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   Published by PLoS Homepage  [13 journals]
  • Biochemical and immunological characterization of a novel monoclonal
           antibody against mouse leukotriene B4 receptor 1

    • Authors: Fumiyuki Sasaki Tomoaki Koga Kazuko Saeki Toshiaki Okuno Saiko Kazuno Tsutomu Fujimura Yasuyuki Ohkawa Takehiko Yokomizo
      Abstract: by Fumiyuki Sasaki, Tomoaki Koga, Kazuko Saeki, Toshiaki Okuno, Saiko Kazuno, Tsutomu Fujimura, Yasuyuki Ohkawa, Takehiko YokomizoLeukotriene B4 (LTB4) receptor 1 (BLT1) is a G protein-coupled receptor expressed in various leukocyte subsets; however, the precise expression of mouse BLT1 (mBLT1) has not been reported because a mBLT1 monoclonal antibody (mAb) has not been available. In this study, we present the successful establishment of a hybridoma cell line (clone 7A8) that produces a high-affinity mAb for mBLT1 by direct immunization of BLT1-deficient mice with mBLT1-overexpressing cells. The specificity of clone 7A8 was confirmed using mBLT1-overexpressing cells and mouse peripheral blood leukocytes that endogenously express BLT1. Clone 7A8 did not cross-react with human BLT1 or other G protein-coupled receptors, including human chemokine (C-X-C motif) receptor 4. The 7A8 mAb binds to the second extracellular loop of mBLT1 and did not affect LTB4 binding or intracellular calcium mobilization by LTB4. The 7A8 mAb positively stained Gr-1-positive granulocytes, CD11b-positive granulocytes/monocytes, F4/80-positive monocytes, CCR2-high and CCR2-low monocyte subsets in the peripheral blood and a CD4-positive T cell subset, Th1 cells differentiated in vitro from naïve CD4-positive T cells. This mAb was able to detect Gr-1-positive granulocytes and monocytes in the spleens of naïve mice by immunohistochemistry. Finally, intraperitoneal administration of 7A8 mAb depleted granulocytes and monocytes in the peripheral blood. We have therefore succeeded in generating a high-affinity anti-mBLT1 mAb that is useful for analyzing mBLT1 expression in vitro and in vivo.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185133
  • The Warburg effect as an adaptation of cancer cells to rapid fluctuations
           in energy demand

    • Authors: Tamir Epstein Robert A. Gatenby Joel S. Brown
      Abstract: by Tamir Epstein, Robert A. Gatenby, Joel S. BrownTo maintain optimal fitness, a cell must balance the risk of inadequate energy reserve for response to a potentially fatal perturbation against the long-term cost of maintaining high concentrations of ATP to meet occasional spikes in demand. Here we apply a game theoretic approach to address the dynamics of energy production and expenditure in eukaryotic cells. Conventionally, glucose metabolism is viewed as a function of oxygen concentrations in which the more efficient oxidation of glucose to CO2 and H2O produces all or nearly all ATP except under hypoxic conditions when less efficient (2 ATP/ glucose vs. about 36ATP/glucose) anaerobic metabolism of glucose to lactic acid provides an emergency backup. We propose an alternative in which energy production is governed by the complex temporal and spatial dynamics of intracellular ATP demand. In the short term, a cell must provide energy for constant baseline needs but also maintain capacity to rapidly respond to fluxes in demand particularly due to external perturbations on the cell membrane. Similarly, longer-term dynamics require a trade-off between the cost of maintaining high metabolic capacity to meet uncommon spikes in demand versus the risk of unsuccessfully responding to threats or opportunities. Here we develop a model and computationally explore the cell’s optimal mix of glycolytic and oxidative capacity. We find the Warburg effect, high glycolytic metabolism even under normoxic conditions, is represents a metabolic strategy that allow cancer cells to optimally meet energy demands posed by stochastic or fluctuating tumor environments.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185085
  • Role of the P2 residue of human alpha 1-antitrypsin in determining target
           protease specificity

    • Authors: Hye-Shin Chung Ji-Sun Kim Sang Mee Lee Soon Jae Park
      Abstract: by Hye-Shin Chung, Ji-Sun Kim, Sang Mee Lee, Soon Jae ParkAlpha 1-antitrypsin (A1AT) is a serine protease inhibitor that mainly inhibits neutrophil elastase in the lungs. A variant of A1AT at the P1 position with methionine 358 to arginine (A1AT-Pittsburgh) is a rapid inhibitor of thrombin with greatly diminished anti-elastase activity. The P2 residue (position 357) of A1AT-Pittsburgh has been shown to play an important role in interactions with thrombin and kallikrein, but the role of P2 residue in wild-type A1AT has largely been unraveled. Here, we investigated the effects of P2 proline substitutions in wild-type A1AT on interactions with porcine pancreatic elastase (PPE) and human neutrophil elastase (HNE). The mutant A1AT proteins (P357A, P357D, P357K, P357L, P357N, P357S, and P357W) were less efficient than the wild-type A1AT at inhibiting PPE and HNE. Among the mutants, P357D did not form a complex with PPE, whereas P357L, P357N, and P357W showed significantly reduced complex formation with PPE. Surprisingly, mass spectrometry analysis revealed that P357D had two cleavage sites after the P9 alanine and the P3 isoleucine residues. Our results indicate that the size and negative charge of the R group of the P2 residue influence the interaction with elastases. Specifically, the negative charge at the P2 residue is disfavored and the resulting conformational changes in the reactive center loop upon interaction with PPE lead to cleavage at new sites. Overall, the results of this study demonstrate a previously unknown role for P2 residue in determining inhibitory specificity of A1AT.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185074
  • Relationships of orientation discrimination threshold and visual acuity
           with macular lesions in age-related macular degeneration

    • Authors: Haojie Fu Bin Zhang Jianliang Tong Harold Bedell Hecheng Zhang Yating Yang Chaochao Nie Yingdong Luo Xiaoling Liu
      Abstract: by Haojie Fu, Bin Zhang, Jianliang Tong, Harold Bedell, Hecheng Zhang, Yating Yang, Chaochao Nie, Yingdong Luo, Xiaoling LiuPurpose To measure visual acuity and metamorphopsia in patients with age-related macular degeneration (AMD) and to explore their relationship with macular lesions. Methods In this cross-sectional study, a total of 32 normal subjects (32 eyes) and 35 AMD patients (35 eyes) were recruited. They were categorized into 4 groups: normal, dry AMD, non-active wet AMD, and active wet AMD. Best-corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study protocol. Metamorphopsia was quantified with the orientation discrimination threshold (ODT). Macular lesions, including drusen, sub-retinal fluid (SRF), intra-retinal fluid (IRF), pigmented epithelium detachment (PED), and scarring, were identified with spectral-domain optical coherence tomography (SD-OCT). A linear regression model was established to identify the relationships between the functional and structural changes. Results BCVA progressively worsened across the normal, dry AMD, non-active wet AMD, and active wet AMD groups (P < 0.001), and ODT increased across the groups (P < 0.001). The correlation between BCVA and ODT varied among the groups. The partial correlation between BCVA and ODT was −0.61 (P < 0.001). Linear regression showed that ODT significantly depended on IRF (β = 0.61, P < 0.001), SRF (β = 0.34, P = 0.003), and scarring (β = 0.26, P = 0.050), while BCVA significantly depended only on scarring (β = −0.52, P < 0.001), and IRF (β = −0.36, P = 0.016). Conclusions From dry AMD to active wet AMD, BCVA gradually worsened while ODT increased. The correlation between BCVA and ODT varied among these groups, indicating that AMD lesions affect them differently. ODT and BCVA should be used concurrently for better monitoring of the disease.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185070
  • The role of the PI3K-Akt signaling pathway in the developmental competence
           of bovine oocytes

    • Authors: Gabriella Mamede Andrade Juliano Coelho da Silveira Claudia Perrini Maite Del Collado Samuel Gebremedhn Dawit Tesfaye Flávio Vieira Meirelles Felipe Perecin
      Abstract: by Gabriella Mamede Andrade, Juliano Coelho da Silveira, Claudia Perrini, Maite Del Collado, Samuel Gebremedhn, Dawit Tesfaye, Flávio Vieira Meirelles, Felipe PerecinThe ovarian follicle encloses oocytes in a microenvironment throughout their growth and acquisition of competence. Evidence suggests a dynamic interplay among follicular cells and oocytes, since they are constantly exchanging “messages”. We dissected bovine ovarian follicles and recovered follicular cells (FCs—granulosa and cumulus cells) and cumulus-oocyte complexes (COCs) to investigate whether the PI3K-Akt signaling pathway impacted oocyte quality. Following follicle rupture, COCs were individually selected for in vitro cultures to track the follicular cells based on oocyte competence to reach the blastocyst stage after parthenogenetic activation. Levels of PI3K-Akt signaling pathway components in FCs correlated with oocyte competence. This pathway is upregulated in FCs from follicles with high-quality oocytes that are able to reach the blastocyst stage, as indicated by decreased levels of PTEN and increased levels of the PTEN regulators bta-miR-494 and bta-miR-20a. Using PI3K-Akt responsive genes, we showed decreased FOXO3a levels and BAX levels in lower quality groups, indicating changes in cell cycle progression, oxidative response and apoptosis. Based on these results, the measurement of levels of PI3K-Akt pathway components in FCs from ovarian follicles carrying oocytes with distinct developmental competences is a useful tool to identify putative molecular pathways involved in the acquisition of oocyte competence.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185045
  • Effects of salinity and drought on growth, ionic relations, compatible
           solutes and activation of antioxidant systems in oleander (Nerium oleander

    • Authors: Dinesh Kumar Mohamad Al Hassan Miguel A. Naranjo Veena Agrawal Monica Boscaiu Oscar Vicente
      Abstract: by Dinesh Kumar, Mohamad Al Hassan, Miguel A. Naranjo, Veena Agrawal, Monica Boscaiu, Oscar VicenteNerium oleander is an ornamental species of high aesthetic value, grown in arid and semi-arid regions because of its drought tolerance, which is also considered as relatively resistant to salt; yet the biochemical and molecular mechanisms underlying oleander’s stress tolerance remain largely unknown. To investigate these mechanisms, one-year-old oleander seedlings were exposed to 15 and 30 days of treatment with increasing salt concentrations, up to 800 mM NaCl, and to complete withholding of irrigation; growth parameters and biochemical markers characteristic of conserved stress-response pathways were then determined in stressed and control plants. Strong water deficit and salt stress both caused inhibition of growth, degradation of photosynthetic pigments, a slight (but statistically significant) increase in the leaf levels of specific osmolytes, and induction of oxidative stress—as indicated by the accumulation of malondialdehyde (MDA), a reliable oxidative stress marker—accompanied by increases in the levels of total phenolic compounds and antioxidant flavonoids and in the specific activities of ascorbate peroxidase (APX) and glutathione reductase (GR). High salinity, in addition, induced accumulation of Na+ and Cl- in roots and leaves and the activation of superoxide dismutase (SOD) and catalase (CAT) activities. Apart from anatomical adaptations that protect oleander from leaf dehydration at moderate levels of stress, our results indicate that tolerance of this species to salinity and water deficit is based on the constitutive accumulation in leaves of high concentrations of soluble carbohydrates and, to a lesser extent, of glycine betaine, and in the activation of the aforementioned antioxidant systems. Moreover, regarding specifically salt stress, mechanisms efficiently blocking transport of toxic ions from the roots to the aerial parts of the plant appear to contribute to a large extent to tolerance in Nerium oleander.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185017
  • News trends and web search query of HIV/AIDS in Hong Kong

    • Authors: Alice P. Y. Chiu Qianying Lin Daihai He
      Abstract: by Alice P. Y. Chiu, Qianying Lin, Daihai HeBackground The HIV epidemic in Hong Kong has worsened in recent years, with major contributions from high-risk subgroup of men who have sex with men (MSM). Internet use is prevalent among the majority of the local population, where they sought health information online. This study examines the impacts of HIV/AIDS and MSM news coverage on web search query in Hong Kong. Methods Relevant news coverage about HIV/AIDS and MSM from January 1st, 2004 to December 31st, 2014 was obtained from the WiseNews databse. News trends were created by computing the number of relevant articles by type, topic, place of origin and sub-populations. We then obtained relevant search volumes from Google and analysed causality between news trends and Google Trends using Granger Causality test and orthogonal impulse function. Results We found that editorial news has an impact on “HIV” Google searches on HIV, with the search term popularity peaking at an average of two weeks after the news are published. Similarly, editorial news has an impact on the frequency of “AIDS” searches two weeks after. MSM-related news trends have a more fluctuating impact on “MSM” Google searches, although the time lag varies anywhere from one week later to ten weeks later. Conclusions This infodemiological study shows that there is a positive impact of news trends on the online search behavior of HIV/AIDS or MSM-related issues for up to ten weeks after. Health promotional professionals could make use of this brief time window to tailor the timing of HIV awareness campaigns and public health interventions to maximise its reach and effectiveness.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0185004
  • Walker occupancy has an impact on changing airborne bacterial communities
           in an underground pedestrian space, as small-dust particles increased with
           raising both temperature and humidity

    • Authors: Torahiko Okubo Takako Osaki Eriko Nozaki Akira Uemura Kouhei Sakai Mizue Matushita Junji Matsuo Shinji Nakamura Shigeru Kamiya Hiroyuki Yamaguchi
      Abstract: by Torahiko Okubo, Takako Osaki, Eriko Nozaki, Akira Uemura, Kouhei Sakai, Mizue Matushita, Junji Matsuo, Shinji Nakamura, Shigeru Kamiya, Hiroyuki YamaguchiAlthough human occupancy is a source of airborne bacteria, the role of walkers on bacterial communities in built environments is poorly understood. Therefore, we visualized the impact of walker occupancy combined with other factors (temperature, humidity, atmospheric pressure, dust particles) on airborne bacterial features in the Sapporo underground pedestrian space in Sapporo, Japan. Air samples (n = 18; 4,800L/each sample) were collected at 8:00 h to 20:00 h on 3 days (regular sampling) and at early morning / late night (5:50 h to 7:50 h / 22:15 h to 24:45 h) on a day (baseline sampling), and the number of CFUs (colony forming units) OTUs (operational taxonomic units) and other factors were determined. The results revealed that temperature, humidity, and atmospheric pressure changed with weather. The number of walkers increased greatly in the morning and evening on each regular sampling day, although total walker numbers did not differ significantly among regular sampling days. A slight increase in small dust particles (0.3–0.5μm) was observed on the days with higher temperature regardless of regular or baseline sampling. At the period on regular sampling, CFU levels varied irregularly among days, and the OTUs of 22-phylum types were observed, with the majority being from Firmicutes or Proteobacteria (γ-), including Staphylococcus sp. derived from human individuals. The data obtained from regular samplings reveled that although no direct interaction of walker occupancy and airborne CFU and OTU features was observed upon Pearson's correlation analysis, cluster analysis indicated an obvious lineage consisting of walker occupancy, CFU numbers, OTU types, small dust particles, and seasonal factors (including temperature and humidity). Meanwhile, at the period on baseline sampling both walker and CFU numbers were similarly minimal. Taken together, the results revealed a positive correlation of walker occupancy with airborne bacteria that increased with increases in temperature and humidity in the presence of airborne small particles. Moreover, the results indicated that small dust particles at high temperature and humidity may be a crucial factor responsible for stabilizing the bacteria released from walkers in built environments. The findings presented herein advance our knowledge and understanding of the relationship between humans and bacterial communities in built environments, and will help improve public health in urban communities.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184980
  • The operation of a Research and Development (R&D) program and its
           significance for practice change in community pharmacy

    • Authors: Andi Hermansyah Erica Sainsbury Ines Krass
      Abstract: by Andi Hermansyah, Erica Sainsbury, Ines KrassBackground Community pharmacy practice in Australia is changing and Research and Development (R&D) in community pharmacy plays an important role in contributing to the changes. A range of Cognitive Pharmacy Services (CPS) were developed from R&D programs, yet their implementation has been minimal indicating slow practice change within community pharmacy. Given the vital role of R&D, little is known about the operation and the extent to which it has been effective in supporting practice change in community pharmacy. Methods In depth, semi-structured interviews were conducted with 27 key stakeholders in the pharmacy and healthcare system in Australia. All interviews were audio-recorded, transcribed ad verbatim and analysed using an inductive approach. Results Participants perceived that the R&D program has played an important role in the advent of CPS. Furthermore, they considered that evidence generated by the R&D projects is a critical influence on policy formulation, funding and implementation of CPS into practice. However, policy decisions and subsequent implementation are also influenced by other factors associated with context and facilitation which in turn foster or inhibit effective Knowledge Translation (KT) in the community pharmacy sector. Conclusion While R&D programs have been viewed as essential for supporting changes in community pharmacy practice through development and funding of CPS, the overall impact has been small, as contemporary practice continues to be predominantly a dispensing model. Given the complexity and dynamic nature of the community pharmacy system, stakeholders must take into account the inter-relationship between context, evidence and facilitation for successful KT in community pharmacy practice.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184954
  • Impedance biosensor for real-time monitoring and prediction of thrombotic
           individual profile in flowing blood

    • Authors: Denise De Zanet Monica Battiston Elisabetta Lombardi Ruben Specogna Francesco Trevisan Luigi De Marco Antonio Affanni Mario Mazzucato
      Abstract: by Denise De Zanet, Monica Battiston, Elisabetta Lombardi, Ruben Specogna, Francesco Trevisan, Luigi De Marco, Antonio Affanni, Mario MazzucatoA new biosensor for the real-time analysis of thrombus formation is reported. The fast and accurate monitoring of the individual thrombotic risk represents a challenge in cardiovascular diagnostics and in treatment of hemostatic diseases. Thrombus volume, as representative index of the related thrombotic status, is usually estimated with confocal microscope at the end of each in vitro experiment, without providing a useful behavioral information of the biological sample such as platelets adhesion and aggregation in flowing blood. Our device has been developed to work either independently or integrated with the microscopy system; thus, images of the fluorescently labeled platelets are acquired in real-time during the whole blood perfusion, while the global electrical impedance of the blood sample is simultaneously monitored between a pair of specifically designed gold microelectrodes. Fusing optical and electrical data with a novel technique, the dynamic of thrombus formation events in flowing blood can be reconstructed in real-time, allowing an accurate extrapolation of the three-dimensional shape and the spatial distribution of platelet thrombi forming and growing within artificial capillaries. This biosensor is accurate and it has been used to discriminate different hemostatic conditions and to identify weakening and detaching platelet aggregates. The results obtained appear compatible with those quantified with the traditional optical method. With advantages in terms of small size, user-friendliness and promptness of response, it is a promising device for the fast and automatic individual health monitoring at the Point of Care (POC).
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184941
  • Elevating serotonin pre-partum alters the Holstein dairy cow hepatic
           adaptation to lactation

    • Authors: Samantha R. Weaver Allan S. Prichard Noah L. Maerz Austin P. Prichard Elizabeth L. Endres Lorenzo E. Hernández-Castellano Matthew S. Akins Rupert M. Bruckmaier Laura L. Hernandez
      Abstract: by Samantha R. Weaver, Allan S. Prichard, Noah L. Maerz, Austin P. Prichard, Elizabeth L. Endres, Lorenzo E. Hernández-Castellano, Matthew S. Akins, Rupert M. Bruckmaier, Laura L. HernandezSerotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184939
  • Crimean-Congo hemorrhagic fever virus nucleocapsid protein has dual RNA
           binding modes

    • Authors: Subbiah Jeeva Sean Pador Brittany Voss Safder Saieed Ganaie Mohammad Ayoub Mir
      Abstract: by Subbiah Jeeva, Sean Pador, Brittany Voss, Safder Saieed Ganaie, Mohammad Ayoub MirCrimean Congo hemorrhagic fever, a zoonotic viral disease, has high mortality rate in humans. There is currently no vaccine for Crimean Congo hemorrhagic fever virus (CCHFV) and chemical interventions are limited. The three negative sense genomic RNA segments of CCHFV are specifically encapsidated by the nucleocapsid protein into three ribonucleocapsids, which serve as templates for the viral RNA dependent RNA polymerase. Here we demonstrate that CCHFV nucleocapsid protein has two distinct binding modes for double and single strand RNA. In the double strand RNA binding mode, the nucleocapsid protein preferentially binds to the vRNA panhandle formed by the base pairing of complementary nucleotides at the 5’ and 3’ termini of viral genome. The CCHFV nucleocapsid protein does not have RNA helix unwinding activity and hence does not melt the duplex vRNA panhandle after binding. In the single strand RNA binding mode, the nucleocapsid protein does not discriminate between viral and non-viral RNA molecules. Binding of both vRNA panhandle and single strand RNA induce a conformational change in the nucleocapsid protein. Nucleocapsid protein remains in a unique conformational state due to simultaneously binding of structurally distinct vRNA panhandle and single strand RNA substrates. Although the role of dual RNA binding modes in the virus replication cycle is unknown, their involvement in the packaging of viral genome and regulation of CCHFV replication in conjunction with RdRp and host derived RNA regulators is highly likely.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184935
  • Timing and adequate attendance of antenatal care visits among women in

    • Authors: Sanni Yaya Ghose Bishwajit Michael Ekholuenetale Vaibhav Shah Bernard Kadio Ogochukwu Udenigwe
      Abstract: by Sanni Yaya, Ghose Bishwajit, Michael Ekholuenetale, Vaibhav Shah, Bernard Kadio, Ogochukwu UdenigweIntroduction Although ANC services are increasingly available to women in low and middle-income countries, their inadequate use persists. This suggests a misalignment between aims of the services and maternal beliefs and circumstances. Owing to the dearth of studies examining the timing and adequacy of content of care, this current study aims to investigate the timing and frequency of ANC visits in Ethiopia. Methods Data was obtained from the nationally representative 2011 Ethiopian Demographic and Health Survey (EDHS) which used a two-stage cluster sampling design to provide estimates for the health and demographic variables of interest for the country. Our study focused on a sample of 10,896 women with history of at least one childbirth event. Percentages of timing and adequacy of ANC visits were conducted across the levels of selected factors. Variables which were associated at 5% significance level were examined in the multivariable logistic regression model for association between timing and frequency of ANC visits and the explanatory variables while controlling for covariates. Furthermore, we presented the approach to estimate marginal effects involving covariate-adjusted logistic regression with corresponding 95%CI of delayed initiation of ANC visits and inadequate ANC attendance. The method used involved predicted probabilities added up to a weighted average showing the covariate distribution in the population. Results Results indicate that 66.3% of women did not use ANC at first trimester and 22.3% had ANC less than 4 visits. The results of this study were unique in that the association between delayed ANC visits and adequacy of ANC visits were examined using multivariable logistic model and the marginal effects using predicted probabilities. Results revealed that older age interval has higher odds of inadequate ANC visits. More so, type of place of residence was associated with delayed initiation of ANC visits, with rural women having the higher odds of delayed initiation of ANC visits (OR = 1.65; 95%CI: 1.26–2.18). However, rural women had 44% reduction in the odds of having inadequate ANC visits. In addition, multi-parity showed higher odds of delayed initiation of ANC visit when compared to the primigravida (OR = 2.20; 95%CI: 1.07–2.69). On the contrary, there was 36% reduction in the odds of multigravida having inadequate ANC visits when compared to the women who were primigravida. There were higher odds of inadequacy in ANC visits among women who engaged in sales/business, agriculture, skilled manual and other jobs when compared to women who currently do not work, after adjusting for covariates. From the predictive margins, assuming the distribution of all covariates remained the same among respondents, but everyone was aged 15–19 years, we would expect 71.8% delayed initiation of ANC visit. If everyone was aged 20-24years, 73.4%; 25-29years, 66.5%; 30-34years, 64.8%; 35-39years, 65.6%; 40-44years, 59.6% and 45-49years, we would expect 70.1% delayed initiation of ANC visit. If instead the distribution of age was as observed and for other covariates remained the same among respondents, but no respondent lived in the rural, we would expect about 61.4% delayed initiation of ANC visit; if however, everyone lived in the rural, and we would expect 71.6% delayed initiation in ANC visit. Model III revealed the predictive margins of all factors examined for delayed initiation for ANC visits, while Model IV presented the predictive marginal effects of the determinants of adequacy of ANC visits. Conclusion The precise mechanism by which these factors affect ANC visits remain blurred at best. There may be factors on the demand side like the women’s empowerment, financial support of the husband, knowledge of ANC visits in the context of timing, frequency and the expectations of ANC visits might be mediating the effects through the factors found associated in this study. Supply side factors like the quality of ANC services, skilled staff, and geographic location of the health centers also mediate their effects through the highlighted factors. Irrespective of the knowledge about the precise mechanism of action, policy makers could focus on improving women’s empowerment, improving women’s education, reducing wealth inequity and facilitating improved utilization of ANC through modifications on the supply side factors such as geographic location and focus on hard to reach women.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184934
  • A nonrandomized trial of vitamin D supplementation for Barrett’s

    • Authors: Linda C. Cummings Prashanthi N. Thota Joseph E. Willis Yanwen Chen Gregory S. Cooper Nancy Furey Beth Bednarchik Bronia M. Alashkar John Dumot Ashley L. Faulx Stephen P. Fink Adam M. Kresak Basel Abusneineh Jill Barnholtz-Sloan Patrick Leahy Martina L. Veigl Amitabh Chak Sanford D. Markowitz
      Abstract: by Linda C. Cummings, Prashanthi N. Thota, Joseph E. Willis, Yanwen Chen, Gregory S. Cooper, Nancy Furey, Beth Bednarchik, Bronia M. Alashkar, John Dumot, Ashley L. Faulx, Stephen P. Fink, Adam M. Kresak, Basel Abusneineh, Jill Barnholtz-Sloan, Patrick Leahy, Martina L. Veigl, Amitabh Chak, Sanford D. MarkowitzBackground Vitamin D deficiency may increase esophageal cancer risk. Vitamin D affects genes regulating proliferation, apoptosis, and differentiation and induces the tumor suppressor 15-hydroxyprostaglandin dehydrogenase (PGDH) in other cancers. This nonrandomized interventional study assessed effects of vitamin D supplementation in Barrett’s esophagus (BE). We hypothesized that vitamin D supplementation may have beneficial effects on gene expression including 15-PGDH in BE. Methods BE subjects with low grade or no dysplasia received vitamin D3 (cholecalciferol) 50,000 international units weekly plus a proton pump inhibitor for 12 weeks. Esophageal biopsies from normal plus metaplastic BE epithelium and blood samples were obtained before and after vitamin D supplementation. Serum 25-hydroxyvitamin D was measured to characterize vitamin D status. Esophageal gene expression was assessed using microarrays. Results 18 study subjects were evaluated. The baseline mean serum 25-hydroxyvitamin D level was 27 ng/mL (normal ≥30 ng/mL). After vitamin D supplementation, 25-hydroxyvitamin D levels rose significantly (median increase of 31.6 ng/mL, p
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184928
  • Stable C and N isotope analysis of hair suggest undernourishment as a
           factor in the death of a mummified girl from late 19th century San
           Francisco, CA

    • Authors: Jelmer W. Eerkens Bryna Hull Jena Goodman Angela Evoy Joshua D. Kapp Sidra Hussain Richard E. Green
      Abstract: by Jelmer W. Eerkens, Bryna Hull, Jena Goodman, Angela Evoy, Joshua D. Kapp, Sidra Hussain, Richard E. GreenThe chance discovery of a 1.5–3.5 years old mummified girl presents a unique opportunity to further our understanding of health and disease among children in 19th Century San Francisco. This study focuses on carbon and nitrogen stable isotope signatures in serial samples of hair that cover the last 14 months of her life. Results suggest an initial omnivorous diet with little input from marine resources or C4 plants. Around six months before death δ15N starts a steady increase, with a noticeable acceleration just two months before she died. The magnitude of δ15N change, +1.5‰ in total, is consistent with severe undernourishment or starvation. Cemetery records from this time period in San Francisco indicate high rates of infant and child mortality, mainly due to bacterial-borne infectious diseases, about two orders of magnitude higher than today. Taken together, we hypothesize that the girl died after a prolonged battle with such an illness. Results highlight the tremendous impacts that modern sanitation and medicine have had since the 1800s on human health and lifespan in the United States.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184921
  • Cesarean section without medical indication and risk of childhood asthma,
           and attenuation by breastfeeding

    • Authors: Shuyuan Chu Qian Chen Yan Chen Yixiao Bao Min Wu Jun Zhang
      Abstract: by Shuyuan Chu, Qian Chen, Yan Chen, Yixiao Bao, Min Wu, Jun ZhangBackground Previous studies suggest that caesarean section (CS) may increase the risk of asthma in children, but none of them could preclude potential confounding effects of underlying medical indications for CS. We aim to assess the association between CS itself (without medical indications) and risk of childhood asthma. Methods We conducted a hospital-based case-control study on childhood asthma with 573 cases and 812 controls in Shanghai. Unconditional logistic regression models in SAS were employed to control for potential confounders. Results Our study found that CS without medical indication was significantly associated with elevated asthma risk (adjusted OR = 1.58 [95% CI 1.17–2.13]). However, this risk was attenuated in children fed by exclusive breastfeeding in the first six months after birth (adjusted OR = 1.39 [95% CI 0.92–2.10]). In contrast, the risk was more prominent in children with non-exclusive breastfeeding or bottle feeding (adjusted OR = 1.91 [95% CI 1.22–2.99]). Conclusions CS without medical indication was associated with an increased risk of childhood asthma. Exclusive breastfeeding in infancy may attenuate this risk.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184920
  • The association between cigarette smoking and inflammation: The Genetic
           Epidemiology Network of Arteriopathy (GENOA) study

    • Authors: Martin Tibuakuu Daisuke Kamimura Sina Kianoush Andrew P. DeFilippis Mahmoud Al Rifai Lindsay M. Reynolds Wendy B. White Kenneth R. Butler Thomas H. Mosley Stephen T. Turner Iftikhar J. Kullo Michael E. Hall Michael J. Blaha
      Abstract: by Martin Tibuakuu, Daisuke Kamimura, Sina Kianoush, Andrew P. DeFilippis, Mahmoud Al Rifai, Lindsay M. Reynolds, Wendy B. White, Kenneth R. Butler, Thomas H. Mosley, Stephen T. Turner, Iftikhar J. Kullo, Michael E. Hall, Michael J. BlahaTo inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184914
  • Expression and prognosis analyses of the Tob/BTG antiproliferative (APRO)
           protein family in human cancers

    • Authors: Yuru Bai Lu Qiao Ning Xie Yongquan Shi Na Liu Jinhai Wang
      Abstract: by Yuru Bai, Lu Qiao, Ning Xie, Yongquan Shi, Na Liu, Jinhai WangBackground Despite advances in early diagnosis and treatment, cancer remains the major cause of mortality in the world. The Tob/BTG antiproliferative (APRO) protein family is reported to participate in diverse human diseases. However, there’s little known about their expression and prognostic values in most human cancers. Methods We performed a detailed cancer vs. normal analysis. The mRNA expression levels of APRO family in various cancers were analyzed via the Oncomine database. Moreover, the Kaplan-Meier Plotter and PrognScan databases were used to evaluate the prognostic values. Results We observed that the mRNA expression levels of TOB1-2 and BTG2 were decreased in most cancers compared with normal tissues, while BTG3 was upregulated in most cancers. In survival analyses based on Kaplan-Meier Plotter, TOB1, BTG1 and BTG4 showed significant associations with survival outcome of different subtypes of breast cancer. Decreased BTG2 was related with poor relapse free survival (RFS) in all subtypes of breast cancer. Especially, besides RFS, reduced BTG2 also indicated worse overall survival and distant metastasis free survival in breast cancer patients who were classified as luminal A. Significant prognostic effects of the whole APRO family were also found in lung adenocarcinoma, but not in squamous cell lung carcinoma. In addition, potential correlations between some APRO family members and survival outcomes were also observed in ovarian, colorectal and brain cancer. Conclusions Some members of APRO family showed significant expression differences between cancer and normal tissues, and could be prognostic biomarkers for defined cancer types.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184902
  • Reduction of organelle motility by removal of potassium and other solutes

    • Authors: John W. Murray David Yin Allan W. Wolkoff
      Abstract: by John W. Murray, David Yin, Allan W. WolkoffThere are surprisingly few studies that describe how the composition of cell culture medium may affect the trafficking of organelles. Here we utilize time lapse multi-channel fluorescent imaging to show that short term exposure of Huh-7 cells to medium lacking potassium, sodium, or chloride strongly reduces but does not eliminate the characteristic back and forth and cell-traversing movement of fluorescent EGF (FL-EGF) containing organelles. We focused on potassium because of its relatively low abundance in media and serum and its energy requiring accumulation into cells. Upon exposure to potassium free medium, organelle motility declined steadily through 90 min and then persisted at a low level. Reduced motility was confirmed in 5 independent cell lines and for organelles of the endocytic pathway (FL-EGF and Lysotracker), autophagosomes (LC3-GFP), and mitochondria (TMRE). As has been previously established, potassium free medium also inhibited endocytosis. We expected that diminished cellular metabolism would precede loss of organelle motility. However, extracellular flux analysis showed near normal mitochondrial oxygen consumption and only a small decrease in extracellular acidification, the latter suggesting decreased glycolysis or proton efflux. Other energy dependent activities such as the accumulation of Lysotracker, TMRE, DiBAC4(3), and the exclusion of propidium iodide remained intact, as did the microtubule cytoskeleton. We took advantage of cell free in vitro motility assays and found that removal of potassium or sodium from the reconstituted cytosolic medium decreased the movement of endosomes on purified microtubules. The results indicate that although changes in proton homeostasis and cell energetics under solute depletion are not fully understood, potassium as well as sodium appear to be directly required by the motile machinery of organelles for optimal trafficking.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184898
  • Acute exposure to blue wavelength light during memory consolidation
           improves verbal memory performance

    • Authors: Anna Alkozei Ryan Smith Natalie S. Dailey Sahil Bajaj William D. S. Killgore
      Abstract: by Anna Alkozei, Ryan Smith, Natalie S. Dailey, Sahil Bajaj, William D. S. KillgoreAcute exposure to light within the blue wavelengths has been shown to enhance alertness and vigilance, and lead to improved speed on reaction time tasks, possibly due to activation of the noradrenergic system. It remains unclear, however, whether the effects of blue light extend beyond simple alertness processes to also enhance other aspects of cognition, such as memory performance. The aim of this study was to investigate the effects of a thirty minute pulse of blue light versus placebo (amber light) exposure in healthy normally rested individuals in the morning during verbal memory consolidation (i.e., 1.5 hours after memory acquisition) using an abbreviated version of the California Verbal Learning Test (CVLT-II). At delayed recall, individuals who received blue light (n = 12) during the consolidation period showed significantly better long-delay verbal recall than individuals who received amber light exposure (n = 18), while controlling for the effects of general intelligence, depressive symptoms and habitual wake time. These findings extend previous work demonstrating the effect of blue light on brain activation and alertness to further demonstrate its effectiveness at facilitating better memory consolidation and subsequent retention of verbal material. Although preliminary, these findings point to a potential application of blue wavelength light to optimize memory performance in healthy populations. It remains to be determined whether blue light exposure may also enhance performance in clinical populations with memory deficits.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184884
  • Exploitation of stable nanostructures based on the mouse polyomavirus for
           development of a recombinant vaccine against porcine circovirus 2

    • Authors: Martin Fraiberk Michaela Hájková Magdaléna Krulová Martina Kojzarová Alena Drda Morávková Ivan Pšikal Jitka Forstová
      Abstract: by Martin Fraiberk, Michaela Hájková, Magdaléna Krulová, Martina Kojzarová, Alena Drda Morávková, Ivan Pšikal, Jitka ForstováThe aim of this study was to develop a suitable vaccine antigen against porcine circovirus 2 (PCV2), the causative agent of post-weaning multi-systemic wasting syndrome, which causes significant economic losses in swine breeding. Chimeric antigens containing PCV2b Cap protein sequences based on the mouse polyomavirus (MPyV) nanostructures were developed. First, universal vectors for baculovirus-directed production of chimeric MPyV VLPs or pentamers of the major capsid protein, VP1, were designed for their exploitation as vaccines against other pathogens. Various strategies were employed based on: A) exposure of selected immunogenic epitopes on the surface of MPyV VLPs by insertion into a surface loop of the VP1 protein, B) insertion of foreign protein molecules inside the VLPs, or C) fusion of a foreign protein or its part with the C-terminus of VP1 protein, to form giant pentamers of a chimeric protein. We evaluated these strategies by developing a recombinant vaccine against porcine circovirus 2. All candidate vaccines induced the production of antibodies against the capsid protein of porcine circovirus after immunization of mice. The candidate vaccine, Var C, based on fusion of mouse polyomavirus and porcine circovirus capsid proteins, could induce the production of antibodies with the highest PCV2 neutralizing capacity. Its ability to induce the production of neutralization antibodies was verified after immunization of pigs. The advantage of this vaccine, apart from its efficient production in insect cells and easy purification, is that it represents a DIVA (differentiating infected from vaccinated animals) vaccine, which also induces an immune response against the mouse polyoma VP1 protein and is thus able to distinguish between vaccinated and naturally infected animals.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184870
  • Rab11 family expression in the human placenta: Localization at the
           maternal-fetal interface

    • Authors: Elizabeth S. Taglauer Patrycja A. Artemiuk Sara R. Hanscom Andrew J. Lindsay Danielle Wuebbolt Fionnuala M. Breathnach Elizabeth C. Tully Amir R. Khan Mary W. McCaffrey
      Abstract: by Elizabeth S. Taglauer, Patrycja A. Artemiuk, Sara R. Hanscom, Andrew J. Lindsay, Danielle Wuebbolt, Fionnuala M. Breathnach, Elizabeth C. Tully, Amir R. Khan, Mary W. McCaffreyRab proteins are a family of small GTPases involved in a variety of cellular processes. The Rab11 subfamily in particular directs key steps of intracellular functions involving vesicle trafficking of the endosomal recycling pathway. This Rab subfamily works through a series of effector proteins including the Rab11-FIPs (Rab11 Family-Interacting Proteins). While the Rab11 subfamily has been well characterized at the cellular level, its function within human organ systems is still being explored. In an effort to further study these proteins, we conducted a preliminary investigation of a subgroup of endosomal Rab proteins in a range of human cell lines by Western blotting. The results from this analysis indicated that Rab11a, Rab11c(Rab25) and Rab14 were expressed in a wide range of cell lines, including the human placental trophoblastic BeWo cell line. These findings encouraged us to further analyse the localization of these Rabs and their common effector protein, the Rab Coupling Protein (RCP), by immunofluorescence microscopy and to extend this work to normal human placental tissue. The placenta is a highly active exchange interface, facilitating transfer between mother and fetus during pregnancy. As Rab11 proteins are closely involved in transcytosis we hypothesized that the placenta would be an interesting human tissue model system for Rab investigation. By immunofluorescence microscopy, Rab11a, Rab11c(Rab25), Rab14 as well as their common FIP effector RCP showed prominent expression in the placental cell lines. We also identified the expression of these proteins in human placental lysates by Western blot analysis. Further, via fluorescent immunohistochemistry, we noted abundant localization of these proteins within key functional areas of primary human placental tissues, namely the outer syncytial layer of placental villous tissue and the endothelia of fetal blood vessels. Overall these findings highlight the expression of the Rab11 family within the human placenta, with novel localization at the maternal-fetal interface.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184864
  • Fractional laser exposure induces neutrophil infiltration (N1 phenotype)
           into the tumor and stimulates systemic anti-tumor immune response

    • Authors: Masayoshi Kawakubo Shadmehr Demehri Dieter Manstein
      Abstract: by Masayoshi Kawakubo, Shadmehr Demehri, Dieter MansteinBackground Ablative fractional photothermolysis (aFP) using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP. Methodology/Principal findings We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25), which expressed a tumor antigen, beta-galactosidase (beta-gal). aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor-infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg), which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP. Conclusion We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184852
  • An analysis of equine round pen training videos posted online: Differences
           between amateur and professional trainers

    • Authors: Erin Kydd Barbara Padalino Cathrynne Henshall Paul McGreevy
      Abstract: by Erin Kydd, Barbara Padalino, Cathrynne Henshall, Paul McGreevyNatural Horsemanship is popular among many amateur and professional trainers and as such, has been the subject of recent scientific enquiry. One method commonly adopted by Natural Horsemanship (NH) trainers is that of round pen training (RPT). RPT sessions are usually split into a series of bouts; each including two phases: chasing/flight and chasing offset/flight offset. However, NH training styles are heterogeneous. This study investigated online videos of RPT to explore the characteristics of RPT sessions and test for differences in techniques and outcomes between amateurs and professionals (the latter being defined as those with accompanying online materials that promote clinics, merchandise or a service to the public). From more than 300 candidate videos, we selected sample files for individual amateur (n = 24) and professional (n = 21) trainers. Inclusion criteria were: training at liberty in a Round Pen; more than one bout and good quality video. Sessions or portions of sessions were excluded if the trainer attached equipment, such as a lunge line, directly to the horse or the horse was saddled, mounted or ridden. The number of bouts and duration of each chasing and non-chasing phase were recorded, and the duration of each RPT session was calculated. General weighted regression analysis revealed that, when compared with amateurs, professionals showed fewer arm movements per bout (p
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184851
  • Identifying novel transcription factors involved in the inflammatory
           response by using binding site motif scanning in genomic regions defined
           by histone acetylation

    • Authors: Peter S. Askovich Stephen A. Ramsey Alan H. Diercks Kathleen A. Kennedy Theo A. Knijnenburg Alan Aderem
      Abstract: by Peter S. Askovich, Stephen A. Ramsey, Alan H. Diercks, Kathleen A. Kennedy, Theo A. Knijnenburg, Alan AderemThe innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes. Because of that, a key challenge to delineating the regulators that control the temporal inflammatory response is that an innate immune regulator that may confer a selective advantage in the wild may be dispensable in the lab setting. In order to better understand the complete transcriptional response of primary macrophages to the bacterial endotoxin lipopolysaccharide (LPS), we designed a method that integrates temporally resolved gene expression and chromatin-accessibility measurements from mouse macrophages. By correlating changes in transcription factor binding site motif enrichment scores, calculated within regions of accessible chromatin, with the average temporal expression profile of a gene cluster, we screened for transcriptional factors that regulate the cluster. We have validated our predictions of LPS-stimulated transcriptional regulators using ChIP-seq data for three transcription factors with experimentally confirmed functions in innate immunity. In addition, we predict a role in the macrophage LPS response for several novel transcription factors that have not previously been implicated in immune responses. This method is applicable to any experimental situation where temporal gene expression and chromatin-accessibility data are available.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184850
  • Loss of liver-specific and sexually dimorphic gene expression by aryl
           hydrocarbon receptor activation in C57BL/6 mice

    • Authors: Rance Nault Kelly A. Fader Jack R. Harkema Tim Zacharewski
      Abstract: by Rance Nault, Kelly A. Fader, Jack R. Harkema, Tim ZacharewskiThe aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that mediates a broad spectrum of species-, strain-, sex-, age-, tissue-, and cell-specific responses elicited by structurally diverse ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dose-dependent effects on liver-specific and sexually dimorphic gene expression were examined in male and female mice gavaged with TCDD every 4 days for 28 or 92 days. RNA-seq data revealed the coordinated repression of 181 genes predominately expressed in the liver including albumin (3.7-fold), α-fibrinogen (14.5-fold), and β-fibrinogen (17.4-fold) in males with corresponding AhR enrichment at 2 hr. Liver-specific genes exhibiting sexually dimorphic expression also demonstrated diminished divergence between sexes. For example, male-biased Gstp1 was repressed 3.0-fold in males and induced 4.5-fold in females, which were confirmed at the protein level. Disrupted regulation is consistent with impaired GHR-JAK2-STAT5 signaling and inhibition of female specific CUX2-mediated transcription as well as the repression of other key transcriptional regulators including Ghr, Stat5b, Bcl6, Hnf4a, Hnf6, Foxa1/2/3, and Zhx2. Attenuated liver-specific and sexually dimorphic gene expression was concurrent with the induction of fetal genes such as alpha-fetoprotein. The results suggest AhR activation causes the loss of liver-specific and sexually dimorphic gene expression producing a functionally “de-differentiated” hepatic phenotype.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184842
  • A set of nutrient limitations trigger yeast cell death in a
           nitrogen-dependent manner during wine alcoholic fermentation

    • Authors: Camille Duc Martine Pradal Isabelle Sanchez Jessica Noble Catherine Tesnière Bruno Blondin
      Abstract: by Camille Duc, Martine Pradal, Isabelle Sanchez, Jessica Noble, Catherine Tesnière, Bruno BlondinYeast cell death can occur during wine alcoholic fermentation. It is generally considered to result from ethanol stress that impacts membrane integrity. This cell death mainly occurs when grape musts processing reduces lipid availability, resulting in weaker membrane resistance to ethanol. However the mechanisms underlying cell death in these conditions remain unclear. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a given nutrient limitation and thus survive starvation. We show here that a set of micronutrients (oleic acid, ergosterol, pantothenic acid and nicotinic acid) in low, growth-restricting concentrations trigger cell death in alcoholic fermentation when nitrogen level is high. We provide evidence that nitrogen signaling is involved in cell death and that either SCH9 deletion or Tor inhibition prevent cell death in several types of micronutrient limitation. Under such limitations, yeast cells fail to acquire any stress resistance and are unable to store glycogen. Unexpectedly, transcriptome analyses did not reveal any major changes in stress genes expression, suggesting that post-transcriptional events critical for stress response were not triggered by micronutrient starvation. Our data point to the fact that yeast cell death results from yeast inability to trigger an appropriate stress response under some conditions of nutrient limitations most likely not encountered by yeast in the wild. Our conclusions provide a novel frame for considering both cell death and the management of nutrients during alcoholic fermentation.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184838
  • Effects of acute administration of donepezil or memantine on
           sleep-deprivation-induced spatial memory deficit in young and aged
           non-human primate grey mouse lemurs (Microcebus murinus)

    • Authors: Anisur Rahman Yves Lamberty Esther Schenker Massimo Cella Solène Languille Régis Bordet Jill Richardson Fabien Pifferi Fabienne Aujard
      Abstract: by Anisur Rahman, Yves Lamberty, Esther Schenker, Massimo Cella, Solène Languille, Régis Bordet, Jill Richardson, Fabien Pifferi, Fabienne AujardThe development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184822
  • Knowledge evolution in physics research: An analysis of bibliographic
           coupling networks

    • Authors: Wenyuan Liu Andrea Nanetti Siew Ann Cheong
      Abstract: by Wenyuan Liu, Andrea Nanetti, Siew Ann CheongEven as we advance the frontiers of physics knowledge, our understanding of how this knowledge evolves remains at the descriptive levels of Popper and Kuhn. Using the American Physical Society (APS) publications data sets, we ask in this paper how new knowledge is built upon old knowledge. We do so by constructing year-to-year bibliographic coupling networks, and identify in them validated communities that represent different research fields. We then visualize their evolutionary relationships in the form of alluvial diagrams, and show how they remain intact through APS journal splits. Quantitatively, we see that most fields undergo weak Popperian mixing, and it is rare for a field to remain isolated/undergo strong mixing. The sizes of fields obey a simple linear growth with recombination. We can also reliably predict the merging between two fields, but not for the considerably more complex splitting. Finally, we report a case study of two fields that underwent repeated merging and splitting around 1995, and how these Kuhnian events are correlated with breakthroughs on Bose-Einstein condensation (BEC), quantum teleportation, and slow light. This impact showed up quantitatively in the citations of the BEC field as a larger proportion of references from during and shortly after these events.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184821
  • Cytokine-induced killer cell delivery enhances the antitumor activity of
           oncolytic reovirus

    • Authors: Xing Zhao Weiwei Ouyang Cariad Chester Shiqi Long Nianxue Wang Zhixu He
      Abstract: by Xing Zhao, Weiwei Ouyang, Cariad Chester, Shiqi Long, Nianxue Wang, Zhixu HeOncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy.
      PubDate: 2017-09-18T21:00:00Z
      DOI: 10.1371/journal.pone.0184816
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