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Journal Cover   F1000Research
  [5 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • Virtual screen for repurposing approved and experimental drugs for
           candidate inhibitors of EBOLA virus infection [v2; indexed,
           http://f1000r.es/53d]

    • Authors: Veljko Veljkovic, Philippe M. Loiseau, Bruno Figadere, Sanja Glisic, Nevena Veljkovic, Vladimir R. Perovic, David P. Cavanaugh, Donald R. Branch
      Abstract: The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.
      PubDate: 2015-02-16T15:48:10Z
      Issue No: Vol. 4 (2015)
       
  • Small molecules with antiviral activity against the Ebola virus [v1;
           indexed, http://f1000r.es/523]

    • Authors: Nadia Litterman, Christopher Lipinski, Sean Ekins
      Abstract: The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus.
      PubDate: 2015-02-09T15:10:45Z
      DOI: 10.12688/f1000research.6120.1
      Issue No: Vol. 4 (2015)
       
  • Strain-specific and pooled genome sequences for populations of Drosophila
           melanogaster from three continents. [v1; indexed, http://f1000r.es/515]

    • Authors: Casey M. Bergman, Penelope R. Haddrill
      Abstract: To contribute to our general understanding of the evolutionary forces that shape variation in genome sequences in nature, we have sequenced genomes from 50 isofemale lines and six pooled samples from populations of Drosophila melanogaster on three continents. Analysis of raw and reference-mapped reads indicates the quality of these genomic sequence data is very high. Comparison of the predicted and experimentally-determined Wolbachia infection status of these samples suggests that strain or sample swaps are unlikely to have occurred in the generation of these data. Genome sequences are freely available in the European Nucleotide Archive under accession ERP009059. Isofemale lines can be obtained from the Drosophila Species Stock Center.
      PubDate: 2015-01-29T11:29:37Z
      DOI: 10.12688/f1000research.6090.1
      Issue No: Vol. 4 (2015)
       
  • Capsaicin from chili (Capsicum spp.) inhibits vascular smooth muscle cell
           proliferation [v1; indexed, http://f1000r.es/4yk]

    • Authors: Rongxia Liu, Elke H. Heiss, Dean Guo, Verena M. Dirsch, Atanas G. Atanasov
      Abstract: Accelerated vascular smooth muscle cell (VSMC) proliferation is implied in cardiovascular disease and significantly contributes to vessel lumen reduction following surgical interventions such as percutaneous transluminal coronary angioplasty or bypass surgery. Therefore, identification and characterization of compounds and mechanisms able to counteract VSMC proliferation is of potential therapeutic relevance. This work reveals the anti-proliferative effect of the natural product capsaicin from Capsicum spp. by quantification of metabolic activity and DNA synthesis in activated VSMC. The observed in vitro activity profile of capsaicin warrants further research on its mechanism of action and potential for therapeutic application.
      PubDate: 2015-01-27T15:35:41Z
      DOI: 10.12688/f1000research.6007.1
      Issue No: Vol. 4 (2015)
       
  • Breaking a Guinness World Record on Hand Sanitizing Relay, initiating a
           call for vital research in overcoming campaign fatigue for hand hygiene
           [v2; indexed, http://f1000r.es/530]

    • Authors: Wing Hong Seto, Kwok-Hung Li, Christina Woon Yee Cheung, Patricia Tai Yin Ching, Benjamin J. Cowling
      Abstract: Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in June 2014 in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines.
      PubDate: 2015-02-16T16:56:56Z
      DOI: 10.12688/f1000research.5403.2
      Issue No: Vol. 3 (2015)
       
  • Longevity of Atlantic Sharpnose Sharks Rhizoprionodon terraenovae and
           Blacknose Sharks Carcharhinus acronotus in the western North Atlantic
           Ocean based on tag-recapture data and direct age estimates [v2; indexed,
           http://f1000r.es/4fj]

    • Authors: Bryan S. Frazier, William B. Driggers III, Glenn F. Ulrich
      Abstract: Longevity of Rhizoprionodon terraenovae and Carcharhinus acronotus in the western North Atlantic Ocean was examined using direct age estimates from vertebral sections and tag-recapture data. Time-at-liberty ranged from 7.7-14.0 years (mean =10.1) for R. terraenovae and 10.9-12.8 years (mean =11.9) for C. acronotus. Maximum estimated longevity was determined to be 19.8 years through tag-recapture data and 18.5 years from direct age estimates for R. terraenovae and 22.8 years through tag-recapture data and 20.5 years through direct age estimates for C. acronotus. These longevity estimates represent a large increase over previous estimates and may have significant effects on analyses that depend on longevity including lifetime fecundity, mortality rates, demographic analyses and stock assessments.
      PubDate: 2015-01-27T15:44:25Z
      DOI: 10.12688/f1000research.4767.2
      Issue No: Vol. 3 (2015)
       
  • Characterizing alpha helical properties of Ebola viral proteins as
           potential targets for inhibition of alpha-helix mediated protein-protein
           interactions [v3; indexed, http://f1000r.es/50u]

    • Authors: Sandeep Chakraborty, Basuthkar J. Rao, Bjarni Asgeirsson, Abhaya Dandekar
      Abstract: Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).
      PubDate: 2015-01-27T10:22:27Z
      DOI: 10.12688/f1000research.5573.3
      Issue No: Vol. 3 (2015)
       
  • Safety, efficacy and utility of methods of transferring adhesive and
           cohesive Escherichia coli cells to microplates to avoid aerosols [v2;
           indexed, http://f1000r.es/4yt]

    • Authors: Bryan Ericksen
      Abstract: The virtual colony count (VCC) microbiological assay has been utilized for over a decade to measure the antimicrobial activity of peptides such as defensins and LL-37 against biosafety level (BSL)-1 and BSL-2 bacteria including Escherichia coli, Staphylococcus aureus, Bacillus cereus, and Enterobacter aerogenes.  In addition, a modified pipetting technique was presented in a 2011 study of defensin activity against the BSL-3 pathogen Bacillus anthracis.  Both studies were published in the journal Antimicrobial Agents and Chemotherapy.  Here I report that the method can also detect cross-contamination caused by aerosols utilizing the VCC method of data analysis by quantitative growth kinetics (QGK).  The QGK threshold time, or Tt, equivalent to the cycle time Ct reported in 1996 by Heid et al., precisely identifies when wells were inoculated.
      PubDate: 2015-01-14T17:22:08Z
      DOI: 10.12688/f1000research.5659.2
      Issue No: Vol. 3 (2015)
       
  • Binding of a fluorescence reporter and a ligand to an odorant-binding
           protein of the yellow fever mosquito, Aedes aegypti [v2; indexed,
           http://f1000r.es/4yp]

    • Authors: Gabriel M. Leal, Walter S. Leal
      Abstract: Odorant-binding proteins (OBPs), also named pheromone-binding proteins when the odorant is a pheromone, are essential for insect olfaction. They solubilize odorants that reach the port of entry of the olfactory system, the pore tubules in antennae and other olfactory appendages. Then, OBPs transport these hydrophobic compounds through an aqueous sensillar lymph to receptors embedded on dendritic membranes of olfactory receptor neurons. Structures of OBPs from mosquito species have shed new light on the mechanism of transport, although there is considerable debate on how they deliver odorant to receptors. An OBP from the southern house mosquito, Culex quinquefasciatus, binds the hydrophobic moiety of a mosquito oviposition pheromone (MOP) on the edge of its binding cavity. Likewise, it has been demonstrated that the orthologous protein from the malaria mosquito binds the insect repellent DEET on a similar edge of its binding pocket. A high school research project was aimed at testing whether the orthologous protein from the yellow fever mosquito, AaegOBP1, binds DEET and other insect repellents, and MOP was used as a positive control. Binding assays using the fluorescence reporter N-phenyl-1-naphtylamine (NPN) were inconclusive. However, titration of NPN fluorescence emission in AaegOBP1 solution with MOP led to unexpected and intriguing results. Quenching was observed in the initial phase of titration, but addition of higher doses of MOP led to a stepwise increase in fluorescence emission coupled with a blue shift, which can be explained at least in part by formation of MOP micelles to house stray NPN molecules.
      PubDate: 2015-01-09T16:54:29Z
      DOI: 10.12688/f1000research.5879.2
      Issue No: Vol. 3 (2015)
       
  • Case Report: Bilateral reexpansion pulmonary edema following treatment of
           a unilateral hemothorax [v1; indexed, http://f1000r.es/4yb]

    • Authors: Steven P de Wolf, Jaap Deunk, Alexander D Cornet, Paul WG Elbers
      Abstract: Bilateral re-expansion pulmonary edema (RPE) is an extremely rare entity. We report the unique case of bilateral RPE following a traumatic, unilateral hemopneumothorax in a young healthy male. Bilateral RPE occurred only one hour after drainage of a unilateral hemopneumothorax. The patient was treated with diuretics and supplemental oxygen. Diagnosis was confirmed by excluding other causes, using laboratory findings, chest radiography, pulmonary and cardiac ultrasound and high resolution computed tomography. His recovery was uneventful. The pathophysiology of bilateral RPE is not well known. Treatment is mainly supportive and consists of diuretics, mechanical ventilation, inotropes and steroids. In case of a pulmonary deterioration after the drainage of a traumatic pneumothorax, bilateral RPE should be considered after exclusion of more common causes of dyspnea.
      PubDate: 2014-12-30T17:10:03Z
      DOI: 10.12688/f1000research.6000.1
      Issue No: Vol. 3 (2014)
       
  • Case Report: Large nested variant urothelial carcinoma –invasive
           malignancy masquerading as low grade disease [v1; indexed,
           http://f1000r.es/4xb]

    • Authors: Andrew Keller, Ai Jye Lim, Ahmad Ali
      Abstract: Introduction The large nested variant of urothelial carcinoma (LNVUC) is a newly described and rare subtype of urothelial carcinoma. It is characterised by bland cytological features and a large nested architecture similar in appearance to low grade urothelial carcinoma with an inverted growth pattern. To date only 23 cases in a single series have been described.   Case Report We describe the case of a 59 year old male with LNVUC whose tumour was initially misdiagnosed as a non-invasive low grade urothelial carcinoma. At a subsequent re-resection, his tumour was correctly re-classified as LNVUC with extensive invasion of the muscularis propria. Radical cystectomy and formation of an ileal conduit was performed. His operative specimen revealed invasion of prostatic stroma and perivesical fat, with all surgical margins clear. He is currently free from clinical recurrence 12 months after his cystectomy.   Conclusion LNVUC is a newly described and rare urothelial carcinoma subtype. It characteristically possesses bland cytological features and may mimic low grade urothelial cancer. Despite its bland appearance it behaves aggressively with invasion, metastasis and death being common.
      PubDate: 2014-12-23T14:21:29Z
      DOI: 10.12688/f1000research.5966.1
      Issue No: Vol. 3 (2014)
       
  • Subdivisions of the adult zebrafish pallium based on molecular marker
           analysis [v1; indexed, http://f1000r.es/4m2]

    • Authors: Julia Ganz, Volker Kroehne, Dorian Freudenreich, Anja Machate, Michaela Geffarth, Ingo Braasch, Jan Kaslin, Michael Brand
      Abstract: Background: The telencephalon shows a remarkable structural diversity among vertebrates. In particular, the everted telencephalon of ray-finned fishes has a markedly different morphology compared to the evaginated telencephalon of all other vertebrates. This difference in development has hampered the comparison between different areas of the pallium of ray-finned fishes and the pallial nuclei of all other vertebrates. Various models of homology between pallial subdivisions in ray-finned fishes and the pallial nuclei in tetrapods have been proposed based on connectional, neurochemical, gene expression and functional data. However, no consensus has been reached so far. In recent years, the analysis of conserved developmental marker genes has assisted the identification of homologies for different parts of the telencephalon among several tetrapod species. Results: We have investigated the gene expression pattern of conserved marker genes in the adult zebrafish (Danio rerio) pallium to identify pallial subdivisions and their homology to pallial nuclei in tetrapods. Combinatorial expression analysis of ascl1a, eomesa, emx1, emx2, emx3, and Prox1 identifies four main divisions in the adult zebrafish pallium. Within these subdivisions, we propose that Dm is homologous to the pallial amygdala in tetrapods and that the dorsal subdivision of Dl is homologous to part of the hippocampal formation in mouse. We have complemented this analysis be examining the gene expression of emx1, emx2 and emx3 in the zebrafish larval brain. Conclusions: Based on our gene expression data, we propose a new model of subdivisions in the adult zebrafish pallium and their putative homologies to pallial nuclei in tetrapods. Pallial nuclei control sensory, motor, and cognitive functions, like memory, learning and emotion. The identification of pallial subdivisions in the adult zebrafish and their homologies to pallial nuclei in tetrapods will contribute to the use of the zebrafish system as a model for neurobiological research and human neurodegenerative diseases.
      PubDate: 2014-12-17T16:21:22Z
      DOI: 10.12688/f1000research.5595.1
      Issue No: Vol. 3 (2014)
       
  • Does apical membrane GLUT2 have a role in intestinal glucose uptake'
           [v1; indexed, http://f1000r.es/4w6]

    • Authors: Richard J Naftalin
      Abstract: It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations.
      PubDate: 2014-12-12T15:55:50Z
      DOI: 10.12688/f1000research.5934.1
      Issue No: Vol. 3 (2014)
       
  • Detection of Burkholderia pseudomallei in Sputum using Selective
           Enrichment Broth and Ashdown’s Medium at Kampong Cham Provincial
           Hospital, Cambodia [v1; indexed, http://f1000r.es/4w7]

    • Authors: Somary Nhem, Joanne Letchford, Chea Meas, Sovanndeth Thann, James C. McLaughlin, Ellen Jo Baron, T. Eoin West
      Abstract: Melioidosis infection, caused by Burkholderia pseudomallei, is increasingly reported in Cambodia. We hypothesized that implementation of an enhanced sputum testing protocol in a provincial hospital diagnostic microbiology laboratory would increase detection of B. pseudomallei. We tested 241 sputum specimens that were deemed acceptable for culture, comparing culture in selective enrichment broth followed by sub-culture on Ashdown’s medium to standard culture methods. Two specimens (0.8%) were positive for B. pseudomallei using the enhanced protocol whereas one specimen (0.4%) was positive using standard methods. These findings demonstrate that B. pseudomallei is rarely detected in sputum at this hospital. The low frequency of B. pseudomallei in sputum specimens precludes drawing any conclusions about the relative benefits of an enhanced sputum testing protocol at this site. Promoting clinician awareness of the infection and encouraging utilization of diagnostic microbiology services are likely to be important factors in facilitating identification of melioidosis.
      PubDate: 2014-12-11T16:52:29Z
      DOI: 10.12688/f1000research.5935.1
      Issue No: Vol. 3 (2014)
       
  • Case Report: A case report of Moyamoya disease in a 36 year old African
           American woman [v1; indexed, http://f1000r.es/4tx]

    • Authors: Rohit Kumar Gudepu, Mohtashim A. Qureshi, Ihtesham A. Qureshi, Lakshman Rao
      Abstract: Moyamoya is a rare idiopathic progressive vaso-occlusive disease characterized by irreversible condition of main blood vessels to the brain as they enter into the skull. We present a case of 36 year old African American female presenting to the Out Patient Clinic with headache which were on and off for 4-6 months and did not relieve on routine medical therapy. It was associated with weakness on right side for last few days. The patient was investigated with CT Angiogram, diagnosed as Moyamoya disease and operated. She has been followed up for the last 5 years and the patient has not complained of any headaches or focal neurological symptoms.
      PubDate: 2014-12-08T17:12:45Z
      DOI: 10.12688/f1000research.5859.1
      Issue No: Vol. 3 (2014)
       
  • Slow progression of exudative age related macular degeneration associated
           with hypertrophy of the retinal pigment epithelium [v1; indexed,
           http://f1000r.es/4or]

    • Authors: Jeffrey Stern, David Eveleth, Jennifer Masula, Sally Temple
      Abstract: Rationale:  Choroidal neovascular (CNV) lesions in younger patients are often accompanied by the appearance of a surrounding ring of pigment that is associated with disease regression or slowed disease progression. In older patients with age-related macular degeneration (AMD), however, hypertrophy of the retinal pigment epithelium (RPE) is known to occur but has not previously been reported to be associated with CNV regression. This report describes the clinical course of a case series of AMD patients with pigment hypertrophy adjacent to CNV associated with stabilization of the CNV lesion. Methods: A retrospective analysis of exudative AMD patients seen by a single retina specialist over a 7-year period. Results: Retrospective analysis of 955 exudative AMD patients revealed pigment hypertrophy associated with CNV in 33 patients. A ring of pigment surrounded CNV in 6 of these. Three representative patients are presented to illustrate the decrease in macular edema, reduced fluorescein leakage and slowed CNV progression that was associated with a pigment ring around CNV in AMD. Pigment hypertrophy was associated with blocked fluorescein leakage and exudative AMD patients with a complete pigment ring maintained stable visual acuity, macular edema, fluorescein leakage and CNV lesion size without treatment for intervals of up to 21 months.  Conclusion:  We report slowed disease progression in AMD patients who develop pigment around CNV. The slow rate of disease progression in the AMD patient subgroup having a pigment ring is a factor to consider in determining the treatment interval for exudative AMD patients.
      PubDate: 2014-12-02T16:45:22Z
      DOI: 10.12688/f1000research.5683.1
      Issue No: Vol. 3 (2014)
       
  • ABS–Scan: In silico alanine scanning mutagenesis for binding
           site residues in protein–ligand complex [v2; indexed,
           http://f1000r.es/4sf]

    • Authors: Praveen Anand, Deepesh Nagarajan, Sumanta Mukherjee, Nagasuma Chandra
      Abstract: Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are calculated by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide a ranked list of residues to the user in order to obtain loss-of-function mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.
      PubDate: 2014-12-01T16:05:37Z
      DOI: 10.12688/f1000research.5165.2
      Issue No: Vol. 3 (2014)
       
  • Interpretation of mRNA splicing mutations in genetic disease: review of
           the literature and guidelines for information-theoretical analysis [v1;
           indexed, http://f1000r.es/4nq]

    • Authors: Natasha Caminsky, Eliseos J. Mucaki, Peter K. Rogan
      Abstract: The interpretation of genomic variants has become one of the paramount challenges in the post-genome sequencing era. In this review we summarize nearly 20 years of research on the applications of information theory (IT) to interpret coding and non-coding mutations that alter mRNA splicing in rare and common diseases. We compile and summarize the spectrum of published variants analyzed by IT, to provide a broad perspective of the distribution of deleterious natural and cryptic splice site variants detected, as well as those affecting splicing regulatory sequences. Results for natural splice site mutations can be interrogated dynamically with Splicing Mutation Calculator, a companion software program that computes changes in information content for any splice site substitution, linked to corresponding publications containing these mutations. The accuracy of IT-based analysis was assessed in the context of experimentally validated mutations. Because splice site information quantifies binding affinity, IT-based analyses can discern the differences between variants that account for the observed reduced (leaky) versus abolished mRNA splicing. We extend this principle by comparing predicted mutations in natural, cryptic, and regulatory splice sites with observed deleterious phenotypic and benign effects. Our analysis of 1727 variants revealed a number of general principles useful for ensuring portability of these analyses and accurate input and interpretation of mutations. We offer guidelines for optimal use of IT software for interpretation of mRNA splicing mutations.
      PubDate: 2014-11-18T14:11:04Z
      DOI: 10.12688/f1000research.5654.1
      Issue No: Vol. 3 (2014)
       
  • Diversity of two-component systems: insights into the signal transduction
           mechanism by the Staphylococcus aureus two-component system GraSR
           [v2; indexed, http://f1000r.es/4qf]

    • Authors: Uzma Muzamal, Daniel Gomez, Fenika Kapadia, Dasantila Golemi-Kotra
      Abstract: The response to cationic antimicrobial peptides (CAMPs) in Staphylococcus aureus relies on a two-component system (TCS), GraSR, an auxiliary protein GraX and an ATP-binding cassette (ABC) transporter, VraF/G. To understand the signal transduction mechanism by GraSR, we investigated the kinase activity of the cytoplasmic domain of histidine kinase GraS and the interaction with its cognate response regulator GraR. We also investigated interactions among the auxiliary protein GraX, GraS/R and the ATPase protein of the ABC transporter, VraF. We found that GraS lacks autophosphorylation activity, unlike a similar histidine kinase, BceS, of Bacillus subtilis. In addition, the interaction between GraS and GraR is very weak in comparison to the stronger interaction observed between BceS and its conjugated response regulator, BceR, suggesting that CAMP signaling may not flow directly from GraS to GraR. We found that the auxiliary protein GraX interacts with VraF and GraR, and requires the histidine phosphotransfer and dimerization domain of GraS to interact with this protein. Further, VraF requires the GraS region that connects the membrane-bound domain with the cytoplasmic domain of this protein for interaction with GraS. The interactions of GraX with GraS/R and VraF indicate that GraX may serve as a scaffold to bring these proteins in close proximity to GraS, plausibly to facilitate activation of GraS to ultimately transduce the signal to GraR.
      PubDate: 2014-11-17T16:57:50Z
      DOI: 10.12688/f1000research.5512.2
      Issue No: Vol. 3 (2014)
       
  • Collaboration for rare disease drug discovery research [v1; indexed,
           http://f1000r.es/4l6]

    • Authors: Nadia K. Litterman, Michele Rhee, David C. Swinney, Sean Ekins
      Abstract: Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives.
      PubDate: 2014-10-31T12:38:53Z
      DOI: 10.12688/f1000research.5564.1
      Issue No: Vol. 3 (2014)
       
  • Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous
           for G6PD A- [v2; indexed, http://f1000r.es/4kn]

    • Authors: Nieves Perdigones, Mariela Morales, Philip Mason, Monica Bessler
      Abstract: We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A-   (G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene.  PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol (GPI)  anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode.
      PubDate: 2014-10-21T15:12:41Z
      DOI: 10.12688/f1000research.4980.2
      Issue No: Vol. 3 (2014)
       
  • Case Report: Bilateral diaphragmatic dysfunction due to Borrelia
           Burgdorferi [v1; indexed, http://f1000r.es/4fe]

    • Authors: Suhail Basunaid, Chris van der Grinten, Nicole Cobben, Astrid Otte, Roy Sprooten, Rohde Gernot
      Abstract: Summary: In this case report we describe a rare case of bilateral diaphragmatic dysfunction due to Lyme disease. Case report: A 62-years-old male presented to the hospital because of flu-like symptoms. During initial evaluation a bilateral diaphragmatic weakness with orthopnea and nocturnal hypoventilation was observed, without a known aetiology. Bilateral diaphragmatic paralysis was confirmed by fluoroscopy with a positive sniff test. The patient was referred to our centre for chronic non-invasive nocturnal ventilation (cNPPV). Subsequent investigations revealed evidence of anti-Borrelia seroactivity in EIA-IgG and IgG-blot, suggesting a recent infection with Lyme disease, and resulted in a 4-week treatment with oral doxycycline. The symptoms of nocturnal hypoventilation were successfully improved with cNPPV. However, our patient still shows impaired diaphragmatic function but he is no longer fully dependent on nocturnal ventilatory support.     Conclusion: Lyme disease should be considered in the differential diagnosis of diaphragmatic dysfunction. It is a tick-borne illness caused by one of the three pathogenic species of the spirochete Borrelia burgdorferi, present in Europe. A delay in recognizing the symptoms can negatively affect the success of treatment. Non-invasive mechanical ventilation (NIV) is considered a treatment option for patients with diaphragmatic paralysis.
      PubDate: 2014-10-06T15:11:34Z
      DOI: 10.12688/f1000research.5375.1
      Issue No: Vol. 3 (2014)
       
  • Preoperative low-dose ketamine has no preemptive analgesic effect in
           opioid-naïve patients undergoing colon surgery when nitrous oxide is
           used - a randomized study [v1; indexed, http://f1000r.es/4bp]

    • Authors: Beatriz Nistal-Nuño, Enrique Freire-Vila, Francisco Castro-Seoane, Manuel Camba-Rodriguez
      Abstract: Background: The analgesic properties of ketamine are associated with its non-competitive antagonism of the N-methyl-D-aspartate receptor; these receptors exhibit an excitatory function on pain transmission and this binding seems to inhibit or reverse the central sensitization of pain. In the literature, the value of this anesthetic for preemptive analgesia in the control of postoperative pain is uncertain. The objective of this study was to ascertain whether preoperative low-dose ketamine reduces postoperative pain and morphine consumption in adults undergoing colon surgery. Methods: In a double-blind, randomized trial, 48 patients were studied. Patients in the ketamine group received 0.5 mg/kg intravenous ketamine before surgical incision, while the control group received normal saline. The postoperative analgesia was achieved with a continuous infusion of morphine at 0.015 mg∙kgˉ¹∙hˉ¹ with the possibility of 0.02 mg/kg bolus every 10 min. Pain was assessed using the Visual Analog Scale (VAS), morphine consumption, and hemodynamic parameters at 0, 1, 2, 4, 8, 12, 16, and 24 hours postoperatively. We quantified times to rescue analgesic (Paracetamol), adverse effects and patient satisfaction. Results: No significant differences were observed in VAS scores between groups (P>0.05), except at 4 hours postoperatively (P=0.040). There were no differences in cumulative consumption of morphine at any time point (P>0.05). We found no significant differences in incremental postoperative doses of morphine consumption in bolus, except at 12 h (P =0.013) and 24 h (P =0.002). The time to first required rescue analgesia was 70 ± 15.491 min in the ketamine group and 44 ± 19.494 min in the control (P>0.05). There were no differences in hemodynamic parameters or patient satisfaction (P>0.05). Conclusions: Preoperative low-dose-ketamine did not show a preemptive analgesic effect or efficacy as an adjuvant for decreasing opioid requirements for postoperative pain in patients receiving intravenous analgesia with morphine after colon surgery.
      PubDate: 2014-09-23T15:38:29Z
      DOI: 10.12688/f1000research.5258.1
      Issue No: Vol. 3 (2014)
       
  • An object oriented implementation of the Yeadon human inertia model [v1;
           indexed, http://f1000r.es/4cr]

    • Authors: Christopher Dembia, Jason K. Moore, Mont Hubbard
      Abstract: We present an open source software implementation of a popular mathematical method developed by M.R. Yeadon for calculating the body and segment inertia parameters of a human body. The software is written in a high level open source language and provides three interfaces for manipulating the data and the model: a Python API, a command-line user interface, and a graphical user interface. Thus the software can fit into various data processing pipelines and requires only simple geometrical measures as input.
      PubDate: 2014-09-17T11:01:52Z
      DOI: 10.12688/f1000research.5292.1
      Issue No: Vol. 3 (2014)
       
  • Directed evolution induces tributyrin hydrolysis in a virulence factor of
           Xylella fastidiosa using a duplicated gene as a template [v1; indexed,
           http://f1000r.es/48i]

    • Authors: Hossein Gouran, Sandeep Chakraborty, Basuthkar J. Rao, Bjarni Asgeirsson, Abhaya Dandekar
      Abstract: Duplication of genes is one of the preferred ways for natural selection to add advantageous functionality to the genome without having to reinvent the wheel with respect to catalytic efficiency and protein stability. The duplicated secretory virulence factors of Xylella fastidiosa (LesA, LesB and LesC), implicated in Pierce's disease of grape and citrus variegated chlorosis of citrus species, epitomizes the positive selection pressures exerted on advantageous genes in such pathogens. A deeper insight into the evolution of these lipases/esterases is essential to develop resistance mechanisms in transgenic plants. Directed evolution, an attempt to accelerate the evolutionary steps in the laboratory, is inherently simple when targeted for loss of function. A bigger challenge is to specify mutations that endow a new function, such as a lost functionality in a duplicated gene. Previously, we have proposed a method for enumerating candidates for mutations intended to transfer the functionality of one protein into another related protein based on the spatial and electrostatic properties of the active site residues (DECAAF). In the current work, we present in vivo validation of DECAAF by inducing tributyrin hydrolysis in LesB based on the active site similarity to LesA. The structures of these proteins have been modeled using RaptorX based on the closely related LipA protein from Xanthomonas oryzae. These mutations replicate the spatial and electrostatic conformation of LesA in the modeled structure of the mutant LesB as well, providing in silico validation before proceeding to the laborious in vivo work. Such focused mutations allows one to dissect the relevance of the duplicated genes in finer detail as compared to gene knockouts, since they do not interfere with other moonlighting functions, protein expression levels or protein-protein interaction.
      PubDate: 2014-09-09T09:47:05Z
      DOI: 10.12688/f1000research.5147.1
      Issue No: Vol. 3 (2014)
       
  • High-Performance Mixed Models Based Genome-Wide Association Analysis with
           omicABEL software [v1; indexed, http://f1000r.es/40b]

    • Authors: Diego Fabregat-Traver, Sodbo Zh. Sharapov, Caroline Hayward, Igor Rudan, Harry Campbell, Yurii Aulchenko, Paolo Bientinesi
      Abstract: To raise the power of genome-wide association studies (GWAS) and avoid false-positive results in structured populations, one can rely on mixed model based tests. When large samples are used, and when multiple traits are to be studied in the ’omics’ context, this approach becomes computationally challenging. Here we consider the problem of mixed-model based GWAS for arbitrary number of traits, and demonstrate that for the analysis of single-trait and multiple-trait scenarios different computational algorithms are optimal. We implement these optimal algorithms in a high-performance computing framework that uses state-of-the-art linear algebra kernels, incorporates optimizations, and avoids redundant computations, increasing throughput while reducing memory usage and energy consumption. We show that, compared to existing libraries, our algorithms and software achieve considerable speed-ups. The OmicABEL software described in this manuscript is available under the GNU GPL v. 3 license as part of the GenABEL project for statistical genomics at http: //www.genabel.org/packages/OmicABEL.
      PubDate: 2014-08-20T16:25:58Z
      DOI: 10.12688/f1000research.4867.1
      Issue No: Vol. 3 (2014)
       
  • Dynamin1 concentration in the prefrontal cortex is associated with
           cognitive impairment in Lewy body dementia [v1; indexed,
           http://f1000r.es/34n]

    • Authors: Julie Vallortigara, Sindhoo Rangarajan, David Whitfield, Amani Alghamdi, David Howlett, Tibor Hortobágyi, Mary Johnson, Johannes Attems, Clive Ballard, Alan Thomas, John O’Brien, Dag Aarsland, Paul Francis
      Abstract: Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer’s disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies). Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.
      PubDate: 2014-05-13T16:00:35Z
      DOI: 10.12688/f1000research.3786.1
      Issue No: Vol. 3 (2014)
       
 
 
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