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   Published by PLoS Homepage  [13 journals]
  • indCAPS: A tool for designing screening primers for CRISPR/Cas9
           mutagenesis events

    • Authors: Charles Hodgens Zachary L. Nimchuk Joseph J. Kieber
      Abstract: by Charles Hodgens, Zachary L. Nimchuk, Joseph J. KieberGenetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence-identified mutations that alter a restriction enzyme recognition site can be readily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) in Arabidopsis thaliana. The tool suggested primers that successfully distinguished between wild-type and edited alleles of a target locus and facilitated the isolation of two novel ahk3 null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles at
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188406
  • Genomic analysis of atypical fibroxanthoma

    • Authors: Kevin Lai Catherine A. Harwood Karin J. Purdie Charlotte M. Proby Irene M. Leigh Namita Ravi Thaddeus W. Mully Lionel Brooks Priscilla M. Sandoval Michael D. Rosenblum Sarah T. Arron
      Abstract: by Kevin Lai, Catherine A. Harwood, Karin J. Purdie, Charlotte M. Proby, Irene M. Leigh, Namita Ravi, Thaddeus W. Mully, Lionel Brooks, Priscilla M. Sandoval, Michael D. Rosenblum, Sarah T. ArronAtypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188272
  • The effect of observing novice and expert performance on acquisition of
           surgical skills on a robotic platform

    • Authors: David J. Harris Samuel J. Vine Mark R. Wilson John S. McGrath Marie-Eve LeBel Gavin Buckingham
      Abstract: by David J. Harris, Samuel J. Vine, Mark R. Wilson, John S. McGrath, Marie-Eve LeBel, Gavin BuckinghamBackground Observational learning plays an important role in surgical skills training, following the traditional model of learning from expertise. Recent findings have, however, highlighted the benefit of observing not only expert performance but also error-strewn performance. The aim of this study was to determine which model (novice vs. expert) would lead to the greatest benefits when learning robotically assisted surgical skills. Methods 120 medical students with no prior experience of robotically-assisted surgery completed a ring-carrying training task on three occasions; baseline, post-intervention and at one-week follow-up. The observation intervention consisted of a video model performing the ring-carrying task, with participants randomly assigned to view an expert model, a novice model, a mixed expert/novice model or no observation (control group). Participants were assessed for task performance and surgical instrument control. Results There were significant group differences post-intervention, with expert and novice observation groups outperforming the control group, but there were no clear group differences at a retention test one week later. There was no difference in performance between the expert-observing and error-observing groups. Conclusions Similar benefits were found when observing the traditional expert model or the error-strewn model, suggesting that viewing poor performance may be as beneficial as viewing expertise in the early acquisition of robotic surgical skills. Further work is required to understand, then inform, the optimal curriculum design when utilising observational learning in surgical training.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188233
  • Suppression of inflammatory and infection responses in lung macrophages by
           eucalyptus oil and its constituent 1,8-cineole: Role of pattern
           recognition receptors TREM-1 and NLRP3, the MAP kinase regulator MKP-1,
           and NFκB

    • Authors: Niket Yadav Harish Chandra
      Abstract: by Niket Yadav, Harish ChandraEucalyptus oil (EO) used in traditional medicine continues to prove useful for aroma therapy in respiratory ailments; however, there is a paucity of information on its mechanism of action and active components. In this direction, we investigated EO and its dominant constituent 1,8–cineole (eucalyptol) using the murine lung alveolar macrophage (AM) cell line MH-S. In an LPS-induced AM inflammation model, pre-treatment with EO significantly reduced (P ≤0.01or 0.05) the pro-inflammatory mediators TNF-α, IL-1 (α and β), and NO, albeit at a variable rate and extent; 1,8-cineole diminished IL-1 and IL-6. In a mycobacterial-infection AM model, EO pre-treatment or post-treatment significantly enhanced (P ≤0.01) the phagocytic activity and pathogen clearance. 1,8-cineole also significantly enhanced the pathogen clearance though the phagocytic activity was not significantly altered. EO or 1,8-cineole pre-treatment attenuated LPS-induced inflammatory signaling pathways at various levels accompanied by diminished inflammatory response. Among the pattern recognition receptors (PRRs) involved in LPS signaling, the TREM pathway surface receptor (TREM-1) was significantly downregulated. Importantly, the pre-treatments significantly downregulated (P ≤0.01) the intracellular PRR receptor NLRP3 of the inflammasome, which is consistent with the decrease in IL-1β secretion. Of the shared downstream signaling cascade for these PRR pathways, there was significant attenuation of phosphorylation of the transcription factor NF-κB and p38 (but increased phosphorylation of the other two MAP kinases, ERK1/2 and JNK1/2). 1,8-cineole showed a similar general trend except for an opposite effect on NF-κB and JNK1/2. In this context, either pre-treatment caused a significant downregulation of MKP-1 phosphatase, a negative regulator of MAPKs. Collectively, our results demonstrate that the anti-inflammatory activity of EO and 1,8-cineole is modulated via selective downregulation of the PRR pathways, including PRR receptors (TREM-1 and NLRP3) and common downstream signaling cascade partners (NF-κB, MAPKs, MKP-1). To our knowledge, this is the first report on the modulatory role of TREM-1 and NLRP3 inflammasome pathways and the MAPK negative regulator MKP-1 in context of the anti-inflammatory potential of EO and its constituent 1,8-cineole.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188232
  • Structure of the human chromosome interaction network

    • Authors: Sergio Sarnataro Andrea M. Chiariello Andrea Esposito Antonella Prisco Mario Nicodemi
      Abstract: by Sergio Sarnataro, Andrea M. Chiariello, Andrea Esposito, Antonella Prisco, Mario NicodemiNew Hi-C technologies have revealed that chromosomes have a complex network of spatial contacts in the cell nucleus of higher organisms, whose organisation is only partially understood. Here, we investigate the structure of such a network in human GM12878 cells, to derive a large scale picture of nuclear architecture. We find that the intensity of intra-chromosomal interactions is power-law distributed. Inter-chromosomal interactions are two orders of magnitude weaker and exponentially distributed, yet they are not randomly arranged along the genomic sequence. Intra-chromosomal contacts broadly occur between epigenomically homologous regions, whereas inter-chromosomal contacts are especially associated with regions rich in highly expressed genes. Overall, genomic contacts in the nucleus appear to be structured as a network of networks where a set of strongly individual chromosomal units, as envisaged in the ‘chromosomal territory’ scenario derived from microscopy, interact with each other via on average weaker, yet far from random and functionally important interactions.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188201
  • Trabecular bone in the calcaneus of runners

    • Authors: Andrew Best Brigitte Holt Karen Troy Joseph Hamill
      Abstract: by Andrew Best, Brigitte Holt, Karen Troy, Joseph HamillTrabecular bone of the human calcaneus is subjected to extreme repetitive forces during endurance running and should adapt in response to this strain. To assess possible bone functional adaptation in the posterior region of the calcaneus, we recruited forefoot-striking runners (n = 6), rearfoot-striking runners (n = 6), and non-runners (n = 6), all males aged 20–41 for this institutionally approved study. Foot strike pattern was confirmed for each runner using a motion capture system. We obtained high resolution peripheral computed tomography scans of the posterior calcaneus for both runners and non-runners. No statistically significant differences were found between runners and nonrunners or forefoot strikers and rearfoot strikers. Mean trabecular thickness and mineral density were greatest in forefoot runners with strong effect sizes (
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188200
  • Medical therapy versus radiofrequency endometrial ablation in the initial
           treatment of heavy menstrual bleeding (iTOM Trial): A clinical and
           economic analysis

    • Authors: Abimbola O. Famuyide Shannon K. Laughlin-Tommaso Sherif A. Shazly Kirsten Hall Long Daniel M. Breitkopf Amy L. Weaver Michaela E. McGree Sherif A. El-Nashar Maureen A. Lemens Matthew R. Hopkins
      Abstract: by Abimbola O. Famuyide, Shannon K. Laughlin-Tommaso, Sherif A. Shazly, Kirsten Hall Long, Daniel M. Breitkopf, Amy L. Weaver, Michaela E. McGree, Sherif A. El-Nashar, Maureen A. Lemens, Matthew R. HopkinsBackground Radiofrequency endometrial ablation (REA) is currently a second line treatment in women with heavy menstrual bleeding (MHB) if medical therapy (MTP) is contraindicated or unsatisfactory. Our objective is to compare the effectiveness and cost burden of MTP and REA in the initial treatment of HMB. Methods We performed a randomized trial at Mayo Clinic Rochester, Minnesota. The planned sample size was 60 patients per arm. A total of 67 women with HMB were randomly allocated to receive oral contraceptive pills (Nordette ®) or Naproxen (Naprosyn®) (n = 33) or REA (n = 34). Primary 12-month outcome measures included menstrual blood loss using pictorial blood loss assessment chart (PBLAC), patients’ satisfaction, and Menorrhagia Multi-Attribute Scale (MMAS). Secondary outcomes were total costs including direct medical and indirect costs associated with healthcare use, patient out-of-pocket costs, and lost work days and activity limitations over 12 months. Results Compared to MTP arm, women who received REA had a significantly lower PBLAC score (median [Interquartile range, IQR]: 0 [0–4] vs. 15 [0–131], p = 0.003), higher satisfaction rates (96.8%vs.63.2%, p = 0.003) and higher MMAS (median [IQR]: 100 [100–100] vs. 100 [87–100], p = 0.12) at 12 months. Direct medical costs were higher for REA ($5,331vs.$2,901, 95% confidence interval (CI) of mean difference:$727,$4,852), however, when indirect costs are included, the difference did not reach statistical significance ($5,469 vs. $3,869, 95% CI of mean difference:-$339, $4,089). Conclusion For women with heavy menstrual bleeding, initial radiofrequency endometrial ablation compared to medical therapy offered superior reduction in menstrual blood loss and improvement in quality of life without significant differences in total costs of care. Clinical trial registration NCT01165307.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188176
  • Effects of a mixed berry beverage on cognitive functions and
           cardiometabolic risk markers; A randomized cross-over study in healthy
           older adults

    • Authors: Anne Nilsson Ilkka Salo Merichel Plaza Inger Björck
      Abstract: by Anne Nilsson, Ilkka Salo, Merichel Plaza, Inger BjörckBackground Berries and associated bioactive compounds, e.g. polyphenols and dietary fibre (DF), may have beneficial implications with respect to the metabolic syndrome, including also cognitive functions. The aim of this study was to evaluate effects on cognitive functions and cardiometabolic risk markers of 5 wk intervention with a mixture of berries, in healthy humans. Methods Forty healthy subjects between 50–70 years old were provided a berry beverage based on a mixture of berries (150g blueberries, 50g blackcurrant, 50g elderberry, 50g lingonberries, 50g strawberry, and 100g tomatoes) or a control beverage, daily during 5 weeks in a randomized crossover design. The control beverage (water based) was matched with respect to monosaccharides, pH, and volume. Cognitive tests included tests of working memory capacity, selective attention, and psychomotor reaction time. Cardiometabolic test variables investigated were blood pressure, fasting blood concentrations of glucose, insulin, blood lipids, inflammatory markers, and markers of oxidative stress. Results The daily amounts of total polyphenols and DF from the berry beverage were 795 mg and 11g, respectively. There were no polyphenols or DF in the control beverage. The berry intervention reduced total- and LDL cholesterol compared to baseline (both P
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188173
  • Developmental patterning of sub-epidermal cells in the outer integument of
           Arabidopsis seeds

    • Authors: Elisa Fiume Olivier Coen Wenjia Xu Loïc Lepiniec Enrico Magnani
      Abstract: by Elisa Fiume, Olivier Coen, Wenjia Xu, Loïc Lepiniec, Enrico MagnaniThe seed, the reproductive unit of angiosperms, is generally protected by the seed coat. The seed coat is made of one or two integuments, each comprising two epidermal cells layers and, in some cases, extra sub-epidermal cell layers. The thickness of the seed-coat affects several aspects of seed biology such as dormancy, germination and mortality. In Arabidopsis, the inner integument displays one or two sub-epidermal cell layers that originate from periclinal cell divisions of the innermost epidermal cell layer. By contrast, the outer integument was considered to be two-cell layered. Here, we show that sub-epidermal chalazal cells grow in between the epidermal outer integument cell layers to create an incomplete three-cell layered outer integument. We found that the MADS box transcription factor TRANSPARENT TESTA 16 represses growth of the chalaza and formation of sub-epidermal outer integument cells. Finally, we demonstrate that sub-epidermal cells of the outer and inner integument respond differently to the repressive mechanism mediated by FERTILIZATION INDEPENDENT SEED Polycomb group proteins and to fertilization signals. Our data suggest that integument cell origin rather than sub-epidermal cell position underlies different responses to fertilization.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188148
  • Association between urinary manganese and blood pressure: Results from
           National Health and Nutrition Examination Survey (NHANES), 2011-2014

    • Authors: Cynthia Wu Jessica G. Woo Nanhua Zhang
      Abstract: by Cynthia Wu, Jessica G. Woo, Nanhua ZhangManganese is a trace mineral required for metabolism, growth and tissue formation, and reproduction. It is mainly obtained through food and water, as well as through occupational exposure. This study used data from National Health and Nutrition Examination Survey, combining the 2011–12 and 2013–14 cycles. We conducted linear regression analyses on urinary manganese and blood pressure. Significant negative associations (p
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188145
  • Prognostic value of pretreatment serum carbohydrate antigen 19-9 level in
           patients with colorectal cancer: A meta-analysis

    • Authors: Zhan Yu Zhen Chen Jian Wu Zhong Li Yugang Wu
      Abstract: by Zhan Yu, Zhen Chen, Jian Wu, Zhong Li, Yugang WuBackground Carbohydrate antigen 19–9 (CA 19–9) is one of the most frequently used tumor markers for gastrointestinal cancer, particularly for diagnostic purposes. However, its value in predicting prognosis remains controversial. In this study, we sought to clarify this by conducting a meta-analysis of relevant studies. Methods We systematically searched several databases, including PubMed, EMBASE and Web of Science for articles pertaining to the relationship between pretreatment serum CA 19–9 levels and prognosis in patients with colorectal cancer (CRC). The reported hazard ratios (HR) of overall survival (OS), disease-free survival (DFS), pooled progression-free survival (PFS) and recurrence-free survival (RFS) in the analyzed studies were compared by fixed effects/random effects models. Results Seventeen studies involving 6434 patients with CRC were included in our meta-analysis. A comprehensive analysis of the collected data revealed that high serum CA 19–9 levels before treatment were significantly associated with poor OS (HR: 1.58, 95% CI: 1.36–1.83, P
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188139
  • Differential immunomodulation in human monocytes versus macrophages by
           filarial cystatin

    • Authors: Gopinath Venugopal Marion Mueller Susanne Hartmann Svenja Steinfelder
      Abstract: by Gopinath Venugopal, Marion Mueller, Susanne Hartmann, Svenja SteinfelderParasitic nematodes have evolved powerful immunomodulatory molecules to enable their survival in immunocompetent hosts by subverting immune responses and minimizing pathological processes. One filarial molecule known to counteract host immune responses by inducing IL-10 and regulatory macrophages in mice is filarial cystatin. During a patent filarial infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. The microfilarial larval stage was formerly shown to induce human regulatory monocytes and macrophages. Thus, here we aim was to determine how filarial cystatin of the human pathogenic filaria Brugia malayi (BmCPI-2) contributes to immune hyporesponsiveness in human monocytes and macrophages elicited by microfilaria. For this purpose, filarial cystatin was depleted from microfilarial lysate (Mf). Detecting the immunomodulatory potential of cystatin-depleted Mf revealed that IL-10, but not IL-8 and IL-6 induction in monocytes and macrophages is dependent on the presence of cystatin. In addition, the Mf-induced expression of the regulatory surface markers PD-L1 and PD-L2 in human monocytes, but not in macrophages, is dependent on cystatin. While Mf-treated monocytes result in decreased CD4+ T-cell proliferation in a co-culture assay, stimulation of T-cells with human monocytes treated with cystatin-depleted Mf lead to a restoration of CD4+ T-cell proliferation. Moreover, IL-10 induction by cystatin within Mf was dependent on p38 and ERK in macrophages, but independent of the ERK pathway in monocytes. These findings indicate that filarial nematodes differentially trigger and exploit various signaling pathways to induce immunomodulation in different myeloid cell subsets.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188138
  • Nematocytes: Discovery and characterization of a novel anculeate hemocyte
           in Drosophila falleni and Drosophila phalerata

    • Authors: Julianna Bozler Balint Z. Kacsoh Giovanni Bosco
      Abstract: by Julianna Bozler, Balint Z. Kacsoh, Giovanni BoscoImmune challenges, such as parasitism, can be so pervasive and deleterious that they constitute an existential threat to a species’ survival. In response to these ecological pressures, organisms have developed a wide array of novel behavioral, cellular, and molecular adaptations. Research into these immune defenses in model systems has resulted in a revolutionary understanding of evolution and functional biology. As the field has expanded beyond the limited number of model organisms our appreciation of evolutionary innovation and unique biology has widened as well. With this in mind, we have surveyed the hemolymph of several non-model species of Drosophila. Here we identify and describe a novel hemocyte, type-II nematocytes, found in larval stages of numerous Drosophila species. Examined in detail in Drosophila falleni and Drosophila phalerata, we find that these remarkable cells are distinct from previously described hemocytes due to their anucleate state (lacking a nucleus) and unusual morphology. Type-II nematocytes are long, narrow cells with spindle-like projections extending from a cell body with high densities of mitochondria and microtubules, and exhibit the ability to synthesize proteins. These properties are unexpected for enucleated cells, and together with our additional characterization, we demonstrate that these type-II nematocytes represent a biological novelty. Surprisingly, despite the absence of a nucleus, we observe through live cell imaging that these cells remain motile with a highly dynamic cellular shape. Furthermore, these cells demonstrate the ability to form multicellular structures, which we suggest may be a component of the innate immune response to macro-parasites. In addition, live cell imaging points to a large nucleated hemocyte, type-I nematocyte, as the progenitor cell, leading to enucleation through a budding or asymmetrical division process rather than nuclear ejection: This study is the first to report such a process of enucleation. Here we describe these cells in detail for the first time and examine their evolutionary history in Drosophila.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188133
  • A qualitative exploration of malaria operational research situation in

    • Authors: IkeOluwapo O. Ajayi Maduka D. Ughasoro Akintayo Ogunwale Oluwaseun Odeyinka Obafemi Babalola Salami Sharafadeen Al-Mukhtar Y. Adamu Olufemi Ajumobi Taiwo Orimogunje Patrick Nguku
      Abstract: by IkeOluwapo O. Ajayi, Maduka D. Ughasoro, Akintayo Ogunwale, Oluwaseun Odeyinka, Obafemi Babalola, Salami Sharafadeen, Al-Mukhtar Y. Adamu, Olufemi Ajumobi, Taiwo Orimogunje, Patrick NgukuBackground Malaria, remains one of the leading causes of high morbidity and mortality in Nigeria despite implementation of several public health interventions for its control. Operational limitations and methodological gaps have been associated with malaria control interventions and research, and these have necessitated the need for a well-tailored Malaria Operational Research (MOR) agenda. However, there is paucity of evidence-based information on relevant stakeholders’ experience, awareness, perceptions and use of MOR and suggestions on setting MOR agenda. As part of a larger study to provide data for national MOR agenda setting, we assessed the MOR research situation from the perspectives of key stakeholders in Nigeria and contribution of MOR to the malaria elimination agenda Methods We conducted key informant interviews among 40 purposively selected stakeholders from the six geo-political zones in Nigeria. Data was collected using a pre-tested key informant interview guide which comprised issues related to experience, awareness, use of MOR and MOR needs, and suggestions for MOR. We conducted a detailed content analysis. Results Half of the participants had participated in MOR. Participants perceived MOR as important. Only few were aware of existing framework for MOR in Nigeria while above half expressed that MOR is yet to be used to inform policy in Nigeria. Participants identified several MOR needs such as development of improved diagnostic techniques, and interventions for promoting early diagnosis, prompt treatment and quality programmatic data. Participants opined the need for country-specific prioritised MOR agenda that cut across malaria thematic areas including malaria prevention and case management. Participants suggested the involvement of various stakeholders and multi-disciplinary approach in setting MOR. Conclusion Although some stakeholders have been involved in MOR, it is still rarely used to inform policy and several needs exist across thematic areas. A broad-based stakeholder involvement, multi-disciplinary approach to agenda setting and its wide dissemination have been suggested.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188128
  • eDNA for detection of five highly invasive molluscs. A case study in urban
           rivers from the Iberian Peninsula

    • Authors: Laura Clusa Laura Miralles Ana Basanta Carmelo Escot Eva García-Vázquez
      Abstract: by Laura Clusa, Laura Miralles, Ana Basanta, Carmelo Escot, Eva García-VázquezBiological invasions are an important threat to biodiversity especially in aquatic ecosystems, and their frequency is generally higher near urban areas. Potentially invasive non-indigenous molluscs were deliberately introduced into European waters for food (Corbicula fluminea) and biocontrol (Melanoides tuberculata), and unintentionally introduced by ballast water (Mytilopsis leucophaeata, Corbicula fluminea), stock contamination (Sinanodonta woodiana), accidental escapes from aquaculture (Sinanodonta woodiana), aquarium trade releases (Melanoides tuberculata) and even attached to aquatic birds (Corbicula fluminea). Three rivers from the Iberian Peninsula were monitored near the three most populated inland cities to evaluate the presence of these invasive molluscs through PCR amplification using taxon-specific primers from eDNA. New primers were designed within 16S rRNA and cytochrome oxidase subunit I genes, tested in silico from BLAST methodology and experimentally in vitro before application in the field. C. fluminea was found in Ebro River (near Zaragoza); M. leucophaeata in Guadalquivir River (near Sevilla). M. tuberculata and S. woodiana were found from enclosed areas (lake and reservoir respectively) upstream, respectively, Zaragoza and Madrid. The new tools are ready to be used in other regions where these species are also invasive.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188126
  • Temozolomide post pazopanib treatment failure in patients with advanced
           sarcoma: A case series

    • Authors: Manojkumar Bupathi John L. Hays James L. Chen
      Abstract: by Manojkumar Bupathi, John L. Hays, James L. ChenBackground Sarcomas are rare, heterogeneous tumors for which prognosis remains dismal in patients with advanced disease. Pazopanib, a vascular endothelial growth factor receptor inhibitor, has shown modest efficacy in patients with soft tissue sarcoma who fail cytotoxic chemotherapy. The cytotoxic agent temozolomide has also demonstrated activity in patients with advanced sarcoma. Objective We performed a retrospective case series to evaluate the feasibility of adding temozolomide to pazopanib in advanced sarcoma patients following single-agent pazopanib failure. Patients and methods Patients with recurrent, metastatic sarcomas who had progressed on single-agent pazopanib and continued on pazopanib with the addition of temozolomide were included in this retrospective analysis to examine the tolerability and responses associated with the treatment combination. Results Nine patients with a range of sarcoma subtypes were identified (55% female; median age, 48 years; median number of therapies prior to pazopanib, 3). All patients received combination therapy. One patient was recently started on therapy and was excluded from the analysis (n = 8 evaluable patients). Median PFS for single-agent pazopanib was 7.5 months (range 2–19). For the eight evaluable patients (63% female), best response at 4 months with pazopanib plus temozolomide was partial response (n = 1), stable disease (n = 3) and progressive disease (n = 4), with a median PFS of 3.5 months (range 0–15). Median PFS with combination treatment in patients with stable disease or response was 8 months (range 5–15). All four patients who achieved clinical benefit remain on therapy and are tolerating the combination therapy with expected but manageable side effects. Conclusions In heavily pretreated patients with advanced sarcoma, the addition of temozolomide to pazopanib was found to be tolerable. Future prospective trials are required to deduce whether temozolomide extends the clinical benefit of pazopanib.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188116
  • Microcirculation in open vs. minimally invasive dorsal stabilization of
           thoracolumbar fractures

    • Authors: Bergita Ganse Miguel Pishnamaz Philipp Kobbe Christian Herren Gertraud Gradl-Dietsch Franziska Böhle Bernd Johannes Bong-Sung Kim Klemens Horst Matthias Knobe
      Abstract: by Bergita Ganse, Miguel Pishnamaz, Philipp Kobbe, Christian Herren, Gertraud Gradl-Dietsch, Franziska Böhle, Bernd Johannes, Bong-Sung Kim, Klemens Horst, Matthias KnobeStandard open and percutaneous minimally invasive surgical procedures co-exist in the treatment of fractures of the thoracolumbar spine. Shorter skin incisions just above the pedicles are used in minimally invasive procedures. Full-length skin incisions and invasive preparations are applied in the standard open approach. While both methods show equivalent rates of intraoperative surgical complications and comparable clinical and radiological outcomes, blood loss and operation time have shown to be decreased in minimally invasive treatment. However, no study so far has investigated differences in microcirculation. This study hypothesized less impairment of microcirculation in the minimally invasive approach compared to the open approach and an improvement of microcirculation over time. A prospective cohort study was conducted using non-invasive laser-Doppler spectrophotometry (an O2C “oxygen to see” device) for measurement of cutaneous and subcutaneous blood oxygenation (SO2), haemoglobin concentration (Hb), and blood flow at depths of 2, 8, and 15 mm at six locations on the skin. Measurements were performed before surgery, 8 and 24 h after surgery, and 2, 4, 7, 12 and 20 days after surgery, however the number of patients measured decreased towards the later time points. Forty patients were included in the study, 20 with each approach (18 females and 22 males). Pair-wise comparison of the types of surgical procedure for each measurement point revealed a significantly higher flow value in the minimally invasive group at one of the measurement points located between the incisions (P = .041). The point-wise analyses of SO2 and Hb did not show significant differences between the approaches. In conclusion, significantly albeit moderately higher flow values could be found in minimally invasive procedures compared to open operations of thoracolumbar fractures in the area of skin that is spared by the incisions.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188115
  • Identification of isolates of the plant pathogen Leptosphaeria maculans
           with resistance to the triazole fungicide fluquinconazole using a novel In
           Planta assay

    • Authors: Angela P. Van de Wouw Vicki L. Elliott Steven Chang Francisco J. López-Ruiz Steven J. Marcroft Alexander Idnurm
      Abstract: by Angela P. Van de Wouw, Vicki L. Elliott, Steven Chang, Francisco J. López-Ruiz, Steven J. Marcroft, Alexander IdnurmLeptosphaeria maculans is the major pathogen of canola (oilseed rape, Brassica napus) worldwide. In Australia, the use of azole fungicides has contributed to the 50-fold increase in canola production in the last 25 years. However, extensive application of fungicides sets the stage for the selection of fungal populations with resistance. A high-throughput in planta assay was developed to allow screening of thousands of isolates from multiple populations. Using this screen, isolates were identified with decreased sensitivity to the fungicide fluquinconazole when applied at field rates as a protective seed dressing: these isolates cause significantly larger lesions on cotyledons and true leaves and increased disease severity at plant maturity. This increased in planta resistance was specific to fluquinconazole, with no cross resistance to flutriafol or tebuconazole/prothioconazole. In a limited set of 22 progeny from a cross between resistant and susceptible parents, resistance segregated in a 1:1 ratio, suggesting a single gene is responsible. A survey of 200 populations from across canola growing regions of Australia revealed fungicide resistance was present in 15% of the populations. Although in vitro analysis of the fungicide resistant isolates showed a significant shift in the average EC50 compared to the sensitive isolates, this was not as evident as the in planta assays. The development of this novel, high-throughput in planta assay has led to the identification of the first fungicide resistant L. maculans isolates, which may pose a threat to the productivity of the Australian canola industry.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188106
  • In-depth phenotypic characterization of multicellular tumor spheroids:
           Effects of 5-Fluorouracil

    • Authors: Angélique Virgone-Carlotta Manon Lemasson Hichem C. Mertani Jean-Jacques Diaz Sylvain Monnier Thomas Dehoux Hélène Delanoë-Ayari Charlotte Rivière Jean-Paul Rieu
      Abstract: by Angélique Virgone-Carlotta, Manon Lemasson, Hichem C. Mertani, Jean-Jacques Diaz, Sylvain Monnier, Thomas Dehoux, Hélène Delanoë-Ayari, Charlotte Rivière, Jean-Paul RieuMultiCellular Tumor Spheroids (MCTS), which mimic the 3-Dimensional (3D) organization of a tumor, are considered as better models than conventional cultures in 2-Dimensions (2D) to study cancer cell biology and to evaluate the response to chemotherapeutic drugs. A real time and quantitative follow-up of MCTS with simple and robust readouts to evaluate drug efficacy is still missing. Here, we evaluate the chemotherapeutic drug 5-Fluorouracil (5-FU) response on the growth and integrity of MCTS two days after treatment of MCTS and for three colorectal carcinoma cell lines with different cohesive properties (HT29, HCT116 and SW480). We found different sensitivity to 5-FU for the three CRC cell lines, ranging from high (SW480), intermediate (HCT116) and low (HT29) and the same hierarchy of CRC cell lines sensitivity is conserved in 2D. We also evidence that 5-FU has a strong impact on spheroid cohesion, with the apparition of a number of single detaching cells from the spheroid in a 5-FU dose- and cell line-dependent manner. We propose an innovative methodology for the chemosensitivity evaluation in 3D MCTS that recapitulates and regionalizes the 5-FU-induced changes within MCTS over time. These robust phenotypic read-outs could be easily scalable for high-throughput drug screening that may include different types of cancer cells to take into account tumor heterogeneity and resistance to treatment.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188100
  • The mitochondrial genome of Muga silkworm (Antheraea assamensis) and its
           comparative analysis with other lepidopteran insects

    • Authors: Deepika Singh Debajyoti Kabiraj Pragya Sharma Hasnahana Chetia Ponnala Vimal Mosahari Kartik Neog Utpal Bora
      Abstract: by Deepika Singh, Debajyoti Kabiraj, Pragya Sharma, Hasnahana Chetia, Ponnala Vimal Mosahari, Kartik Neog, Utpal BoraMuga (Antheraea assamensis) is an economically important silkmoth endemic to the states of Assam and Meghalaya in India and is the producer of the strongest known commercial silk. However, there is a scarcity of genomic and proteomic data for understanding the organism at a molecular level. Our present study is on decoding the complete mitochondrial genome (mitogenome) of A. assamensis using next generation sequencing technology and comparing it with other available lepidopteran mitogenomes. Mitogenome of A. assamensis is an AT rich circular molecule of 15,272 bp (A+T content ~80.2%). It contains 37 genes comprising of 13 protein coding genes (PCGs), 22 tRNA and 2 rRNA genes along with a 328 bp long control region. Its typical tRNAMet-tRNAIle-tRNAGln arrangement differed from ancestral insects (tRNAIle-tRNAGln-tRNAMet). Two PCGs cox1 and cox2 were found to have CGA and GTG as start codons, respectively as reported in some lepidopterans. Interestingly, nad4l gene showed higher transversion mutations at intra-species than inter-species level. All PCGs evolved under strong purifying selection with highest evolutionary rates observed for atp8 gene while lowest for cox1 gene. We observed the typical clover-leaf shaped secondary structures of tRNAs with a few exceptions in case of tRNASer1 and tRNATyr where stable DHU and TΨC loop were absent. A significant number of mismatches (35) were found to spread over 19 tRNA structures. The control region of mitogenome contained a six bp (CTTAGA/G) deletion atypical of other Antheraea species and lacked tandem repeats. Phylogenetic position of A. assamensis was consistent with the traditional taxonomic classification of Saturniidae. The complete annotated mitogenome is available in GenBank (Accession No. KU379695). To the best of our knowledge, this is the first report on complete mitogenome of A. assamensis.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188077
  • Brain response to luminance-based and motion-based stimulation using
           inter-modulation frequencies

    • Authors: Xin Zhang Guanghua Xu Jun Xie Xun Zhang
      Abstract: by Xin Zhang, Guanghua Xu, Jun Xie, Xun ZhangSteady state visual evoked potential (SSVEP)-based brain computer interface (BCI) has advantages of high information transfer rate (ITR), less electrodes and little training. So it has been widely investigated. However, the available stimulus frequencies are limited by brain responses. Simultaneous modulation of stimulus luminance is a novel method to resolve this problem. In this study, three experiments were devised to gain a deeper understanding of the brain response to the stimulation using inter-modulation frequencies. First, luminance-based stimulation using one to five inter-modulation frequencies was analyzed for the first time. The characteristics of the brain responses to the proposed stimulation were reported. Second, the motion-based stimulation with equal luminance using inter-modulation frequencies was also proposed for the first time. The response of the brain under these conditions were similar to that of luminance-based stimulation which can induce combination frequencies. And an elementary analysis was conducted to explain the reason of the occurrence of combination frequencies. Finally, the online test demonstrated the efficacy of our proposed two stimulation methods for BCI. The average ITRs reached 34.7836 bits/min and 39.2856 bits/min for luminance-based and motion-based stimulation respectively. This study demonstrated that the simultaneous modulation of stimulus luminance could extend to at least five frequencies to induce SSVEP and the brain response to the stimulus still maintained a certain positive correlation with luminance. And not only luminance-based stimulation, but also motion-based stimulation with equal luminance can elicit inter-modulation frequencies to effectively increase the number of targets for multi-class SSVEP.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188073
  • Prognostic significance of cyclin D1 protein expression and gene
           amplification in invasive breast carcinoma

    • Authors: Angela B. Ortiz Diego Garcia Yolanda Vicente Magda Palka Carmen Bellas Paloma Martin
      Abstract: by Angela B. Ortiz, Diego Garcia, Yolanda Vicente, Magda Palka, Carmen Bellas, Paloma MartinThe oncogenic capacity of cyclin D1 has long been established in breast cancer. CCND1 amplification has been identified in a subset of patients with poor prognosis, but there are conflicting data regarding the predictive value of cyclin D1 protein overexpression. This study was designed to analyze the expression of cyclin D1 and its correlation with CCND1 amplification and their prognostic implications in invasive breast cancer. By using the tissue microarray technique, we performed an immunohistochemical study of ER, PR, HER2, p53, cyclin D1, Ki67 and p16 in 179 invasive breast carcinoma cases. The FISH method was performed to detect HER2/Neu and CCND1 amplification. High cyclin D1 expression was identified in 94/179 (52%) of invasive breast cancers. Cyclin D1 overexpression and CCND1 amplification were significantly associated (p = 0.010). Overexpression of cyclin D1 correlated with ER expression, PR expression and Luminal subtypes (p
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188068
  • Transcriptome profiling of claw muscle of the mud crab (Scylla
           paramamosain) at different fattening stages

    • Authors: Qingling Jiang Chenchang Bao Ya’nan Yang An Liu Fang Liu Huiyang Huang Haihui Ye
      Abstract: by Qingling Jiang, Chenchang Bao, Ya’nan Yang, An Liu, Fang Liu, Huiyang Huang, Haihui YeIn crustaceans, muscle growth and development is complicated, and to date substantial knowledge gaps exist. In this study, the claw muscle, hepatopancreas and nervous tissue of the mud crab (Scylla paramamosain) were collected at three fattening stages for sequence by the Illumina sequencing. A total of 127.87 Gb clean data with no less than 3.94 Gb generated for each sample and the cycleQ30 percentages were more than 86.13% for all samples. De Bruijn assembly of these clean data produced 94,853 unigenes, thereinto, 50,059 unigenes were found in claw muscle. A total of 121 differentially expressed genes (DEGs) were revealed in claw muscle from the three fattening stages with a Padj value < 0.01, including 63 genes with annotation. Functional annotation and enrichment analysis showed that the DEGs clusters represented the predominant gene catalog with roles in biochemical processes (glycolysis, phosphorylation and regulation of transcription), molecular function (ATP binding, 6-phosphofructokinase activity, and sequence-specific DNA binding) and cellular component (6-phosphofructokinase complex, plasma membrane, and integral component of membrane). qRT-PCR was employed to further validate certain DEGs. Single nucleotide polymorphism (SNP) analysis obtained 159,322, 125,963 and 166,279 potential SNPs from the muscle transcriptome at stage B, stage C and stage D, respectively. In addition, there were sixteen neuropeptide transcripts being predicted in the claw muscle. The present study provides a comprehensive transcriptome of claw muscle of S. paramamosain during fattening, providing a basis for screening the functional genes that may affect muscle growth of S. paramamosain.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188067
  • Is species richness driving intra- and interspecific interactions and
           temporal activity overlap of a hantavirus host' An experimental test

    • Authors: André V. Rubio Ivan Castro-Arellano James N. Mills Rurik List Rafael Ávila-Flores Gerardo Suzán
      Abstract: by André V. Rubio, Ivan Castro-Arellano, James N. Mills, Rurik List, Rafael Ávila-Flores, Gerardo SuzánHigh species diversity of the potential animal host community for a zoonotic pathogen may reduce pathogen transmission among the most competent host, a phenomenon called the “dilution effect”, but the mechanisms driving this effect have been little studied. One proposed mechanism is “encounter reduction” where host species of low-competency decrease contact rates between infected and susceptible competent hosts, especially in directly transmitted diseases. We conducted an experiment in outdoor enclosures in northwestern Mexico where we manipulated rodent assemblages to assess the effect of species richness on the frequency of intra- and interspecific interactions and activity patterns of a hantavirus reservoir host (North American deermouse; Peromyscus maniculatus). Trials consisted of three treatments of rodent assemblages that differed in species richness, but had equal abundance of deermice; treatment 1 consisted of only deermice, treatment 2 included deermice and one non-competent host species, and treatment 3 included two non-competent host species in addition to deermice. To measure interactions and temporal activity, we strategically deployed foraging stations and infrared cameras. We did not find differences in the frequency of intraspecific interactions of deermice among treatments, but there were significantly more interspecific interactions between deermouse and non-competent hosts in treatment 2 than treatment 3, which is explained by the identity of the non-competent host species. In addition, there were differences in activity patterns between rodent species, and also between deermice from treatment 1 and treatment 2. These results indicate that at least at a small-scale analysis, the co-occurrence with other species in the study area does not influence the frequency of intraspecific interactions of deermice, and that deermice may be changing their activity patterns to avoid a particular non-competent host species (Dipodomys merriami). In conclusion, in this deermouse-hantavirus system a potential dilution effect would not be through intraspecific encounter reduction in the most competent hantavirus host. To identify variables of host assemblages that can influence pathogen transmission, we highlight the need to address the identity of species and the composition of assemblages, not only host species richness or diversity.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188060
  • Fast, axis-agnostic, dynamically summarized storage and retrieval for mass
           spectrometry data

    • Authors: Kyle Handy Jebediah Rosen André Gillan Rob Smith
      Abstract: by Kyle Handy, Jebediah Rosen, André Gillan, Rob SmithMass spectrometry, a popular technique for elucidating the molecular contents of experimental samples, creates data sets comprised of millions of three-dimensional (m/z, retention time, intensity) data points that correspond to the types and quantities of analyzed molecules. Open and commercial MS data formats are arranged by retention time, creating latency when accessing data across multiple m/z. Existing MS storage and retrieval methods have been developed to overcome the limitations of retention time-based data formats, but do not provide certain features such as dynamic summarization and storage and retrieval of point meta-data (such as signal cluster membership), precluding efficient viewing applications and certain data-processing approaches. This manuscript describes MzTree, a spatial database designed to provide real-time storage and retrieval of dynamically summarized standard and augmented MS data with fast performance in both m/z and RT directions. Performance is reported on real data with comparisons against related published retrieval systems.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188059
  • The associations between magnetic resonance imaging findings and low back
           pain: A 10-year longitudinal analysis

    • Authors: Juichi Tonosu Hiroyuki Oka Akiro Higashikawa Hiroshi Okazaki Sakae Tanaka Ko Matsudaira
      Abstract: by Juichi Tonosu, Hiroyuki Oka, Akiro Higashikawa, Hiroshi Okazaki, Sakae Tanaka, Ko MatsudairaPurpose To conduct a 10-year longitudinal analysis of the relationship between magnetic resonance imaging (MRI) findings and low back pain (LBP). Materials and methods Ninety-one volunteers with a history of LBP, but without current LBP were recruited between 2005 and 2006. Participants’ baseline demographics and MRI findings were recorded. All volunteers were invited for a follow-up MRI in 2016; of these, 49 volunteers (53.8%) participated in the follow-up. We enquired whether they had LBP history during the 10 years between the baseline and follow-up examinations. Sagittal T1 and T2-weighted MRI were used to assess the intervertebral space from T12/L1 to L5/S1. We evaluated the presence of disc degeneration by Pfirrmann’s grading system, disc bulging, high intensity zone (HIZ), spondylolisthesis, and any type of Modic changes in the follow-up MRIs. We compared the follow-up MRI findings with the baseline findings; the progress of each finding over the 10 years were also compared between the groups with (n = 36) and without (n = 13) LBP. Results Average age of the study participants at follow-up was 44.8 years; 25 were female and 24 were male. Average age, sex, body mass index, and smoking habits of those who did and did not participate in the follow-up study, as well as the demographic characteristics of those who did and did not have LBP history during the 10 years, were not significantly different. Compared with the group without LBP history, the group that had LBP history during the 10 years did not have a significantly increased prevalence of disc degeneration, disc bulging, and HIZ in the follow-up and baseline MRIs. Spondylolisthesis and any type of Modic changes were also not associated with LBP history during the 10 years. Conclusions Follow-up MRI findings consistent with Pfirrmann grading ≥4, disc bulging, HIZ, spondylolisthesis, and any type of Modic changes were not associated with LBP history during the 10 years between the baseline and follow-up study. The progresses of these findings were also not associated with the LBP history. In addition, baseline MRI findings were not associated with LBP history during the 10 years; therefore, our data suggest that baseline MRI findings cannot predict future LBP.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188057
  • Domestic sheep show average Coxiella burnetii seropositivity generations
           after a sheep-associated human Q fever outbreak and lack detectable
           shedding by placental, vaginal, and fecal routes

    • Authors: Ryan D. Oliveira Michelle R. Mousel Kristy L. Pabilonia Margaret A. Highland J. Bret Taylor Donald P. Knowles Stephen N. White
      Abstract: by Ryan D. Oliveira, Michelle R. Mousel, Kristy L. Pabilonia, Margaret A. Highland, J. Bret Taylor, Donald P. Knowles, Stephen N. WhiteCoxiella burnetii is a globally distributed zoonotic bacterial pathogen that causes abortions in ruminant livestock. In humans, an influenza-like illness results with the potential for hospitalization, chronic infection, abortion, and fatal endocarditis. Ruminant livestock, particularly small ruminants, are hypothesized to be the primary transmission source to humans. A recent Netherlands outbreak from 2007–2010 traced to dairy goats resulted in over 4,100 human cases with estimated costs of more than 300 million euros. Smaller human Q fever outbreaks of small ruminant origin have occurred in the United States, and characterizing shedding is important to understand the risk of future outbreaks. In this study, we assessed bacterial shedding and seroprevalence in 100 sheep from an Idaho location associated with a 1984 human Q fever outbreak. We observed 5% seropositivity, which was not significantly different from the national average of 2.7% for the U.S. (P>0.05). Furthermore, C. burnetii was not detected by quantitative PCR from placentas, vaginal swabs, or fecal samples. Specifically, a three-target quantitative PCR of placenta identified 0.0% shedding (exact 95% confidence interval: 0.0%-2.9%). While presence of seropositive individuals demonstrates some historical C. burnetii exposure, the placental sample confidence interval suggests 2016 shedding events were rare or absent. The location maintained the flock with little or no depopulation in 1984 and without C. burnetii vaccination during or since 1984. It is not clear how a zero-shedding rate was achieved in these sheep beyond natural immunity, and more work is required to discover and assess possible factors that may contribute towards achieving zero-shedding status. We provide the first U.S. sheep placental C. burnetii shedding update in over 60 years and demonstrate potential for C. burnetii shedding to reach undetectable levels after an outbreak event even in the absence of targeted interventions, such as vaccination.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188054
  • Escitalopram and NHT normalized stress-induced anhedonia and molecular
           neuroadaptations in a mouse model of depression

    • Authors: Or Burstein Motty Franko Eyal Gale Assaf Handelsman Segev Barak Shai Motsan Alon Shamir Roni Toledano Omri Simhon Yafit Hirshler Gang Chen Ravid Doron
      Abstract: by Or Burstein, Motty Franko, Eyal Gale, Assaf Handelsman, Segev Barak, Shai Motsan, Alon Shamir, Roni Toledano, Omri Simhon, Yafit Hirshler, Gang Chen, Ravid DoronAnhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188043
  • Lack of mitochondrial MutS homolog 1 in Toxoplasma gondii disrupts
           maintenance and fidelity of mitochondrial DNA and reveals metabolic

    • Authors: Tamila Garbuz Gustavo Arrizabalaga
      Abstract: by Tamila Garbuz, Gustavo ArrizabalagaThe importance of maintaining the fidelity of the mitochondrial genome is underscored by the presence of various repair pathways within this organelle. Presumably, the repair of mitochondrial DNA would be of particular importance in organisms that possess only a single mitochondrion, like the human pathogens Plasmodium falciparum and Toxoplasma gondii. Understanding the machinery that maintains mitochondrial DNA in these parasites is of particular relevance, as mitochondrial function is a validated and effective target for anti-parasitic drugs. We previously determined that the Toxoplasma MutS homolog TgMSH1 localizes to the mitochondrion. MutS homologs are key components of the nuclear mismatch repair system in mammalian cells, and both yeast and plants possess MutS homologs that localize to the mitochondria where they regulate DNA stability. Here we show that the lack of TgMSH1 results in accumulation of single nucleotide variations in mitochondrial DNA and a reduction in mitochondrial DNA content. Additionally, parasites lacking TgMSH1 function can survive treatment with the cytochrome b inhibitor atovaquone. While the Tgmsh1 knockout strain has several missense mutations in cytochrome b, none affect amino acids known to be determinants of atovaquone sensitivity and atovaquone is still able to inhibit electron transport in the Tgmsh1 mutants. Furthermore, culture of Tgmsh1 mutant in the presence atovaquone leads to parasites with enhanced atovaquone resistance and complete shutdown of respiration. Thus, parasites lacking TgMSH1 overcome the disruption of mitochondrial DNA by adapting their physiology allowing them to forgo the need for oxidative phosphorylation. Consistent with this idea, the Tgmsh1 mutant is resistant to mitochondrial inhibitors with diverse targets and exhibits reduced ability to grow in the absence of glucose. This work shows TgMSH1 as critical for the maintenance and fidelity of the mitochondrial DNA in Toxoplasma, reveals a novel mechanism for atovaquone resistance, and exposes the physiological plasticity of this important human pathogen.
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188040
  • Soluble glycoprotein VI, a specific marker of platelet activation is
           increased in the plasma of subjects with seropositive rheumatoid arthritis

    • Authors: John R. Stack Anne Madigan Laura Helbert Eimear Dunne Elizabeth E. Gardiner Robert K. Andrews Roisin Finan Elizabeth Smyth Dermot Kenny Geraldine M. McCarthy
      Abstract: by John R. Stack, Anne Madigan, Laura Helbert, Eimear Dunne, Elizabeth E. Gardiner, Robert K. Andrews, Roisin Finan, Elizabeth Smyth, Dermot Kenny, Geraldine M. McCarthyObjectives Anti-citrullinated protein antibodies (ACPA) have been shown to cause platelet activation in vitro, through the low-affinity immunoglobulin G (IgG) receptor (FcγRIIa) on platelets. Platelet activation via engagement of FcγRIIa results in proteolytic cleavage and shedding of platelet specific glycoprotein VI (GPVI) which can be detected in the plasma as soluble GPVI (sGPVI). We hypothesized that plasma levels of sGPVI would be increased among patients with seropositive RA as a consequence of antibody-induced platelet activation and GPVI shedding. Methods Samples from 84 patients with RA (65 seropositive and 19 seronegative) and 67 healthy controls were collected prospectively and analysed for sGPVI using a standardised ELISA. Results Patients with seropositive RA had significantly higher levels of sGPVI compared to seronegative RA and controls. Median (IQR) sGPVI levels were 4.2 ng/ml (3.2, 8.0) in seropositve RA, 2.2 ng/ml (1.5, 3.5) in seronegative RA and 2.2 ng/ml (1.6, 3.4) in controls (p
      PubDate: 2017-11-15T22:00:00Z
      DOI: 10.1371/journal.pone.0188027
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