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Journal Cover F1000Research
  [SJR: 0.56]   [H-I: 9]   [4 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • STAT5 and CD4+ T Cell Immunity [version 1; referees: 4 approved]

    • Authors: David L. Owen, Michael A. Farrar
      Abstract: STAT5 plays a critical role in the development and function of many cell types. Here, we review the role of STAT5 in the development of T lymphocytes in the thymus and its subsequent role in the differentiation of distinct CD4+ helper and regulatory T-cell subsets.
      PubDate: 2017-01-11T14:02:11Z
      DOI: 10.12688/f1000research.9838.1
      Issue No: Vol. 6 (2017)
       
  • biojs-io-biom, a BioJS component for handling data in Biological
           Observation Matrix (BIOM) format [version 2; referees: 1 approved, 2
           approved with reservations]

    • Authors: Markus J. Ankenbrand, Niklas Terhoeven, Sonja Hohlfeld, Frank Förster, Alexander Keller
      Abstract: The Biological Observation Matrix (BIOM) format is widely used to store data from high-throughput studies. It aims at increasing interoperability of bioinformatic tools that process this data. However, due to multiple versions and implementation details, working with this format can be tricky. Currently, libraries in Python, R and Perl are available, whilst such for JavaScript are lacking. Here, we present a BioJS component for parsing BIOM data in all format versions. It supports import, modification, and export via a unified interface. This module aims to facilitate the development of web applications that use BIOM data. Finally, we demonstrate its usefulness by two applications that already use this component. Availability: https://github.com/molbiodiv/biojs-io-biom, https://dx.doi.org/10.5281/zenodo.218277
      PubDate: 2017-01-09T14:33:01Z
      DOI: 10.12688/f1000research.9618.2
      Issue No: Vol. 5 (2017)
       
  • Molecular underpinnings of neurodegenerative disorders: striatal-enriched
           protein tyrosine phosphatase signaling and synaptic plasticity [version 1;
           referees: 3 approved]

    • Authors: Paul J. Lombroso, Marilee Ogren, Pradeep Kurup, Angus C. Nairn
      Abstract: This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer’s and Parkinson’s disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity.
      PubDate: 2016-12-29T16:56:54Z
      DOI: 10.12688/f1000research.8571.1
      Issue No: Vol. 5 (2016)
       
  • Advances in urethral stricture management [version 1; referees: 4
           approved]

    • Authors: Maxx A. Gallegos, Richard A. Santucci
      Abstract: Urethral stricture/stenosis is a narrowing of the urethral lumen. These conditions greatly impact the health and quality of life of patients. Management of urethral strictures/stenosis is complex and requires careful evaluation. The treatment options for urethral stricture vary in their success rates. Urethral dilation and internal urethrotomy are the most commonly performed procedures but carry the lowest chance for long-term success (0–9%). Urethroplasty has a much higher chance of success (85–90%) and is considered the gold-standard treatment. The most common urethroplasty techniques are excision and primary anastomosis and graft onlay urethroplasty. Anastomotic urethroplasty and graft urethroplasty have similar long-term success rates, although long-term data have yet to confirm equal efficacy. Anastomotic urethroplasty may have higher rates of sexual dysfunction. Posterior urethral stenosis is typically caused by previous urologic surgery. It is treated endoscopically with radial incisions. The use of mitomycin C may decrease recurrence. An exciting area of research is tissue engineering and scar modulation to augment stricture treatment. These include the use of acellular matrices or tissue-engineered buccal mucosa to produce grafting material for urethroplasty. Other experimental strategies aim to prevent scar formation altogether.
      PubDate: 2016-12-23T15:51:24Z
      DOI: 10.12688/f1000research.9741.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding neutrophils [version 1; referees: 2
           approved]

    • Authors: Justin F. Deniset, Paul Kubes
      Abstract: Neutrophils have long been regarded as key effectors of the innate immune response during acute inflammation. Recent evidence has revealed a greater functional diversity for these cells than previously appreciated, expanding roles for neutrophils in adaptive immunity and chronic pathologies. In this review, we summarize some of the evolving paradigms in the neutrophil field and highlight key advances that have contributed to our understanding of neutrophil behavior and function in vivo. We examine the concept of neutrophil subsets and polarization, we discuss novel immunomodulatory roles for neutrophils in shaping the immune response, and, finally, we identify technical advances that will further enhance our ability to track the function and fate of neutrophils.
      PubDate: 2016-12-23T14:52:24Z
      DOI: 10.12688/f1000research.9691.1
      Issue No: Vol. 5 (2016)
       
  • Recapitulating phylogenies using k-mers: from trees to networks [version
           2; referees: 2 approved]

    • Authors: Guillaume Bernard, Mark A. Ragan, Cheong Xin Chan
      Abstract: Ernst Haeckel based his landmark Tree of Life on the supposed ontogenic recapitulation of phylogeny, i.e. that successive embryonic stages during the development of an organism re-trace the morphological forms of its ancestors over the course of evolution. Much of this idea has since been discredited. Today, phylogenies are often based on families of molecular sequences. The standard approach starts with a multiple sequence alignment, in which the sequences are arranged relative to each other in a way that maximises a measure of similarity position-by-position along their entire length. A tree (or sometimes a network) is then inferred. Rigorous multiple sequence alignment is computationally demanding, and evolutionary processes that shape the genomes of many microbes (bacteria, archaea and some morphologically simple eukaryotes) can add further complications. In particular, recombination, genome rearrangement and lateral genetic transfer undermine the assumptions that underlie multiple sequence alignment, and imply that a tree-like structure may be too simplistic. Here, using genome sequences of 143 bacterial and archaeal genomes, we construct a network of phylogenetic relatedness based on the number of shared k-mers (subsequences at fixed length k). Our findings suggest that the network captures not only key aspects of microbial genome evolution as inferred from a tree, but also features that are not treelike. The method is highly scalable, allowing for investigation of genome evolution across a large number of genomes. Instead of using specific regions or sequences from genome sequences, or indeed Haeckel’s idea of ontogeny, we argue that genome phylogenies can be inferred using k-mers from whole-genome sequences. Representing these networks dynamically allows biological questions of interest to be formulated and addressed quickly and in a visually intuitive manner.
      PubDate: 2016-12-23T14:23:15Z
      DOI: 10.12688/f1000research.10225.2
      Issue No: Vol. 5 (2016)
       
  • Agents to reduce cytokine storm [version 1; referees: 3 approved]

    • Authors: Herwig Gerlach
      Abstract: The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term “cytokine storm” in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock.
      PubDate: 2016-12-22T16:57:28Z
      DOI: 10.12688/f1000research.9092.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding antiphospholipid syndrome [version 1;
           referees: 2 approved]

    • Authors: Maria Laura Bertolaccini, Giovanni Sanna
      Abstract: Antiphospholipid syndrome (APS), also known as Hughes Syndrome, is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. A patient with APS must meet at least one of two clinical criteria (vascular thrombosis or complications of pregnancy) and at least one of two laboratory criteria including the persistent presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and/or anti-b2 glycoprotein I (anti-b2GPI) antibodies of IgG or IgM isotype at medium to high titres in patient’s plasma. However, several other autoantibodies targeting other coagulation cascade proteins (i.e. prothrombin) or their complex with phospholipids (i.e. phosphatidylserine/prothrombin complex), or to some domains of β2GPI, have been proposed to be also relevant to APS. In fact, the value of testing for new aPL specificities in the identification of APS in thrombosis and/or pregnancy morbidity patients is currently being investigated.
      PubDate: 2016-12-22T16:54:38Z
      DOI: 10.12688/f1000research.9717.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in the management of liposarcoma [version 1; referees: 2
           approved]

    • Authors: Nadar A. Nassif, William Tseng, Camille Borges, Peter Chen, Burton Eisenberg
      Abstract: Liposarcoma is the most common soft tissue sarcoma. With its various subtypes, the natural history of this disease can vary significantly from a locally recurrent tumor to a highly malignant one carrying a poor prognosis. Progress in the understanding of the specific molecular abnormalities in liposarcoma provides greater opportunity for new treatment modalities. Although surgical resection and radiation therapy remain the keystones for the management of primary liposarcoma, the inclusion of novel agents that target known abnormalities in advanced liposarcoma enhances the potential for improved outcomes.
      PubDate: 2016-12-22T16:35:12Z
      DOI: 10.12688/f1000research.10050.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding and managing chordomas [version 1;
           referees: 2 approved]

    • Authors: Carl Youssef, Salah Aoun, Jessica R. Moreno, Carlos A. Bagley
      Abstract: Chordomas are rare primary bone tumors arising from embryonic remnants of the notochord. They are slow-growing, locally aggressive, and destructive and typically involve the axial skeleton. Genetic studies have identified several mutations implicated in the pathogenesis of these tumors. Treatment poses a challenge given their insidious progression, degree of local invasion at presentation, and high recurrence rate. They tend to respond poorly to conventional chemotherapy and radiation. This makes radical resection the mainstay of their treatment. Recent advances in targeted chemotherapy and focused particle beam radiation, however, have improved the management and prognosis of these tumors.
      PubDate: 2016-12-22T11:24:43Z
      DOI: 10.12688/f1000research.9499.1
      Issue No: Vol. 5 (2016)
       
  • Respiratory syncytial virus infection: an innate perspective [version 1;
           referees: 4 approved]

    • Authors: Cecilia Johansson
      Abstract: Respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in children and adults. However, infection with this virus sometimes leads to severe lower respiratory disease and is the major cause of infant hospitalisations in the developed world. Several risk factors such as baby prematurity and congenital heart disease are known to predispose towards severe disease but previously healthy, full-term infants can also develop bronchiolitis and viral pneumonia during RSV infection. The causes of severe disease are not fully understood but may include dysregulation of the immune response to the virus, resulting in excessive recruitment and activation of innate and adaptive immune cells that can cause damage. This review highlights recent discoveries on the balancing act of immune-mediated virus clearance versus immunopathology during RSV infection.
      PubDate: 2016-12-21T16:49:43Z
      DOI: 10.12688/f1000research.9637.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding and managing Crohn’s disease [version
           1; referees: 4 approved]

    • Authors: Eduard F. Stange, Jan Wehkamp
      Abstract: There is consensus that inflammatory bowel diseases (IBDs) are the result of “dysregulated” immune reactivity towards commensal microorganisms in the intestine. This gut microbiome is clearly altered in IBD, but its primary or secondary role is still debated. The focus has shifted from adaptive to innate immunity, with its multitude of receptor molecules (Toll-like and NOD receptors) and antibacterial effector molecules (defensins, cathelicidin, and others). The latter appear to be at least partly deficient at different intestinal locations. Host genetics also support the notion that microbe–host interaction at the mucosa is the prime site of pathogenesis. In contrast, even the latest therapeutic antibodies are directed against secondary targets like cytokines and integrins identified decades ago. These so-called “biologicals” have disappointing long-term results, with the majority of patients not achieving remission in the long run. A promising approach is the development of novel drugs like defensin-derived molecules that substitute for the missing endogenous antibacterials.
      PubDate: 2016-12-21T16:06:02Z
      DOI: 10.12688/f1000research.9890.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding and managing liver transplantation
           [version 1; referees: 3 approved]

    • Authors: Francesco Paolo Russo, Alberto Ferrarese, Alberto Zanetto
      Abstract: Liver transplantation (LT) has been established as the most effective treatment modality for end-stage liver disease over the last few decades. Currently, patient and graft survival after LT are excellent, with 1- and 5-year survival of 90% and 80%, respectively. However, the timing of referral to LT is crucial for improving survival benefit and outcome. The current shortage of donors and the increasing demand for LT currently lengthen the waiting time. Thus, waiting list mortality is about 10–15%, according to the geographical area. For this reason, over the last several years, alternatives to deceased donor LT and new options for prioritizing patients on the waiting list have been proposed.
      PubDate: 2016-12-21T16:03:27Z
      DOI: 10.12688/f1000research.8768.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding photosynthesis [version 1; referees: 3
           approved]

    • Authors: Ulf-Ingo Flügge, Peter Westhoff, Dario Leister
      Abstract: Photosynthesis is central to all life on earth, providing not only oxygen but also organic compounds that are synthesized from atmospheric CO2 and water using light energy as the driving force. The still-increasing world population poses a serious challenge to further enhance biomass production of crop plants. Crop yield is determined by various parameters, inter alia by the light energy conversion efficiency of the photosynthetic machinery. Photosynthesis can be looked at from different perspectives: (i) light reactions and carbon assimilation, (ii) leaves and canopy structure, and (ii) source-sink relationships. In this review, we discuss opportunities and prospects to increase photosynthetic performance at the different layers, taking into account the recent progress made in the respective fields.
      PubDate: 2016-12-21T12:15:11Z
      DOI: 10.12688/f1000research.9744.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in understanding Lynch syndrome [version 1; referees: 3
           approved]

    • Authors: Sherief Shawki, Matthew F. Kalady
      Abstract: Colorectal cancer affects about 4.4% of the population and is a leading cause of cancer-related death in the United States. Approximately 10% to 20% of cases occur within a familial pattern, and Lynch syndrome is the most common hereditary colorectal cancer syndrome. Lynch syndrome is a hereditary predisposition to forming colorectal and extracolonic cancers, caused by a germline mutation in one of the DNA mismatch repair genes. Identifying at-risk patients and making a correct diagnosis are the keys to successful screening and interventions which will decrease formation of and death from cancers. Knowledge of the genetics and the natural history of Lynch syndrome has continued to be uncovered in recent years, leading to a better grasp on how these patients and their families should be managed. Recent developments include the approach to diagnostic testing, more precise definitions of the syndrome and risk stratification based on gene mutations, surgical decision-making, and chemoprevention.
      PubDate: 2016-12-21T11:29:00Z
      DOI: 10.12688/f1000research.9654.1
      Issue No: Vol. 5 (2016)
       
  • Recent advances in the understanding and management of atrial
           fibrillation: a focus on stroke prevention [version 1; referees: 3
           approved]

    • Authors: Farhan Shahid, Eduard Shantsila, Gregory Y. H. Lip
      Abstract: Atrial fibrillation (AF) is associated with an increased risk of stroke compared with the general population. It is anticipated that by 2030 an estimated 14–17 million patients will be diagnosed with this most prevalent arrhythmia within the European Union. AF-related stroke confers a higher mortality and morbidity risk, and thus early detection and assessment for the initiation of effective stroke prevention with oral anticoagulation (OAC) is crucial. Recent guidelines point to the use of non-vitamin K antagonist OACs (NOACs) where appropriate in stroke prevention of patients with non-valvular AF. At present, there are four NOACS available, with no direct head-to-head comparisons to suggest the superiority of one drug over another. Simple and practical risk assessment tools have evolved over the years to facilitate stroke and bleeding risk assessment in busy clinics and wards to aid decision-making. At present, the CHA2DS2VASc (congestive heart failure, hypertension, age 65–74/>75, diabetes mellitus, stroke/transient ischemic attack/thromboembolism, vascular disease, female sex) score is recommended by many international guidelines as a simple and practical method of assessing stroke risk in such patients. Alongside this, use of the HAS BLED (hypertension systolic blood pressure >160 mmHg, abnormal liver/renal function [with creatinine ≥200 μmol/L], stroke, bleeding history or predisposition, labile international normalized ratio [range 65], concomitant drugs/alcohol) score aims to identify patients at high risk of bleeding for more regular review and follow-up and draws attention to potentially reversible bleeding risk factors. The aim of this review article is to provide an overview of recent advances in the understanding and management of AF with a focus on stroke prevention.
      PubDate: 2016-12-20T16:34:19Z
      DOI: 10.12688/f1000research.10176.1
      Issue No: Vol. 5 (2016)
       
  • New discoveries in the molecular landscape of bladder cancer [version 1;
           referees: 2 approved]

    • Authors: Roger Li, Woonyoung Choi, J.E. Ferguson 3rd, Michael J. Metcalfe, Ashish M. Kamat
      Abstract: We are currently on the cusp of exponential growth in the understanding of the molecular landscape of bladder cancer. Emerging data regarding the mutational burden and targetable genomic and protein alterations in bladder cancer have allowed us to tap into treatments directed toward specific molecular characteristics of bladder cancer. In parallel, these developments will enable us to better select patients for existing treatments of bladder cancer in a step toward personalized therapy. The present article reviews select discoveries that have advanced our understanding of bladder cancer and gives a glimpse of the exciting opportunities on the not-so-distant horizon.
      PubDate: 2016-12-19T14:34:36Z
      DOI: 10.12688/f1000research.10031.1
      Issue No: Vol. 5 (2016)
       
  • Hemodynamic monitoring in the critically ill: an overview of current
           cardiac output monitoring methods [version 1; referees: 3 approved]

    • Authors: Johan Huygh, Yannick Peeters, Jelle Bernards, Manu L. N. G. Malbrain
      Abstract: Critically ill patients are often hemodynamically unstable (or at risk of becoming unstable) owing to hypovolemia, cardiac dysfunction, or alterations of vasomotor function, leading to organ dysfunction, deterioration into multi-organ failure, and eventually death. With hemodynamic monitoring, we aim to guide our medical management so as to prevent or treat organ failure and improve the outcomes of our patients. Therapeutic measures may include fluid resuscitation, vasopressors, or inotropic agents. Both resuscitation and de-resuscitation phases can be guided using hemodynamic monitoring. This monitoring itself includes several different techniques, each with its own advantages and disadvantages, and may range from invasive to less- and even non-invasive techniques, calibrated or non-calibrated. This article will discuss the indications and basics of monitoring, further elaborating on the different techniques of monitoring.
      PubDate: 2016-12-16T16:26:33Z
      DOI: 10.12688/f1000research.8991.1
      Issue No: Vol. 5 (2016)
       
  • Preliminary results on the control of Aedes spp. in a remote Guatemalan
           community vulnerable to dengue, chikungunya and Zika virus: community
           participation and use of low-cost ecological ovillantas for mosquito
           control [version 2; referees: 1 approved, 3 approved with reservations]

    • Authors: Gerard Ulibarri, Angel Betanzos, Mireya Betanzos, Juan Jacobo Rojas
      Abstract: Objective: To study the effectiveness of an integrated intervention of health worker training, a low-cost ecological mosquito ovitrap, and community engagement on Aedes spp. mosquito control over 10 months in 2015 in an urban remote community in Guatemala at risk of dengue, chikungunya and Zika virus transmission. Methods: We implemented a three-component integrated intervention consisting of: web-based training of local health personnel in vector control, cluster-randomized assignment of an ecological modified ovitrap (ovillantas: ovi=egg, llanta=tire) or standard ovitraps to capture Aedes spp. mosquito eggs (no efforts have been taken to determine the exact Aedes species at this moment), and community engagement to promote participation of community members and health personnel in the understanding and maintenance of ovitraps for mosquito control. The intervention was implemented in local collaboration with Guatemala’s  Ministry of Health’s Vector Control Programme, and in international collaboration with the National Institute of Public Health in Mexico. Findings: Eighty percent of the 25 local health personnel enrolled in the training programme received accreditation of their improved knowledge of vector control. When ovillantas were used in a cluster of ovitraps (several in proximity), significantly more eggs were trapped by  ecological ovillantas than standard ovitraps over the 10 month (42 week) study period (t=5.2577; p
      PubDate: 2016-12-16T14:57:40Z
      DOI: 10.12688/f1000research.8461.2
      Issue No: Vol. 5 (2016)
       
  • Remote ischaemic preconditioning: closer to the mechanism' [version 1;
           referees: 3 approved]

    • Authors: Jonathan M. Gleadle, Annette Mazzone
      Abstract: Brief periods of ischaemia followed by reperfusion of one tissue such as skeletal muscle can confer subsequent protection against ischaemia-induced injury in other organs such as the heart. Substantial evidence of this effect has been accrued in experimental animal models. However, the translation of this phenomenon to its use as a therapy in ischaemic disease has been largely disappointing without clear evidence of benefit in humans. Recently, innovative experimental observations have suggested that remote ischaemic preconditioning (RIPC) may be largely mediated through hypoxic inhibition of the oxygen-sensing enzyme PHD2, leading to enhanced levels of alpha-ketoglutarate and subsequent increases in circulating kynurenic acid (KYNA). These observations provide vital insights into the likely mechanisms of RIPC and a route to manipulating this mechanism towards therapeutic benefit by direct alteration of KYNA, alpha-ketoglutarate levels, PHD inhibition, or pharmacological targeting of the incompletely understood cardioprotective mechanism activated by KYNA.
      PubDate: 2016-12-13T11:04:44Z
      DOI: 10.12688/f1000research.9633.1
      Issue No: Vol. 5 (2016)
       
  • Candida antifungal drug resistance in sub-Saharan African populations: A
           systematic review [version 1; referees: 2 approved]

    • Authors: Charlene Wilma Joyce Africa, Pedro Miguel dos Santos Abrantes
      Abstract: Background: Candida infections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection. Objectives: This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa. Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinical Candida isolates from sub-Saharan African countries using Pubmed and Google Scholar. Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences in Candida species prevalence and resistance patterns were identified. Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected by Candida drug resistance.  Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the high Candida drug resistance levels seen to be emerging in sub-Saharan Africa.
      PubDate: 2016-12-08T12:39:07Z
      DOI: 10.12688/f1000research.10327.1
      Issue No: Vol. 5 (2016)
       
  • Selective inhibition of ASIC1a confers functional and morphological
           neuroprotection following traumatic spinal cord injury [version 2;
           referees: 2 approved]

    • Authors: Liam M. Koehn, Natassya M. Noor, Qing Dong, Sing-Yan Er, Lachlan D. Rash, Glenn F. King, Katarzyna M. Dziegielewska, Norman R. Saunders, Mark D. Habgood
      Abstract: Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a “treatment window” through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.
      PubDate: 2016-12-07T11:33:06Z
      DOI: 10.12688/f1000research.9094.2
      Issue No: Vol. 5 (2016)
       
  • Validation of commercially available sphingosine kinase 2 antibodies for
           use in immunoblotting, immunoprecipitation and immunofluorescence [version
           1; referees: 2 approved]

    • Authors: Heidi A. Neubauer, Stuart M. Pitson
      Abstract: Sphingosine kinase 2 (SK2) is a ubiquitously expressed lipid kinase that has important, albeit complex and poorly understood, roles in regulating cell survival and cell death. In addition to being able to promote cell cycle arrest and apoptosis under certain conditions, it has recently been shown that SK2 can promote neoplastic transformation and tumorigenesis in vivo. Therefore, well validated and reliable tools are required to study and better understand the true functions of SK2. Here, we compare two commercially available SK2 antibodies: a rabbit polyclonal antibody from Proteintech that recognizes amino acids 266-618 of human SK2a, and a rabbit polyclonal antibody from ECM Biosciences that recognizes amino acids 36-52 of human SK2a. We examine the performance of these antibodies for use in immunoblotting, immunoprecipitation and immunofluorescence staining of endogenous SK2, using human HEK293 and HeLa cell lines, as well as mouse embryonic fibroblasts (MEFs). Furthermore, we assess the specificity of these antibodies to the target protein through the use of siRNA-mediated SK2 knockdown and SK2 knockout (Sphk2-/-) MEFs. Our results demonstrate that the Proteintech anti-SK2 antibody reproducibly displayed superior sensitivity and selectivity towards SK2 in immunoblot analyses, while the ECM Biosciences anti-SK2 antibody was reproducibly superior for SK2 immunoprecipitation and detection by immunofluorescence staining. Notably, both antibodies produced non-specific bands and staining in the MEFs, which was not observed with the human cell lines. Therefore, we conclude that the Proteintech SK2 antibody is a valuable reagent for use in immunoblot analyses, and the ECM Biosciences SK2 antibody is a useful tool for SK2 immunoprecipitation and immunofluorescence staining, at least in the human cell lines employed in this study.
      PubDate: 2016-12-06T16:45:47Z
      DOI: 10.12688/f1000research.10336.1
      Issue No: Vol. 5 (2016)
       
  • DRIMSeq: a Dirichlet-multinomial framework for multivariate count outcomes
           in genomics [version 2; referees: 2 approved]

    • Authors: Malgorzata Nowicka, Mark D. Robinson
      Abstract: There are many instances in genomics data analyses where measurements are made on a multivariate response. For example, alternative splicing can lead to multiple expressed isoforms from the same primary transcript. There are situations where differences (e.g. between normal and disease state) in the relative ratio of expressed isoforms may have significant phenotypic consequences or lead to prognostic capabilities. Similarly, knowledge of single nucleotide polymorphisms (SNPs) that affect splicing, so-called splicing quantitative trait loci (sQTL) will help to characterize the effects of genetic variation on gene expression. RNA sequencing (RNA-seq) has provided an attractive toolbox to carefully unravel alternative splicing outcomes and recently, fast and accurate methods for transcript quantification have become available. We propose a statistical framework based on the Dirichlet-multinomial distribution that can discover changes in isoform usage between conditions and SNPs that affect relative expression of transcripts using these quantifications. The Dirichlet-multinomial model naturally accounts for the differential gene expression without losing information about overall gene abundance and by joint modeling of isoform expression, it has the capability to account for their correlated nature. The main challenge in this approach is to get robust estimates of model parameters with limited numbers of replicates. We approach this by sharing information and show that our method improves on existing approaches in terms of standard statistical performance metrics. The framework is applicable to other multivariate scenarios, such as Poly-A-seq or where beta-binomial models have been applied (e.g., differential DNA methylation). Our method is available as a Bioconductor R package called DRIMSeq.
      PubDate: 2016-12-06T11:36:38Z
      DOI: 10.12688/f1000research.8900.2
      Issue No: Vol. 5 (2016)
       
  • COP-eration for global food security [version 1; referees: 2 approved]

    • Authors: Erick de la Barrera
      Abstract: Mexico is hosting the 13th Conference of the Parts (COP-13) on the Convention on Biological Diversity. Participants will have another opportunity to "integrate biodiversity for wellbeing." Considering that food production is a major driver for the loss of biological diversity, despite the fact that ample genetic reservoirs are crucial for the persistence of agriculture in a changing world, food can be a conduit for bringing biodiversity into people's minds and government agendas. If this generation is going to "live in harmony with nature," as the Aichi Biodiversity Targets indicate, such an integration needs to be developed between the agricultural and environmental sectors throughout the world, especially as an increasingly urban civilization severs its cultural connections to food origin.
      PubDate: 2016-12-05T14:14:17Z
      DOI: 10.12688/f1000research.10323.1
      Issue No: Vol. 5 (2016)
       
  • CanVar: A resource for sharing germline variation in cancer patients
           [version 1; referees: 2 approved]

    • Authors: Daniel Chubb, Peter Broderick, Sara E. Dobbins, Richard S. Houlston
      Abstract: The advent of high-throughput sequencing has accelerated our ability to discover genes predisposing to disease and is transforming clinical genomic sequencing. In both contexts knowledge of the spectrum and frequency of genetic variation in the general population and in disease cohorts is vital to the interpretation of sequencing data. While population level data is becoming increasingly available from publicly accessible sources, as exemplified by The Exome Aggregation Consortium (ExAC), the availability of large-scale disease-specific frequency information is limited. These data are of particular importance to contextualise findings from clinical mutation screens and small gene discovery projects. This is especially true for cancer, which is typified by a number of hereditary predisposition syndromes.  Although mutation frequencies in tumours are available from resources such as Cosmic and The Cancer Genome Atlas, a similar facility for germline variation is lacking. Here we present the Cancer Variation Resource (CanVar) an online database which has been developed using the ExAC framework to provide open access to germline variant frequency data from the sequenced exomes of cancer patients. In its first release, CanVar catalogues the exomes of 1,006 familial early-onset colorectal cancer (CRC) patients sequenced at The Institute of Cancer Research. It is anticipated that CanVar will host data for additional cancers, providing a resource for others studying cancer predisposition and an example of how the research community can utilise the ExAC framework to share sequencing data.
      PubDate: 2016-12-05T12:42:56Z
      DOI: 10.12688/f1000research.10058.1
      Issue No: Vol. 5 (2016)
       
  • Updating Darwin: Information and entropy drive the evolution of life
           [version 1; referees: 2 approved]

    • Authors: Irun R. Cohen
      Abstract: The evolution of species, according to Darwin, is driven by struggle – by competition between variant autonomous individuals for survival of the fittest and reproductive advantage; the outcome of this struggle for survival is natural selection. The Neo-Darwinians reframed natural selection in terms of DNA: inherited genotypes directly encode expressed phenotypes; a fit phenotype means a fit genotype – thus the evolution of species is the evolution of selfish, reproducing individual genotypes.              Four general characteristics of advanced forms of life are not easily explained by this Neo-Darwinian paradigm: 1) Dependence on cooperation rather than on struggle, manifested by the microbiome, ecosystems and altruism; 2) The pursuit of diversity rather than optimal fitness, manifested by sexual reproduction; 3) Life’s investment in programmed death, rather then in open-ended survival; and 4) The acceleration of complexity, despite its intrinsic fragility.               Here I discuss two mechanisms that can resolve these paradoxical features; both mechanisms arise from viewing life as the evolution of information. Information has two inevitable outcomes; it increases by autocatalyis and it is destroyed by entropy. On the one hand, the autocalalysis of information inexorably drives the evolution of complexity, irrespective of its fragility. On the other hand, only those strategic arrangements that accommodate the destructive forces of entropy survive – cooperation, diversification, and programmed death result from the entropic selection of evolving species. Physical principles of information and entropy thus fashion the evolution of life.
      PubDate: 2016-12-01T14:11:40Z
      DOI: 10.12688/f1000research.10289.1
      Issue No: Vol. 5 (2016)
       
  • Approaches to R education in Canadian universities [version 1; referees: 1
           approved, 2 approved with reservations]

    • Authors: Michael A. Carson, Nathan Basiliko
      Abstract: Introduction: R language is a powerful tool used in a wide array of research disciplines and owes a large amount of its success to its open source and adaptable nature. The popularity of R has grown rapidly over the past two decades and the number of users and packages is increasing at a near exponential rate. This rapid growth has prompted a number of formal and informal online and text resources, the volume of which is beginning to present challenges to novices learning R. Students are often first exposed to R in upper division undergraduate classes or during their graduate studies. The way R is presented likely has consequences for the fundamental understanding of the program and language itself; user comprehension of R may be better if learning the language itself followed by conducting analyses, compared to someone who is learning another subject (e.g. statistics) using R for the first time. Consequently, an understanding of the approaches to R education is critical. Methods: To establish how students are exposed to R, we used a survey to evaluate the current use in Canadian university courses, including the context in which R is presented and the types of uses of R in the classroom. Additionally, we looked at the reasons professors either do or don’t use/teach R. Results: We found that R is used in a broad range of course disciplines beyond statistics (e.g. ecology) and just over one half of Canadian universities have at least one course that uses R. Discussion and Conclusions: Developing programming-literate students is of utmost importance and our hope is that this benchmark study will influence how post-secondary educators, as well as other programmers, approach R, specifically when developing educational and supplemental content in online, text, and package-specific formats aiding in student’s comprehension of the R language.
      PubDate: 2016-11-30T15:53:44Z
      DOI: 10.12688/f1000research.10232.1
      Issue No: Vol. 5 (2016)
       
  • Dynamics of tRNA fragments and their targets in aging mammalian brain
           [version 1; referees: 2 approved]

    • Authors: Spyros Karaiskos, Andrey Grigoriev
      Abstract: Background: The progress of next-generation sequencing technologies has unveiled various non-coding RNAs that have previously been considered products of random degradation and attracted only minimal interest. Among small RNA families, microRNA (miRNAs) have traditionally been considered key post-transcriptional regulators. However, recent studies have reported evidence for widespread presence of fragments of tRNA molecules (tRFs) across a range of organisms and tissues, and of tRF involvement in Argonaute complexes. Methods:To elucidate potential tRF functionality, we compared available RNA sequencing datasets derived from the brains of young, mid-aged and old rats. Using sliding 7-mer windows along a tRF, we searched for putative seed sequences with high numbers of conserved complementary sites within 3' UTRs of 23 vertebrate genomes. We analyzed Gene Ontology term enrichment of predicted tRF targets and compared their transcript levels with targets of miRNAs in the context of age. Results and Discussion: We detected tRFs originating from 3’- and 5’-ends of tRNAs in rat brains at significant levels. These fragments showed dynamic changes: 3’ tRFs monotonously increased with age, while 5’ tRFs displayed less consistent patterns. Furthermore, 3’ tRFs showed a narrow size range compared to 5’ tRFs, suggesting a difference in their biogenesis mechanisms. Similar to our earlier results in Drosophila and compatible with other experimental findings, we found “seed” sequence locations on both ends of different tRFs. Putative targets of these fragments were found to be enriched in neuronal and developmental functions. Comparison of tRFs and miRNAs increasing in abundance with age revealed small, but distinct changes in brain target transcript levels for these two types of small RNA, with the higher proportion of tRF targets decreasing with age. We also illustrated the utility of tRF analysis for annotating tRNA genes in sequenced genomes.
      PubDate: 2016-11-24T16:29:44Z
      DOI: 10.12688/f1000research.10116.1
      Issue No: Vol. 5 (2016)
       
  • YeATSAM analysis of the walnut and chickpea transcriptome reveals key
           genes undetected by current annotation tools [version 1; referees: 2
           approved, 1 not approved]

    • Authors: Sandeep Chakraborty, Pedro J. Martínez-García, Abhaya M. Dandekar
      Abstract: Background: The transcriptome, a treasure trove of gene space information, remains severely under-used by current genome annotation methods. Methods: Here, we present an annotation method in the YeATS suite (YeATSAM), based on information encoded by the transcriptome, that demonstrates artifacts of the assembler, which must be addressed to achieve proper annotation. Results and Discussion: YeATSAM was applied to the transcriptome obtained from twenty walnut tissues and compared to MAKER-P annotation of the recently published walnut genome sequence (WGS). MAKER-P and YeATSAM both failed to annotate several hundred proteins found by the other. Although many of these unannotated proteins have repetitive sequences (possibly transposable elements), other crucial proteins were excluded by each method. An egg cell-secreted protein and a homer protein were undetected by YeATSAM, although these did not produce any transcripts. Importantly, MAKER-P failed to classify key photosynthesis-related proteins, which we show emanated from Trinity assembly artifacts potentially not handled by MAKER-P. Also, no proteins from the large berberine bridge enzyme (BBE) family were annotated by MAKER-P. BBE is implicated in biosynthesis of several alkaloids metabolites, like anti-microbial berberine. As further validation, YeATSAM identified ~1000 genes that are not annotated in the NCBI database by Gnomon. YeATSAM used a RNA-seq derived chickpea (Cicer arietinum L.) transcriptome assembled using Newbler v2.3. Conclusions: Since the current version of YeATSAM does not have an ab initio module, we suggest a combined annotation scheme using both MAKER-P and YeATSAM to comprehensively and accurately annotate the WGS.
      PubDate: 2016-11-17T16:26:46Z
      DOI: 10.12688/f1000research.10040.1
      Issue No: Vol. 5 (2016)
       
  • Survival prognosis and variable selection: A case study for metastatic
           castrate resistant prostate cancer patients [version 1; referees: 2
           approved]

    • Authors: Søren Wengel Mogensen, Anne H. Petersen, Ann-Sophie Buchardt, Niels Richard Hansen
      Abstract: Survival prognosis is challenging, and accurate prediction of individual survival times is often very difficult. Better statistical methodology and more data can help improve the prognostic models, but it is important that methods and data usages are evaluated properly. The Prostate Cancer DREAM Challenge offered a framework for training and blinded validation of prognostic models using a large and rich dataset on patients diagnosed with metastatic castrate resistant prostate cancer. Using the Prostate Cancer DREAM Challenge data we investigated and compared an array of methods combining imputation techniques of missing values for prognostic variables with tree-based and lasso-based variable selection and model fitting methods. The benchmark metric used was integrated AUC (iAUC), and all methods were benchmarked using cross-validation on the training data as well as via the blinded validation. We found that survival forests without prior variable selection achieved the best overall performance (cv-iAUC = 0.70, validation-iACU = 0.78), while a generalized additive model was best among those methods that used explicit prior variable selection (cv-iAUC = 0.69, validation-iACU = 0.76). Our findings largely concurred with previous results in terms of the choice of important prognostic variables, though we did not find the level of prostate specific antigen to have prognostic value given the other variables included in the data.
      PubDate: 2016-11-16T11:15:36Z
      DOI: 10.12688/f1000research.8427.1
      Issue No: Vol. 5 (2016)
       
  • Surgical proficiency decreases the rate of healing abnormalities using
           anterior transobturator mesh in cystocele women [version 1; referees: 2
           approved]

    • Authors: Jin-Sung Yuk, Yong Jin Kim, Kyong Wook Yi, Jun-Young Hur, Jung-Ho Shin
      Abstract: Aims: The objective of this study is to report the outcomes of cystocele repair with anterior transobutrator mesh kits.  Methods: 119 consecutive women with cystoceles were treated between January 2006 and November 2010 by a single surgeon at a university hospital using the anterior transobturator mesh kit procedure. Postoperative follow-up visits were scheduled at 1, 6, and 12 months after surgery. Results: A total of 114 women who were operated on with the anterior transobturator mesh kit completed 12 months of follow-up. The population had a mean age of 65.8 ± 7.0, a body mass index of 25.1 ± 3.0, and a parity average of 4.0 ± 1.7. An overall anatomic cure was reported for 108 patients (94.7%). The Ba point of the POP-Q exam used for grading cystoceles decreased significantly from 2.5 ± 1.6 cm to -2.8 ± 0.8 cm after 12 months (P < 0.01). One patient (0.9%) presented with bladder perforation, and five patients (4.4%) showed with healing abnormalities. Surgical case volume was negatively correlated with healing abnormalities after adjusting for age, body mass index, operation time, and parity (P = 0.15).  Conclusion: The surgeon’s experience decreases the incidence of healing abnormalities using anterior transobturator mesh in cystocele women. The anatomical cure rate of anterior transobturator mesh is quite good.
      PubDate: 2016-11-10T16:17:37Z
      DOI: 10.12688/f1000research.10012.1
      Issue No: Vol. 5 (2016)
       
  • The TrialsTracker: Automated ongoing monitoring of failure to share
           clinical trial results by all major companies and research institutions
           [version 1; referees: 2 approved]

    • Authors: Anna Powell-Smith, Ben Goldacre
      Abstract: Background: Failure to publish trial results is a prevalent ethical breach with a negative impact on patient care. Audit is an important tool for quality improvement. We set out to produce an online resource that automatically identifies the sponsors with the best and worst record for failing to share trial results. Methods: A tool was produced that identifies all completed trials from clinicaltrials.gov, searches for results in the clinicaltrials.gov registry and on PubMed, and presents summary statistics for each sponsor online. Results: The TrialsTracker tool is now available. Results are consistent with previous publication bias cohort studies using manual searches. The prevalence of missing studies is presented for various classes of sponsor. All code and data is shared. Discussion: We have designed, built, and launched an easily accessible online service, the TrialsTracker, that identifies sponsors who have failed in their duty to make results of clinical trials available, and which can be maintained at low cost. Sponsors who wish to improve their performance metrics in this tool can do so by publishing the results of their trials.
      PubDate: 2016-11-03T15:55:51Z
      Issue No: Vol. 5 (2016)
       
  • Processes of believing: Where do they come from' What are they good
           for' [version 1; referees: 2 approved, 1 approved with reservations]

    • Authors: Rüdiger J. Seitz, Raymond F. Paloutzian, Hans-Ferdinand Angel
      Abstract: Despite the long scholarly discourse in Western theology and philosophy on religion, spirituality, and faith, explanations of what a belief and what believing is are still lacking. Recently, cognitive neuroscience research addressed the human capacity of believing. We present evidence suggesting that believing is a human brain function which results in probabilistic representations with attributes of personal meaning and value and thereby guides individuals’ behavior. We propose that the same mental processes operating on narratives and rituals constitute belief systems in individuals and social groups. Our theoretical model of believing is suited to account for secular and non-secular belief formation.
      PubDate: 2016-10-25T10:59:18Z
      DOI: 10.12688/f1000research.9773.1
      Issue No: Vol. 5 (2016)
       
  • Flow cytometry dataset for cells collected from touched surfaces [version
           2; referees: 2 approved]

    • Authors: Ye Jin Kwon, Cristina E. Stanciu, M. Katherine Philpott, Christopher J. Ehrhardt
      Abstract: ‘Touch’ or trace cell mixtures submitted as evidence are a significant problem for forensic laboratories as they can render resulting genetic profiles difficult or even impossible to interpret. Optical signatures that distinguish epidermal cell populations from different contributors could facilitate the physical separation of mixture components prior to genetic analysis, and potentially the downstream production of single source profiles and/or simplified mixtures.  This dataset comprises the results from antibody hybridization surveys using Human Leukocyte Antigen (HLA) and Cytokeratin (CK) probes, as well as surveys of optical properties of deposited cells, including forward scatter (FSC), side scatter (SSC), and fluorescence emissions in the Allophycocyanin (APC) channel.  All analyses were performed on “touch” samples deposited by several different contributors on multiple days to assess inter- and intra-contributor variability.
      PubDate: 2016-10-07T10:57:41Z
      DOI: 10.12688/f1000research.8338.2
      Issue No: Vol. 5 (2016)
       
 
 
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