crystals. The results identified the Cry1Ac protein and a Cry2A-type protein in all isolates, Cry1Ea in 3 of them and Cry1Aa in one. The sequence analysis of the new vip3 genes showed that they had a high similarity to either vip3Aa , vip3Af or vip3Ag (94–100%). The vip3Aa gene of the 6A Bt isolate was cloned and sequenced. The protein was named Vip3Aa65 by the Bacillus thuringiensis Nomenclature Committee. The expressed and purified Vip3Aa65 protein was tested against five lepidopteran species and its toxicity compared to that of a reference protein (Vip3Aa16). Both proteins had similar toxicity against Grapholita molesta and Helicoverpa armigera , whereas Vip3Aa65 was less active than Vip3Aa16 against three species from the Spodoptera genus. A tetrameric structure of the Vip3Aa65 protein was detected by gel filtration chromatography. The study revealed some isolates with high insecticidal activity which can be considered promising candidates to be used in pest control.
    Electronic ISSN: 1932-6203
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  • 43
    Publication Date: 2018-11-02
    Description: by Anthony R. Marshak, Kenneth L. Heck Jr., Zachary R. Jud Indo-Pacific red lionfish ( Pterois volitans ) have invaded the western Atlantic, and most recently the northern Gulf of Mexico (nGOM), at a rapid pace. Given their generalist habitat affinities and diet, and strong ecological overlap with members of the commercially valuable snapper-grouper complex, increased density and abundance of lionfish could result in significant competitive interactions with nGOM commercially important species. We experimentally investigated the intensity of behavioral interactions between lionfish and indigenous, abundant and economically important juvenile nGOM red snapper ( Lutjanus campechanus ), and other increasingly abundant juvenile tropical snapper species (gray snapper— L . griseus and lane snapper— L . synagris ) in large outdoor mesocosms to examine snapper vulnerabilities to lionfish competition. When paired with lionfish, red snapper swimming activity (i.e., time swimming and roving around experimental tank or at structure habitat during experiments) was significantly lower than in intraspecific control trials, but gray and lane snapper swimming activities in the presence of lionfish did not significantly differ from their intraspecific controls. Additionally in paired trials, red and lane snapper swimming activities were significantly lower than those of lionfish, while no significant difference in swimming activities was observed between lionfish and gray snapper. We found that red snapper prey consumption rates in the presence of lionfish were significantly lower than in their intraspecific 3-individual control trials, but when paired together no significant differences in prey consumption rates between red snapper and lionfish were observed. When paired with lane or gray snapper, lionfish were observed having comparatively higher prey consumption than snappers, or as observed in lionfish intraspecific 1-individual controls. However, lane and gray snapper consumption rates in the presence of lionfish did not significantly differ from those in intraspecific controls. These findings suggest that competition between juvenile snappers and invasive lionfish may be variable, with lionfish exhibiting differing degrees of competitive dominance and snappers exhibiting partial competitive vulnerability and resistance to lionfish. While the degree of intensity at which these interactions may occur in nGOM reefs may differ from those observed in our findings, this study enables greater understanding of the potential ecological effects of red lionfish on native reef fishes.
    Electronic ISSN: 1932-6203
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  • 44
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Simiao Chen, Michael Kuhn, Klaus Prettner, David E. Bloom We develop and calibrate a dynamic production function model to assess how noncommunicable diseases (NCDs) will affect U.S. productive capacity in 2015–2050. In this framework, aggregate output is produced according to a human capital–augmented production function that accounts for the effects of projected disease prevalence. NCDs influence the economy through the following pathways: 1) when working-age individuals die of a disease, aggregate output undergoes a direct loss because physical capital can only partially substitute for the loss of human capital in the production process. 2) If working-age individuals suffer from a disease but do not die from it, then, depending on the condition’s severity, they tend to be less productive, might work less, or might retire earlier. 3) Current NCD interventions such as medical treatments and prevention require substantial resources. Part of these resources could otherwise be used for productive investments in infrastructure, education, or research and development. This implies a loss of savings across the population and hampers economy-wide physical capital accumulation. Our results indicate a total loss of USD94.9 trillion (in constant 2010 USD) due to all NCDs. Mental health conditions and cardiovascular diseases impose the highest burdens, followed by cancer, diabetes, and chronic respiratory diseases. In per capita terms, the economic burden of all NCDs in 2015–2050 is USD265,000. The total NCD burden roughly corresponds to an annual tax rate of 10.8% on aggregate income.
    Electronic ISSN: 1932-6203
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  • 45
    Publication Date: 2018-11-02
    Description: by Gang Dong, Zhengzao Wang, Xianqiang Mao Maintaining crop outputs to feed its large population with limited resources while simultaneously mitigating carbon emissions are great challenges for China. Improving the efficiency of resource use in crop production is important in reducing carbon emissions. This paper constructs a methodological framework combining emergy-based indicator accounting and a nonseparable undesirable output slack-based measurement (SBM) data envelopment analysis (DEA) model. This framework is used to explore the efficiency of inputs and outputs and the greenhouse gas (GHG) emissions reduction potential for crop production systems, using Zhejiang province, China, as a case study. It is found that an emergy synthesis and a nonseparable undesirable output SBM-DEA framework is compatible with the case study. Crop production in Zhejiang province has relied heavily on an increase in agrochemical inputs to maintain agricultural output. Energy and chemical fertilizer use are determined as the province’s major carbon emissions sources. Although carbon emissions per unit of monetary output has decreased sharply, the carbon emissions per unit emergy output has increased, demonstrating a high carbon intensity reality. The DEA highlighted the differences in crop production efficiency, resource factor redundancy and carbon mitigation potential in the different prefectures of the province. To conclude this research, policies to support low carbon agriculture development, including subsidizing low carbon agriculture technology development and expansion and the cancellation of subsidies to high carbon production factors, such as chemical fertilizer production and sales, are discussed to conclude the research.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 46
    Publication Date: 2018-11-02
    Description: by Erika Pineda, Magali Thonnus, Muriel Mazet, Arnaud Mourier, Edern Cahoreau, Hanna Kulyk, Jean-William Dupuy, Marc Biran, Cyril Masante, Stefan Allmann, Loïc Rivière, Brice Rotureau, Jean-Charles Portais, Frédéric Bringaud The bloodstream forms of Trypanosoma brucei (BSF), the parasite protist causing sleeping sickness, primarily proliferate in the blood of their mammalian hosts. The skin and adipose tissues were recently identified as additional major sites for parasite development. Glucose was the only carbon source known to be used by bloodstream trypanosomes to feed their central carbon metabolism, however, the metabolic behaviour of extravascular tissue-adapted parasites has not been addressed yet. Since the production of glycerol is an important primary function of adipocytes, we have adapted BSF trypanosomes to a glucose-depleted but glycerol-rich culture medium (CMM_Glyc/GlcNAc) and compared their metabolism and proteome to those of parasites grown in standard glucose-rich conditions (CMM_Glc). BSF were shown to consume 2-folds more oxygen per consumed carbon unit in CMM_Glyc/GlcNAc and were 11.5-times more sensitive to SHAM, a specific inhibitor of the plant-like alternative oxidase (TAO), which is the only mitochondrial terminal oxidase expressed in BSF. This is consistent with ( i ) the absolute requirement of the mitochondrial respiratory activity to convert glycerol into dihydroxyacetone phosphate, as deduced from the updated metabolic scheme and ( ii ) with the 1.8-fold increase of the TAO expression level compared to the presence of glucose. Proton NMR analysis of excreted end products from glycerol and glucose metabolism showed that these two carbon sources are metabolised through the same pathways, although the contributions of the acetate and succinate branches are more important in the presence of glycerol than glucose (10.2% versus 3.4% of the excreted end products, respectively). In addition, metabolomic analyses by mass spectrometry showed that, in the absence of glucose, 13 C-labelled glycerol was incorporated into hexose phosphates through gluconeogenesis. As expected, RNAi-mediated down-regulation of glycerol kinase expression abolished glycerol metabolism and was lethal for BSF grown in CMM_Glyc/GlcNAc. Interestingly, BSF have adapted their metabolism to grow in CMM_Glyc/GlcNAc by concomitantly increasing their rate of glycerol consumption and decreasing that of glucose. However, the glycerol kinase activity was 7.8-fold lower in CMM_Glyc/GlcNAc, as confirmed by both western blotting and proteomic analyses. This suggests that the huge excess in glycerol kinase that is not absolutely required for glycerol metabolism, might be used for another yet undetermined non-essential function in glucose rich-conditions. Altogether, these data demonstrate that BSF trypanosomes are well-adapted to glycerol-rich conditions that could be encountered by the parasite in extravascular niches, such as the skin and adipose tissues.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 47
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-02
    Description: by Philip Goulder, Steven G. Deeks In this brief review and perspective, we address the question of whether the immune responses that bring about immune control of acute HIV infection are the same as, or distinct from, those that maintain long-term viral suppression once control of viremia has been achieved. To this end, we describe the natural history of elite and post-treatment control, noting the lack of data regarding what happens acutely. We review the evidence suggesting that the two clinical phenotypes may differ in terms of the mechanisms required to achieve and maintain control, as well as the level of inflammation that persists once a steady state is achieved. We then describe the evidence from longitudinal studies of controllers who fail and studies of biologic sex (male versus female), age (children versus adults), and simian immunodeficiency virus (SIV) (pathogenic/experimental versus nonpathogenic/natural infection). Collectively, these studies demonstrate that the battle between the inflammatory and anti-inflammatory pathways during acute infection has long-term consequences, both for the degree to which control is maintained and the health of the individual. Potent and stringent control of HIV may be required acutely, but once control is established, the chronic inflammatory response can be detrimental. Interventional approaches designed to bring about HIV cure and/or remission should be nuanced accordingly.
    Print ISSN: 1553-7366
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  • 48
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-03
    Description: by Andrei P. Kirilenko, Svetlana Stepchenkova This paper uses text data mining to identify long-term developments in tourism academic research from the perspectives of thematic focus, geography, and gender of tourism authorship. Abstracts of papers published in the period of 1970–2017 in high-ranking tourist journals were extracted from the Scopus database and served as data source for the analysis. Fourteen subject areas were identified using the Latent Dirichlet Allocation (LDA) text mining approach. LDA integrated with GIS information allowed to obtain geography distribution and trends of scholarly output, while probabilistic methods of gender identification based on social network data mining were used to track gender dynamics with sufficient confidence. The findings indicate that, while all 14 topics have been prominent from the inception of tourism studies to the present day, the geography of scholarship has notably expanded and the share of female authorship has increased through time and currently almost equals that of male authorship.
    Electronic ISSN: 1932-6203
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  • 49
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    Publication Date: 2018-11-03
    Description: by Cheng Liu, Jiaoyuan Li, William Steele, Xiangming Fang Food safety is a global public health issue, which often arises from asymmetric information between consumers and suppliers. With the development of information technology in human life, building a food traceability information sharing platform is viewed as one of the best ways to overcome the trust crisis and resolve the problem of information asymmetry in China. However, among the myriad information available from the food supply chain, there is a lack of knowledge on consumer preference. Based on the best-worst scaling approach, this paper investigated consumer preferences for vegetable, pork, and dairy product traceability information. Specifically, this paper measured the relative importance that consumers place on the traceable information. The results indicate that consumers have varying priorities for information in different cases. “Pesticide/veterinary use,” “picking/slaughtering date,” and “fertilizer/feed use” are the most preferred traceable information for Chinese consumers in the case of vegetables, while “picking/slaughtering date” and “history of illness and taking protective measures” are the most preferred information in the case of pork. In the case of dairy products, consumers prefer “processing information,” “environmental information of the origin,” and “traceable tag certification information” most. The results of this study call for the direct involvement of the Chinese government in the food safety information sharing system as following. First, given consumers’ diverse preferences, different types of traceable information should be recorded into the information sharing platform depending on food types. Second, the government could promote the step-by-step construction of such a platform based on the priority of consumers’ preferences. Third, new technology should be applied to guarantee the reliability of traceable information. Finally, local preferences in terms of the way consumers receive and understand information should be taken into consideration.
    Electronic ISSN: 1932-6203
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  • 50
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    Publication Date: 2018-11-03
    Description: by Emma Aguila, Mariana López-Ortega, Luis Miguel Gutiérrez Robledo Non-contributory pension programs in the developing world seek to provide older adults with an income that may improve their health and wellbeing in old age by enabling access to health care and better nutrition. There is no previous evidence of the effects of non-contributory pensions on frailty, a comprehensive measure of health and well-being of the oldest old. We aimed to estimate the effects of non-contributory pension programs on frailty of older adults in the state of Yucatan, Mexico. We use rich panel data, including objective markers and self-reported assessments of health and well-being, for 944 adults at least 70 years of age in two communities of Yucatan, Mexico. The first wave was collected in 2008; the second wave was collected in 2010, 18 months after implementation of a monthly state pension in one community and 12 months after a federal pension paid every two months in the other. We found the state pension led to a statistically significant decrease in the severity of frailty for women, but the federal pension was associated with an increase. We found no statistically significant change in the frailty index for men in either community. Among explanations for these findings are monthly payments being more likely to be spent on health care, medicines, and more regular food expenditures, enabling women who previously lacked independent means of support to increase their longer-term health. The federal program paid every two months led to irregular patterns of food expenditure and increased ownership of durable goods but had no effects on health care utilization, subsequently leading to deterioration in longer-term health for women.
    Electronic ISSN: 1932-6203
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  • 51
    Publication Date: 2018-11-06
    Description: by Cherilyn N. McLester, Brett S. Nickerson, Brian M. Kliszczewicz, Courtenay S. Hicks, Cassie M. Williamson, Emily E. Bechke, John R. McLester The purpose of this investigation was to determine the validity of 4-compartment (4C) model body fat percent (BF%) estimates when using dual energy x-ray absorptiometry (DXA) derived body volume (BV) equations (4C-DXA1 and 4C-DXA2) in adults with varying body mass index (BMI) and waist circumference (WC) classifications. Each model was compared to a criterion 4C model with air-displacement plethysmography (ADP) generated BV (4C-ADP). Participants were categorized as normal weight (n = 40; NW = BMI
    Electronic ISSN: 1932-6203
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  • 52
    Publication Date: 2018-11-06
    Description: by Xi-Hsuan Lin, Kuo-Hung Huang, Wei-Hung Chuang, Jiing-Chyuan Luo, Chung-Chi Lin, Po-Hsiang Ting, Shih-Hao Young, Wen-Liang Fang, Ming-Chih Hou, Fa-Yauh Lee Long term effects of subtotal gastrectomy on gut microbiota modifications with subsequent metabolic profiles are limited. We aimed to investigate and compare long-term effects of metabolic profiles and microbiota status in early gastric cancer patients post curative subtotal gastrectomy to the controls. In this cross-sectional study, we analyzed type II diabetes mellitus and metabolic syndrome occurrence in two groups: 111 patients after curative subtotal gastrectomy with Billroth II (BII) anastomosis and Roux-en-Y gastrojejuno (RYGJ) anastomosis and 344 age-sex matched controls. Fecal samples from those with BII, RYGJ, and controls were analyzed by next-generation sequencing method. Metabolic syndrome and type II diabetes mellitus occurrences were significantly lower in patients after subtotal gastrectomy with RYGJ than in controls over the long term (〉 8 years) follow-up (P 〈 0.05). The richness and diversity of gut microbiota significantly increased after subtotal gastrectomy with RYGJ (P 〈 0.05). Compared with the control group, the principal component analysis revealed significant differences in bacterial genera abundance after subtotal gastrectomy with BII and RYGJ (P 〈 0.001). Genera of Oscillospira , Prevotella , Coprococcus , Veillonella , Clostridium , Desulfovibrio , Anaerosinus , Slackia , Oxalobacter , Victivallis , Butyrivibrio , Sporobacter , and Campylobacter shared more abundant roles both in the RYGJ group and BII groups. Early gastric cancer patients after subtotal gastrectomy with RYGJ had a lower occurrence of metabolic syndrome and type II diabetes mellitus than the controls during long term follow-up. In parallel with the metabolic improvements, gut microbial richness and diversity also significantly increased after subtotal gastrectomy with RYGJ.
    Electronic ISSN: 1932-6203
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  • 53
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    Publication Date: 2018-11-06
    Description: by Gokhan Hacisalihoglu, Sarfo Kantanka, Nathan Miller, Jeffery L. Gustin, A. Mark Settles Seeds planted in early spring frequently experience low temperature stress in the soil during germination and early plant growth. Seed pretreatments such as priming have been shown to ameliorate the negative effects of cold soil in some crops. However, the potential beneficial effects of priming have not been widely investigated for Zea mays (maize). To investigate seed priming effects, 24 diverse maize inbred lines were primed using a synthetic solid matrix, Micro-Cel E, and then exposed to 10°C soil conditions. Six DSLR cameras captured time lapsed images of emerging seedlings. Manual scoring was used to determine treatment effects on three seedling emergence metrics. Chilling substantially reduced total emergence for two of 24 genotypes evaluated. For these genotypes, priming provided protection allowing nearly full emergence. Priming significantly reduced mean emergence time and increased the emergence uniformity of chilling sensitive genotypes. The results suggest that the cold sensitive genotypes may benefit from priming pretreatment. Kernel density, weight, oil, protein, and starch traits, as determined by single-kernel near infrared spectroscopy, were not correlated with seedling emergence traits supporting a conclusion that early seedling performance cannot be determined from these maize kernel characteristics.
    Electronic ISSN: 1932-6203
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  • 54
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    Publication Date: 2018-11-06
    Description: by Anthony L. Baker, Talima Pearson, Jason W. Sahl, Crystal Hepp, Erin P. Price, Derek S. Sarovich, Mark Mayo, Apichai Tuanyok, Bart J. Currie, Paul Keim, Jeffrey Warner Burkholderia pseudomallei is the environmental bacillus that causes melioidosis; a disease clinically significant in Australia and Southeast Asia but emerging in tropical and sub-tropical regions around the globe. Previous studies have placed the ancestral population of the organism in Australia with a single lineage disseminated to Southeast Asia. We have previously characterized B . pseudomallei isolates from New Guinea and the Torres Strait archipelago; remote regions that share paleogeographic ties with Australia. These studies identified regional biogeographical boundaries. In this study, we utilize whole-genome sequencing to reconstruct ancient evolutionary relationships and ascertain correlations between paleogeography and present-day distribution of this bacterium in Australasia. Our results indicate that B . pseudomallei from New Guinea fall into a single clade within the Australian population. Furthermore, clades from New Guinea are region-specific; an observation possibly linked to limited recent anthropogenic influence in comparison to mainland Australia and Southeast Asia. Isolates from the Torres Strait archipelago were distinct yet scattered among those from mainland Australia. These results provide evidence that the New Guinean and Torres Strait lineages may be remnants of an ancient portion of the Australian population. Rising sea levels isolated New Guinea and the Torres Strait Islands from each other and the Australian mainland, and may have allowed long-term isolated evolution of these lineages, providing support for a theory of microbial biogeography congruent with that of macro flora and fauna. Moreover, these findings indicate that contemporary microbial biogeography theories should consider recent and ongoing impacts of globalisation and human activity.
    Electronic ISSN: 1932-6203
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  • 55
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    Publication Date: 2018-11-06
    Description: by EunJin Ahn, GeunJoo Choi, Hyun Kang, ChongWha Baek, YongHun Jung, YoungCheol Woo, SiRa Bang We aimed to compare the effectiveness of supraglottic airway devices as a strategy for unassisted tracheal intubation. Accordingly, we searched the OVID-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, KoreaMed, and Google Scholar databases to identify all relevant randomized controlled trials (RCTs) on supraglottic airway devices as a strategy for tracheal intubation published until May 2017. The primary outcome was the overall success rate of intubation by the intention to treat (ITT) strategy. The secondary outcomes of the study were the overall success rate of tracheal intubation by the per protocol (PP) strategy and the success rate of tracheal intubation at first attempt by ITT and PP. We conducted a network meta-analysis with a mixed-treatment comparison method to combine direct and indirect comparisons among supraglottic airway devices. Of 1396 identified references, 16 RCTs (2014 patients) evaluated unassisted intubation with supraglottic airway devices. Patients were grouped according to the type of device used: LMA-CTrach, LMA-Fastrach, Air-Q, i-gel, CobraPLA, Ambu-Aura, or single-use LMA devices. Based on the surface under the cumulative ranking curve, the three best supraglottic airway devices for use as a strategy for unassisted tracheal intubation were LMA-CTrach (which included video-assisted tracheal tube guidance), single-use LMA-Fastrach, and LMA-Fastrach. LMA-Fastrach showed a higher success rate of intubation than did i-gel, CobraPLA, Air-Q, and Ambu-Aura. However, this study was limited by the small number of eligible RCTs. Therefore, well-designed RCTs performed on large patient populations are required to increase the confidence of the results.
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  • 56
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    Publication Date: 2018-11-06
    Description: by Ting-Yu Yen, Wei-Liang Shih, Yi-Chuan Huang, Jian-Te Lee, Li-Min Huang, Luan-Yin Chang Objective To evaluate the association of enterovirus 71 (EV71) susceptibility and clinical severity with polymorphisms in EV71 receptors, including human scavenger receptor class B member 2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), and annexin II (ANXA2). Methods We enrolled laboratory-confirmed EV71 cases and healthy age- and gender-matched controls in Taiwan from 2000 to 2012. We detected genetic polymorphisms in SCARB2, PSGL-1, and ANXA2 and correlated the results with EV71 susceptibility and severity. Results We collected 599 EV71 cases and 98 controls. Among EV71 patients, the male to female ratio was 1.61, and the mean age was 2.99±2.47 years. For clinical severity, 117 (19.6%) had severe central nervous system involvement with or without cardiopulmonary failure. For outcomes, 46 (7.7%) had sequelae, and 14 (2.3%) died. SCARB2 polymorphisms (rs6824953 and rs11097262) were associated with susceptibility to EV71 infection (OR 1.60, 95% CI 1.07–2.39; and OR 1.64, 95% CI 1.09–2.47, respectively). PSGL-1 polymorphisms (rs7137098 and rs8179137) were significantly associated with severe EV71 infection (OR 1.46, 95% CI 1.1–1.96; and OR 1.47, 95% CI 1.07–2.03, respectively). Conclusions SCARB2 polymorphisms (rs6824953 and rs11097262) might be associated with EV71 susceptibility. PSGL-1 polymorphisms (rs7137098 and rs8179137) were associated with severe EV71 infection.
    Electronic ISSN: 1932-6203
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  • 57
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    Publication Date: 2018-11-07
    Description: by Jesse A. Pfammatter, Rachel A. Bergstrom, Eli P. Wallace, Rama K. Maganti, Mathew V. Jones Quantification of interictal spikes in EEG may provide insight on epilepsy disease burden, but manual quantification of spikes is time-consuming and subject to bias. We present a probability-based, automated method for the classification and quantification of interictal events, using EEG data from kainate- and saline-injected mice (C57BL/6J background) several weeks post-treatment. We first detected high-amplitude events, then projected event waveforms into Principal Components space and identified clusters of spike morphologies using a Gaussian Mixture Model. We calculated the odds-ratio of events from kainate- versus saline-treated mice within each cluster, converted these values to probability scores, P(kainate), and calculated an Hourly Epilepsy Index for each animal by summing the probabilities for events where the cluster P(kainate) 〉 0.5 and dividing the resultant sum by the record duration. This Index is predictive of whether an animal received an epileptogenic treatment (i.e., kainate), even if a seizure was never observed. We applied this method to an out-of-sample dataset to assess epileptiform spike morphologies in five kainate mice monitored for ~1 month. The magnitude of the Index increased over time in a subset of animals and revealed changes in the prevalence of epileptiform (P(kainate) 〉 0.5) spike morphologies. Importantly, in both data sets, animals that had electrographic seizures also had a high Index. This analysis is fast, unbiased, and provides information regarding the salience of spike morphologies for disease progression. Future refinement will allow a better understanding of the definition of interictal spikes in quantitative and unambiguous terms.
    Electronic ISSN: 1932-6203
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  • 58
    Publication Date: 2018-11-07
    Description: by Konstantinos A. Toulis, Chao Q. Jiang, Karla Hemming, Krishnarajah Nirantharakumar, Kar K. Cheng, Tai H. Lam, G. Neil Thomas Background To evaluate the additional discriminatory performance of adiponectin, leptin, and their ratio in the identification of impaired glucose tolerance (IGT) in men and women without diabetes on top of conventional risk factors. Methods & results A total of 698 subjects underwent an oral glucose tolerance test (oGTT) and adipocytokine measurements. A comprehensive stepwise selection procedure was performed, followed by c-statistics and integrated discrimination improvement (IDI) analysis. In males, adiponectin levels were significantly lower in the IGT group compared to the non-IGT group (Whitney U test, p 〈 10–4), whereas leptin levels were significantly higher (p = 0.009) in IGT group. In females, adiponectin and leptin levels were not significantly different between groups (Mann-Whitney U test, p = 0.073 and p = 0.08, respectively). Adjusting for the most informative, sex-specific, clinical and biochemical factors, adiponectin, leptin and their ratio were not found to be significant predictors of the response to the glucose load, when modelled as continuous terms or tertiles. In males, the area-under-the-curve (AUC) for adiponectin was estimated at 0.620 (95% CI: 0.558–0.682) and the addition of adiponectin into the basic model provided a ΔAUC benefit of 0.004, showing no additional discriminatory benefit on top of conventional risk factors (IDI p-value: 0.27), nor did the addition of leptin or their ratio. The results were similar in females. Conclusions In Chinese individuals without diabetes, no significant evidence for the potential discriminatory value of adiponectin, leptin or their ratio in the identification of IGT on top of conventional risk factors was observed.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 59
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-07
    Description: by Mika Mizoguchi, Yuko Ishida, Mizuho Nosaka, Akihiko Kimura, Yumi Kuninaka, Tamaki Yahata, Sakiko Nanjo, Saori Toujima, Sawako Minami, Kazuhiko Ino, Naofumi Mukaida, Toshikazu Kondo Preterm labor (PTL) is the most common cause of neonatal death and long-term adverse outcome. The pharmacological agents for PTL prevention are palliative and frequently fail to prevent PTL and improve neonatal outcome. It is essential to fully understand the molecular mechanisms of PTL in order to develop novel therapeutic methods against PTL. Several lines of evidence indicate some chemokines are expressed in gestational tissues during labor or PTL. To reveal the pathophysiological roles of the CX3CL1-CX3CR1 axis in PTL, we performed present study using LPS-induced PTL mice model in CX3CR1-deficient ( Cx3cr1 -/- ) mice. We indicated that PTL was suppressed in Cx3cr1 -/- mice and immunoneutralization of CX3CL1 in WT mice. From immunohistochemical and the gene expression analyses, the CX3CL1-CX3CR1 axis has detrimental roles in PTL through intrauterine recruitment of macrophages and the enhancement of macrophage-derived inflammatory mediators. Thus, the CX3CL1-CX3CR1 axis may be a good molecular target for preventing PTL.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 60
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-07
    Description: by Rajiv Ravi, Nor Shaida Husna Zulkrnin, Nurul Nadiah Rozhan, Nik Raihan Nik Yusoff, Mohd Sukhairi Mat Rasat, Muhammad Iqbal Ahmad, Intan H. Ishak, Mohamad Faiz Mohd Amin Background The resistance problem of dengue vectors to different classes of insecticides that are used for public health has raised concerns about vector control programmes. Hence, the discovery of alternative compounds that would enhance existing tools is important for overcoming the resistance problem of using insecticides in vectors and ensuring a chemical-free environment. The larvicidal effects of Azolla pinnata extracts by using two different extraction methods with methanol solvent against Aedes in early 4 th instar larvae was conducted. Methods The fresh Azolla pinnata plant from Kuala Krai, Kelantan, Malaysia was used for crude extraction using Soxhlet and maceration methods. Then, the chemical composition of extracts and its structure were identified using GCMS-QP2010 Ultra (Shimadzu). Next, following the WHO procedures for larval bioassays, the extracts were used to evaluate the early 4 th instar larvae of Aedes mosquito vectors. Results The larvicidal activity of Azolla pinnata plant extracts evidently affected the early 4 th instar larvae of Aedes aegypti mosquito vectors. The Soxhlet extraction method had the highest larvicidal effect against Ae . aegypti early 4 th instar larvae, with LC50 and LC95 values of 1093 and 1343 mg/L, respectively. Meanwhile, the maceration extraction compounds were recorded with the LC50 and LC95 values of 1280 and 1520 mg/L, respectively. The larvae bioassay test for Ae . albopictus showed closely similar values in its Soxhlet extraction, with LC50 and LC95 values of 1035 and 1524 mg/L, compared with the maceration extraction LC50 and LC95 values of 1037 and 1579 mg/L, respectively. The non-target organism test on guppy fish, Poecilia reticulata , showed no mortalities and posed no toxic effects. The chemical composition of the Azolla pinnata plant extract has been found and characterized as having 18 active compounds for the Soxhlet method and 15 active compounds for the maceration method. Conclusions Our findings showed that the crude extract of A . pinnata bioactive molecules are effective and have the potential to be developed as biolarvicides for Aedes mosquito vector control. This study recommends future research on the use of active ingredients isolated from A . pinnata extracts and their evaluation against larvicidal activity of Aedes in small-scale field trials for environmentally safe botanical insecticide invention.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 61
    Publication Date: 2018-11-07
    Description: by Fernanda Costa Svedman, Warangkana Lohcharoenkal, Matteo Bottai, Suzanne Egyhazi Brage, Enikö Sonkoly, Johan Hansson, Andor Pivarcsi, Hanna Eriksson Background Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers. Materials and methods EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. Results Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8–1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13–0.52, P
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 62
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-07
    Description: by Danielle Jacobson, Emily Glazer, Robin Mason, Deanna Duplessis, Kimberly Blom, Janice Du Mont, Navmeet Jassal, Gillian Einstein Many of the Somali women who have immigrated to other countries, including Canada, have experienced Female Genital Circumcision/ Mutilation/ Cutting (FGC). While there is literature on the medical aspects of FGC, we were interested in understanding the daily life experiences and bodily sensations of Somali-Canadian women in the context of FGC. Fourteen women living in the Greater Toronto Area were interviewed. Interview data were analyzed using a phenomenological approach. We found that the memory of the ceremonial cutting was vivid but was frequently described with acceptance and resignation–as something that just is; that was normal given the particular context, familial and cultural, and their young age. Most of the women recounted experiencing pain and discomfort throughout their adult lives but were intent on not noticing or giving the pain any power; they considered themselves healthy. The following themes emerged from our interviews: Every Body Had It : Discussing FGC , I’m Normal Aren’t I ?, and Feeling in My Body– all themes that work at normalizing their bodies in a society that they know views them as different. They dealt with both pain and pleasure in the context of their busy lives suggesting resilience in spite of the day-to-day difficulties of daily life.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 63
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-07
    Description: by José Miguel Martínez-Paz, Francisco Gomariz-Castillo, Francisco Pellicer-Martínez Irrigated agriculture is a key activity in water resources management at the river basin level in arid and semi-arid areas, since this sector consumes the largest part of the water resources overall. The current study proposes a methodology to evaluate the water footprint (WF) of the irrigated agriculture sector at the river basin level, through a simulation of the anthropised water cycle combining a hydrological model and a decision support system. The main difference from the approaches that have already been used is that the new methodology includes the limitations of the system for the exploitation of water resources where the irrigated areas are located, and it considers the hydrological principles governed by the law of continuity of mass. Water footprint accounting was carried out for the Segura River Basin (South-eastern Spain), applying the methodology proposed and another that is usually applied. The results of the two methodologies were compared, revealing significant differences in the values of the WF, basically due to the blue component. The methodology that is usually applied overestimated the WF of the agriculture in the basin since supply deficits were not taken into account, providing results that would only be possible if there were no spatial or temporal restrictions to water use. So, in order to make the WF indicator useful in water resources management plans, it is necessary to adapt the computations to the main characteristics of the water exploitation system of the whole basin under study, respecting the hydrological principles of the water cycle: regulation and transport infrastructure, the real water resources available and the priority of access to water between concurrent water uses.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 64
    Publication Date: 2018-11-07
    Description: by Chao Wu, Yang Jiao, Manli Shen, Chen Pan, Guo Cheng, Danmei Jia, Jing Zhu, Long Zhang, Min Zheng, Junling Jia Background Key regulators of developmental processes can be prioritized through integrated analysis of ChIP-Seq data of master transcriptional factors (TFs) such as Nanog and Oct4, active histone modifications (HMs) such as H3K4me3 and H3K27ac, and repressive HMs such as H3K27me3. Recent studies show that broad enrichment signals such as super-enhancers and broad H3K4me3 enrichment signals play more dominant roles than short enrichment signals of the master TFs and H3K4me3 in epigenetic regulatory mechanism. Besides the broad enrichment signals, up to ten thousands of short enrichment signals of these TFs and HMs exist in genome. Prioritization of these broad enrichment signals from ChIP-Seq data is a prerequisite for such integrated analysis. Results Here, we present a method named Clustering-Local-Unique-Enriched-Signals (CLUES), which uses an adaptive-size-windows strategy to identify enriched regions (ERs) and cluster them into broad enrichment signals. Tested on 62 ENCODE ChIP-Seq datasets of Ctcf and Nrsf, CLUES performs equally well as MACS2 regarding prioritization of ERs with the TF’s motif. Tested on 165 ENCODE ChIP-Seq datasets of H3K4me3, H3K27me3, and H3K36me3, CLUES performs better than existing algorithms on prioritizing broad enrichment signals implicating cell functions influenced by epigenetic regulatory mechanism in cells. Most importantly, CLUES helps to confirm several novel regulators of mouse ES cell self-renewal and pluripotency through integrated analysis of prioritized broad enrichment signals of H3K4me3, H3K27me3, Nanog and Oct4 with the support of a CRISPR/Cas9 negative selection genetic screen. Conclusions CLUES holds promise for prioritizing broad enrichment signals from ChIP-Seq data. The download site for CLUES is https://github.com/Wuchao1984/CLUESv1.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 65
    Publication Date: 2018-11-07
    Description: by Keith Crosby, Anthony M. Crown, Brittany L. Roberts, Hilda Brown, Jacob I. Ayers, David R. Borchelt Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis (fALS) induce the protein to misfold and aggregate. Missense mutations at more than 80 different amino acid positions have been associated with disease. How these mutations heighten the propensity of SOD1 to misfold and aggregate is unclear. With so many mutations, it is possible that more than one mechanism of aggregation may be involved. Of many possible mechanisms to explain heightened aggregation, one that has been suggested is that mutations that eliminate charged amino acids could diminish repulsive forces that would inhibit aberrant protein:protein interactions. Mutations at twenty-one charged residues in SOD1 have been associated with fALS, but of the 11 Lys residues in the protein, only 1 has been identified as mutated in ALS patients. Here, we examined whether loss of positively charged surface Lys residues in SOD1 would induce misfolding and formation of intracellular inclusions. We mutated four different Lys residues (K30, K36, K75, K91) in SOD1 that are not particularly well conserved, and expressed these variants as fusion proteins with yellow fluorescent protein (YFP) to assess inclusion formation. We also assessed whether these mutations induced binding to a conformation-restricted SOD1 antibody, designated C4F6, which recognizes non-natively folded protein. Although we observed some mutations to cause enhanced C4F6 binding, we did not observe that mutations that reduce charge at these positions caused the protein to form intracellular inclusions. Our findings may have implications for the low frequency of mutations at Lys residues SOD1 in ALS patients.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 66
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-10
    Description: by Hongyang Li, Xin-Qiu Yao, Barry J. Grant GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. There are three major GTPase superfamilies: Ras-like GTPases, heterotrimeric G proteins and protein-synthesizing GTPases. Although they contain similar nucleotide-binding sites, the detailed mechanisms by which these structurally and functionally diverse superfamilies operate remain unclear. Here we compare and contrast the structural dynamic mechanisms of each superfamily using extensive molecular dynamics (MD) simulations and subsequent network analysis approaches. In particular, dissection of the cross-correlations of atomic displacements in both the GTP and GDP-bound states of Ras, transducin and elongation factor EF-Tu reveals analogous dynamic features. This includes similar dynamic communities and subdomain structures (termed lobes). For all three proteins the GTP-bound state has stronger couplings between equivalent lobes. Network analysis further identifies common and family-specific residues mediating the state-specific coupling of distal functional sites. Mutational simulations demonstrate how disrupting these couplings leads to distal dynamic effects at the nucleotide-binding site of each family. Collectively our studies extend current understanding of GTPase allosteric mechanisms and highlight previously unappreciated similarities across functionally diverse families.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 67
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-10
    Description: by Rebecca C. Poulos, Yuen T. Wong, Regina Ryan, Herbert Pang, Jason W. H. Wong Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types. We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter. We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types. Our analysis led to the identification of 39 significant associations between driver mutations and mutational signatures (P 〈 0.004, with a false discovery rate of 〈 5%). We first validate our methodology by establishing statistical links for known and novel associations between driver mutations and the mutational signature arising from Polymerase Epsilon proofreading deficiency. We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair. We also identify negative associations (odds ratio 〈 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively. Our study provides statistical foundations for hypothesised links between otherwise independent biological processes and we uncover previously unexplored relationships between driver mutations and mutagenic processes during cancer development. These associations give insights into how cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into cancer pathogenesis.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 68
    Publication Date: 2018-11-10
    Description: by Zhuan Qin, Jiagang Tu, Tao Lin, Steven J. Norris, Chunhao Li, Md A. Motaleb, Jun Liu Periplasmic flagella are essential for the distinct morphology and motility of spirochetes. A flagella-specific type III secretion system (fT3SS) composed of a membrane-bound export apparatus and a cytosolic ATPase complex is responsible for the assembly of the periplasmic flagella. Here, we deployed cryo-electron tomography (cryo-ET) to visualize the fT3SS machine in the Lyme disease spirochete Borrelia burgdorferi . We show, for the first time, that the cytosolic ATPase complex is attached to the flagellar C-ring through multiple spokes to form the “spoke and hub” structure in B . burgdorferi . This structure not only strengthens structural rigidity of the round-shaped C-ring but also appears to rotate with the C-ring. Our studies provide structural insights into the unique mechanisms underlying assembly and rotation of the periplasmic flagella and may provide the basis for the development of novel therapeutic strategies against several pathogenic spirochetes.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 69
    Publication Date: 2018-11-10
    Description: by Shengjie Lai, Michael A. Johansson, Wenwu Yin, Nicola A. Wardrop, Willem G. van Panhuis, Amy Wesolowski, Moritz U. G. Kraemer, Isaac I. Bogoch, Dylain Kain, Aidan Findlater, Marc Choisy, Zhuojie Huang, Di Mu, Yu Li, Yangni He, Qiulan Chen, Juan Yang, Kamran Khan, Andrew J. Tatem, Hongjie Yu Due to worldwide increased human mobility, air-transportation data and mathematical models have been widely used to measure risks of global dispersal of pathogens. However, the seasonal and interannual risks of pathogens importation and onward transmission from endemic countries have rarely been quantified and validated. We constructed a modelling framework, integrating air travel, epidemiological, demographical, entomological and meteorological data, to measure the seasonal probability of dengue introduction from endemic countries. This framework has been applied retrospectively to elucidate spatiotemporal patterns and increasing seasonal risk of dengue importation from South-East Asia into China via air travel in multiple populations, Chinese travelers and local residents, over a decade of 2005–15. We found that the volume of airline travelers from South-East Asia into China has quadrupled from 2005 to 2015 with Chinese travelers increased rapidly. Following the growth of air traffic, the probability of dengue importation from South-East Asia into China has increased dramatically from 2005 to 2015. This study also revealed seasonal asymmetries of transmission routes: Sri Lanka and Maldives have emerged as origins; neglected cities at central and coastal China have been increasingly vulnerable to dengue importation and onward transmission. Compared to the monthly occurrence of dengue reported in China, our model performed robustly for importation and onward transmission risk estimates. The approach and evidence could facilitate to understand and mitigate the changing seasonal threat of arbovirus from endemic regions.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 70
    Publication Date: 2018-11-10
    Description: by E. Gezelius, A. Flou Kristensen, P. O. Bendahl, Y. Hisada, S. Risom Kristensen, L. Ek, B. Bergman, M. Wallberg, U. Falkmer, N. Mackman, S. Pedersen, M. Belting Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study ( N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin ( P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04–1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 71
    Publication Date: 2018-11-10
    Description: by Agnieszka Magryś, Kamil Deryło, Agnieszka Bogut, Alina Olender, Marek Tchórzewski Staphylococcus epidermidis small colony variants can survive inside macrophages and their survival has been proposed as a pivotal process in the pathogenesis of biomaterial associated infections. In the present study the intracellular location of clinical isolates of SCV and parental wild type strains inside macrophages was determined. Furthermore, the effect of IFN-γ and rapamycin on the level of SCV/WT as well as lysosomes colocalisation and iNOS induction in THP-activated macrophages in response to WT and SCV strains of Staphylococcus epidermidis were examined. It was demonstrated that SCV strain of S . epidermidis can survive and persist inside macrophages and its intracellular survival is supported by the induction of phagosomal acidification. The ability to reduce the high proportion of LysoTracker positive SCV containing phagosomes was exclusively found when IFN-γ was used. The findings suggest that IFN-γ mediates SCV killing via two distinct mechanisms, phagosome alkalisation and an increased iNOS synthesis, so the cytokine may control S . epidermidis WT and SCV infection in macrophages. Staphylococcus epidermidis SCV is a less potent stimulus of iNOS than the WT strain and the feature may help SCV to persist in hostile environment of macrophages. Rapamycin treatment did not influence the iNOS synthesis but reduced the percentage of both bacterial strains within acidic organelles. However, the percentage of SCV within LysoTracker positive organelles, even though reduced comparing to non-primed cells, was higher than in the WT strain indicating that Staphylococcus epidermidis possesses unique metabolic features allowing SCV to survive within macrophages.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 72
    Publication Date: 2018-11-10
    Description: by Yaroslav V. Radzyukevich, Ninel I. Kosyakova, Isabella R. Prokhorenko Purpose House dust mites Dermatophagoides pteronyssinus are the main source of major inhalatory allergens inducing inflammatory response. Mite extract contain both allergenic proteins and lipopolysaccharides (LPS). The main allergenic protein, Der p 2, is a functional homolog of sMD-2, a protein providing blood cell response on LPS. Der p 2 may restore the response to LPS in absence of MD-2, but its interaction with LPS in whole blood is unknown. We studied the effect of Der p 2 on LPS-mediated activation of human whole blood cells. Methods Interaction of Der p 2 and LPS was studied on eight healthy donors. The whole blood was incubated with extract of house dust mite Dermatophagoides pteronyssinus (DP-e), recombinant antigenic protein Der p 2 variant 5 (rDep 2), Escherichia coli lipopolysaccharide and their combination. Supernatants were collected for ELISA analysis of protein content. Activation degree was determined by change in concentration of TNF-α, IL-8, IL-1Ra cytokines and sMD-2 protein. Results extract of mite Dermatophagoides pteronyssinus (DP-e) possessed weak inherent activity and did not cause significant increase of cytokine production. Simultaneous activation of blood cells by LPS and DP-e led to considerable increase of pro-inflammatory cytokine production. We have shown the intrinsic inducing activity of Der p 2 allergen on sMD-2 protein and TNF-α cytokine expression. Conclusions Der p 2 allergen enhances the response of human whole blood cells to external LPS by inducing additional expression of LPS-transporting protein sMD-2. The obtained data show an important role of LPS contamination of allegrens in the progress of allergic inflammatory response.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 73
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-10
    Description: by Tom E. P. Kimkes, Matthias Heinemann For proper biofilm formation, bacteria must have mechanisms in place to sense adhesion to surfaces. In Escherichia coli , the CpxAR and RcsCDB systems have been reported to sense surfaces. The CpxAR system is widely considered to be responsible for sensing attachment, specifically to hydrophobic surfaces. Here, using both single-cell and population-level analyses, we confirm RcsCDB activation upon surface contact, but find that the CpxAR system is not activated, in contrast to what had earlier been reported. Thus, the role of CpxAR in surface sensing and initiation of biofilm formation should be reconsidered.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 74
    Publication Date: 2018-11-10
    Description: by Cheng-Shyuan Rau, Pao-Jen Kuo, Peng-Chen Chien, Chun-Ying Huang, Hsiao-Yun Hsieh, Ching-Hua Hsieh Background The purpose of this study was to build a model of machine learning (ML) for the prediction of mortality in patients with isolated moderate and severe traumatic brain injury (TBI). Methods Hospitalized adult patients registered in the Trauma Registry System between January 2009 and December 2015 were enrolled in this study. Only patients with an Abbreviated Injury Scale (AIS) score ≥ 3 points related to head injuries were included in this study. A total of 1734 (1564 survival and 170 non-survival) and 325 (293 survival and 32 non-survival) patients were included in the training and test sets, respectively. Results Using demographics and injury characteristics, as well as patient laboratory data, predictive tools (e.g., logistic regression [LR], support vector machine [SVM], decision tree [DT], naive Bayes [NB], and artificial neural networks [ANN]) were used to determine the mortality of individual patients. The predictive performance was evaluated by accuracy, sensitivity, and specificity, as well as by area under the curve (AUC) measures of receiver operator characteristic curves. In the training set, all five ML models had a specificity of more than 90% and all ML models (except the NB) achieved an accuracy of more than 90%. Among them, the ANN had the highest sensitivity (80.59%) in mortality prediction. Regarding performance, the ANN had the highest AUC (0.968), followed by the LR (0.942), SVM (0.935), NB (0.908), and DT (0.872). In the test set, the ANN had the highest sensitivity (84.38%) in mortality prediction, followed by the SVM (65.63%), LR (59.38%), NB (59.38%), and DT (43.75%). Conclusions The ANN model provided the best prediction of mortality for patients with isolated moderate and severe TBI.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 75
    Publication Date: 2018-11-10
    Description: by Quoc C. Vuong, Angela Owen, Kehinde Akin-Akinyosoye, Vera Araujo-Soares There is accumulating evidence that task demands and psychological states can affect perceived pain intensity. Different accounts have been proposed to explain this attenuation based either on how limited attentional resources are allocated to the pain stimulus or on how the threat value of the pain stimulus biases attention. However, the evidence for both proposals remains mixed. Here we introduce an incremental dual-task paradigm in which participants were asked to detect pain on their fingertip without any additional tasks during baseline phases or while concurrently detecting visual targets during task phases. The force applied to participants’ fingertip in all phases increased incrementally until they detected moderate pain. In Experiment 1, we used coloured shapes and in Experiment 2 we used affective images as visual targets. We also manipulated the threat value of the pain stimulus in Experiment 2. For both experiments, we found that a concurrent task attenuated perceived pain intensity: mean force was significantly greater for the same moderate pain during task compared to baseline phases. Furthermore although task difficulty and affective content did not affect pain perception, the threat value of the pain stimulus moderated the magnitude of pain attenuation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 76
    Publication Date: 2018-11-10
    Description: by Catherine A. Sullivan, Jose M. Cacicedo, Iniya Rajendran, Devin W. Steenkamp Aims Increased proinsulin (PI) compared to C-peptide (CP) concentrations have been reported, both prior to type 1 diabetes mellitus (T1D) onset, as well as early in disease. In this pilot study, we sought to define the normal PI secretion in a healthy cohort and compare this to a local T1D cohort and a separate well-defined nationally representative T1D cohort with measurable CP. Methods Thirteen healthy subjects and 12 T1D subjects with T1D 〉3 years from the local T1D cohort completed mixed meal tolerance tests (MMTT) with PI and CP measured over 90 and 240 minutes. The change in CP (maximum versus baseline, ΔCP) during MMTT in the T1D Exchange T1D cohort was stratified according to non-fasting PI concentrations, based on a fasting PI threshold, as defined by the healthy control group. Results The maximum fasting PI in the control group was 6 pmol/L. Individuals from the T1D Exchange with a non-fasting PI ≥ 6 pmol/L had a lower ΔCP during a MMTT, compared to those with a PI 〈 6 pmol/L. While only three individuals from the local T1D cohort had measurable CP and PI during the MMTT, those with a greater ΔCP had lower PI secretion. Conclusion While all T1D subjects from the T1D Exchange secreted measurable non-fasting PI, those with a greater non-fasting PI demonstrated a decrease in ΔCP during the MMTT. PI may be preferentially secreted compared to CP in some individuals with long standing T1D.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 77
    Publication Date: 2018-11-09
    Description: by Ulrike Held, Jakob M. Burgstaller, Maria M. Wertli, Giuseppe Pichierri, Sebastian Winklhofer, Florian Brunner, François Porchet, Mazda Farshad, Johann Steurer Background Approximately two thirds of patients with lumbar spinal stenosis (LSS) who undergo surgical treatment benefit from the surgery. The objective of this study was to derive a prognostic probability function (PPF) to identify patients with a high probability of post-surgical improvement because there is currently no method available. Methods In this multicenter, prospective, observational study, we collected data from eight medical centers in Switzerland in which patients underwent surgery for LSS. The endpoints were meaningful clinically important differences (MCID) in pain and disability one year after baseline. We developed a PPF named PROCESS (PostopeRative OutComE Spinal Stenosis), based on a large set of prognostic indicators extracted from the literature. The PPF was derived using data from a random subset of two thirds of the patients and validated in the remaining third. We addressed overfitting by shrinking the regression coefficients. The area under the ROC curve (AUC) and calibration determined the accuracy of the PPF. Results In this study, 452 LSS patients received surgery. 73% of the 300 patients in the derivation subset reached an MCID in pain and 68% reached an MCID in disability. The corresponding values were 70% and 63% in the validation subset, respectively. In the derivation subsample, the AUC was 0.64 (95% CI 0.57 to 0.71) for of the PPF predicting MCID in pain and 0.71 (0.64 to 0.77) for MCID in disability, after shrinkage. The corresponding numbers were 0.62 (0.52 to 0.72) and 0.70 (0.60 to 0.79) in the validation subsample, and the PPF showed good calibration. Conclusions Surgical treatment for patients with lumbar spinal stenosis is being performed with increasing frequency. PROCESS is conditional on the individual pattern of preoperatively available prognostic indicators, and may be helpful for clinicians in counselling patients and in guiding the discussion on individual treatment decision in the era of personalized medicine.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 78
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    Public Library of Science (PLoS)
    Publication Date: 2018-11-09
    Description: by Malik Benmachiche, Pedro Marques-Vidal, Gérard Waeber, Marie Méan Objective To compare in-hospital mortality in unselected adult patients according to N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Method Retrospective study including 3833 adult patients (median age 72 years, 45% women) hospitalized between January 2013 and April 2015 in a Swiss university hospital, with at least one NT-proBNP level measurement during hospitalization. Patients were categorized in quintiles regarding their highest NT-proBNP level. In-hospital mortality and length of stay (LOS) were compared between the highest and the other quintiles. Results In-hospital mortality rate and LOS (average±standard deviation) were higher in the fifth quintile than in the others (6.5% vs 20.3%, and 20.8±24.0 vs. 14.9±26.5 days respectively, both p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 79
    Publication Date: 2018-11-09
    Description: by Jon J. Smith, Elijah Turner, Andreas Möller, R. M. Joeckel, Rick E. Otto This paper documents the first U-Pb zircon ages for Ashfall Fossil Beds (Nebraska, USA), a terrestrial Konservat-Lagerstätte mass-death assemblage that is arguably the most diverse of its type and age. The Ashfall tephra was correlated with ignimbrites from the Bruneau-Jarbidge volcanic field (12.7–10.5 Ma) in southwest Idaho based on geochemical analysis. The methods and geochemical data supporting the original age assessment of the ash bed, however, were never published, and there has been a persistent misconception that dateable heavy minerals (e.g., zircon) are absent. Notwithstanding, we recovered abundant zircons from Ashfall Fossil Beds, and from an ash bed ~6 km to the southeast at Grove Lake, Nebraska, and analyzed them through LA-ICP-MS. Our new zircon U-Pb age of 11.86 ± 0.13 Ma substantiates correlation of the Ashfall Fossil Beds deposit to tuffs originating from the Bruneau-Jarbidge caldera (~12.7–10.5 Ma). Our U-Pb zircon age of 6.42 ± 0.06 Ma for the Grove Lake ash bed coincides with supervolcanic activity in the Heise volcanic field (6.6–4.3 Ma) in eastern Idaho. These new dates improve age constraints of strata comprising the Ogallala Group and the important paleontological site. Moreover, we find that detrital and airfall zircons are unevenly distributed in the stratified ash beds we describe herein and presumably in similar deposits worldwide. Therefore, a higher-resolution sampling scheme is necessary in such cases.
    Electronic ISSN: 1932-6203
    Topics: Medicine ,