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F1000Research
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  This is an Open Access Journal Open Access journal
     ISSN (Online) 2046-1402
     Published by Faculty of 1000 Homepage  [1 journal]
  • A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola
           virus [v2; indexed, http://f1000r.es/4wt]

    • Authors: Sean Ekins, Joel S. Freundlich, Megan Coffee
      Abstract: We are currently faced with a global infectious disease crisis which has been anticipated for decades. While many promising biotherapeutics are being tested, the search for a small molecule has yet to deliver an approved drug or therapeutic for the Ebola or similar filoviruses that cause haemorrhagic fever. Two recent high throughput screens published in 2013 did however identify several hits that progressed to animal studies that are FDA approved drugs used for other indications. The current computational analysis uses these molecules from two different structural classes to construct a common features pharmacophore. This ligand-based pharmacophore implicates a possible common target or mechanism that could be further explored. A recent structure based design project yielded nine co-crystal structures of pyrrolidinone inhibitors bound to the viral protein 35 (VP35). When receptor-ligand pharmacophores based on the analogs of these molecules and the protein structures were constructed, the molecular features partially overlapped with the common features of solely ligand-based pharmacophore models based on FDA approved drugs. These previously identified FDA approved drugs with activity against Ebola were therefore docked into this protein. The antimalarials chloroquine and amodiaquine docked favorably in VP35. We propose that these drugs identified to date as inhibitors of the Ebola virus may be targeting VP35. These computational models may provide preliminary insights into the molecular features that are responsible for their activity against Ebola virus in vitro and in vivo and we propose that this hypothesis could be readily tested.
      PubDate: 2014-12-12T15:58:58Z
      DOI: 10.12688/f1000research.5741.2
      Issue No: Vol. 3 (2014)
       
  • Fourier transform infrared spectroscopy study of ligand
           photodissociation and migration in inducible nitric oxide synthase [v2;
           indexed, http://f1000r.es/4w9]

    • Authors: Michael Horn, Karin Nienhaus, Gerd Ulrich Nienhaus
      Abstract: Inducible nitric oxide synthase (iNOS) is a homodimeric heme enzyme that catalyzes the formation of nitric oxide (NO) from dioxygen and L-arginine (L-Arg) in a two-step process. The produced NO can either diffuse out of the heme pocket into the surroundings or it can rebind to the heme iron and inhibit enzyme action. Here we have employed Fourier transform infrared (FTIR) photolysis difference spectroscopy at cryogenic temperatures, using the carbon monoxide (CO) and NO stretching bands as local probes of the active site of iNOS. Characteristic changes were observed in the spectra of the heme-bound ligands upon binding of the cofactors. Unlike photolyzed CO, which becomes trapped in well-defined orientations, as indicated by sharp photoproduct bands, photoproduct bands of NO photodissociated from the ferric heme iron were not visible, indicating that NO does not reside in the protein interior in a well-defined location or orientation. This may be favorable for NO release from the enzyme during catalysis because it reduces self-inhibition. Moreover, we used temperature derivative spectroscopy (TDS) with FTIR monitoring to explore the dynamics of NO and carbon monoxide (CO) inside iNOS after photodissociation at cryogenic temperatures. Only a single kinetic photoproduct state was revealed, but no secondary docking sites as in hemoglobins. Interestingly, we observed that intense illumination of six-coordinate ferrous iNOSoxy-NO ruptures the bond between the heme iron and the proximal thiolate to yield five-coordinate ferric iNOSoxy-NO, demonstrating the strong trans effect of the heme-bound NO.
      PubDate: 2014-12-12T15:54:19Z
      DOI: 10.12688/f1000research.5836.2
      Issue No: Vol. 3 (2014)
       
  • Rice (Oryza) hemoglobins [v2; indexed, http://f1000r.es/4vp]

    • Authors: Raúl Arredondo-Peter, Jose F. Moran, Gautam Sarath
      Abstract: Hemoglobins (Hbs) corresponding to non-symbiotic (nsHb) and truncated (tHb) Hbs have been identified in rice (Oryza). This review discusses the major findings from the current studies on rice Hbs. At the molecular level, a family of the nshb genes, consisting of hb1, hb2, hb3, hb4 and hb5, and a single copy of the thb gene exist in Oryza sativa var. indica and O. sativa var. japonica, Hb transcripts coexist in rice organs and Hb polypeptides exist in rice embryonic and vegetative organs and in the cytoplasm of differentiating cells. At the structural level, the crystal structure of rice Hb1 has been elucidated, and the structures of the other rice Hbs have been modeled. Kinetic analysis indicated that rice Hb1 and 2, and possibly rice Hb3 and 4, exhibit a very high affinity for O2, whereas rice Hb5 and tHb possibly exhibit a low to moderate affinity for O2. Based on the accumulated information on the properties of rice Hbs and data from the analysis of other plant and non-plant Hbs, it is likely that Hbs play a variety of roles in rice organs, including O2-transport, O2-sensing, NO-scavenging and redox-signaling. From an evolutionary perspective, an outline for the evolution of rice Hbs is available. Rice nshb and thb genes vertically evolved through different lineages, rice nsHbs evolved into clade I and clade II lineages and rice nshbs and thbs evolved under the effect of neutral selection. This review also reveals lacunae in our ability to completely understand rice Hbs. Primary lacunae are the absence of experimental information about the precise functions of rice Hbs, the properties of modeled rice Hbs and the cis-elements and trans-acting factors that regulate the expression of rice hb genes, and the partial understanding of the evolution of rice Hbs.
      PubDate: 2014-12-11T16:50:16Z
      DOI: 10.12688/f1000research.5530.2
      Issue No: Vol. 3 (2014)
       
  • Case Report: Mammary and rectal metastases from an ovarian cancer: report
           

    • Authors: Mounia Amzerin, Camilo Garcia, Claudia Stanciu, Isabelle Veys, Ahmad Awada, Hassan Errihani, Andrea Gombos
      Abstract: In this paper we report two interesting cases of metastatic ovarian cancer. The first case is a patient who developed rectal and breast metastases mimicking an inflammatory breast cancer. In the second case, subclinical breast and axillary lymph node metastases were revealed by PET/CT. Metastases in the breast originating from solid tumors are extremely rare. The ovarian primitive is the fourth most common origin. The occurrence of breast metastasis is associated with an advanced disease and a poor prognosis. Their incidence is increasing since they are found more often due to better imaging techniques and to better treatment that, accordingly, improve patients’ survival. Thus, unusual sites of metastases are more and more reported. Indeed, some authors reported the occurrence of colorectal metastases from ovarian cancer. However, they remain much less frequent.
      PubDate: 2014-12-09T16:43:44Z
      DOI: 10.12688/f1000research.2644.2
      Issue No: Vol. 3 (2014)
       
  • Discovery of functional non-coding conserved regions in the
           α-synuclein gene locus [v2; indexed, http://f1000r.es/4v9]

    • Authors: Lori Sterling, Michael Walter, Dennis Ting, Birgitt Schüle
      Abstract: Several single nucleotide polymorphisms (SNPs) and the Rep-1 microsatellite marker of the α-synuclein ( SNCA) gene have consistently been shown to be associated with Parkinson’s disease, but the functional relevance is unclear. Based on these findings we hypothesized that conserved cis-regulatory elements in the SNCA genomic region regulate expression of SNCA, and that SNPs in these regions could be functionally modulating the expression of SNCA, thus contributing to neuronal demise and predisposing to Parkinson’s disease. In a pair-wise comparison of a 206kb genomic region encompassing the SNCA gene, we revealed 34 evolutionary conserved DNA sequences between human and mouse. All elements were cloned into reporter vectors and assessed for expression modulation in dual luciferase reporter assays.  We found that 12 out of 34 elements exhibited either an enhancement or reduction of the expression of the reporter gene. Three elements upstream of the SNCA gene displayed an approximately 1.5 fold (p
      PubDate: 2014-12-08T17:08:27Z
      DOI: 10.12688/f1000research.3281.2
      Issue No: Vol. 3 (2014)
       
  • Characterization of the truncated hemoglobin THB1 from protein extracts of
           Chlamydomonas reinhardtii [v1; indexed, http://f1000r.es/4ub]

    • Authors: Eric A. Johnson, Juliette T.J. Lecomte
      Abstract: Truncated hemoglobins (TrHbs) belong to the hemoglobin superfamily, but unlike their distant vertebrate relatives, little is known about their principal physiologic functions.  Several TrHbs have been studied in vitro using engineered recombinant peptides.  These efforts have resulted in a wealth of knowledge about the chemical properties of TrHbs and have generated interesting functional leads. However, questions persist as to how closely these engineered proteins mimic their counterparts within the native cell. In this report, we examined THB1, one of several TrHbs from the model organism Chlamydomonas reinhardtii. The recombinant THB1 (rTHB1) has favorable solubility and stability properties and is an excellent candidate for in vitro characterization. Linking rTHB1 to the in vivo protein is a critical step in understanding the physiologic function of this protein. Using a simplified three-step purification protocol, 3.5-L batches of algal culture were processed to isolate 50–60 μL fractions enriched in THB1. These fractions of C. reinhardtii proteins were then subjected to physical examination. Using gel mobility, optical absorbance and immunoreactivity, THB1 was identified in these enriched fractions and its presence correlated with that of a heme molecule. Mass spectrometry confirmed this cofactor to be a type b heme and revealed that the native protein contains a co-translational modification consistent with amino-terminal acetylation following initial methionine cleavage.
      PubDate: 2014-12-04T11:35:48Z
      DOI: 10.12688/f1000research.5873.1
      Issue No: Vol. 3 (2014)
       
  • Working memory training shows immediate and long-term effects on cognitive
           performance in children [v2; indexed, http://f1000r.es/4rj]

    • Authors: Fiona Pugin, Andreas J. Metz, Madlaina Stauffer, Martin Wolf, Oskar G. Jenni, Reto Huber
      Abstract: Working memory is important for mental reasoning and learning processes. Several studies in adults and school-age children have shown performance improvement in cognitive tests after working memory training. Our aim was to examine not only immediate but also long-term effects of intensive working memory training on cognitive performance tests in children. Fourteen healthy male subjects between 10 and 16 years trained a visuospatial n-back task over 3 weeks (30 min daily), while 15 individuals of the same age range served as a passive control group. Significant differences in immediate (after 3 weeks of training) and long-term effects (after 2-6 months) in an auditory n-back task were observed compared to controls (2.5 fold immediate and 4.7 fold long-term increase in the training group compared to the controls). The improvement was more pronounced in subjects who improved their performance during the training. Other cognitive functions (matrices test and Stroop task) did not change when comparing the training group to the control group. We conclude that visuospatial working memory training in children boosts performance in similar memory tasks such as the auditory n-back task. The sustained performance improvement several months after the training supports the effectiveness of the training.
      PubDate: 2014-11-27T14:39:05Z
      DOI: 10.12688/f1000research.3665.2
      Issue No: Vol. 3 (2014)
       
  • Connecting undergraduate science education with the needs of today’s
           graduates [v1; indexed, http://f1000r.es/4pl]

    • Authors: Viviane Callier, Richard H. Singiser, Nathan L. Vanderford
      Abstract: Undergraduate science programs are not providing graduates with the knowledgebase and skills they need to be successful on today’s job market. Curricular changes relevant to today’s marketplace and more opportunities for internships and work experience during students’ secondary education would facilitate a smoother transition to the working world and help employers find graduates that possess both the hard and soft skills needed in the workplace. In this article, we discuss these issues and offer solutions that would generate more marketplace-ready undergraduates.
      PubDate: 2014-11-14T16:16:21Z
      Issue No: Vol. 3 (2014)
       
  • Does the linear Sry transcript function as a ceRNA for miR-138' The
           sense of antisense [v2; indexed, http://f1000r.es/4pd]

    • Authors: Javier Tadeo Granados-Riveron, Guillermo Aquino-Jarquin
      Abstract: Recently, the sex determining region Y (Sry) and the cerebellar degeneration-related protein 1 (CDR1as) RNA transcripts have been described to function as a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7, respectively. A special feature of the Sry gene is its ability to generate linear and circular transcripts, both transcribed in the sense orientation. Here we remark that both sense (e.g. Sry RNA) and antisense (e.g. CDR1as) transcripts could circularize and behave as miRNAs sponges, and importantly, that also protein-coding segments of mRNAs could also assume this role. Thus, it is reasonable to think that the linear Sry sense transcript could additionally act as a miRNA sponge, or as an endogenous competing RNA for miR-138.
      PubDate: 2014-11-13T10:42:05Z
      DOI: 10.12688/f1000research.3872.2
      Issue No: Vol. 3 (2014)
       
  • The Open Science Peer Review Oath [v1; indexed, http://f1000r.es/4ou]

    • Authors: Jelena Aleksic, Adrian Alexa, Teresa K Attwood, Neil Chue Hong, Martin Dahlö, Robert Davey, Holger Dinkel, Konrad U Förstner, Ivo Grigorov, Jean-Karim Hériché, Leo Lahti, Dan MacLean, Michael L Markie, Jenny Molloy, Maria Victoria Schneider, Camille Scott, Richard Smith-Unna, Bruno Miguel Vieira, as part of the AllBio: Open Science & Reproducibility Best Practice Workshop
      Abstract: One of the foundations of the scientific method is to be able to reproduce experiments and corroborate the results of research that has been done before. However, with the increasing complexities of new technologies and techniques, coupled with the specialisation of experiments, reproducing research findings has become a growing challenge. Clearly, scientific methods must be conveyed succinctly, and with clarity and rigour, in order for research to be reproducible. Here, we propose steps to help increase the transparency of the scientific method and the reproducibility of research results: specifically, we introduce a peer-review oath and accompanying manifesto. These have been designed to offer guidelines to enable reviewers (with the minimum friction or bias) to follow and apply open science principles, and support the ideas of transparency, reproducibility and ultimately greater societal impact. Introducing the oath and manifesto at the stage of peer review will help to check that the research being published includes everything that other researchers would need to successfully repeat the work. Peer review is the lynchpin of the publishing system: encouraging the community to consciously (and conscientiously) uphold these principles should help to improve published papers, increase confidence in the reproducibility of the work and, ultimately, provide strategic benefits to authors and their institutions. Future incarnations of the various national Research Excellence Frameworks (REFs) will evolve away from simple citations towards measurable societal value and impact. The proposed manifesto aspires to facilitate this goal by making transparency, reproducibility and citizen-scientist engagement (with the knowledge-creation and dissemination processes) the default parameters for performing sound research.
      PubDate: 2014-11-12T15:15:31Z
      DOI: 10.12688/f1000research.5686.1
      Issue No: Vol. 3 (2014)
       
  • APOC3 may not be a predictor of risk of ischemic vascular disease in the
           Chinese population [v1; indexed, http://f1000r.es/4oi]

    • Authors: Liang Tang, Zhi-Peng Cheng, Qing-Yun Wang, Wei Zeng, Hui Liu, Ying-Ying Wu, Bei Hu, Yu Hu
      Abstract: The genetic background of ischemic vascular disease is actively being explored. Several studies have shown that inhibition of APOC3 significantly reduces plasma levels of apolipoprotein C3 and triglycerides. Recently, the TG and HDL Working Group and Jørgensen et al. reported that loss-of-function mutations in APOC3 are associated with decreased triglyceride levels and a reduced risk of ischemic vascular disease in European and African individuals. We performed a replication study in 4470 Chinese participants. The coding regions of APOC3 were amplified and re-sequenced. However, only synonymous and intronic variants with no functional consequences were identified. None of the loss-of-function mutations reported in European and African individuals were observed. Therefore, APOC3 may not be an ideal predictor for risk of ischemic vascular disease in the Chinese population.
      PubDate: 2014-11-07T16:58:04Z
      DOI: 10.12688/f1000research.5676.1
      Issue No: Vol. 3 (2014)
       
  • Case Report: Rare occurrence of Pseudomonas aeruginosa osteomyelitis of
           the right clavicle in a patient with IgA nephropathy [v1; indexed,
           http://f1000r.es/37r]

    • Authors: Aishwarya Damodaran, Anusha Rohit, Georgi Abraham, Sanjeev Nair, Anand Yuvaraj
      Abstract: We describe the case of a 47 year old patient with proven primary IgA nephropathy who presented with osteomyelitis of the medial end of the right clavicle. The patient was not on immunosuppressive medications. He underwent aspiration curettage and CT scan of the clavicle which yielded pus that grew Pseudomonas aeruginosa. Following treatment with appropriate antibiotic therapy the patient presented a complete recovery of the lesion with no loss of renal function. This case highlights the importance of positive cultures in the choice of the appropriate therapy in an extremely rare case of an immunocompetent patient with osteomyelitis of the clavicle.
      PubDate: 2014-11-06T12:19:40Z
      DOI: 10.12688/f1000research.3891.1
      Issue No: Vol. 3 (2014)
       
  • Cytoscape tools for the web age: D3.js and Cytoscape.js exporters [v2;
           indexed, http://f1000r.es/4k7]

    • Authors: Keiichiro Ono, Barry Demchak, Trey Ideker
      Abstract: In this paper we present new data export modules for Cytoscape 3 that can generate network files for Cytoscape.js and D3.js. Cytoscape.js exporter is implemented as a core feature of Cytoscape 3, and D3.js exporter is available as a Cytoscape 3 app. These modules enable users to seamlessly export network and table data sets generated in Cytoscape to popular JavaScript library readable formats. In addition, we implemented template web applications for browser-based interactive network visualization that can be used as basis for complex data visualization applications for bioinformatics research. Example web applications created with these tools demonstrate how Cytoscape works in modern data visualization workflows built with traditional desktop tools and emerging web-based technologies. This interactivity enables researchers more flexibility than with static images, thereby greatly improving the quality of insights researchers can gain from them.
      PubDate: 2014-10-28T09:58:48Z
      Issue No: Vol. 3 (2014)
       
  • Hot topics at the intersection of aging and energetics: Diabetes/insulin
           resistance, Sirtuins, and the Microbiome [v1; indexed,
           http://f1000r.es/4mw]

    • Authors: Dudley W. Lamming
      Abstract: A recent review in F1000Research identified the “top research priorities identified in leading publications” at the interface of Aging and Energetics. The authors identified the ten most-cited papers in each of the years 2010 through 2013, and used these forty papers to identify thematic categories. However, the search methodology used by the authors omitted many high-impact aging manuscripts. Minor modifications in the authors’ search methodology finds that Diabetes/insulin resistance, Sirtuins, and the Microbiome are also top thematic categories.
      PubDate: 2014-10-28
      DOI: 10.12688/f1000research.5625.1
      Issue No: Vol. 3 (2014)
       
  • Viewing multiple sequence alignments with the JavaScript Sequence
           Alignment Viewer (JSAV) [v1; indexed, http://f1000r.es/4io]

    • Authors: Andrew C. R. Martin
      Abstract: The JavaScript Sequence Alignment Viewer (JSAV) is designed as a simple-to-use JavaScript component for displaying sequence alignments on web pages. The display of sequences is highly configurable with options to allow alternative coloring schemes, sorting of sequences and ’dotifying’ repeated amino acids. An option is also available to submit selected sequences to another web site, or to other JavaScript code. JSAV is implemented purely in JavaScript making use of the JQuery and JQuery-UI libraries. It does not use any HTML5-specific options to help with browser compatibility. The code is documented using JSDOC and is available from http://www.bioinf.org.uk/software/jsav/.
      PubDate: 2014-10-23T11:00:38Z
      DOI: 10.12688/f1000research.5486.1
      Issue No: Vol. 3 (2014)
       
  • The proteasome activity reporter GFP-Cl1 is degraded by autophagy in the
           aging model Podospora anserina [v1; indexed, http://f1000r.es/4e9]

    • Authors: Matthias Wiemer, Heinz D. Osiewacz
      Abstract: The degradation of damaged proteins is an important vital function especially during aging and stress. The ubiquitin proteasome system is one of the major cellular machineries for protein degradation. Health and longevity are associated with high proteasome activity. To demonstrate such a role in aging of Podospora anserina, we first analyzed the transcript and protein abundance of selected proteasome components in wild-type cultures of different age. No significant differences were observed. Next, in order to increase the overall proteasome abundance we generated strains overexpressing the catalytic proteasome subunits PaPRE2 and PaPRE3. Although transcript levels were strongly increased, no substantial effect on the abundance of the corresponding proteins was observed. Finally, the analysis of the P. anserina strains expressing the sequence coding for the CL1 degron fused to the Gfp gene revealed no evidence for degradation of the GFP-CL1 fusion protein by the proteasome. Instead, our results demonstrate the degradation of the CL1-degron sequence via autophagy, indicating that basal autophagy appears to be a very effective protein quality control pathway in P. anserina.
      PubDate: 2014-09-30T15:42:19Z
      DOI: 10.12688/f1000research.5337.1
      Issue No: Vol. 3 (2014)
       
  • Estrogen as Jekyll and Hyde: regulation of cell death [v2; indexed,
           http://f1000r.es/4fh]

    • Authors: Wen Zhou, Xiaoxia Zhu
      Abstract: Sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Unexpectedly, physiological level of estrogen together with a novel IKKα inhibitor BAY11-7082 could effectively induce cell apoptosis in ER-positive breast cancer cells, suggesting combining estrogen with IKKα inhibition may be beneficial for breast cancer patients. This opinion article touches upon the dual role estrogen played in inducing cancer cell death and asks whether use of estrogen in combination with IKKα-targeted therapy would be possible reconsider the newly identified crosstalk between ER and NFκB pathway which can be utilized to switch the effects of estrogen on cell death.
      PubDate: 2014-09-29
      DOI: 10.12688/f1000research.4753.2
      Issue No: Vol. 3 (2014)
       
  • [18F]-T807 tauopathy PET imaging in chronic traumatic encephalopathy [v1;
           indexed, http://f1000r.es/4fb]

    • Authors: Sam Gandy, Steven T. DeKosky
      Abstract: A new molecular ligand for positron emission tomography (PET) of the human brain, [18F]-T807, is under investigation for the antemortem detection of pathological neurofibrillary aggregates, which are evidence of neurofibrillary tangle (NFT) diseases, also known as tauopathies. Repetitive mild traumatic brain injuries in athletes and battlefield veterans are associated with one such tauopathy, known as chronic traumatic encephalopathy (CTE). In a recent case report, a former NFL player with clinically probable CTE and a concurrent Progressive Supranuclear Palsy (PSP) –like syndrome was studied using [18F]-T807. The interpretation of this player’s [18F]-T807 PET imaging was complicated by the overlap of tracer uptake in brain regions involved in CTE and PSP with regions associated with either nonspecific [18F]-T807 ligand binding or “aging-associated” binding of [18F]-T807 to authentic tauopathy known to be associated with aging and disease severity (i.e., NFT in the mesial temporal lobe). The implications of these data for the utility of [18F]-T807 in the pre-mortem detection of CTE are summarized.
      PubDate: 2014-09-29
      DOI: 10.12688/f1000research.5372.1
      Issue No: Vol. 3 (2014)
       
  • Using Twitter to investigate opinions about multiple sclerosis treatments:
           a descriptive, exploratory study [v1; indexed, http://f1000r.es/4bu]

    • Authors: Sreeram Ramagopalan, Radek Wasiak, Andrew P. Cox
      Abstract: Background: Multiple sclerosis (MS) is a common complex disorder, with new treatment options emerging each year. Social media is being increasingly used to investigate opinions about drugs, diseases and procedures. In this descriptive exploratory study, we sought to investigate opinions about currently available MS treatments. Methods: The Twitter resource Topsy was searched for tweets mentioning the following MS treatments: Aubagio, Avonex, Betaferon or Betaseron, Copaxone, Extavia, Gilenya, Lemtrada, Novantrone, Rebif, Tysabri and Tecfidera between 1 Jan 2006 to 31 Jul 2014. Tweets were normalised and sentiment analysis performed. Results: In total, there were 60037 unique tweets mentioning an MS treatment. About half of the tweets contained non-neutral sentiment. Mean sentiment scores were different for treatments ranging from -0.191to 0.282 when investigating all tweets. These differences in sentiment scores between treatments were statistically significant (P
      PubDate: 2014-09-10T14:53:39Z
      DOI: 10.12688/f1000research.5263.1
      Issue No: Vol. 3 (2014)
       
  • Active transmembrane drug transport in microgravity: a validation study
           using an ABC transporter model [v1; indexed, http://f1000r.es/41n]

    • Authors: Sergi Vaquer, Elisabet Cuyàs, Arnau Rabadán, Albert González, Felip Fenollosa, Rafael de la Torre
      Abstract: Abstract Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay® (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-β-glucuronide (E17βG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and interesting research lines in biology and human physiology with the potential for significant benefits for both space and terrestrial medicine.
      PubDate: 2014-08-21T09:49:48Z
      DOI: 10.12688/f1000research.4909.1
      Issue No: Vol. 3 (2014)
       
 
 
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