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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]
  • Overstimulation of the inhibitory nervous system plays a role in the
           pathogenesis of neuromuscular and neurological diseases: a novel
           hypothesis [version 2; referees: 2 approved]

    • Authors: Bert Tuk
      Abstract: Based upon a thorough review of published clinical observations regarding the inhibitory system, I hypothesize that this system may play a key role in the pathogenesis of a variety of neuromuscular and neurological diseases. Specifically, excitatory overstimulation, which is commonly reported in neuromuscular and neurological diseases, may be a homeostatic response to inhibitory overstimulation. Involvement of the inhibitory system in disease pathogenesis is highly relevant, given that most approaches currently being developed for treating neuromuscular and neurological diseases focus on reducing excitatory activity rather than reducing inhibitory activity.
      PubDate: 2016-08-19T15:15:34Z
      DOI: 10.12688/f1000research.8774.2
      Issue No: Vol. 5 (2016)
  • The rise and fall of infectious disease in a warmer world [version 1;
           referees: 2 approved]

    • Authors: Kevin D. Lafferty, Erin A. Mordecai
      Abstract: Now-outdated estimates proposed that climate change should have increased the number of people at risk of malaria, yet malaria and several other infectious diseases have declined. Although some diseases have increased as the climate has warmed, evidence for widespread climate-driven disease expansion has not materialized, despite increased research attention. Biological responses to warming depend on the non-linear relationships between physiological performance and temperature, called the thermal response curve. This leads performance to rise and fall with temperature. Under climate change, host species and their associated parasites face extinction if they cannot either thermoregulate or adapt by shifting phenology or geographic range. Climate change might also affect disease transmission through increases or decreases in host susceptibility and infective stage (and vector) production, longevity, and pathology. Many other factors drive disease transmission, especially economics, and some change in time along with temperature, making it hard to distinguish whether temperature drives disease or just correlates with disease drivers. Although it is difficult to predict how climate change will affect infectious disease, an ecological approach can help meet the challenge.
      PubDate: 2016-08-19T14:23:50Z
      DOI: 10.12688/f1000research.8766.1
      Issue No: Vol. 5 (2016)
  • Herpes simplex virus and the lexicon of latency and reactivation: a call
           for defining terms and building an integrated collective framework
           [version 1; referees: 2 approved]

    • Authors: Nancy M. Sawtell, Richard L. Thompson
      Abstract: The field of herpes simplex virus (HSV) latency and reactivation has been marked by controversy, which is not unexpected considering the complexities of the biology involved. While controversy is an important tool for digging to the bottom of difficult issues, we propose that unproductive conflict in the field arises in part from poorly defined terminology and the need for a collective framework. The uses of advanced global molecular and next-generation sequencing approaches and an increasing array of in vitro model systems have provided new molecular-level insights into HSV latency and reactivation, with the promise of expanding our concepts of these processes. However, our current framework and language are inadequate to effectively integrate new data streams into the established theories. In this brief perspective, we look back into the past to examine when and how the lexicon of HSV latency and reactivation arose in the literature and its evolution. We propose to open a dialogue among investigators for the purpose of updating and clearly defining terms used to describe these processes and to build a collective integrated framework to move our field forward.
      PubDate: 2016-08-19T13:34:22Z
      DOI: 10.12688/f1000research.8886.1
      Issue No: Vol. 5 (2016)
  • Linking Α to Ω: diverse and dynamic RNA-based mechanisms to
           regulate gene expression by 5′-to-3′ communication [version 1;
           referees: 2 approved]

    • Authors: Megan E. Filbin, Jeffrey S. Kieft
      Abstract: Communication between the 5′ and 3′ ends of a eukaryotic messenger RNA (mRNA) or viral genomic RNA is a ubiquitous and important strategy used to regulate gene expression. Although the canonical interaction between initiation factor proteins at the 5′ end of an mRNA and proteins bound to the polyadenylate tail at the 3′ end is well known, in fact there are many other strategies used in diverse ways. These strategies can involve “non-canonical” proteins, RNA structures, and direct RNA-RNA base-pairing between distal elements to achieve 5′-to-3′ communication. Likewise, the communication induced by these interactions influences a variety of processes linked to the use and fate of the RNA that contains them. Recent studies are revealing how dynamic these interactions are, possibly changing in response to cellular conditions or to link various phases of the mRNA’s life, from translation to decay. Thus, 5′-to-3′ communication is about more than just making a closed circle; the RNA elements and associated proteins are key players in controlling gene expression at the post-transcriptional level.
      PubDate: 2016-08-19T13:26:27Z
      DOI: 10.12688/f1000research.7913.1
      Issue No: Vol. 5 (2016)
  • Fine tuning of cytosolic Ca2+ oscillations [version 1; referees: 3

    • Abstract: Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca2+ exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca2+ changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca2+ are controlled not only by the frequency of Ca2+ oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca2+ stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca2+ oscillations. The main characteristics of the Ca2+ exchange fluxes with these compartments are also reviewed.
      PubDate: 2016-08-19T10:10:18Z
      DOI: 10.12688/f1000research.8438.1
      Issue No: Vol. 5 (2016)
  • Advances in gene therapy for muscular dystrophies [version 1; referees: 2

    • Authors: Hayder Abdul-Razak, Alberto Malerba, George Dickson
      Abstract: Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.
      PubDate: 2016-08-18T09:55:42Z
      DOI: 10.12688/f1000research.8735.1
      Issue No: Vol. 5 (2016)
  • Autosomal dominant polycystic kidney disease: recent advances in clinical
           management [version 1; referees: 2 approved]

    • Authors: Zhiguo Mao, Jiehan Chong, Albert C. M. Ong
      Abstract: The first clinical descriptions of autosomal dominant polycystic kidney disease (ADPKD) go back at least 500 years to the late 16th century. Advances in understanding disease presentation and pathophysiology have mirrored the progress of clinical medicine in anatomy, pathology, physiology, cell biology, and genetics. The identification of PKD1 and PKD2, the major genes mutated in ADPKD, has stimulated major advances, which in turn have led to the first approved drug for this disorder and a fresh reassessment of patient management in the 21st century. In this commentary, we consider how clinical management is likely to change in the coming decade.
      PubDate: 2016-08-18T09:09:53Z
      DOI: 10.12688/f1000research.9045.1
      Issue No: Vol. 5 (2016)
  • Developing new therapeutic approaches for rheumatoid arthritis: the
           continuing challenges of clinical assessments [version 1; referees: 3

    • Authors: David L. Scott
      Abstract: The management of rheumatoid arthritis has changed dramatically over the last three decades. Improvements in clinical assessment have been a key driver of these changes. However, in the last five years, three areas of unresolved uncertainty have dominated specialist thinking in the field. These challenges comprise identifying the optimal management target, determining how best to reach this target by using intensive treatments, and individualising management because not all patients need or respond to identical treatments. The key problem that links each of these areas is balancing different types of evidence and is most readily appreciated in relation to treatment intensity. Giving more intensive therapy improves outcomes but also increases risks and, with biologic treatments, substantially increases drug costs. Specialists and healthcare funders need to agree on how best to rationalise optimal care for patients with what is most effective and safe and what is affordable.
      PubDate: 2016-08-17T13:06:40Z
      DOI: 10.12688/f1000research.8812.1
      Issue No: Vol. 5 (2016)
  • Vitamin D supplementation: less controversy, more guidance needed [version
           1; referees: 3 approved]

    • Authors: Caroline S. Stokes, Frank Lammert
      Abstract: Vitamin D is a secosteroid hormone with multiple functions that extend beyond the regulation of intestinal calcium absorption. In recent years, the publication of research articles investigating associations between vitamin D status and health has reached an all-time high, and an increase in supplementation studies has followed. Given the pleiotropic effects of vitamin D, the scientific focus has gone beyond its known classic benefits on skeletal health to include diabetes and cardiovascular, neurological, respiratory, renal, and liver diseases, yet numerous conflicting findings continue to emerge. This review presents some examples of recent work within the context of controversies surrounding vitamin D and highlights key factors that should be considered when designing vitamin D supplementation regimens.
      PubDate: 2016-08-17T09:18:36Z
      DOI: 10.12688/f1000research.8863.1
      Issue No: Vol. 5 (2016)
  • Recent advances in the treatment of hip fractures in the elderly [version
           1; referees: 2 approved]

    • Authors: Joshua C. Rozell, Mark Hasenauer, Derek J. Donegan, Mark Neuman
      Abstract: The treatment of hip fractures in the elderly represents a major public health priority and a source of ongoing debate among orthopaedic surgeons and anesthesiologists. Most of these injuries are treated with surgery in an expedient fashion. From the surgical perspective, there are certain special considerations in this population including osteoporosis, pre-existing arthritis, age, activity level, and overall health that contribute to the type of surgical fixation performed. Open reduction and internal fixation versus arthroplasty remain the two major categories of treatment. While the indications and treatment algorithms still remain controversial, the overall goal for these patients is early mobilization and prevention of morbidity and mortality. The use of preoperative, regional anesthesia has aided in this effort. The purpose of this review article is to examine the various treatment modalities for hip fractures in the elderly and discuss the most recent evidence in the face of a rapidly aging population.
      PubDate: 2016-08-11T14:50:36Z
      DOI: 10.12688/f1000research.8172.1
      Issue No: Vol. 5 (2016)
  • Intracellular targeting with engineered proteins [version 1; referees: 2

    • Authors: Shane Miersch, Sachdev S. Sidhu
      Abstract: If the isolation, production, and clinical use of insulin marked the inception of the age of biologics as therapeutics, the convergence of molecular biology and combinatorial engineering techniques marked its coming of age. The first wave of recombinant protein-based drugs in the 1980s demonstrated emphatically that proteins could be engineered, formulated, and employed for clinical advantage. Yet despite the successes of protein-based drugs such as antibodies, enzymes, and cytokines, the druggable target space for biologics is currently restricted to targets outside the cell. Insofar as estimates place the number of proteins either secreted or with extracellular domains in the range of 8000 to 9000, this represents only one-third of the proteome and circumscribes the pathways that can be targeted for therapeutic intervention. Clearly, a major objective for this field to reach maturity is to access, interrogate, and modulate the majority of proteins found inside the cell. However, owing to the large size, complex architecture, and general cellular impermeability of existing protein-based drugs, this poses a daunting challenge. In recent years, though, advances on the two related fronts of protein engineering and drug delivery are beginning to bring this goal within reach. First, prompted by the restrictions that limit the applicability of antibodies, intense efforts have been applied to identifying and engineering smaller alternative protein scaffolds for the modulation of intracellular targets. In parallel, innovative solutions for delivering proteins to the intracellular space while maintaining their stability and functional activity have begun to yield successes. This review provides an overview of bioactive intrabodies and alternative protein scaffolds amenable to engineering for intracellular targeting and also outlines advances in protein engineering and formulation for delivery of functional proteins to the interior of the cell to achieve therapeutic action.
      PubDate: 2016-08-10T14:10:37Z
      DOI: 10.12688/f1000research.8915.1
      Issue No: Vol. 5 (2016)
  • Perinatal neuroprotection update [version 1; referees: 2 approved]

    • Authors: Angie C. Jelin, Kirsten Salmeen, Dawn Gano, Irina Burd, Mari-Paule Thiet
      Abstract: Antepartum, intrapartum, and neonatal events can result in a spectrum of long-term neurological sequelae, including cerebral palsy, cognitive delay, schizophrenia, and autism spectrum disorders [1]. Advances in obstetrical and neonatal care have led to survival at earlier gestational ages and consequently increasing numbers of periviable infants who are at significant risk for long-term neurological deficits. Therefore, efforts to decrease and prevent cerebral insults attempt not only to decrease preterm delivery but also to improve neurological outcomes in infants delivered preterm. We recently published a comprehensive review addressing the impacts of magnesium sulfate, therapeutic hypothermia, delayed cord clamping, infections, and prevention of preterm delivery on the modification of neurological risk [2]. In this review, we will briefly provide updates to the aforementioned topics as well as an expansion on avoidance of toxin and infections, specifically the Zika virus.
      PubDate: 2016-08-09T11:28:12Z
      DOI: 10.12688/f1000research.8546.1
      Issue No: Vol. 5 (2016)
  • Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief
           review and recent update [version 1; referees: 2 approved]

    • Authors: Jung Yong Hong, Cheolwon Suh, Won Seog Kim
      Abstract: Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL.
      PubDate: 2016-08-08T13:25:32Z
      DOI: 10.12688/f1000research.8790.1
      Issue No: Vol. 5 (2016)
  • Case Report: ALCAPA syndrome: successful repair with an anatomical and
           physiological alternative surgical technique [version 2; referees: 2

    • Abstract: Anomalous left coronary artery from the pulmonary artery, or ALCAPA syndrome, is a rare congenital cardiac disease that can cause myocardial infarction, heart failure and even death in paediatric patients. Only few untreated patients survive until adult age. Here we present the case of a 33-year-old female patient with paroxysmal tachycardia, syncope and mild exertional dyspnoea. She was diagnosed with ALCAPA syndrome and underwent surgical correction with an alternative technique of left main coronary artery extension to the aorta.
      PubDate: 2016-08-03T11:29:26Z
      DOI: 10.12688/f1000research.8823.2
      Issue No: Vol. 5 (2016)
  • Recent advances in cohesin biology [version 1; referees: 4 approved]

    • Authors: Susannah Rankin, Dean S. Dawson
      Abstract: Sister chromatids are tethered together from the time they are formed in S-phase until they separate at anaphase. A protein complex called cohesin is responsible for holding the sister chromatids together and serves important roles in chromosome condensation, gene regulation, and the repair of DNA damage. Cohesin contains an open central pore and becomes topologically engaged with its DNA substrates. Entrapped DNA can be released either by the opening of a gate in the cohesin ring or by proteolytic cleavage of a component of the ring. This review summarizes recent research that provides important new insights into how DNA enters and exits the cohesin ring and how the rings behave on entrapped DNA molecules to provide functional cohesion.
      PubDate: 2016-08-03T11:07:35Z
      DOI: 10.12688/f1000research.8881.1
      Issue No: Vol. 5 (2016)
  • Biomedical Mutation Analysis (BMA): A software tool for analyzing
           mutations associated with antiviral resistance [version 2; referees: 2

    • Authors: Karina Salvatierra, Hector Florez
      Abstract: Introduction: Hepatitis C virus (HCV) is considered a major public health problem, with 200 million people infected worldwide. The treatment for HCV chronic infection with pegylated interferon alpha plus ribavirin inhibitors is unspecific; consequently, the treatment is effective in only 50% of patients infected. This has prompted the development of direct-acting antivirals (DAA) that target virus proteins. These DAA have demonstrated a potent effect in vitro and in vivo; however, virus mutations associated with the development of resistance have been described. Objective: To design and develop an online information system for detecting mutations in amino acids known to be implicated in resistance to DAA. Materials and methods:    We have used computer applications, technological tools, standard languages, infrastructure systems and algorithms, to analyze positions associated with resistance to DAA for the NS3, NS5A, and NS5B genes of HCV. Results: We have designed and developed an online information system named Biomedical Mutation Analysis (BMA), which allows users to calculate changes in nucleotide and amino acid sequences for each selected sequence from conventional Sanger and cloning sequencing using a graphical interface. Conclusion: BMA quickly, easily and effectively analyzes mutations, including complete documentation and examples. Furthermore, the development of different visualization techniques allows proper interpretation and understanding of the results. The data obtained using BMA will be useful for the assessment and surveillance of HCV resistance to new antivirals, and for the treatment regimens by selecting those DAA to which the virus is not resistant, avoiding unnecessary treatment failures. The software is available at:
      PubDate: 2016-08-02T13:42:51Z
      DOI: 10.12688/f1000research.8740.2
      Issue No: Vol. 5 (2016)
  • Disorders of gastrointestinal hypomotility [version 1; referees: 2

    • Authors: Klaus Bielefeldt, Ashok Tuteja, Salman Nusrat
      Abstract: Ingestion and digestion of food as well as expulsion of residual material from our gastrointestinal tract requires normal propulsive, i.e. motor, function. Hypomotility refers to inherited or acquired changes that come with decreased contractile forces or slower transit. It not only often causes symptoms but also may compromise nutritional status or lead to other complications. While severe forms, such as pseudo-obstruction or ileus, may have a tremendous functional impact, the less severe forms of hypomotility may well be more relevant, as they contribute to common disorders, such as functional dyspepsia, gastroparesis, chronic constipation, and irritable bowel syndrome (IBS). Clinical testing can identify changes in contractile activity, defined by lower amplitudes or abnormal patterns, and the related effects on transit. However, such biomarkers show a limited correlation with overall symptom severity as experienced by patients. Similarly, targeting hypomotility with pharmacological interventions often alters gut motor function but does not consistently improve symptoms. Novel diagnostic approaches may change this apparent paradox and enable us to obtain more comprehensive information by integrating data on electrical activity, mechanical forces, patterns, wall stiffness, and motions with information of the flow of luminal contents. New drugs with more selective effects or more specific delivery may improve benefits and limit adverse effects. Lastly, the complex regulation of gastrointestinal motility involves the brain-gut axis as a reciprocal pathway for afferent and efferent signaling. Considering the role of visceral input in emotion and the effects of emotion on visceral activity, understanding and managing hypomotility disorders requires an integrative approach based on the mind-body continuum or biopsychosocial model of diseases.
      PubDate: 2016-08-01T14:29:07Z
      DOI: 10.12688/f1000research.8658.1
      Issue No: Vol. 5 (2016)
  • Autophagy- An emerging target for melanoma therapy [version 1; referees: 2

    • Authors: Abibatou Ndoye, Ashani T. Weeraratna
      Abstract: Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation.
      PubDate: 2016-07-29T10:45:45Z
      DOI: 10.12688/f1000research.8347.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding neurotrophin signaling [version 1;
           referees: 2 approved]

    • Authors: Mark Bothwell
      Abstract: The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75NTR, a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively. However, both receptor classes also possess neurotrophin-independent signaling functions. Signaling functions of p75NTR and Trk receptors are each influenced by the other class of receptors. This review focuses on the mechanisms responsible for the functional interplay between the two neurotrophin receptor signaling systems.
      PubDate: 2016-07-28T15:00:20Z
      DOI: 10.12688/f1000research.8434.1
      Issue No: Vol. 5 (2016)
  • A current view of serotonin transporters [version 1; referees: 3 approved]

    • Authors: Louis J. De Felice
      Abstract: Serotonin transporters (SERTs) are largely recognized for one aspect of their function—to transport serotonin back into the presynaptic terminal after its release. Another aspect of their function, however, may be to generate currents large enough to have physiological consequences. The standard model for electrogenic transport is the alternating access model, in which serotonin is transported with a fixed ratio of co-transported ions resulting in net charge per cycle. The alternating access model, however, cannot account for all the observed currents through SERT or other monoamine transporters.  Furthermore, SERT agonists like ecstasy or antagonists like fluoxetine generate or suppress currents that the standard model cannot support.  Here we survey evidence for a channel mode of transport in which transmitters and ions move through a pore. Available structures for dopamine and serotonin transporters, however, provide no evidence for a pore conformation, raising questions of whether the proposed channel mode actually exists or whether the structural data are perhaps missing a transient open state.
      PubDate: 2016-07-28T13:29:18Z
      DOI: 10.12688/f1000research.8384.1
      Issue No: Vol. 5 (2016)
  • An overview of cutaneous T cell lymphomas [version 1; referees: 2

    • Authors: Nooshin Bagherani, Bruce R. Smoller
      Abstract: Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields.
      PubDate: 2016-07-28T11:29:16Z
      DOI: 10.12688/f1000research.8829.1
      Issue No: Vol. 5 (2016)
  • Recent advances in pathogenesis, assessment, and treatment of
           atherosclerosis [version 1; referees: 3 approved]

    • Authors: J. David Spence
      Abstract: In recent years, there have been a number of advances in the pathogenesis and treatment of atherosclerosis and in assessing prognosis in carotid atherosclerosis. Risk stratification to improve vascular prevention by identifying patients most likely to benefit from intensive therapy is much improved by measuring carotid plaque burden. In patients with asymptomatic carotid stenosis, a number of modalities can be used to identify the 10-15% who could benefit from endarterectomy or stenting. Transcranial Doppler embolus detection, echolucency and ulceration on 3D ultrasound, intraplaque hemorrhage on magnetic resonance imaging (MRI), and reduced cerebrovascular reserve are useful already; new approaches including plaque texture on ultrasound and imaging of plaque inflammation and early calcification on positron emission tomography/computed tomography (PET/CT) are in development. The discovery that the intestinal microbiome produces vasculotoxic metabolites from dietary constituents such as carnitine in meat (particularly red meat) and phosphatidylcholine from egg yolk and other sources has revolutionized nutritional aspects of vascular prevention. Because many of these vasculotoxic metabolites are removed by the kidney, it is particularly important in patients with renal failure to limit their intake of red meat and egg yolk. A new approach to lowering low-density lipoprotein (LDL) cholesterol by blocking the action of an enzyme that destroys LDL receptors promises to revolutionize vascular prevention once less costly treatments are developed, and a new approach to vascular prevention—“treating arteries instead of risk factors”—shows promise but requires randomized trials. These advances all promise to help in the quest to prevent strokes in high-risk patients.
      PubDate: 2016-07-28T09:34:17Z
      DOI: 10.12688/f1000research.8459.1
      Issue No: Vol. 5 (2016)
  • Mapping paths: new approaches to dissect eukaryotic signaling circuitry
           [version 1; referees: 3 approved]

    • Authors: Nebibe Mutlu, Anuj Kumar
      Abstract: Eukaryotic cells are precisely “wired” to coordinate changes in external and intracellular signals with corresponding adjustments in the output of complex and often interconnected signaling pathways. These pathways are critical in understanding cellular growth and function, and several experimental trends are emerging with applicability toward more fully describing the composition and topology of eukaryotic signaling networks. In particular, recent studies have implemented CRISPR/Cas-based screens in mouse and human cell lines for genes involved in various cell growth and disease phenotypes. Proteomic methods using mass spectrometry have enabled quantitative and dynamic profiling of protein interactions, revealing previously undiscovered complexes and allele-specific protein interactions. Methods for the single-cell study of protein localization and gene expression have been integrated with computational analyses to provide insight into cell signaling in yeast and metazoans. In this review, we present an overview of exemplary studies using the above approaches, relevant for the analysis of cell signaling and indeed, more broadly, for many modern biological applications.
      PubDate: 2016-07-27T15:00:03Z
      DOI: 10.12688/f1000research.8818.1
      Issue No: Vol. 5 (2016)
  • Tuning cell migration: contractility as an integrator of intracellular
           signals from multiple cues [version 1; referees: 2 approved]

    • Authors: Francois Bordeleau, Cynthia A. Reinhart-King
      Abstract: There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors.
      PubDate: 2016-07-26T13:43:02Z
      DOI: 10.12688/f1000research.7884.1
      Issue No: Vol. 5 (2016)
  • A multi-site cutting device implements efficiently the divide-and-conquer
           strategy in tumor sampling [version 2; referees: 2 approved, 1 approved
           with reservations]

    • Authors: Jose I. Lopez, Jesus M. Cortes
      Abstract: We recently showed that in order to detect intra-tumor heterogeneity a Divide-and-Conquer (DAC) strategy of tumor sampling outperforms current routine protocols. This paper is a continuation of this work, but here we focus on DAC implementation in the Pathology Laboratory. In particular, we describe a new simple method that makes use of a cutting grid device and is applied to clear cell renal cell carcinomas for DAC implementation. This method assures a thorough sampling of large surgical specimens, facilitates the demonstration of intratumor heterogeneity, and saves time to pathologists in the daily practice. The method involves the following steps: 1. Thin slicing of the tumor (by hand or machine), 2. Application of a cutting grid to the slices (e.g., a French fry cutter), resulting in multiple tissue cubes with fixed position within the slice, 3. Selection of tissue cubes for analysis, and finally, 4. Inclusion of selected cubes into a cassette for histological processing (with about eight tissue fragments within each cassette). Thus, using our approach in a 10 cm in-diameter-tumor we generate 80 tumor tissue fragments placed in 10 cassettes and, notably, in a tenth of time. Eighty samples obtained across all the regions of the tumor will assure a much higher performance in detecting intratumor heterogeneity, as proved recently with synthetic data.
      PubDate: 2016-07-26T13:39:23Z
      DOI: 10.12688/f1000research.9091.2
      Issue No: Vol. 5 (2016)
  • Regenerating the liver: not so simple after all' [version 1; referees:
           3 approved]

    • Authors: Malcolm R. Alison, Wey-Ran Lin
      Abstract: Under normal homeostatic conditions, hepatocyte renewal is a slow process and complete turnover likely takes at least a year. Studies of hepatocyte regeneration after a two-thirds partial hepatectomy (2/3 PH) have strongly suggested that periportal hepatocytes are the driving force behind regenerative re-population, but recent murine studies have brought greater complexity to the issue. Although periportal hepatocytes are still considered pre-eminent in the response to 2/3 PH, new studies suggest that normal homeostatic renewal is driven by pericentral hepatocytes under the control of Wnts, while pericentral injury provokes the clonal expansion of a subpopulation of periportal hepatocytes expressing low levels of biliary duct genes such as Sox9 and osteopontin. Furthermore, some clarity has been given to the debate on the ability of biliary-derived hepatic progenitor cells to generate physiologically meaningful numbers of hepatocytes in injury models, demonstrating that under appropriate circumstances these cells can re-populate the whole liver.
      PubDate: 2016-07-26T13:09:11Z
      DOI: 10.12688/f1000research.8827.1
      Issue No: Vol. 5 (2016)
  • Gallstones: new insights into an old story [version 1; referees: 3

    • Authors: Evan Tiderington, Sum P. Lee, Cynthia W. Ko
      Abstract: Gallstones, particularly cholesterol gallstones, are common in Western populations and may cause symptoms such as biliary colic or complications such as acute cholecystitis or gallstone pancreatitis. Recent studies have allowed for a better understanding of the risk of symptoms or complications in patients with gallstones. In addition, newer data suggest an association of gallstones with overall mortality, cardiovascular disease, gastrointestinal cancers, and non-alcoholic fatty liver disease. Knowledge of appropriate indications and timing of cholecystectomy, particularly for mild biliary pancreatitis, has gradually accumulated. Lastly, there are exciting possibilities for novel agents to treat or prevent cholesterol stone disease. This review covers new advances in our understanding of the natural history, clinical associations, and management of gallstone disease.
      PubDate: 2016-07-26T12:58:52Z
      DOI: 10.12688/f1000research.8874.1
      Issue No: Vol. 5 (2016)
  • Novel insights into mitotic chromosome condensation [version 1; referees:
           2 approved]

    • Authors: Ewa Piskadlo, Raquel A. Oliveira
      Abstract: The fidelity of mitosis is essential for life, and successful completion of this process relies on drastic changes in chromosome organization at the onset of nuclear division. The mechanisms that govern chromosome compaction at every cell division cycle are still far from full comprehension, yet recent studies provide novel insights into this problem, challenging classical views on mitotic chromosome assembly. Here, we briefly introduce various models for chromosome assembly and known factors involved in the condensation process (e.g. condensin complexes and topoisomerase II). We will then focus on a few selected studies that have recently brought novel insights into the mysterious way chromosomes are condensed during nuclear division.
      PubDate: 2016-07-25T14:21:22Z
      DOI: 10.12688/f1000research.8727.1
      Issue No: Vol. 5 (2016)
  • Horizontal gene transfer: essentiality and evolvability in prokaryotes,
           and roles in evolutionary transitions [version 1; referees: 2 approved]

    • Authors: Eugene V. Koonin
      Abstract: The wide spread of gene exchange and loss in the prokaryotic world has prompted the concept of ‘lateral genomics’ to the point of an outright denial of the relevance of phylogenetic trees for evolution. However, the pronounced coherence congruence of the topologies of numerous gene trees, particularly those for (nearly) universal genes, translates into the notion of a statistical tree of life (STOL), which reflects a central trend of vertical evolution. The STOL can be employed as a framework for reconstruction of the evolutionary processes in the prokaryotic world. Quantitatively, however, horizontal gene transfer (HGT) dominates microbial evolution, with the rate of gene gain and loss being comparable to the rate of point mutations and much greater than the duplication rate. Theoretical models of evolution suggest that HGT is essential for the survival of microbial populations that otherwise deteriorate due to the Muller’s ratchet effect. Apparently, at least some bacteria and archaea evolved dedicated vehicles for gene transfer that evolved from selfish elements such as plasmids and viruses. Recent phylogenomic analyses suggest that episodes of massive HGT were pivotal for the emergence of major groups of organisms such as multiple archaeal phyla as well as eukaryotes. Similar analyses appear to indicate that, in addition to donating hundreds of genes to the emerging eukaryotic lineage, mitochondrial endosymbiosis severely curtailed HGT. These results shed new light on the routes of evolutionary transitions, but caution is due given the inherent uncertainty of deep phylogenies.
      PubDate: 2016-07-25T13:11:11Z
      DOI: 10.12688/f1000research.8737.1
      Issue No: Vol. 5 (2016)
  • Varicocele – a case for early intervention [version 1; referees: 3

    • Authors: Phil V. Bach, Bobby B. Najari, Marc Goldstein
      Abstract: Testicular varicocele, which is defined as the dilation of the veins draining the testicle, has long been associated with a detrimental effect on testicular function. Despite a lack of high-quality, prospective data, recent evidence has shed light on potential links between varicocele and male infertility and serum testosterone levels. Similarly, varicocele repair has increasingly been shown to have a beneficial impact on pregnancy rates, semen parameters, and on improving serum testosterone in adult men. Numerous studies have assessed the optimal technique for varicocele repair and the bulk of the evidence has shown the microsurgical inguinal/subinguinal approach to have the highest success rates, the lowest overall complication rates, and the lowest recurrence rates. The management of varicocele in adolescents remains a clinical conundrum, but contemporary evidence suggests early deleterious effects of varicocele on testicular function in some patients. Well-designed prospective trials are critical to delineate the true impact and role of varicocele repair on male infertility and hypogonadism in adult and adolescent men.
      PubDate: 2016-07-22T14:38:45Z
      DOI: 10.12688/f1000research.7179.1
      Issue No: Vol. 5 (2016)
  • Networks of fibers and factors: regulation of capsule formation in
           Cryptococcus neoformans [version 1; referees: 5 approved]

    • Abstract: The ability of the pathogenic fungus Cryptococcus neoformans to cause life-threatening meningoencephalitis in immunocompromised individuals is due in large part to elaboration of a capsule consisting of polysaccharide fibers. The size of the cell-associated capsule is remarkably responsive to a variety of environmental and host conditions, but the mechanistic details of the regulation, synthesis, trafficking, and attachment of the polysaccharides are poorly understood. Recent studies reveal a complex network of transcription factors that influence capsule elaboration in response to several different signals of relevance to disease (e.g., iron deprivation). The emerging complexity of the network is consistent with the diversity of conditions that influence the capsule and illustrates the responsiveness of the fungus to both the environment and mammalian hosts.
      PubDate: 2016-07-22T09:53:01Z
      DOI: 10.12688/f1000research.8854.1
      Issue No: Vol. 5 (2016)
  • Does sadness impair color perception' Flawed evidence and faulty
           methods [version 1; referees: 2 approved]

    • Authors: Alex O. Holcombe, Nicholas J. L. Brown, Patrick T. Goodbourn, Alexander Etz, Sebastian Geukes
      Abstract: In their 2015 paper, Thorstenson, Pazda, and Elliot offered evidence from two experiments that perception of colors on the blue–yellow axis was impaired if the participants had watched a sad movie clip, compared to participants who watched clips designed to induce a happy or neutral mood. Subsequently, these authors retracted their article, citing a mistake in their statistical analyses and a problem with the data in one of their experiments. Here, we discuss a number of other methodological problems with Thorstenson et al.’s experimental design, and also demonstrate that the problems with the data go beyond what these authors reported. We conclude that repeating one of the two experiments, with the minor revisions proposed by Thorstenson et al., will not be sufficient to address the problems with this work.
      PubDate: 2016-07-21T09:59:02Z
      DOI: 10.12688/f1000research.9202.1
      Issue No: Vol. 5 (2016)
  • Long noncoding RNAs in hematopoiesis [version 1; referees: 2 approved]

    • Authors: Xu Zhang, Wenqian Hu
      Abstract: Mammalian development is under tight control to ensure precise gene expression. Recent studies reveal a new layer of regulation of gene expression mediated by long noncoding RNAs. These transcripts are longer than 200nt that do not have functional protein coding capacity. Interestingly, many of these long noncoding RNAs are expressed with high specificity in different types of cells, tissues, and developmental stages in mammals, suggesting that they may have functional roles in diverse biological processes. Here, we summarize recent findings of long noncoding RNAs in hematopoiesis, which is one of the best-characterized mammalian cell differentiation processes. Then we provide our own perspectives on future studies of long noncoding RNAs in this field.
      PubDate: 2016-07-20T15:37:59Z
      DOI: 10.12688/f1000research.8349.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding cardiac contractility in health and
           disease [version 1; referees: 4 approved]

    • Authors: Ken T. MacLeod
      Abstract: The aim of this review is to provide the reader with a synopsis of some of the emerging ideas and experimental findings in cardiac physiology and pathophysiology that were published in 2015. To provide context for the non-specialist, a brief summary of cardiac contraction and calcium (Ca) regulation in the heart in health and disease is provided. Thereafter, some recently published articles are introduced that indicate the current thinking on (1) the Ca regulatory pathways modulated by Ca/calmodulin-dependent protein kinase II, (2) the potential influences of nitrosylation by nitric oxide or S-nitrosated proteins, (3) newly observed effects of reactive oxygen species (ROS) on contraction and Ca regulation following myocardial infarction and a possible link with changes in mitochondrial Ca, and (4) the effects of some of these signaling pathways on late Na current and pro-arrhythmic afterdepolarizations as well as the effects of transverse tubule disturbances.
      PubDate: 2016-07-20T15:19:56Z
      DOI: 10.12688/f1000research.8661.1
      Issue No: Vol. 5 (2016)
  • How much is a pheromone worth' [version 1; referees: 2 approved]

    • Authors: Jose Mauricio S. Bento, Jose Roberto P. Parra, Silvia H. G. de Miranda, Andrea C. O. Adami, Evaldo F. Vilela, Walter S. Leal
      Abstract: Pheromone-baited traps have been widely used in integrated pest management programs, but their economic value for growers has never been reported.  We analyzed the economic benefits of long-term use of traps baited with the citrus fruit borer Gymnandrosoma aurantianum sex pheromone in Central-Southern Brazil. Our analysis show that from 2001 to 2013 citrus growers avoided accumulated pest losses of 132.7 million to 1.32 billion USD in gross revenues, considering potential crop losses in the range of 5 to 50%. The area analyzed, 56,600 to 79,100 hectares of citrus (20.4 to 29.4 million trees), corresponds to 9.7 to 13.5% of the total area planted with citrus in the state of São Paulo. The data show a benefit-to-cost ratio of US$ 2,655 to US$ 26,548 per dollar spent on research with estimated yield loss prevented in the range of 5-50%, respectively. This study demonstrates that, in addition to the priceless benefits for the environment, sex pheromones are invaluable tools for growers as their use for monitoring populations allows rational and reduced use of insecticides, a win-win situation.
      PubDate: 2016-07-20T10:56:03Z
      DOI: 10.12688/f1000research.9195.1
      Issue No: Vol. 5 (2016)
  • search.bioPreprint: a discovery tool for cutting edge, preprint biomedical
           research articles [version 2; referees: 2 approved]

    • Authors: Carrie L. Iwema, John LaDue, Angela Zack, Ansuman Chattopadhyay
      Abstract: The time it takes for a completed manuscript to be published traditionally can be extremely lengthy. Article publication delay, which occurs in part due to constraints associated with peer review, can prevent the timely dissemination of critical and actionable data associated with new information on rare diseases or developing health concerns such as Zika virus. Preprint servers are open access online repositories housing preprint research articles that enable authors (1) to make their research immediately and freely available and (2) to receive commentary and peer review prior to journal submission. There is a growing movement of preprint advocates aiming to change the current journal publication and peer review system, proposing that preprints catalyze biomedical discovery, support career advancement, and improve scientific communication. While the number of articles submitted to and hosted by preprint servers are gradually increasing, there has been no simple way to identify biomedical research published in a preprint format, as they are not typically indexed and are only discoverable by directly searching the specific preprint server websites. To address this issue, we created a search engine that quickly compiles preprints from disparate host repositories and provides a one-stop search solution. Additionally, we developed a web application that bolsters the discovery of preprints by enabling each and every word or phrase appearing on any web site to be integrated with articles from preprint servers. This tool, search.bioPreprint, is publicly available at
      PubDate: 2016-07-20T10:54:27Z
      DOI: 10.12688/f1000research.8798.2
      Issue No: Vol. 5 (2016)
  • Detecting variable responses in time-series using repeated measures ANOVA:
           Application to physiologic challenges [version 2; referees: 2 approved]

    • Authors: Paul M. Macey, Philip J. Schluter, Katherine E. Macey, Ronald M. Harper
      Abstract: We present an approach to analyzing physiologic timetrends recorded during a stimulus by comparing means at each time point using repeated measures analysis of variance (RMANOVA). The approach allows temporal patterns to be examined without an a priori model of expected timing or pattern of response. The approach was originally applied to signals recorded from functional magnetic resonance imaging (fMRI) volumes-of-interest (VOI) during a physiologic challenge, but we have used the same technique to analyze continuous recordings of other physiological signals such as heart rate, breathing rate, and pulse oximetry. For fMRI, the method serves as a complement to whole-brain voxel-based analyses, and is useful for detecting complex responses within pre-determined brain regions, or as a post-hoc analysis of regions of interest identified by whole-brain assessments. We illustrate an implementation of the technique in the statistical software packages R and SAS. VOI timetrends are extracted from conventionally preprocessed fMRI images. A timetrend of average signal intensity across the VOI during the scanning period is calculated for each subject. The values are scaled relative to baseline periods, and time points are binned. In SAS, the procedure PROC MIXED implements the RMANOVA in a single step. In R, we present one option for implementing RMANOVA with the mixed model function “lme”. Model diagnostics, and predicted means and differences are best performed with additional libraries and commands in R; we present one example. The ensuing results allow determination of significant overall effects, and time-point specific within- and between-group responses relative to baseline. We illustrate the technique using fMRI data from two groups of subjects who underwent a respiratory challenge. RMANOVA allows insight into the timing of responses and response differences between groups, and so is suited to physiologic testing paradigms eliciting complex response patterns.
      PubDate: 2016-07-08T10:43:06Z
      DOI: 10.12688/f1000research.8252.2
      Issue No: Vol. 5 (2016)
  • Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based
           therapy for hepatitis C virus (HCV) infection-related diseases in the era
           of direct-acting antiviral agents [version 2; referees: 2 approved]

    • Authors: Sara Kishta, Reem EI-Shenawy, Sobhy Kishta
      Abstract: Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.
      PubDate: 2016-07-07T13:33:19Z
      DOI: 10.12688/f1000research.7970.2
      Issue No: Vol. 5 (2016)
  • An open RNA-Seq data analysis pipeline tutorial with an example of
           reprocessing data from a recent Zika virus study [version 1; referees: 2

    • Authors: Zichen Wang, Avi Ma'ayan
      Abstract: RNA-seq analysis is becoming a standard method for global gene expression profiling. However, open and standard pipelines to perform RNA-seq analysis by non-experts remain challenging due to the large size of the raw data files and the hardware requirements for running the alignment step. Here we introduce a reproducible open source RNA-seq pipeline delivered as an IPython notebook and a Docker image. The pipeline uses state-of-the-art tools and can run on various platforms with minimal configuration overhead. The pipeline enables the extraction of knowledge from typical RNA-seq studies by generating interactive principal component analysis (PCA) and hierarchical clustering (HC) plots, performing enrichment analyses against over 90 gene set libraries, and obtaining lists of small molecules that are predicted to either mimic or reverse the observed changes in mRNA expression. We apply the pipeline to a recently published RNA-seq dataset collected from human neuronal progenitors infected with the Zika virus (ZIKV). In addition to confirming the presence of cell cycle genes among the genes that are downregulated by ZIKV, our analysis uncovers significant overlap with upregulated genes that when knocked out in mice induce defects in brain morphology. This result potentially points to the molecular processes associated with the microcephaly phenotype observed in newborns from pregnant mothers infected with the virus. In addition, our analysis predicts small molecules that can either mimic or reverse the expression changes induced by ZIKV. The IPython notebook and Docker image are freely available at: and
      PubDate: 2016-07-05T11:58:00Z
      Issue No: Vol. 5 (2016)
  • Circadian clock regulation of skeletal muscle growth and repair [version
           1; referees: 2 approved]

    • Authors: Somik Chatterjee, Ke Ma
      Abstract: Accumulating evidence indicates that the circadian clock, a transcriptional/translational feedback circuit that generates ~24-hour oscillations in behavior and physiology, is a key temporal regulatory mechanism involved in many important aspects of muscle physiology. Given the clock as an evolutionarily-conserved time-keeping mechanism that synchronizes internal physiology to environmental cues, locomotor activities initiated by skeletal muscle enable entrainment to the light-dark cycles on earth, thus ensuring organismal survival and fitness. Despite the current understanding of the role of molecular clock in preventing age-related sarcopenia, investigations into the underlying molecular pathways that transmit clock signals to the maintenance of skeletal muscle growth and function are only emerging. In the current review, the importance of the muscle clock in maintaining muscle mass during development, repair and aging, together with its contribution to muscle metabolism, will be discussed. Based on our current understandings of how tissue-intrinsic muscle clock functions in the key aspects muscle physiology, interventions targeting the myogenic-modulatory activities of the clock circuit may offer new avenues for prevention and treatment of muscular diseases. Studies of mechanisms underlying circadian clock function and regulation in skeletal muscle warrant continued efforts.
      PubDate: 2016-06-30T10:27:38Z
      DOI: 10.12688/f1000research.9076.1
      Issue No: Vol. 5 (2016)
  • Robust de novo pathway enrichment with KeyPathwayMiner 5 [version 1;
           referees: 2 approved]

    • Authors: Nicolas Alcaraz, Markus List, Martin Dissing-Hansen, Marc Rehmsmeier, Qihua Tan, Jan Mollenhauer, Henrik J. Ditzel, Jan Baumbach
      Abstract: Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks that are enriched for differentially active entities from a series of molecular profiles encoded as binary indicator matrices. Since interaction networks constantly evolve, an important question is how robust the extracted results are when the network is modified. We enable users to study this effect through several network perturbation techniques and over a range of perturbation degrees. In addition, users may now provide a gold-standard set to determine how enriched extracted pathways are with relevant genes compared to randomized versions of the original network.
      PubDate: 2016-06-28T13:53:23Z
      DOI: 10.12688/f1000research.9054.1
      Issue No: Vol. 5 (2016)
  • MEPPitope: spatial, electrostatic and secondary structure perturbations in
           the post-fusion Dengue virus envelope protein highlights known epitopes
           and conserved residues in the Zika virus [version 1; referees: 3 approved]

    • Authors: Sandeep Chakraborty
      Abstract: The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV), provides key insights in developing strategies for tackling ZIKV. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with significant spatial and electrostatic perturbations. In the current work, MEPP analyzed the pre-and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes (His317, Tyr299, Glu26, Arg188, etc.) (MEPPitope). These residues are overwhelmingly conserved in ZIKV and all DENV serotypes. Characterization of α-helices in E-proteins show that α1 is not conserved in the sequence space of ZIKV and DENV. Furthermore, perturbation of α1 in the post-fusion DENV structure includes a known epitope Asp215, a residue absent in the pre-fusion α1. A cationic β-sheet in the GAG-binding domain that is stereochemically equivalent in ZIKV and all DENV serotypes is also highlighted due to a residue pair (Arg286-Arg288) that has a significant electrostatic polarity reversal upon fusion. Finally, two highly conserved residues (Thr32 and Thr40), with little emphasis in existing literature, are found to have significant electrostatic perturbation. Thus, a combination of different computational methods enable the rapid and rational detection of critical residues that can be made the target of small drugs, or as epitopes in the search for an elusive therapy or vaccine that neutralizes multiple members of the Flaviviridae family.
      PubDate: 2016-06-03T16:04:57Z
      DOI: 10.12688/f1000research.8853.1
      Issue No: Vol. 5 (2016)
  • Teaching and learning based on peer review: a realistic approach in
           forensic sciences [version 1; referees: 2 approved]

    • Abstract: Teaching and learning methods need a continuous upgrade in higher education. However it is also true that some of the modern methodologies do not reduce or prevent school failure. Perhaps the real limitation is the inability to identify the true reasons that may explain it or ignore/undervalue the problem. In our opinion, one of the current constraints of the teaching/learning process is the excess of and inadequate bibliography recommended by the teacher, which results in continuous student difficulties and waste of time in searching and selecting useful information. The need to change the paradigm of the teaching/learning process comes also from employers. They claim forensic experts armed with useful knowledge to face professional life. It is therefore mandatory to identify the new needs and opportunities regarding pedagogical methodologies. This article reflects on the recent importance of peer review in teaching/learning forensic sciences based on the last 10 years of pedagogical experience inseparably from the scientific activity.
      PubDate: 2016-05-31T15:19:53Z
      DOI: 10.12688/f1000research.8726.1
      Issue No: Vol. 5 (2016)
  • Are scientific abstracts written in poetic verse an effective
           representation of the underlying research' [version 2; referees: 1
           approved, 2 approved with reservations]

    • Authors: Sam Illingworth
      Abstract: The central purpose of science is to explain. However, who is that explanation for, and how is this explanation communicated once it has been deduced' Scientific research is typically communicated via papers in journals, with an abstract presented as a summary of that explanation. However, in many instances they may be written in a manner which is non-communicatory to a lay reader. This study begins to investigate if poetry could be used as an alternative form of communication, by first assessing if poetic verse is an effective form of communication to other scientists. In order to assess this suitability, a survey was conducted in which two different groups of participants were asked questions based on a scientific abstract. One group of participants was given the original scientific abstract, whilst the second group was instead given a poem written about the scientific study. Quantitative analysis found that whilst a scientific audience found a poetic interpretation of a scientific abstract to be no less interesting or inspiring than the original prose, they did find it to be less accessible. However, further qualitative analysis suggested that the poem did a good job in conveying a similar meaning to that presented in the original abstract. The results of this study indicate that whilst for a scientific audience poetry should not replace the prose abstract, it could be used alongside the original format to inspire the reader to find out more about the topic. Further research is needed to investigate the effectiveness of this approach for a general audience.
      PubDate: 2016-04-26T10:01:54Z
      DOI: 10.12688/f1000research.7783.2
      Issue No: Vol. 5 (2016)
  • An assay to measure poly(ADP ribose) glycohydrolase (PARG) activity in
           cells [version 1; referees: 2 approved]

    • Authors: Dominic I. James, Stephen Durant, Kay Eckersley, Emma Fairweather, Louise A. Griffiths, Nicola Hamilton, Paul Kelly, Mark O'Connor, Kerry Shea, Ian D. Waddell, Donald J. Ogilvie
      Abstract: After a DNA damage signal multiple polymers of ADP ribose attached to poly(ADP) ribose (PAR) polymerases (PARPs) are broken down by the enzyme poly(ADP) ribose glycohydrolase (PARG). Inhibition of PARG leads to a failure of DNA repair and small molecule inhibition of PARG has been a goal for many years. To determine whether biochemical inhibitors of PARG are active in cells we have designed an immunofluorescence assay to detect nuclear PAR after DNA damage. This 384-well assay is suitable for medium throughput high-content screening and can detect cell-permeable inhibitors of PARG from nM to µM potency. In addition, the assay has been shown to work in murine cells and in a variety of human cancer cells. Furthermore, the assay is suitable for detecting the DNA damage response induced by treatment with temozolomide and methylmethane sulfonate (MMS). Lastly, the assay has been shown to be robust over a period of several years.
      PubDate: 2016-04-25T10:05:22Z
      DOI: 10.12688/f1000research.8463.1
      Issue No: Vol. 5 (2016)
  • Comparing efficacy of a sweep net and a dip method for collection of
           mosquito larvae in large bodies of water in South Africa [version 1;
           referees: 2 approved]

    • Authors: Katherine K. Brisco, Anthony J. Cornel, Yoosook Lee, Joel Mouatcho, Leo Braack
      Abstract: In this study we tested an alternative method for collecting mosquito larvae called the sweep net catch method and compared its efficiency to that of the traditional dip method. The two methods were compared in various water bodies within Kruger National Park and Lapalala Wilderness area, South Africa. The sweep net catch method performed 5 times better in the collection of Anopheles larvae and equally as well as the dip method in the collection of Culex larvae (p =8.58 x 10-5). Based on 15 replicates the collector’s experience level did not play a significant role in the relative numbers of larvae collected using either method. This simple and effective sweep net catch method will greatly improve the mosquito larval sampling capacity in the field setting.
      PubDate: 2016-04-21T13:09:56Z
      DOI: 10.12688/f1000research.8351.1
      Issue No: Vol. 5 (2016)
  • The effects of an editor serving as one of the reviewers during the
           peer-review process [version 1; referees: 1 approved, 2 approved with

    • Authors: Marco Giordan, Attila Csikasz-Nagy, Andrew M. Collings, Federico Vaggi
      Abstract: Background Publishing in scientific journals is one of the most important ways in which scientists disseminate research to their peers and to the wider public. Pre-publication peer review underpins this process, but peer review is subject to various criticisms and is under pressure from growth in the number of scientific publications.   Methods Here we examine an element of the editorial process at eLife, in which the Reviewing Editor usually serves as one of the referees, to see what effect this has on decision times, decision type, and the number of citations. We analysed a dataset of 8,905 research submissions to eLife since June 2012, of which 2,750 were sent for peer review, using R and Python to perform the statistical analysis.   Results The Reviewing Editor serving as one of the peer reviewers results in faster decision times on average, with the time to final decision ten days faster for accepted submissions (n=1,405) and 5 days faster for papers that were rejected after peer review (n=1,099). There was no effect on whether submissions were accepted or rejected, and a very small (but significant) effect on citation rates for published articles where the Reviewing Editor served as one of the peer reviewers.   Conclusions An important aspect of eLife’s peer-review process is shown to be effective, given that decision times are faster when the Reviewing Editor serves as a reviewer. Other journals hoping to improve decision times could consider adopting a similar approach.
      PubDate: 2016-04-14T13:22:28Z
      DOI: 10.12688/f1000research.8452.1
      Issue No: Vol. 5 (2016)
  • Antimicrobial susceptibility and clarithromycin resistance
           patterns of Helicobacter pylori clinical isolates in Vietnam [version
           1; referees: 2 approved]

    • Authors: Camelia Quek, Son T. Pham, Kieu T. Tran, Binh T. Pham, Loc V. Huynh, Ngan B.L. Luu, Thao K.T. Le, Kelly Quek, Van H. Pham
      Abstract: Helicobacter pylori is a gastric pathogen that causes several gastroduodenal disorders such as peptic ulcer disease and gastric cancer.  Eradication efforts of H. pylori are often hampered by antimicrobial resistance in many countries, including Vietnam.  Here, the study aimed to investigate the occurrence of antimicrobial resistance among H. pylori clinical isolates across 13 hospitals in Vietnam.  The study further evaluated the clarithromycin resistance patterns of H. pylori strains.  In order to address the study interests, antimicrobial susceptibility testing, epsilometer test and PCR-based sequencing were performed on a total of 193 strains isolated from patients, including 136 children (3–15 years of age) and 57 adults (19–69 years of age).  Antimicrobial susceptibility testing showed that the overall resistance to amoxicillin, clarithromycin, levofloxacin, metronidazole, and tetracycline was 10.4%, 85.5%, 24.4%, 37.8%, and 23.8% respectively.  The distribution of minimum inhibitory concentrations (MICs) of clarithromycin-resistant strains was 85.5% with MIC >0.5 μg/mL.  The majority of the clarithromycin resistant isolates (135 of 165 subjects) have MICs ranging from 2 μg/mL to 16 μg/mL.  Furthermore, sequencing detection of mutations in 23S rRNA gene revealed that strains resistant and susceptible to clarithromycin contained both A2143G and T2182C mutations.  Of all isolates, eight clarithromycin-resistant isolates (MIC >0.5 μg/mL) had no mutations in the 23S rRNA gene.  Collectively, these results demonstrated that a proportion of clarithromycin-resistant H. pylori strains, which are not related to the 23S rRNA gene mutations, could be potentially related to other mechanisms such as the presence of an efflux pump or polymorphisms in the CYP2C19 gene.  Therefore, the present study suggests that providing susceptibility testing prior to treatment or alternative screening strategies for antimicrobial resistance is important for future clinical practice.  Further studies on clinical guidelines and treatment efficacy are pivotal for successful eradication of H. pylori infection.
      PubDate: 2016-04-13T13:39:59Z
      DOI: 10.12688/f1000research.8239.1
      Issue No: Vol. 5 (2016)
  • Case Report: Elevated CPK, an indicator of idiopathic inflammatory
           myopathy' [version 1; referees: 2 approved]

    • Authors: Hina N. Khan, Usman Jilani, Shitij Arora
      Abstract: Polymyositis is a rare disease with incidence rates at about 1 per 100,000 people annually. In this case report we will review a case of proximal muscle weakness with an elevated creatine phosphokinase that was initially misdiagnosed twice as rhabdomyolysis. Therefore, emphasizing that idiopathic inflammatory myopathy is a potential cause of myasthenia that must be considered in the differential. The case will also describe the current treatment and treatment response in polymyositis.
      PubDate: 2016-02-12T10:33:32Z
      DOI: 10.12688/f1000research.7681.1
      Issue No: Vol. 5 (2016)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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