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Journal Cover F1000Research
  [SJR: 0.219]   [H-I: 3]   [4 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • Statin-induced diabetes: incidence, mechanisms, and implications [version
           1; referees: 2 approved]

    • Authors: Om P. Ganda
      Abstract: Persuasive data from many randomized controlled trials and large, long-term observational studies indicate a modestly increased risk for the emergence of new diabetes after statin initiation. Several meta-analyses of many statin trials as well as longitudinal population-based studies suggest that the risk factors for diabetes in statin-treated persons include underlying risk for diabetes at baseline (specifically features of metabolic syndrome), the intensity of statin therapy, certain genetic traits independent of diabetes risk, and adherence to lifestyle factors. Limited data suggest statins modestly worsen hyperglycemia and A1c levels in those with pre-existing diabetes or glucose intolerance. The precise mechanism(s) of diabetogenesis with statin therapy are unclear, but impaired insulin sensitivity and compromised β cell function via enhanced intracellular cholesterol uptake due to inhibition of intracellular cholesterol synthesis by statins, as well as other mechanisms, may be involved. Furthermore, while statins are known to have anti-inflammatory effects, it is hypothesized that, under dysmetabolic conditions, they might have pro-inflammatory effects via induction of certain inflammasomes. This concept requires further elucidation in the human. Finally, it is clear that the risk–benefit ratio for cardiovascular disease events is strongly in favor of statin therapy in those at risk, despite the emergence of new diabetes. Adherence to lifestyle regimen is critical in the prevention of new diabetes on statins.
      PubDate: 2016-06-24T15:38:30Z
      DOI: 10.12688/f1000research.8629.1
      Issue No: Vol. 5 (2016)
  • Models of intestinal infection by Salmonella enterica: introduction of a
           new neonate mouse model [version 1; referees: 2 approved]

    • Authors: Marc Schulte, Michael Hensel
      Abstract: Salmonella enterica serovar Typhimurium is a foodborne pathogen causing inflammatory disease in the intestine following diarrhea and is responsible for thousands of deaths worldwide. Many in vitro investigations using cell culture models are available, but these do not represent the real natural environment present in the intestine of infected hosts. Several in vivo animal models have been used to study the host-pathogen interaction and to unravel the immune responses and cellular processes occurring during infection. An animal model for Salmonella-induced intestinal inflammation relies on the pretreatment of mice with streptomycin. This model is of great importance but still shows limitations to investigate the host-pathogen interaction in the small intestine in vivo. Here, we review the use of mouse models for Salmonella infections and focus on a new small animal model using 1-day-old neonate mice. The neonate model enables researchers to observe infection of both the small and large intestine, thereby offering perspectives for new experimental approaches, as well as to analyze the Salmonella-enterocyte interaction in the small intestine in vivo.
      PubDate: 2016-06-24T14:31:23Z
      DOI: 10.12688/f1000research.8468.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding ichthyosis pathogenesis [version 1;
           referees: 2 approved]

    • Authors: Nareh V. Marukian, Keith A. Choate
      Abstract: The ichthyoses, also known as disorders of keratinization (DOK), encompass a heterogeneous group of skin diseases linked by the common finding of abnormal barrier function, which initiates a default compensatory pathway of hyperproliferation, resulting in the characteristic clinical manifestation of localized and/or generalized scaling. Additional cutaneous findings frequently seen in ichthyoses include generalized xerosis, erythroderma, palmoplantar keratoderma, hypohydrosis, and recurrent infections. In 2009, the Ichthyosis Consensus Conference established a classification consensus for DOK based on pathophysiology, clinical manifestations, and mode of inheritance. This nomenclature system divides DOK into two main groups: nonsyndromic forms, with clinical findings limited to the skin, and syndromic forms, with involvement of additional organ systems. Advances in next-generation sequencing technology have allowed for more rapid and cost-effective genetic analysis, leading to the identification of novel, rare mutations that cause DOK, many of which represent phenotypic expansion. This review focuses on new findings in syndromic and nonsyndromic ichthyoses, with emphasis on novel genetic discoveries that provide insight into disease pathogenesis.
      PubDate: 2016-06-24T14:25:13Z
      DOI: 10.12688/f1000research.8584.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding transcription termination by RNA
           polymerase II [version 1; referees: 2 approved]

    • Authors: Travis J. Loya, Daniel Reines
      Abstract: Transcription termination is a fundamental process in which RNA polymerase ceases RNA chain extension and dissociates from the chromatin template, thereby defining the end of the transcription unit. Our understanding of the biological role and functional importance of termination by RNA polymerase II and the range of processes in which it is involved has grown significantly in recent years. A large set of nucleic acid-binding proteins and enzymes have been identified as part of the termination machinery. A greater appreciation for the coupling of termination to RNA processing and metabolism has been recognized. In addition to serving as an essential step at the end of the transcription cycle, termination is involved in the regulation of a broad range of cellular processes. More recently, a role for termination in pervasive transcription, non-coding RNA regulation, genetic stability, chromatin remodeling, the immune response, and disease has come to the fore. Interesting mechanistic questions remain, but the last several years have resulted in significant insights into termination and an increasing recognition of its biological importance.
      PubDate: 2016-06-23T13:51:06Z
      DOI: 10.12688/f1000research.8455.1
      Issue No: Vol. 5 (2016)
  • Recent insights into the molecular mechanisms of the NLRP3 inflammasome
           activation [version 1; referees: 2 approved]

    • Abstract: Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K+ efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation.
      PubDate: 2016-06-22T13:33:02Z
      DOI: 10.12688/f1000research.8614.1
      Issue No: Vol. 5 (2016)
  • Super resolution microscopy is poised to reveal new insights into the
           formation and maturation of dendritic spines [version 1; referees: 2

    • Authors: Cristina M. Robinson, Mikin R. Patel, Donna J. Webb
      Abstract: Dendritic spines and synapses are critical for neuronal communication, and they are perturbed in many neurological disorders; however, the study of these structures in living cells has been hindered by their small size. Super resolution microscopy, unlike conventional light microscopy, is diffraction unlimited and thus is well suited for imaging small structures, such as dendritic spines and synapses. Super resolution microscopy has already revealed important new information about spine and synapse morphology, actin remodeling, and nanodomain composition in both healthy cells and diseased states. In this review, we highlight the advancements in probes that make super resolution more amenable to live-cell imaging of spines and synapses. We also discuss recent data obtained by super resolution microscopy that has advanced our knowledge of dendritic spine and synapse structure, organization, and dynamics in both healthy and diseased contexts. Finally, we propose a series of critical questions for understanding spine and synapse formation and maturation that super resolution microscopy is poised to answer.
      PubDate: 2016-06-22T13:24:24Z
      DOI: 10.12688/f1000research.8649.1
      Issue No: Vol. 5 (2016)
  • Stroke rehabilitation research needs to be different to make a difference
           [version 1; referees: 2 approved]

    • Authors: Cathy M. Stinear
      Abstract: Stroke continues to be a major cause of adult disability. In contrast to progress in stroke prevention and acute medical management, there have been no major breakthroughs in rehabilitation therapies. Most stroke rehabilitation trials are conducted with patients at the chronic stage of recovery and this limits their translation to clinical practice. Encouragingly, several multi-centre rehabilitation trials, conducted during the first few weeks after stroke, have recently been reported; however, all were negative. There is a renewed focus on improving the quality of stroke rehabilitation research through greater harmonisation and standardisation of terminology, trial design, measures, and reporting. However, there is also a need for more pragmatic trials to test interventions in a way that assists their translation to clinical practice. Novel interventions with a strong mechanistic rationale need to be tested in both explanatory and pragmatic trials if we are to make a meaningful difference to stroke rehabilitation practice and outcomes.
      PubDate: 2016-06-22T13:11:38Z
      DOI: 10.12688/f1000research.8722.1
      Issue No: Vol. 5 (2016)
  • Chemotherapy-induced peripheral neuropathy: an update on the current
           understanding [version 1; referees: 2 approved]

    • Authors: James Addington, Miriam Freimer
      Abstract: Chemotherapy-induced peripheral neuropathy is a common side effect of selected chemotherapeutic agents. Previous work has suggested that patients often under report the symptoms of chemotherapy-induced peripheral neuropathy and physicians fail to recognize the presence of such symptoms in a timely fashion. The precise pathophysiology that underlies chemotherapy-induced peripheral neuropathy, in both the acute and the chronic phase, remains complex and appears to be medication specific. Recent work has begun to demonstrate and further clarify potential pathophysiological processes that predispose and, ultimately, lead to the development of chemotherapy-induced peripheral neuropathy. There is increasing evidence that the pathway to neuropathy varies with each agent. With a clearer understanding of how these agents affect the peripheral nervous system, more targeted treatments can be developed in order to optimize treatment and prevent long-term side effects.
      PubDate: 2016-06-22T12:54:39Z
      DOI: 10.12688/f1000research.8053.1
      Issue No: Vol. 5 (2016)
  • Lovastatin lactone may improve irritable bowel syndrome with constipation
           (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway
           [version 3; referees: 2 approved, 1 approved with reservations]

    • Authors: Steven M. Muskal, Joe Sliman, John Kokai-Kun, Mark Pimentel, Vince Wacher, Klaus Gottlieb
      Abstract: Methane produced by the methanoarchaeon Methanobrevibacter smithii (M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings. METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea: M. smithii and Methanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures. RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo. CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligand in silico and thus could inhibit the activity of the key M. smithii methanogenesis enzyme mtd in vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.
      PubDate: 2016-06-22T09:19:51Z
      DOI: 10.12688/f1000research.8406.3
      Issue No: Vol. 5 (2016)
  • “The molecule’s the thing:” the promise of molecular
           modeling and dynamic simulations in aiding the prioritization and
           interpretation of genomic testing results [version 2; referees: 2
           approved, 1 approved with reservations]

    • Authors: Gavin R. Oliver, Michael T. Zimmerman, Eric W. Klee, Raul A. Urrutia
      Abstract: Clinical genomics is now a reality and lies at the heart of individualized medicine efforts. The success of these approaches is evidenced by the increasing volume of publications that report causal links between genomic variants and disease. In spite of early success, clinical genomics currently faces significant challenges in establishing the relevance of the majority of variants identified by next generation sequencing tests. Indeed, the majority of mutations identified are harbored by proteins whose functions remain elusive. Herein we describe the current scenario in genomic testing and in particular the burden of variants of uncertain significance (VUSs). We highlight a role for molecular modeling and molecular dynamic simulations as tools that can significantly increase the yield of information to aid in the evaluation of pathogenicity. Though the application of these methodologies to the interpretation of variants identified by genomic testing is not yet widespread, we predict that an increase in their use will significantly benefit the mission of clinical genomics for individualized medicine.
      PubDate: 2016-06-21T11:28:47Z
      DOI: 10.12688/f1000research.8600.2
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding and treating vasculitis [version 1;
           referees: 2 approved]

    • Authors: Matthew J. Koster, Kenneth J. Warrington
      Abstract: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are near universally fatal conditions if untreated. Although effective therapeutic options are available for these diseases, treatment regimens are associated with both short- and long-term adverse effects. The recent identification of effective B-cell-targeted therapy with an anti-CD20 monoclonal antibody has transformed the treatment landscape of AAV. Questions, nevertheless, remain regarding the appropriate timing, dose, frequency, duration, and long-term effects of treatment. The aim of this article is to provide an overview of the current information, recent advances, ongoing clinical trials, and future treatment possibilities in AAV.
      PubDate: 2016-06-20T10:39:09Z
      DOI: 10.12688/f1000research.8403.1
      Issue No: Vol. 5 (2016)
  • Recent advances in primary Sjogren's syndrome [version 1; referees: 3

    • Authors: Nicholas Holdgate, E. Wiliam St.Clair
      Abstract: Primary Sjögren’s syndrome, a chronic inflammatory process, is among the most commonly occurring rheumatologic diseases. The clinical hallmark of this disease is exocrine gland dysfunction, resulting predominately in dry eyes and dry mouth. However, the disease often extends beyond the exocrine glands to seriously affect other organs systems, such as the lungs, kidneys, and nervous system. Moreover, patients with primary Sjögren’s syndrome develop non-Hodgkin’s B cell lymphoma at a substantially higher rate than the general population. New research has improved our understanding of disease mechanisms, with notable advances in our knowledge about the genetic susceptibility of disease, the molecular details of the chronic inflammatory response in the salivary glands, and the complex role of the type 1 interferon pathway. The pipeline of drugs under development for the treatment of primary Sjögren’s syndrome is enriched with novel biologics and small molecular entities targeting the pathogenic process. Herein, we summarize the latest advances in elucidating the pathogenesis of primary Sjögren’s syndrome and highlight new drugs in clinical development aiming to reverse the glandular dysfunction and favorably impact the systemic features of this disease.
      PubDate: 2016-06-17T15:45:47Z
      DOI: 10.12688/f1000research.8352.1
      Issue No: Vol. 5 (2016)
  • The changing faces of cholangitis [version 1; referees: 2 approved]

    • Authors: Sum P. Lee, Joseph R. Roberts, Rahul Kuver
      Abstract: A variety of diseases are included under the umbrella term ‘cholangitis’, including hepatobiliary diseases with an autoimmune pathogenesis (such as primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-associated sclerosing cholangitis) and disease processes associated with intraductal stones and infectious etiologies (such as ascending bacterial cholangitis, recurrent pyogenic cholangitis, and liver fluke-associated cholangitis). Recent advances in the pathophysiologic bases of these disorders, particularly with respect to the autoimmune variety, are allowing improved diagnosis and prognostication as well as providing the opportunity to refine and re-imagine treatment modalities. The aim of this review is to highlight selected advances in cholangitis research that point to novel insights into the pathophysiology, diagnosis, and treatment of this diverse array of disorders.
      PubDate: 2016-06-17T11:37:25Z
      DOI: 10.12688/f1000research.8745.1
      Issue No: Vol. 5 (2016)
  • Case Report: Kikuchi-Fujimoto disease: a diagnostic and therapeutic
           dilemma following pretransplant nephrectomy for a 2.35 Kg kidney [version
           1; referees: 2 approved]

    • Authors: Arvind P. Ganpule, Jaspreet Singh Chabra, Abhishek G. Singh, Gopal R. Tak, Shailesh Soni, Ravindra Sabnis, Mahesh Desai
      Abstract: Kikuchi-Fujimoto disease (KFD) is an extremely rare disease with a worldwide distribution and higher prevalence in Asians. It is a benign and self-limiting disorder, characterized by regional cervical lymphadenopathy accompanied with mild fever and night sweats. Lymph node histopathology is diagnostic and treating physicians should be aware of this entity as it may mimic other systemic diseases like systemic lupus erythematosus, tuberculosis, malignant lymphoma, and more rarely adenocarcinoma. Key features on lymph node biopsy are fragmentation, necrosis and karyorrhexis. Treatment includes symptomatic care, analgesics-antipyretics, corticosteroids and spontaneous recovery occurs in 1 to 4 months. We report a case of adult polycystic kidney disease (ADPKD) with end stage renal disease and episodes of fever and cervical lymphadenopathy. The infectious screen was negative and on extensive workup, the patient was found to have histiocytic-necrotizing lymphadenitis, which clinched the diagnosis of KFD.
      PubDate: 2016-06-17T09:57:23Z
      DOI: 10.12688/f1000research.8992.1
      Issue No: Vol. 5 (2016)
  • Yersinia virulence factors - a sophisticated arsenal for combating
           host defences [version 1; referees: 2 approved]

    • Authors: Steve Atkinson, Paul Williams
      Abstract: The human pathogens Yersinia pseudotuberculosis and Yersinia enterocolitica cause enterocolitis, while Yersinia pestis is responsible for pneumonic, bubonic, and septicaemic plague. All three share an infection strategy that relies on a virulence factor arsenal to enable them to enter, adhere to, and colonise the host while evading host defences to avoid untimely clearance. Their arsenal includes a number of adhesins that allow the invading pathogens to establish a foothold in the host and to adhere to specific tissues later during infection. When the host innate immune system has been activated, all three pathogens produce a structure analogous to a hypodermic needle. In conjunction with the translocon, which forms a pore in the host membrane, the channel that is formed enables the transfer of six ‘effector’ proteins into the host cell cytoplasm. These proteins mimic host cell proteins but are more efficient than their native counterparts at modifying the host cell cytoskeleton, triggering the host cell suicide response. Such a sophisticated arsenal ensures that yersiniae maintain the upper hand despite the best efforts of the host to counteract the infecting pathogen.
      PubDate: 2016-06-14T15:14:00Z
      DOI: 10.12688/f1000research.8466.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding apicomplexan parasites [version 1;
           referees: 2 approved]

    • Authors: Frank Seeber, Svenja Steinfelder
      Abstract: Intracellular single-celled parasites belonging to the large phylum Apicomplexa are amongst the most prevalent and morbidity-causing pathogens worldwide. In this review, we highlight a few of the many recent advances in the field that helped to clarify some important aspects of their fascinating biology and interaction with their hosts. Plasmodium falciparum causes malaria, and thus the recent emergence of resistance against the currently used drug combinations based on artemisinin has been of major interest for the scientific community. It resulted in great advances in understanding the resistance mechanisms that can hopefully be translated into altered future drug regimens. Apicomplexa are also experts in host cell manipulation and immune evasion. Toxoplasma gondii and Theileria sp., besides Plasmodium sp., are species that secrete effector molecules into the host cell to reach this aim. The underlying molecular mechanisms for how these proteins are trafficked to the host cytosol (T. gondii and Plasmodium) and how a secreted protein can immortalize the host cell (Theileria sp.) have been illuminated recently. Moreover, how such secreted proteins affect the host innate immune responses against T. gondii and the liver stages of Plasmodium has also been unraveled at the genetic and molecular level, leading to unexpected insights. Methodological advances in metabolomics and molecular biology have been instrumental to solving some fundamental puzzles of mitochondrial carbon metabolism in Apicomplexa. Also, for the first time, the generation of stably transfected Cryptosporidium parasites was achieved, which opens up a wide variety of experimental possibilities for this understudied, important apicomplexan pathogen.
      PubDate: 2016-06-14T14:55:02Z
      DOI: 10.12688/f1000research.7924.1
      Issue No: Vol. 5 (2016)
  • Case Report: Prune perineum syndrome: a rare case with an unfavourable
           outcome [version 2; referees: 2 approved, 1 approved with reservations]

    • Abstract: Prune perineum syndrome (PPS) is a rare anomaly, with only two previous case reports, both dying in the perinatal period. We report the first case of PPS that reached childhood. The patient presented with a hypoplastic genitalia and bilateral cryptorchidism. There was no evidence of an anal orifice. A significant prune-like mass was observed, extending from the perineum to both gluteal regions and to a cephalic mid-line bony prominence, with a 1cm central orifice that discharged urine. MRI confirmed the previous findings and revealed a right crossed ectopic kidney, intestinal malrotation, a hypoplastic infrarenal inferior vena cava and a hypoplastic right iliac artery. Endoscopic evaluation through the orifice revealed a cavity lined by urothelial mucosa, with a small communication to the anterior urethra in its anterior wall. A staged reconstruction was planned, with a first-step urinary diversion through a continent abdominal reservoir associated to bilateral orchiopexy. He was discharged from the hospital three weeks later under intermittent catheterization. The next surgical step would be the resection of the perineal mass and its cavity associated to the removal of the prominent sacrococcygeal bones. Unfortunately, four months after the first surgery the patient developed an acute abdomen and was submitted to a laparotomy that revealed a necrotic ileal segment secondary to obstructive adherences. He developed severe malabsorption followed by septic shock, dying five weeks after the procedure. Due to the lack of literature, there is no consensus for the management of these cases. The wish of the family for a better quality of life and social acceptance, compelled us to perform a urinary diversion, to be followed by a plastic and orthopedic reconstruction. Despite the successful initial result, the patient developed a late abdominal obstruction that was misdiagnosed, precipitating his untimely death five months after the first procedure.
      PubDate: 2016-06-10T10:02:05Z
      DOI: 10.12688/f1000research.8246.2
      Issue No: Vol. 5 (2016)
  • Mitral valve repair [version 1; referees: 3 approved]

    • Authors: Alberto Pozzoli, Michele De Bonis, Ottavio Alfieri
      Abstract: Mitral regurgitation (MR) is the most common valvular heart disease in the Western world. The MR can be either organic (mainly degenerative in Western countries) or functional (secondary to left ventricular remodeling in the context of ischemic or idiopathic dilated cardiomyopathy). Degenerative and functional MR are completely different disease entities that pose specific decision-making problems and require different management. The natural history of severe degenerative MR is clearly unfavorable. However, timely and effective correction of degenerative MR is associated with a normalization of life expectancy. By contrast, the prognostic impact of the correction of functional MR is still debated and controversial. In this review, we discuss the optimal treatment of both degenerative and functional MR, taking into account current surgical and percutaneous options. In addition, since a clear understanding of the etiology and mechanisms of valvular dysfunction is important to guide the timing and choice of treatment, the role of the heart team and of echo imaging in the management of MR is addressed as well.
      PubDate: 2016-06-10T08:47:24Z
      DOI: 10.12688/f1000research.7521.1
      Issue No: Vol. 5 (2016)
  • RiboProfiling: a Bioconductor package for standard Ribo-seq pipeline
           processing [version 1; referees: 2 approved]

    • Authors: Alexandra Popa, Kevin Lebrigand, Agnes Paquet, Nicolas Nottet, Karine Robbe-Sermesant, Rainer Waldmann, Pascal Barbry
      Abstract: The ribosome profiling technique (Ribo-seq) allows the selective sequencing of translated RNA regions. Recently, the analysis of genomic sequences associated to Ribo-seq reads has been widely employed to assess their coding potential. These analyses led to the identification of differentially translated transcripts under different experimental conditions, and/or ribosome pausing on codon motifs. In the context of the ever-growing need for tools analyzing Ribo-seq reads, we have developed ‘RiboProfiling’, a new Bioconductor open-source package. ‘RiboProfiling’ provides a full pipeline to cover all key steps for the analysis of ribosome footprints. This pipeline has been implemented in a single R workflow. The package takes an alignment (BAM) file as input and performs ribosome footprint quantification at a transcript level. It also identifies footprint accumulation on particular amino acids or multi amino-acids motifs. Report summary graphs and data quantification are generated automatically. The package facilitates quality assessment and quantification of Ribo-seq experiments. Its implementation in Bioconductor enables the modeling and statistical analysis of its output through the vast choice of packages available in R. This article illustrates how to identify codon-motifs accumulating ribosome footprints, based on data from Escherichia coli.
      PubDate: 2016-06-09T15:10:21Z
      DOI: 10.12688/f1000research.8964.1
      Issue No: Vol. 5 (2016)
  • Digital methodology to implement the ECOUTER engagement process [version
           1; referees: 2 approved]

    • Authors: Rebecca C. Wilson, Oliver W. Butters, Tom Clark, Joel Minion, Andrew Turner, Madeleine J. Murtagh
      Abstract: ECOUTER (Employing COnceptUal schema for policy and Translation Engagement in Research) – French for ‘to listen’ – is a new stakeholder engagement method incorporating existing evidence to help participants draw upon their own knowledge of cognate issues and interact on a topic of shared concern. The results of an ECOUTER can form the basis of recommendations for research, governance, practice and/or policy. This paper describes the development of a digital methodology for the ECOUTER engagement process based on currently available mind mapping freeware software. The implementation of an ECOUTER process tailored to applications within health studies are outlined for both online and face-to-face scenarios. Limitations of the present digital methodology are discussed, highlighting the requirement of a purpose built software for ECOUTER research purposes.
      PubDate: 2016-06-09T15:03:40Z
      DOI: 10.12688/f1000research.8786.1
      Issue No: Vol. 5 (2016)
  • A step-by-step overview of the dynamic process of epitope selection by
           major histocompatibility complex class II for presentation to helper T
           cells [version 1; referees: 4 approved]

    • Authors: Scheherazade Sadegh-Nasseri
      Abstract: T cell antigen receptors (TCRs) expressed on cytotoxic or helper T cells can only see their specific target antigen as short sequences of peptides bound to the groove of proteins of major histocompatibility complex (MHC) class I, and class II respectively. In addition to the many steps, several participating proteins, and multiple cellular compartments involved in the processing of antigens, the MHC structure, with its dynamic and flexible groove, has perfectly evolved as the underlying instrument for epitope selection. In this review, I have taken a step-by-step, and rather historical, view to describe antigen processing and determinant selection, as we understand it today, all based on decades of intense research by hundreds of laboratories.
      PubDate: 2016-06-09T14:35:51Z
      DOI: 10.12688/f1000research.7664.1
      Issue No: Vol. 5 (2016)
  • A cross-package Bioconductor workflow for analysing methylation array data
           [version 1; referees: 3 approved, 1 approved with reservations]

    • Authors: Jovana Maksimovic, Belinda Phipson, Alicia Oshlack
      Abstract: Methylation in the human genome is known to be associated with development and disease. The Illumina Infinium methylation arrays are by far the most common way to interrogate methylation across the human genome. This paper provides a Bioconductor workflow using multiple packages for the analysis of methylation array data. Specifically, we demonstrate the steps involved in a typical differential methylation analysis pipeline including: quality control, filtering, normalization, data exploration and statistical testing for probe-wise differential methylation. We further outline other analyses such as differential methylation of regions, differential variability analysis, estimating cell type composition and gene ontology testing. Finally, we provide some examples of how to visualise methylation array data.
      PubDate: 2016-06-08T15:13:18Z
      DOI: 10.12688/f1000research.8839.1
      Issue No: Vol. 5 (2016)
  • What does the UK public want from academic science communication'
           [version 1; referees: 3 approved]

    • Authors: James Redfern, Sam Illingworth, Joanna Verran
      Abstract: The overall aim of public academic science communication is to engage a non-scientist with a particular field of science and/or research topic, often driven by the expertise of the academic. An e-survey was designed to provide insight into respondent’s current and future engagement with science communication activities. Respondents provided a wide range of ideas and concerns as to the ‘common practice’ of academic science communication, and whilst they support some of these popular approaches (such as open-door events and science festivals), there are alternatives that may enable wider engagement. Suggestions of internet-based approaches and digital media were strongly encouraged, and although respondents found merits in methods such as science festivals, limitations such as geography, time and topic of interest were a barrier to engagement for some. Academics and scientists need to think carefully about how they plan their science communication activities and carry out evaluations, including considering the point of view of the public, as although defaulting to hands-on open door events at their university may seem like the expected standard, it may not be the best way to reach the intended audience.
      PubDate: 2016-06-07T15:29:39Z
      DOI: 10.12688/f1000research.8815.1
      Issue No: Vol. 5 (2016)
  • Analyzing compound activity records and promiscuity degrees in light of
           publication statistics [version 1; referees: 2 approved]

    • Abstract: For the generation of contemporary databases of bioactive compounds, activity information is usually extracted from the scientific literature. However, when activity data are analyzed, source publications are typically no longer taken into consideration. Therefore, compound activity data selected from ChEMBL were traced back to thousands of original publications, activity records including compound, assay, and target information were systematically generated, and their distributions across the literature were determined. In addition, publications were categorized on the basis of activity records. Furthermore, compound promiscuity, defined as the ability of small molecules to specifically interact with multiple target proteins, was analyzed in light of publication statistics, thus adding another layer of information to promiscuity assessment. It was shown that the degree of compound promiscuity was not influenced by increasing numbers of source publications. Rather, most non-promiscuous as well as promiscuous compounds, regardless of their degree of promiscuity, originated from single publications, which emerged as a characteristic feature of the medicinal chemistry literature.
      PubDate: 2016-06-06T10:59:55Z
      DOI: 10.12688/f1000research.8792.1
      Issue No: Vol. 5 (2016)
  • Where are the female science professors' A personal perspective
           [version 1; referees: 2 approved]

    • Authors: Shina Caroline Lynn Kamerlin
      Abstract: The first woman to earn a Professorship at a University in Europe was Laura Maria Caterina Bassi, who earned a professorship in physics at the University of Bologna in 1732. Almost 300 years and three waves of feminism later, in 2016, women typically still only comprise 20% (or less) of the number of full professors in Europe. This opinion article will discuss the experiences of being a female academic today and the factors contributing to the academic gender gap from the perspective of a “young” natural scientist, as well as providing constructive suggestions for strategies to empower women in the academic world.
      PubDate: 2016-06-06T09:53:35Z
      DOI: 10.12688/f1000research.8889.1
      Issue No: Vol. 5 (2016)
  • Active learning in the lecture theatre using 3D printed objects [version
           2; referees: 2 approved]

    • Authors: David P. Smith
      Abstract: The ability to conceptualize 3D shapes is central to understanding biological processes. The concept that the structure of a biological molecule leads to function is a core principle of the biochemical field. Visualisation of biological molecules often involves vocal explanations or the use of two dimensional slides and video presentations. A deeper understanding of these molecules can however be obtained by the handling of objects. 3D printed biological molecules can be used as active learning tools to stimulate engagement in large group lectures. These models can be used to build upon initial core knowledge which can be delivered in either a flipped form or a more didactic manner. Within the teaching session the students are able to learn by handling, rotating and viewing the objects to gain an appreciation, for example, of an enzyme’s active site or the difference between the major and minor groove of DNA. Models and other artefacts can be handled in small groups within a lecture theatre and act as a focal point to generate conversation. Through the approach presented here core knowledge is first established and then supplemented with high level problem solving through a "Think-Pair-Share" cooperative learning strategy. The teaching delivery was adjusted based around experiential learning activities by moving the object from mental cognition and into the physical environment. This approach led to students being able to better visualise biological molecules and a positive engagement in the lecture. The use of objects in teaching allows the lecturer to create interactive sessions that both challenge and enable the student.
      PubDate: 2016-06-03T15:13:41Z
      DOI: 10.12688/f1000research.7632.2
      Issue No: Vol. 5 (2016)
  • Multiple statistical tests: lessons from a d20 [version 1; referees: 2

    • Authors: Christopher R. Madan
      Abstract: Statistical analyses are often conducted with α=.05. When multiple statistical tests are conducted, this procedure needs to be adjusted to compensate for the otherwise inflated Type I error. In some instances in tabletop gaming, sometimes it is desired to roll a 20-sided dice (or `d20') twice and take the greater outcome. Here I draw from probability theory and the case of a d20, where the probability of obtaining any specific outcome is 1/20, to determine the probability of obtaining a specific outcome (Type-I error) at least once across repeated, independent statistical tests.
      PubDate: 2016-06-02T16:15:35Z
      DOI: 10.12688/f1000research.8834.1
      Issue No: Vol. 5 (2016)
  • Complex mechanisms linking neurocognitive dysfunction to insulin
           resistance and other metabolic dysfunction [version 2; referees: 2

    • Authors: Luke E. Stoeckel, Zoe Arvanitakis, Sam Gandy, Dana Small, C. Ronald Kahn, Alvaro Pascual-Leone, Aaron Pawlyk, Robert Sherwin, Philip Smith
      Abstract: Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer’s disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled “The Intersection of Metabolic and Neurocognitive Dysfunction”, to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.
      PubDate: 2016-06-02T15:08:43Z
      DOI: 10.12688/f1000research.8300.2
      Issue No: Vol. 5 (2016)
  • Molecular studies of exercise, skeletal muscle, and ageing [version 1;
           referees: 2 approved]

    • Authors: James A. Timmons, Iain J. Gallagher
      Abstract: The purpose of an F1000 review is to reflect on the bigger picture, exploring controversies and new concepts as well as providing opinion as to what is limiting progress in a particular field. We reviewed about 200 titles published in 2015 that included reference to ‘skeletal muscle, exercise, and ageing’ with the aim of identifying key articles that help progress our understanding or research capacity while identifying methodological issues which represent, in our opinion, major barriers to progress. Loss of neuromuscular function with chronological age impacts on both health and quality of life. We prioritised articles that studied human skeletal muscle within the context of age or exercise and identified new molecular observations that may explain how muscle responds to exercise or age. An important aspect of this short review is perspective: providing a view on the likely ‘size effect’ of a potential mechanism on physiological capacity or ageing.
      PubDate: 2016-06-02T14:36:42Z
      DOI: 10.12688/f1000research.8255.1
      Issue No: Vol. 5 (2016)
  • Dynamics of cell polarity in tissue morphogenesis: a comparative view from
           Drosophila and Ciona [version 1; referees: 2 approved]

    • Authors: Michael T. Veeman, Jocelyn A. McDonald
      Abstract: Tissues in developing embryos exhibit complex and dynamic rearrangements that shape forming organs, limbs, and body axes. Directed migration, mediolateral intercalation, lumen formation, and other rearrangements influence the topology and topography of developing tissues. These collective cell behaviors are distinct phenomena but all involve the fine-grained control of cell polarity. Here we review recent findings in the dynamics of polarized cell behavior in both the Drosophila ovarian border cells and the Ciona notochord. These studies reveal the remarkable reorganization of cell polarity during organ formation and underscore conserved mechanisms of developmental cell polarity including the Par/atypical protein kinase C (aPKC) and planar cell polarity pathways. These two very different model systems demonstrate important commonalities but also key differences in how cell polarity is controlled in tissue morphogenesis. Together, these systems raise important, broader questions on how the developmental control of cell polarity contributes to morphogenesis of diverse tissues across the metazoa.
      PubDate: 2016-06-02T10:38:44Z
      DOI: 10.12688/f1000research.8011.1
      Issue No: Vol. 5 (2016)
  • Increasing both the public health potential of basic research and the
           scientist satisfaction. An international survey of bio-scientists [version
           2; referees: 2 approved]

    • Authors: Carmen Sorrentino, Andrea Boggio, Stefano Confalonieri, David Hemenway, Giorgio Scita, Andrea Ballabeni
      Abstract: Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists’ attitudes towards these factors. The present survey asked about the scientists’ motivations, goals and perspectives along with their attitudes concerning  policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a “basic bibliography” for each new approved drug.
      PubDate: 2016-06-01T13:02:53Z
      DOI: 10.12688/f1000research.7683.2
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding idiopathic pulmonary fibrosis [version 1;
           referees: 2 approved]

    • Abstract: Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs.   Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.
      PubDate: 2016-05-31T10:29:36Z
      DOI: 10.12688/f1000research.8209.1
      Issue No: Vol. 5 (2016)
  • Advancing cardiovascular tissue engineering [version 1; referees: 3

    • Authors: George A. Truskey
      Abstract: Cardiovascular tissue engineering offers the promise of biologically based repair of injured and damaged blood vessels, valves, and cardiac tissue. Major advances in cardiovascular tissue engineering over the past few years involve improved methods to promote the establishment and differentiation of induced pluripotent stem cells (iPSCs), scaffolds from decellularized tissue that may produce more highly differentiated tissues and advance clinical translation, improved methods to promote vascularization, and novel in vitro microphysiological systems to model normal and diseased tissue function. iPSC technology holds great promise, but robust methods are needed to further promote differentiation. Differentiation can be further enhanced with chemical, electrical, or mechanical stimuli.
      PubDate: 2016-05-31T10:21:36Z
      DOI: 10.12688/f1000research.8237.1
      Issue No: Vol. 5 (2016)
  • Recent advances in managing and understanding diabetic nephropathy
           [version 1; referees: 3 approved]

    • Authors: Sydney C.W. Tang, Gary C.W. Chan, Kar Neng Lai
      Abstract: Diabetic nephropathy is the commonest cause of end-stage renal disease in most developed economies. Current standard of care for diabetic nephropathy embraces stringent blood pressure control via blockade of the renin-angiotensin-aldosterone system and glycemia control. Recent understanding of the pathophysiology of diabetic nephropathy has led to the development of novel therapeutic options. This review article focuses on available data from landmark studies on the main therapeutic approaches and highlights some novel management strategies.
      PubDate: 2016-05-31T09:34:14Z
      DOI: 10.12688/f1000research.7693.1
      Issue No: Vol. 5 (2016)
  • Diabetic macular edema: it is more than just VEGF [version 1; referees: 2

    • Authors: Michael A. Singer, Daniel S. Kermany, Jana Waters, Michael E. Jansen, Lyndon Tyler
      Abstract: Diabetic macular edema is a serious visual complication of diabetic retinopathy. This article reviews the history of previous and current therapies, including laser therapy, anti-vascular endothelial growth factor agents, and corticosteroids, that have been used to treat this condition. In addition, it proposes new ways to use them in combination in order to decrease treatment burden and potentially address other causes besides vascular endothelial growth factor for diabetic macular edema.
      PubDate: 2016-05-27T14:24:02Z
      DOI: 10.12688/f1000research.8265.1
      Issue No: Vol. 5 (2016)
  • Improving outcome of sensorimotor functions after traumatic spinal cord
           injury [version 1; referees: 2 approved]

    • Authors: Volker Dietz
      Abstract: In the rehabilitation of a patient suffering a spinal cord injury (SCI), the exploitation of neuroplasticity is well established. It can be facilitated through the training of functional movements with technical assistance as needed and can improve outcome after an SCI. The success of such training in individuals with incomplete SCI critically depends on the presence of physiological proprioceptive input to the spinal cord leading to meaningful muscle activations during movement performances. Some actual preclinical approaches to restore function by compensating for the loss of descending input to spinal networks following complete/incomplete SCI are critically discussed in this report. Electrical and pharmacological stimulation of spinal neural networks is still in the experimental stage, and despite promising repair studies in animal models, translations to humans up to now have not been convincing. It is possible that a combination of techniques targeting the promotion of axonal regeneration is necessary to advance the restoration of function. In the future, refinement of animal models according to clinical conditions and requirements may contribute to greater translational success.
      PubDate: 2016-05-27T14:13:03Z
      DOI: 10.12688/f1000research.8129.1
      Issue No: Vol. 5 (2016)
  • Recent advances in managing a spinal cord injury secondary to trauma
           [version 1; referees: 2 approved]

    • Authors: Christopher S. Ahuja, Allan R. Martin, Michael Fehlings
      Abstract: Traumatic spinal cord injuries (SCIs) affect 1.3 million North Americans, producing devastating physical, social, and vocational impairment. Pathophysiologically, the initial mechanical trauma is followed by a significant secondary injury which includes local ischemia, pro-apoptotic signaling, release of cytotoxic factors, and inflammatory cell infiltration. Expedient delivery of medical and surgical care during this critical period can improve long-term functional outcomes, engendering the concept of “Time is Spine”. We emphasize the importance of expeditious care while outlining the initial clinical and radiographic assessment of patients. Key evidence-based early interventions (surgical decompression, blood pressure augmentation, and methylprednisolone) are also reviewed, including findings of the landmark Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). We then describe other neuroprotective approaches on the edge of translation such as the sodium-channel blocker riluzole, the anti-inflammatory minocycline, and therapeutic hypothermia. We also review promising neuroregenerative therapies that are likely to influence management practices over the next decade including chondroitinase, Rho-ROCK pathway inhibition, and bioengineered strategies. The importance of emerging neural stem cell therapies to remyelinate denuded axons and regenerate neural circuits is also discussed. Finally, we outline future directions for research and patient care.
      PubDate: 2016-05-27T14:07:00Z
      DOI: 10.12688/f1000research.7586.1
      Issue No: Vol. 5 (2016)
  • Some vexations that challenge viral immunology [version 1; referees: 2

    • Authors: Barry T. Rouse, Scott N. Mueller
      Abstract: The field of viral immunology seeks to understand mechanisms of virus-host interaction with a view of applying this knowledge to the design of effective vaccines and immunomodulators that control viral infections. This brief review discusses several areas of the field that hold substantial promise for translation, but where further work is critically required to find solutions. We emphasize that our fundamental understanding of virus-host relationships is moving in leaps and bounds, but we lag behind in applying this knowledge to the successful control of many viral infections.
      PubDate: 2016-05-27T10:57:01Z
      DOI: 10.12688/f1000research.8391.1
      Issue No: Vol. 5 (2016)
  • Non-ionotropic signaling by the NMDA receptor: controversy and opportunity
           [version 1; referees: 2 approved]

    • Authors: John A. Gray, Karen Zito, Johannes W. Hell
      Abstract: Provocative emerging evidence suggests that the N-methyl-D-aspartate (NMDA) receptor can signal in the absence of ion flux through the receptor. This non-ionotropic signaling is thought to be due to agonist-induced conformational changes in the receptor, independently of channel opening. Non-ionotropic NMDA receptor signaling has been proposed to be sufficient to induce synaptic long-term depression (LTD), directly challenging the decades-old model that prolonged low-level calcium influx is required to induce LTD. Here, we briefly review these recent findings, focusing primarily on the potential role of non-ionotropic signaling in NMDA receptor-mediated LTD. Further reports concerning additional roles of non-ionotropic NMDA receptor signaling are also discussed. If validated, this new view of NMDA receptor-mediated signaling will usher in an exciting new era of exploring synapse function and dysfunction.
      PubDate: 2016-05-26T15:48:46Z
      DOI: 10.12688/f1000research.8366.1
      Issue No: Vol. 5 (2016)
  • Targeting the latent reservoir to achieve functional HIV cure [version 1;
           referees: 3 approved]

    • Authors: Daniele C. Cary, B. Matija Peterlin
      Abstract: While highly active anti-retroviral therapy has greatly improved the lives of HIV-infected individuals, current treatments are unable to completely eradicate the virus. This is due to the presence of HIV latently infected cells which harbor transcriptionally silent HIV. Latent HIV does not replicate or produce viral proteins, thereby preventing efficient targeting by anti-retroviral drugs. Strategies to target the HIV latent reservoir include viral reactivation, enhancing host defense mechanisms, keeping latent HIV silent, and using gene therapy techniques to knock out or reactivate latent HIV. While research into each of these areas has yielded promising results, currently no one mechanism eradicates latent HIV. Instead, combinations of these approaches should be considered for a potential HIV functional cure.
      PubDate: 2016-05-26T15:37:03Z
      DOI: 10.12688/f1000research.8109.1
      Issue No: Vol. 5 (2016)
  • Members of the genus Burkholderia: good and bad guys [version 1; referees:
           3 approved]

    • Authors: Leo Eberl, Peter Vandamme
      Abstract: In the 1990s several biocontrol agents on that contained Burkholderia strains were registered by the United States Environmental Protection Agency (EPA). After risk assessment these products were withdrawn from the market and a moratorium was placed on the registration of Burkholderia-containing products, as these strains may pose a risk to human health. However, over the past few years the number of novel Burkholderia species that exhibit plant-beneficial properties and are normally not isolated from infected patients has increased tremendously. In this commentary we wish to summarize recent efforts that aim at discerning pathogenic from beneficial Burkholderia strains.
      PubDate: 2016-05-26T12:56:17Z
      DOI: 10.12688/f1000research.8221.1
      Issue No: Vol. 5 (2016)
  • The germinal center antibody response in health and disease [version 1;
           referees: 2 approved]

    • Authors: Anthony L. DeFranco
      Abstract: The germinal center response is the delayed but sustained phase of the antibody response that is responsible for producing high-affinity antibodies of the IgG, IgA and/or IgE isotypes. B cells in the germinal center undergo re-iterative cycles of somatic hypermutation of immunoglobulin gene variable regions, clonal expansion, and Darwinian selection for cells expressing higher-affinity antibody variants. Alternatively, selected B cells can terminally differentiate into long-lived plasma cells or into a broad diversity of mutated memory B cells; the former secrete the improved antibodies to fight an infection and to provide continuing protection from re-infection, whereas the latter may jumpstart immune responses to subsequent infections with related but distinct infecting agents. Our understanding of the molecules involved in the germinal center reaction has been informed by studies of human immunodeficiency patients with selective defects in the production of antibodies. Recent studies have begun to reveal how innate immune recognition via Toll-like receptors can enhance the magnitude and selective properties of the germinal center, leading to more effective control of infection by a subset of viruses. Just as early insights into the nature of the germinal center found application in the development of the highly successful conjugate vaccines, more recent insights may find application in the current efforts to develop new generations of vaccines, including vaccines that can induce broadly protective neutralizing antibodies against influenza virus or HIV-1.
      PubDate: 2016-05-25T15:57:40Z
      DOI: 10.12688/f1000research.7717.1
      Issue No: Vol. 5 (2016)
  • Focusing super resolution on the cytoskeleton [version 1; referees: 3

    • Authors: Eric A. Shelden, Zachary T. Colburn, Jonathan C.R. Jones
      Abstract: Super resolution imaging is becoming an increasingly important tool in the arsenal of methods available to cell biologists. In recognition of its potential, the Nobel Prize for chemistry was awarded to three investigators involved in the development of super resolution imaging methods in 2014. The availability of commercial instruments for super resolution imaging has further spurred the development of new methods and reagents designed to take advantage of super resolution techniques. Super resolution offers the advantages traditionally associated with light microscopy, including the use of gentle fixation and specimen preparation methods, the ability to visualize multiple elements within a single specimen, and the potential to visualize dynamic changes in living specimens over time. However, imaging of living cells over time is difficult and super resolution imaging is computationally demanding. In this review, we discuss the advantages/disadvantages of different super resolution systems for imaging fixed live specimens, with particular regard to cytoskeleton structures.
      PubDate: 2016-05-25T11:24:51Z
      DOI: 10.12688/f1000research.8233.1
      Issue No: Vol. 5 (2016)
  • Infrastructure for genomic interactions: Bioconductor classes for Hi-C,
           ChIA-PET and related experiments [version 1; referees: 2 approved]

    • Authors: Aaron T. L. Lun, Malcolm Perry, Elizabeth Ing-Simmons
      Abstract: The study of genomic interactions has been greatly facilitated by techniques such as chromatin conformation capture with high-throughput sequencing (Hi-C). These genome-wide experiments generate large amounts of data that require careful analysis to obtain useful biological conclusions. However, development of the appropriate software tools is hindered by the lack of basic infrastructure to represent and manipulate genomic interaction data. Here, we present the InteractionSet package that provides classes to represent genomic interactions and store their associated experimental data, along with the methods required for low-level manipulation and processing of those classes. The InteractionSet package exploits existing infrastructure in the open-source Bioconductor project, while in turn being used by Bioconductor packages designed for higher-level analyses. For new packages, use of the functionality in InteractionSet will simplify development, allow access to more features and improve interoperability between packages.
      PubDate: 2016-05-20T13:31:39Z
      DOI: 10.12688/f1000research.8759.1
      Issue No: Vol. 5 (2016)
  • Hypnotic drug risks of mortality, infection, depression, and cancer: but
           lack of benefit [version 1; referees: 2 approved]

    • Authors: Daniel F. Kripke
      Abstract: This is a review of hypnotic drug risks and benefits, reassessing and updating advice presented to the Commissioner of the Food and Drug Administration (United States FDA). Almost every month, new information appears about the risks of hypnotics (sleeping pills). This review includes new information on the growing USA overdose epidemic, eight new epidemiologic studies of hypnotics’ mortality not available for previous compilations, and new emphasis on risks of short-term hypnotic prescription. The most important risks of hypnotics include excess mortality, especially overdose deaths, quiet deaths at night, infections, cancer, depression and suicide, automobile crashes, falls, and other accidents, and hypnotic-withdrawal insomnia. The short-term use of one-two prescriptions is associated with greater risk per dose than long-term use. Hypnotics are usually prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse, not better, and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders might offer safer and more effective alternative approaches to insomnia.
      PubDate: 2016-05-19T15:08:53Z
      DOI: 10.12688/f1000research.8729.1
      Issue No: Vol. 5 (2016)
  • The GenABEL Project for statistical genomics [version 1; referees: 2

    • Authors: Lennart C. Karssen, Cornelia M. van Duijn, Yurii S. Aulchenko
      Abstract: Development of free/libre open source software is usually done by a community of people with an interest in the tool. For scientific software, however, this is less often the case. Most scientific software is written by only a few authors, often a student working on a thesis. Once the paper describing the tool has been published, the tool is no longer developed further and is left to its own device. Here we describe the broad, multidisciplinary community we formed around a set of tools for statistical genomics. The GenABEL project for statistical omics actively promotes open interdisciplinary development of statistical methodology and its implementation in efficient and user-friendly software under an open source licence. The software tools developed withing the project collectively make up the GenABEL suite, which currently consists of eleven tools. The open framework of the project actively encourages involvement of the community in all stages, from formulation of methodological ideas to application of software to specific data sets. A web forum is used to channel user questions and discussions, further promoting the use of the GenABEL suite. Developer discussions take place on a dedicated mailing list, and development is further supported by robust development practices including use of public version control, code review and continuous integration. Use of this open science model attracts contributions from users and developers outside the “core team”, facilitating agile statistical omics methodology development and fast dissemination.
      PubDate: 2016-05-19T11:27:08Z
      DOI: 10.12688/f1000research.8733.1
      Issue No: Vol. 5 (2016)
  • Priority regions for research on dryland cereals and legumes [version 1;
           referees: 2 approved]

    • Authors: Glenn Hyman, Elizabeth Barona, Chandrashekhar Biradar, Edward Guevara, John Dixon, Steve Beebe, Silvia Elena Castano, Tunrayo Alabi, Murali Krishna Gumma, Shoba Sivasankar, Ovidio Rivera, Herlin Espinosa, Jorge Cardona
      Abstract: Dryland cereals and legumes  are important crops in farming systems across the world.  Yet they are frequently neglected among the priorities for international agricultural research and development, often due to lack of information on their magnitude and extent. Given what we know about the global distribution of dryland cereals and legumes, what regions should be high priority for research and development to improve livelihoods and food security' This research evaluated the geographic dimensions of these crops and the farming systems where they are found worldwide. The study employed geographic information science and data to assess the key farming systems and regions for these crops. Dryland cereal and legume crops should be given high priority in 18 farming systems worldwide, where their cultivated area comprises more than 160 million ha. These regions include the dryer areas of South Asia, West and East Africa, the Middle East and North Africa, Central America and other parts of Asia. These regions are prone to drought and heat stress, have limiting soil constraints, make up half of the global population and account for 60 percent of the global poor and malnourished. The dryland cereal and legume crops and farming systems merit more research and development attention to improve productivity and address development problems. This project developed an open access dataset and information resource that provides the basis for future analysis of the geographic dimensions of dryland cereals and legumes.
      PubDate: 2016-05-13T10:46:49Z
      DOI: 10.12688/f1000research.8657.1
      Issue No: Vol. 5 (2016)
  • Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human
           epidermal keratinocytes and melanocytes modulated by
           alpha-melanocyte-stimulating hormone [version 1; referees: 2 approved]

    • Abstract: Alpha-melanocyte-stimulating hormone (alpha-MSH) increases melanogenesis and protects from UV-induced DNA damage. However, its effect on mitochondrial DNA (mtDNA) damage is unknown. We have addressed this issue in a pilot study using human epidermal keratinocytes and melanocytes incubated with alpha-MSH and irradiated with UVB. Real-time touchdown PCR was used to quantify total and deleted mtDNA. The deletion detected encompassed the common deletion but was more sensitive to detection. There were 4.4 times more mtDNA copies in keratinocytes than in melanocytes. Irradiation alone did not affect copy numbers. Alpha-MSH slightly increased copy numbers in both cell types in the absence of UVB and caused a similar small decrease in copy number with dose in both cell types. Deleted copies were nearly twice as frequent in keratinocytes as in melanocytes. Alpha-MSH reduced the frequency of deleted copies by half in keratinocytes but not in melanocytes. UVB dose dependently led to an increase in the deleted copy number in alpha-MSH-treated melanocytes. UVB irradiation had little effect on deleted copy number in alpha-MSH-treated keratinocytes. In summary, alpha-MSH enhances mtDNA damage in melanocytes presumably by increased melanogenesis, while α-MSH is protective in keratinocytes, the more so in the absence of irradiation.
      PubDate: 2016-05-12T14:40:53Z
      DOI: 10.12688/f1000research.8582.1
      Issue No: Vol. 5 (2016)
  • Case Report: Cervical chondrocalcinosis as a complication of Gitelman
           syndrome [version 1; referees: 2 approved]

    • Authors: Zahra Iqbal, Paul Mead, John A. Sayer
      Abstract: Gitelman syndrome is an inherited tubulopathy leading to a hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria. Most cases are due to mutations in SLC12A3, encoding the apical thiazide sensitive co-transporter in the distal convoluted tubule. Musculoskeletal effects of Gitelman syndrome are common, including muscle weakness, tetany and cramps. Chronic hypomagnesaemia can lead to chondrocalcinosis, which often affects knees but can affect other joints. Here we present a case of Gitelman syndrome complicated by cervical chondrocalcinosis leading to neck pain and numbness of the fingers. Treatments directed at correcting both hypokalaemia and hypomagnesaemia were initiated and allowed conservative non-surgical management of the neck pain. Recognition of chondrocalcinosis is important and treatments must be individualised to correct the underlying hypomagnesaemia.
      PubDate: 2016-05-12T10:19:04Z
      DOI: 10.12688/f1000research.8732.1
      Issue No: Vol. 5 (2016)
  • A curated transcriptome dataset collection to investigate the development
           and differentiation of the human placenta and its associated pathologies
           [version 2; referees: 2 approved]

    • Authors: Alexandra K. Marr, Sabri Boughorbel, Scott Presnell, Charlie Quinn, Damien Chaussabel, Tomoshige Kino
      Abstract: Compendia of large-scale datasets made available in public repositories provide a precious opportunity to discover new biomedical phenomena and to fill gaps in our current knowledge. In order to foster novel insights it is necessary to ensure that these data are made readily accessible to research investigators in an interpretable format. Here we make a curated, public, collection of transcriptome datasets relevant to human placenta biology available for further analysis and interpretation via an interactive data browsing interface. We identified and retrieved a total of 24 datasets encompassing 759 transcriptome profiles associated with the development of the human placenta and associated pathologies from the NCBI Gene Expression Omnibus (GEO) and present them in a custom web-based application designed for interactive query and visualization of integrated large-scale datasets ( We also performed quality control checks using relevant biological markers. Multiple sample groupings and rank lists were subsequently created to facilitate data query and interpretation. Via this interface, users can create web-links to customized graphical views which may be inserted into manuscripts for further dissemination, or e-mailed to collaborators for discussion. The tool also enables users to browse a single gene across different projects, providing a mechanism for  developing new perspectives on the role of a molecule of interest across multiple biological states. The dataset collection we created here is available at:
      PubDate: 2016-05-11T14:08:22Z
      Issue No: Vol. 5 (2016)
  • IL-6 stimulates a concentration-dependent increase in MCP-1 in
           immortalised human brain endothelial cells [version 2; referees: 1
           approved, 2 approved with reservations]

    • Authors: Jai Min Choi, Odunayo O. Rotimi, Simon J. O'Carroll, Louise F.B. Nicholson
      Abstract: Systemic inflammation is associated with neurodegeneration, with elevated interleukin-6 (IL-6) in particular being correlated with an increased risk of dementia. The brain endothelial cells of the blood brain barrier (BBB) serve as the interface between the systemic circulation and the brain microenvironment and are therefore likely to be a key player in the development of neuropathology associated with systemic inflammation. Endothelial cells are known to require soluble IL-6 receptor (sIL-6R) in order to respond to IL-6, but studies in rat models have shown that this is not the case for brain endothelial cells and studies conducted in human cells are limited. Here we report for the first time that the human cerebral microvascular cell line, hCMVEC, uses the classical mIL-6R signalling pathway in response to IL-6 in a concentration-dependent manner as measured by the production of monocyte chemotactic protein (MCP-1). This novel finding highlights a unique characteristic of human brain endothelial cells and that further investigation into the phenotype of this cell type is needed to elucidate the mechanisms of BBB pathology in inflammatory conditions.
      PubDate: 2016-05-11T13:37:26Z
      DOI: 10.12688/f1000research.8153.2
      Issue No: Vol. 5 (2016)
  • The natural defense system and the normative self model [version 1;
           referees: 2 approved]

    • Authors: Philippe Kourilsky
      Abstract: Infectious agents are not the only agressors, and the immune system is not the sole defender of the organism. In an enlarged perspective, the ‘normative self model’ postulates that a ‘natural defense system’ protects man and other complex organisms against the environmental and internal hazards of life, including infections and cancers. It involves multiple error detection and correction mechanisms that confer robustness to the body at all levels of its organization. According to the model, the self relies on a set of physiological norms, and NONself (meaning : Non Obedient to the Norms of the self) is anything ‘off-norms’. The natural defense system comprises a set of ‘civil defenses’ (to which all cells in organs and tissues contribute), and a ‘professional army ‘, made of a smaller set of mobile cells. Mobile and non mobile cells differ in their tuning abilities. Tuning extends the recognition capabilities of NONself by the mobile cells, which increase their defensive function. To prevent them to drift, which would compromise self/NONself discrimination, the more plastic mobile cells need to periodically refer to the more stable non mobile cells to keep within physiological standards.
      PubDate: 2016-05-03T15:18:28Z
      DOI: 10.12688/f1000research.8518.1
      Issue No: Vol. 5 (2016)
  • Time for sharing data to become routine: the seven excuses for not doing
           so are all invalid [version 1; referees: 2 approved, 1 approved with

    • Authors: Richard Smith, Ian Roberts
      Abstract: Data are more valuable than scientific papers but researchers are incentivised to publish papers not share data. Patients are the main beneficiaries of data sharing but researchers have several incentives not to share: others might use their data to get ahead in the academic rat race; they might be scooped; their results might not be replicable; competitors may reach different conclusions; their data management might be exposed as poor; patient confidentiality might be breached; and technical difficulties make sharing impossible. All of these barriers can be overcome and researchers should be rewarded for sharing data. Data sharing must become routine.
      PubDate: 2016-04-29T13:16:27Z
      DOI: 10.12688/f1000research.8422.1
      Issue No: Vol. 5 (2016)
  • The expanding regulatory universe of p53 in gastrointestinal cancer
           [version 1; referees: 2 approved]

    • Authors: Andrew Fesler, Ning Zhang, Jingfang Ju
      Abstract: Tumor suppresser gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. As a transcription factor, p53 regulates a number of important protein coding genes to control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. In addition, p53 is also able to activate the expression of a number of small non-coding microRNAs (miRNAs) through direct binding to the promoter region of these miRNAs.  Many miRNAs have been identified to be potential tumor suppressors by regulating key effecter target mRNAs. Our understanding of the regulatory network of p53 has recently expanded to include long non-coding RNAs (lncRNAs). Like miRNA, lncRNAs have been found to play important roles in cancer biology.  With our increased understanding of the important functions of these non-coding RNAs and their relationship with p53, we are gaining exciting new insights into the biology and function of cells in response to various growth environment changes. In this review we summarize the current understanding of the ever expanding involvement of non-coding RNAs in the p53 regulatory network and its implications for our understanding of gastrointestinal cancer.
      PubDate: 2016-04-26T15:08:10Z
      DOI: 10.12688/f1000research.8363.1
      Issue No: Vol. 5 (2016)
  • A computer model simulating human glucose absorption and metabolism in
           health and metabolic disease states [version 1; referees: 2 approved, 1
           approved with reservations]

    • Authors: Richard J. Naftalin
      Abstract: A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage.
      PubDate: 2016-04-12T11:54:28Z
      DOI: 10.12688/f1000research.8299.1
      Issue No: Vol. 5 (2016)
  • CyLineUp: A Cytoscape app for visualizing data in network small multiples
           [version 1; referees: 2 approved]

    • Abstract: CyLineUp is a Cytoscape 3 app for the projection of high-throughput measurement data from multiple experiments/samples on a network or pathway map using “small multiples”. This visualization method allows for easy comparison of different experiments in the context of the network or pathway. The user can import various kinds of measurement data and select any appropriate Cytoscape network or WikiPathways pathway map. CyLineUp creates small multiples by replicating the loaded network as many times as there are experiments/samples (e.g. time points, stress conditions, tissues, etc.). The measurement data for each experiment are then mapped onto the nodes (genes, proteins etc.) of the corresponding network using a color gradient. Each step of creating the visualization can be customized to the user’s needs. The results can be exported as a high quality vector image.
      PubDate: 2016-04-11T13:53:48Z
      DOI: 10.12688/f1000research.8402.1
      Issue No: Vol. 5 (2016)
  • A curated transcriptome dataset collection to investigate the functional
           programming of human hematopoietic cells in early life [version 1;
           referees: 2 approved]

    • Authors: Mahbuba Rahman, Sabri Boughorbel, Scott Presnell, Charlie Quinn, Chiara Cugno, Damien Chaussabel, Nico Marr
      Abstract: Compendia of large-scale datasets made available in public repositories provide an opportunity to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to research investigators for interpretation. Here we make available a collection of transcriptome datasets to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom web application called the Gene Expression Browser (GXB), which was designed for interactive query and visualization of integrated large-scale data. Quality control checks were performed. Multiple sample groupings and gene rank lists were created allowing users to reveal age-related differences in transcriptome profiles, changes in the gene expression of neonatal hematopoietic cells to a variety of immune stimulators and modulators, as well as during cell differentiation. Available demographic, clinical, and cell phenotypic information can be overlaid with the gene expression data and used to sort samples. Web links to customized graphical views can be generated and subsequently inserted in manuscripts to report novel findings. GXB also enables browsing of a single gene across projects, thereby providing new perspectives on age- and developmental stage-specific expression of a given gene across the human hematopoietic system. This dataset collection is available at:
      PubDate: 2016-03-30T10:59:34Z
      DOI: 10.12688/f1000research.8375.1
      Issue No: Vol. 5 (2016)
  • A pilot trial to examine the association between circulating endothelial
           cell levels and vascular injury in patients with diabetes and chronic
           kidney disease [version 1; referees: 2 approved]

    • Authors: Shayan Shirazian, Candace Grant, Vikash Rambhujun, Ritika Sharma, Ronak Patel, Shahidul Islam, Joseph Mattana
      Abstract: Objective While albuminuria is a marker for progressive chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM), both albuminuric and normoalbuminuric patients appear prone to vascular injury. This pilot study examines the association between circulating endothelial cell (CEC) levels and vascular injury in patients with T2DM and CKD. Methods In this cross-sectional study, eligible adult patients had T2DM, and stage 3 CKD (estimated glomerular filtration rate between 30 and 60 mL/min/1.73m2). CEC levels were tested by Janssen Diagnostics, LLC using an immuno-magnetic bead-based assay. CEC levels were compared to levels in a previously tested normal population. Correlations between CEC levels and other vascular injury markers (urine albumin, von-Willebrand factor antigen, hs-CRP, uric acid) were performed. Results Patients included 40 adults of which nineteen were normoalbuminuric.  Mean CEC levels (38.7, SD 38.1 cells) were significantly higher than the normal population (M = 21±18 cells, p
      PubDate: 2016-03-07T16:14:22Z
      DOI: 10.12688/f1000research.8005.1
      Issue No: Vol. 5 (2016)
  • Tripartite genome of all species [version 1; referees: 1 approved, 2
           approved with reservations]

    • Authors: MengPing Long, TaoBo Hu
      Abstract: Neutral theory has dominated the molecular evolution field for more than half a century, but it has been severely challenged by the recently emerged Maximum Genetic Diversity (MGD) theory. However, based on our recent work of tripartite human genome architecture, we found that MGD theory may have overlooked the regulatory but variable genomic regions that increase with species complexity. Here we propose a new molecular evolution theory named Increasing Functional Variation (IFV) hypothesis. According to the IFV hypothesis, the genome of all species is divided into three regions that are ‘functional and invariable’, ‘functional and variable’ and ‘non-functional and variable’. While the ‘non-functional and variable’ region decreases as species become more complex, the other two regions increase.
      PubDate: 2016-02-19T14:50:01Z
      DOI: 10.12688/f1000research.8008.1
      Issue No: Vol. 5 (2016)
  • Prediction of fine-tuned promoter activity from DNA sequence [version 1;
           referees: 1 approved, 2 approved with reservations]

    • Authors: Geoffrey Siwo, Andrew Rider, Asako Tan, Richard Pinapati, Scott Emrich, Nitesh Chawla, Michael Ferdig
      Abstract: The quantitative prediction of transcriptional activity of genes using promoter sequence is fundamental to the engineering of biological systems for industrial purposes and understanding the natural variation in gene expression. To catalyze the development of new algorithms for this purpose, the Dialogue on Reverse Engineering Assessment and Methods (DREAM) organized a community challenge seeking predictive models of promoter activity given normalized promoter activity data for 90 ribosomal protein promoters driving expression of a fluorescent reporter gene. By developing an unbiased modeling approach that performs an iterative search for predictive DNA sequence features using the frequencies of various k-mers, inferred DNA mechanical properties and spatial positions of promoter sequences, we achieved the best performer status in this challenge. The specific predictive features used in the model included the frequency of the nucleotide G, the length of polymeric tracts of T and TA, the frequencies of 6 distinct trinucleotides and 12 tetranucleotides, and the predicted protein deformability of the DNA sequence. Our method accurately predicted the activity of 20 natural variants of ribosomal protein promoters (Spearman correlation r = 0.73) as compared to 33 laboratory-mutated variants of the promoters (r = 0.57) in a test set that was hidden from participants. Notably, our model differed substantially from the rest in 2 main ways: i) it did not explicitly utilize transcription factor binding information implying that subtle DNA sequence features are highly associated with gene expression, and ii) it was entirely based on features extracted exclusively from the 100 bp region upstream from the translational start site demonstrating that this region encodes much of the overall promoter activity. The findings from this study have important implications for the engineering of predictable gene expression systems and the evolution of gene expression in naturally occurring biological systems.
      PubDate: 2016-02-11T13:38:30Z
      DOI: 10.12688/f1000research.7485.1
      Issue No: Vol. 5 (2016)
  • Case Report: Acute obstructive hydrocephalus associated with
           infratentorial extra-axial fluid collection following foramen magnum
           decompression and durotomy for Chiari malformation type I [version 1;
           referees: 2 approved]

    • Authors: Sunil Munakomi, Binod Bhattarai, Pramod Chaudhary
      Abstract: Acute obstructive hydrocephalus due to infratentorial extra-axial fluid collection (EAFC) is an extremely rare complication of foramen magnum decompression (FMD) and durotomy for Chiari malformation type I. Presence of infratentorial  EAFC invariably causes obstruction at the level of the fourth ventricle or aqueduct of Silvius, thereby indicating its definitive role in hydrocephalus. Pathogenesis of EAFC is said to be a local arachnoid tear as a result of durotomy, as this complication is not described in FMD without durotomy. Controversy exists in management. Usually EAFC is said to resolve with conservative management; so hydrocephalus doesn’t require treatment. However, in this case EAFC was progressive and ventriculo-peritoneal shunting (VPS) was needed for managing progressive and symptomatic hydrocephalus.
      PubDate: 2016-01-07T15:03:11Z
      DOI: 10.12688/f1000research.7627.1
      Issue No: Vol. 5 (2016)
  • The possible importance of income and education as covariates in cohort
           studies that investigate the relationship between diet and disease
           [version 2; referees: 2 approved]

    • Authors: Norman Temple
      Abstract: Background:  Many cohort studies have been carried out that have provided information on the relationship between diet and health-related outcomes. Omission of important covariates during multivariate analysis may give rise to error due to residual confounding. A possibly important covariate is socioeconomic status (SES) as this is related to both diet and health. Objective: To determine the frequency with which different measures of SES are included as covariates during multivariate analysis of cohort studies that investigated the relationship between diet and health. Methodology:  An analysis was carried out of 76 randomly selected papers from 66 cohort studies. The papers covered many dietary variables and a wide variety of diseases/health-related outcomes. The cohort studies were carried out in many different locations and the subjects varied widely in age. Results:  Approximately two-thirds of the papers (65.8%) used at least one measure of SES as a covariate. Education was used most often (60.5% of papers), followed by income (14.4%) and social class (2.6%). More than one measure of SES was used in 11.8% of papers. Conclusions:  Failure to include income (or another measure of present SES, such as occupation) may be a common source of error in cohort studies. Over-reliance on education may be particularly important as it is likely to be a weaker measure of present SES than is income. There is a need for more research on this question. SES in childhood is almost never included in multivariate analysis in cohort studies carried out on adults. This could also play a significant role in disease risk in middle age or later. Very little is known regarding whether this is also a source of residual confounding.
      PubDate: 2016-05-18T14:34:14Z
      DOI: 10.12688/f1000research.6929.2
      Issue No: Vol. 4 (2016)
  • Cannabis microbiome sequencing reveals several mycotoxic fungi native to
           dispensary grade Cannabis flowers [version 2; referees: 2 approved]

    • Authors: Kevin McKernan, Jessica Spangler, Lei Zhang, Vasisht Tadigotla, Yvonne Helbert, Theodore Foss, Douglas Smith
      Abstract: The Center for Disease Control estimates 128,000 people in the U.S. are hospitalized annually due to food borne illnesses. This has created a demand for food safety testing targeting the detection of pathogenic mold and bacteria on agricultural products. This risk extends to medical Cannabis and is of particular concern with inhaled, vaporized and even concentrated Cannabis products . As a result, third party microbial testing has become a regulatory requirement in the medical and recreational Cannabis markets, yet knowledge of the Cannabis microbiome is limited. Here we describe the first next generation sequencing survey of the fungal communities found in dispensary based Cannabis flowers by ITS2 sequencing, and demonstrate the sensitive detection of several toxigenic Penicillium and Aspergillus species, including P. citrinum and P. paxilli, that were not detected by one or more culture-based methods currently in use for safety testing.
      PubDate: 2016-05-10T15:07:15Z
      DOI: 10.12688/f1000research.7507.2
      Issue No: Vol. 4 (2016)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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