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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]
  • The myofibroblast in wound healing and fibrosis: answered and unanswered
           questions [version 1; referees: 2 approved]

    • Authors: Marie-Luce Bochaton-Piallat, Giulio Gabbiani, Boris Hinz
      Abstract: The discovery of the myofibroblast has allowed definition of the cell responsible for wound contraction and for the development of fibrotic changes. This review summarizes the main features of the myofibroblast and the mechanisms of myofibroblast generation. Myofibroblasts originate from a variety of cells according to the organ and the type of lesion. The mechanisms of myofibroblast contraction, which appear clearly different to those of smooth muscle cell contraction, are described. Finally, we summarize the possible strategies in order to reduce myofibroblast activities and thus influence several pathologies, such as hypertrophic scars and organ fibrosis.
      PubDate: 2016-04-26T11:30:36Z
      DOI: 10.12688/f1000research.8190.1
      Issue No: Vol. 5 (2016)
  • Extracorporeal membrane oxygenation 2016: an update [version 1; referees:
           3 approved]

    • Authors: Warwick Butt, Graeme MacLaren
      Abstract: The use of extracorporeal membrane oxygenation (ECMO) is an important issue for intensivists, critical care nurses, surgeons, cardiologists, and many others. There has been a continued increase in the number of centres performing ECMO. This review examines novel applications and recent trends in the use of ECMO over the last 2 years. These include ECMO to facilitate the safe use of other treatments, changing the timing of initiation, newer equipment and better biocompatibility, and the ability of ECMO programs to essentially choose which cluster of potential complications they are prepared to accept. ECMO continues to evolve, diversify in its applications, and improve in safety.
      PubDate: 2016-04-26T10:09:09Z
      DOI: 10.12688/f1000research.8320.1
      Issue No: Vol. 5 (2016)
  • The dynamics of spatio-temporal Rho GTPase signaling: formation of
           signaling patterns [version 1; referees: 2 approved]

    • Authors: Rafael Dominik Fritz, Olivier Pertz
      Abstract: Rho GTPases are crucial signaling molecules that regulate a plethora of biological functions. Traditional biochemical, cell biological, and genetic approaches have founded the basis of Rho GTPase biology. The development of biosensors then allowed measuring Rho GTPase activity with unprecedented spatio-temporal resolution. This revealed that Rho GTPase activity fluctuates on time and length scales of tens of seconds and micrometers, respectively. In this review, we describe Rho GTPase activity patterns observed in different cell systems. We then discuss the growing body of evidence that upstream regulators such as guanine nucleotide exchange factors and GTPase-activating proteins shape these patterns by precisely controlling the spatio-temporal flux of Rho GTPase activity. Finally, we comment on additional mechanisms that might feed into the regulation of these signaling patterns and on novel technologies required to dissect this spatio-temporal complexity.
      PubDate: 2016-04-26T10:07:46Z
      DOI: 10.12688/f1000research.7370.1
      Issue No: Vol. 5 (2016)
  • A divide-and-conquer strategy in tumor sampling enhances detection of
           intratumor heterogeneity in routine pathology: A modeling approach in
           clear cell renal cell carcinoma [version 2; referees: 3 approved]

    • Abstract: Intratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far.  Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection.
      PubDate: 2016-04-25T14:34:59Z
      DOI: 10.12688/f1000research.8196.2
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding Kaposi’s sarcoma-associated
           herpesvirus [version 1; referees: 2 approved]

    • Authors: Nathan J. Dissinger, Blossom Damania
      Abstract: Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic human herpesvirus. KSHV is associated with three cancers in the human population: KS, primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). KS is the leading cause of cancer in HIV-infected individuals. In this review, we discuss the most recent discoveries behind the mechanisms of KSHV latency maintenance and lytic replication. We also review current therapies for KSHV-associated cancers.
      PubDate: 2016-04-25T14:08:59Z
      DOI: 10.12688/f1000research.7612.1
      Issue No: Vol. 5 (2016)
  • Early detection of lung cancer [version 1; referees: 3 approved]

    • Authors: David E. Midthun
      Abstract: Most patients with lung cancer are diagnosed when they present with symptoms, they have advanced stage disease, and curative treatment is no longer an option. An effective screening test has long been desired for early detection with the goal of reducing mortality from lung cancer. Sputum cytology, chest radiography, and computed tomography (CT) scan have been studied as potential screening tests. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in mortality with low-dose CT (LDCT) screening, and guidelines now endorse annual LDCT for those at high risk. Implementation of screening is underway with the desire that the benefits be seen in clinical practice outside of a research study format. Concerns include management of false positives, cost, incidental findings, radiation exposure, and overdiagnosis. Studies continue to evaluate LDCT screening and use of biomarkers in risk assessment and diagnosis in attempt to further improve outcomes for patients with lung cancer.
      PubDate: 2016-04-25T14:02:31Z
      DOI: 10.12688/f1000research.7313.1
      Issue No: Vol. 5 (2016)
  • Updates in diabetic peripheral neuropathy [version 1; referees: 3

    • Authors: Kelsey Juster-Switlyk, A. Gordon Smith
      Abstract: Diabetes has become one of the largest global health-care problems of the 21st century. According to the Centers for Disease Control and Prevention, the population prevalence of diabetes in the US is approaching 10% and is increasing by 5% each year. Diabetic neuropathy is the most common complication associated with diabetes mellitus. Diabetes causes a broad spectrum of neuropathic complications, including acute and chronic forms affecting each level of the peripheral nerve, from the root to the distal axon. This review will focus on the most common form, distal symmetric diabetic polyneuropathy. There has been an evolution in our understanding of the pathophysiology and the management of diabetic polyneuropathy over the past decade. We highlight these new perspectives and provide updates from the past decade of research.
      PubDate: 2016-04-25T13:56:25Z
      DOI: 10.12688/f1000research.7898.1
      Issue No: Vol. 5 (2016)
  • Beta cell antigens in type 1 diabetes: triggers in pathogenesis and
           therapeutic targets [version 1; referees: 3 approved]

    • Abstract: Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.
      PubDate: 2016-04-22T15:32:47Z
      DOI: 10.12688/f1000research.7411.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding and treating ARDS [version 1; referees: 2

    • Authors: Rebecca M. Baron, Bruce D. Levy
      Abstract: Acute respiratory distress syndrome represents a complex syndrome with considerable morbidity and mortality, for which there exist no targeted treatment strategies. However, recent advances in clinical care have improved outcomes, and we will review a number of these approaches here, as well as explore the mechanisms underlying the benefit of intervention that might point us in the direction toward future treatment and preventive strategies for this devastating syndrome.
      PubDate: 2016-04-22T10:05:54Z
      DOI: 10.12688/f1000research.7646.1
      Issue No: Vol. 5 (2016)
  • Update on the pathogenesis of Scleroderma: focus on circulating progenitor
           cells [version 1; referees: 2 approved]

    • Authors: Alexandra Maria Giovanna Brunasso, Cesare Massone
      Abstract: In systemic sclerosis (SSc), the development of fibrosis seems to be a consequence of the initial ischemic process related to an endothelial injury. The initial trigger event in SSc is still unknown, but circulating progenitor cells (CPCs) might play a key role. Such cells have the ability to traffic into injury sites, exhibiting inflammatory features of macrophages, tissue remodeling properties of fibroblasts, and vasculogenesis functions of endothelial cells. The different subsets of CPCs described thus far in SSc arise from a pool of circulating monocyte precursors (CD14+ cells) and probably correspond to a different degree of differentiation of a single cell of origin. Several subsets of CPCs have been described in patients with SSc, all have a monocytic origin but may or may not express CD14, and all of these cells have the ability to give origin to endothelial cells, or collagen (Col)-producing cells, or both. We were able to identify six subsets of CPCs: pluripotent stem cells (CD14+, CD45+, and CD34+), monocyte-derived multipotential cells (MOMCs) or monocyte-derived mesenchymal progenitors (CD14+, CD45+, CD34+, Col I+, CD11b+, CD68+, CD105+, and VEGFR1+), early endothelial progenitor cells (EPCs) or monocytic pro-angiogenic hematopoietic cells or circulating hematopoietic cells (CD14+, CD45+, CD34low/−, VEGFR2+/−, CXCR4+, c-kit+, and DC117+), late EPCs (CD14−, CD133+, VEGFR2+, CD144+ [VE-cadherin+], and CD146+), fibroblast-like cells (FLCs)/circulating Col-producing monocytes (CD14+, CD45+, CD34+/−, and Col I+), and fibrocytes (CD14−, CD45+, CD34+, Col I+, and CXCR4+). It has been demonstrated that circulating CD14+ monocytes with an activated phenotype are increased in patients with SSc when compared with normal subjects. CD14+, CD34+, and Col I+ spindle-shaped cells have been found in increased numbers in lungs of SSc patients with interstitial lung disease. Elevated blood amounts of early EPCs have been found in patients with SSc by different groups of researchers and such levels correlate directly with the interstitial lung involvement. The prevalence of hematopoietic markers expressed by CPCs that migrate from blood into injury sites in SSc differs and changes according to the degree of differentiation. CXCR4 is the most commonly expressed marker, followed by CD34 and CD45 at an end stage of differentiation. Such difference also indicates a continuous process of cell differentiation that might relate to the SSc clinical phenotype (degree of fibrosis and vascular involvement). A deeper understanding of the role of each subtype of CPCs in the development of the disease will help us to better classify patients in order to offer them targeted approaches in the future.
      PubDate: 2016-04-22T09:44:43Z
      DOI: 10.12688/f1000research.7986.1
      Issue No: Vol. 5 (2016)
  • Advances in laparoscopic urologic surgery techniques [version 1; referees:
           3 approved]

    • Authors: Haidar M. Abdul-Muhsin, Mitchell R. Humphreys
      Abstract: The last two decades witnessed the inception and exponential implementation of key technological advancements in laparoscopic urology. While some of these technologies thrived and became part of daily practice, others are still hindered by major challenges. This review was conducted through a comprehensive literature search in order to highlight some of the most promising technologies in laparoscopic visualization, augmented reality, and insufflation. Additionally, this review will provide an update regarding the current status of single-site and natural orifice surgery in urology.
      PubDate: 2016-04-21T16:17:48Z
      DOI: 10.12688/f1000research.7660.1
      Issue No: Vol. 5 (2016)
  • Recent advances in the understanding of male lower urinary tract symptoms
           (LUTS) [version 1; referees: 2 approved]

    • Authors: Arman A. Kahokehr, Peter J. Gilling
      Abstract: In this review, we have looked at three important areas in understanding male lower urinary tract symptoms. These are improvement in terminology, detrusor underactivity, and nocturia. Benign prostatic hyperplasia leading to bladder outlet obstruction has been covered in a previous review.
      PubDate: 2016-04-21T14:39:36Z
      DOI: 10.12688/f1000research.8638.1
      Issue No: Vol. 5 (2016)
  • Statin non-adherence: clinical consequences and proposed solutions
           [version 1; referees: 2 approved]

    • Authors: Robert S. Rosenson
      Abstract: Large controlled clinical trials have demonstrated reductions with statin therapy in cardiovascular events in patients presenting with acute coronary syndromes and stable coronary heart disease and individuals at high risk of a cardiovascular event. In trials of acute coronary syndromes and stable coronary heart disease, high-intensity statin therapy is more effective in the prevention of recurrent cardiovascular events than low-intensity statin therapy. Thus, evidence-based guidelines recommend in-hospital initiation of high-intensity statin therapy for all acute coronary syndrome patients. Clinical trials report high adherence to and low discontinuation of high-intensity statin therapy; however, in clinical practice, high-intensity statins are prescribed to far fewer patients, who often discontinue their statin after the first refill. A coordinated effort among the patient, provider, pharmacist, health system, and insurer is necessary to improve utilization and persistence of prescribed medications. The major cause for statin discontinuations reported by patients is perceived adverse events. Evaluation of potential adverse events requires validated tools to distinguish between statin-associated adverse events versus non-specific complaints. Treatment options for statin-intolerant patients include the use of a different statin, often at a lower dose or frequency. In order to lower LDL cholesterol, lower doses of statins may be combined with ezetimibe or bile acid sequestrants. Newer treatment options for patients with statin-associated muscle symptoms may include proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.
      PubDate: 2016-04-21T13:28:35Z
      DOI: 10.12688/f1000research.8215.1
      Issue No: Vol. 5 (2016)
  • Molecular biology of breast tumors and prognosis [version 1; referees: 3

    • Authors: Gustavo Baldassarre, Barbara Belletti
      Abstract: Breast cancer is the most common cancer among women worldwide. Great scientific, economical, and organizational efforts are in place to understand the causes of onset, identify the critical molecular players of progression, and define new lines of intervention providing more benefits and less toxicity. These efforts have certainly not been vain, since overall survival, especially in specific subsets of breast cancer, has greatly improved during the last decades. At present, breast cancer patients’ treatment and care have reached a high standard of quality, and currently one of the most urgent needs resides in the necessity to better distinguish the tumors that need to be more aggressively treated and identify the best therapeutic option tailored to each patient. This objective will be achievable only if the information clarifying the biology of breast cancer can be successfully transferred to the clinic. A common effort by scientists and clinicians toward this integration and toward the use of multidisciplinary approaches will be necessary to reach this important goal.
      PubDate: 2016-04-21T08:59:27Z
      DOI: 10.12688/f1000research.8158.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding and managing cholestasis [version 1;
           referees: 2 approved]

    • Authors: Martin Wagner, Michael Trauner
      Abstract: Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, fibroblast growth factor 19, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.
      PubDate: 2016-04-19T14:49:30Z
      DOI: 10.12688/f1000research.8012.1
      Issue No: Vol. 5 (2016)
  • Recent advances in psychological therapies for eating disorders [version
           1; referees: 2 approved]

    • Authors: Glenn Waller
      Abstract: Recent years have seen substantial consolidation and development of the evidence base for psychological therapies for eating disorders. This review summarises the key changes over that time period. Specific forms of cognitive behavioural therapy and family-based treatment have consolidated and extended their positions as treatments of choice despite the development of novel approaches. However, there is still a significant need for further development and testing to improve recovery rates, particularly in anorexia nervosa.
      PubDate: 2016-04-19T11:35:23Z
      DOI: 10.12688/f1000research.7618.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding myelofibrosis and essential
           thrombocythemia [version 1; referees: 2 approved]

    • Authors: William Vainchenker, Stefan N. Constantinescu, Isabelle Plo
      Abstract: The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery of CALR mutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient’s constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the development of JAK2 inhibitors.
      PubDate: 2016-04-19T10:09:33Z
      DOI: 10.12688/f1000research.8081.1
      Issue No: Vol. 5 (2016)
  • Wnt signaling in cancer stem cells and colon cancer metastasis [version 1;
           referees: 3 approved]

    • Authors: Sayon Basu, Gal Haase, Avri Ben-Ze'ev
      Abstract: Overactivation of Wnt signaling is a hallmark of colorectal cancer (CRC). The Wnt pathway is a key regulator of both the early and the later, more invasive, stages of CRC development. In the normal intestine and colon, Wnt signaling controls the homeostasis of intestinal stem cells (ISCs) that fuel, via proliferation, upward movement of progeny cells from the crypt bottom toward the villus and differentiation into all cell types that constitute the intestine. Studies in recent years suggested that cancer stem cells (CSCs), similar to ISCs of the crypts, consist of a small subpopulation of the tumor and are responsible for the initiation and progression of the disease. Although various ISC signature genes were also identified as CRC markers and some of these genes were even demonstrated to have a direct functional role in CRC development, the origin of CSCs and their contribution to cancer progression is still debated. Here, we describe studies supporting a relationship between Wnt-regulated CSCs and the progression of CRC.
      PubDate: 2016-04-19T09:52:13Z
      DOI: 10.12688/f1000research.7579.1
      Issue No: Vol. 5 (2016)
  • Recent advances in managing and understanding
           nephrolithiasis/nephrocalcinosis [version 1; referees: 2 approved]

    • Authors: Giovanni Gambaro, Alberto Trinchieri
      Abstract: Urinary stone disease is a very common disease whose prevalence is still increasing. Stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance. The increasing concentration of lithogenic solutes along the different segments of the nephron involves supersaturation conditions leading to the formation, growth, and aggregation of crystals. Crystalline aggregates can grow free in the tubular lumen or coated on the wall of the renal tubule. Plugs of crystalline material have been highlighted in the tubular lumen in some patients, but crystalline growth starting from plaques of calcium phosphate within the renal papillae has been demonstrated in others. Urinary supersaturation is the result of a complex interaction between predisposing genetic features and environmental factors. Dietary intake is certainly the most important environmental risk factor. In particular, an insufficient intake of dietary calcium (
      PubDate: 2016-04-18T13:59:14Z
      DOI: 10.12688/f1000research.7126.1
      Issue No: Vol. 5 (2016)
  • Plant Heat Adaptation: priming in response to heat stress [version 1;
           referees: 2 approved]

    • Abstract: Abiotic stress is a major threat to crop yield stability. Plants can be primed by heat stress, which enables them to subsequently survive temperatures that are lethal to a plant in the naïve state. This is a rapid response that has been known for many years and that is highly conserved across kingdoms. Interestingly, recent studies in Arabidopsis and rice show that this thermo-priming lasts for several days at normal growth temperatures and that it is an active process that is genetically separable from the priming itself. This is referred to as maintenance of acquired thermotolerance or heat stress memory. Such a memory conceivably has adaptive advantages under natural conditions, where heat stress often is chronic or recurring. In this review, I will focus on recent advances in the mechanistic understanding of heat stress memory.
      PubDate: 2016-04-18T10:58:35Z
      DOI: 10.12688/f1000research.7526.1
      Issue No: Vol. 5 (2016)
  • The big challenges in modeling human and environmental well-being [version
           1; referees: 3 approved]

    • Authors: Shripad Tuljapurkar
      Abstract: This article is a selective review of quantitative research, historical and prospective, that is needed to inform sustainable development policy. I start with a simple framework to highlight how demography and productivity shape human well-being. I use that to discuss three sets of issues and corresponding challenges to modeling: first, population prehistory and early human development and their implications for the future; second, the multiple distinct dimensions of human and environmental well-being and the meaning of sustainability; and, third, inequality as a phenomenon triggered by development and models to examine changing inequality and its consequences. I conclude with a few words about other important factors: political, institutional, and cultural.
      PubDate: 2016-04-13T16:04:12Z
      DOI: 10.12688/f1000research.7636.1
      Issue No: Vol. 5 (2016)
  • MetaNetVar: Pipeline for applying network analysis tools for genomic
           variants analysis [version 1; referees: 2 approved]

    • Authors: Eric Moyer, Megan Hagenauer, Matthew Lesko, Felix Francis, Oscar Rodriguez, Vijayaraj Nagarajan, Vojtech Huser, Ben Busby
      Abstract: Network analysis can make variant analysis better. There are existing tools like HotNet2 and dmGWAS that can provide various analytical methods. We developed a prototype of a pipeline called MetaNetVar that allows execution of multiple tools. The code is published at A working prototype is published as an Amazon Machine Image - ami-4510312f .
      PubDate: 2016-04-13T14:17:34Z
      DOI: 10.12688/f1000research.8288.1
      Issue No: Vol. 5 (2016)
  • Alanylated lipoteichoic acid primer in Bacillus subtilis [version 2;
           referees: 2 approved]

    • Authors: Yu Luo
      Abstract: Lipoteichoic acid is a major lipid-anchored polymer in Gram-positive bacteria such as Bacillus subtilis. This polymer typically consists of repeating phosphate-containing units and therefore has a predominant negative charge. The repeating units are attached to a glycolipid anchor which has a diacylglycerol (DAG) moiety attached to a dihexopyranose head group. D-alanylation is known as the major modification of type I and type IV lipoteichoic acids, which partially neutralizes the polymer and plays important roles in bacterial survival and resistance to the host immune system. The biosynthesis pathways of the glycolipid anchor and lipoteichoic acid have been fully characterized. However, the exact mechanism of D-alanyl transfer from the cytosol to cell surface lipoteichoic acid remains unclear. Here I report the use of mass spectrometry in the identification of possible intermediate species in the biosynthesis and D-alanylation of lipoteichoic acid: the glycolipid anchor, nascent lipoteichoic acid primer with one phosphoglycerol unit, as well as mono- and di-alanylated forms of the lipoteichoic acid primer. Monitoring these species as well as the recently reported D-alanyl-phosphatidyl glycerol should aid in shedding light on the mechanism of the D-alanylation pathway of lipoteichoic acid.
      PubDate: 2016-04-11T14:47:35Z
      DOI: 10.12688/f1000research.8007.2
      Issue No: Vol. 5 (2016)
  • The academic, economic and societal impacts of Open Access: an
           evidence-based review [version 1; referees: 2 approved]

    • Abstract: Ongoing debates surrounding Open Access to the scholarly literature are multifaceted and complicated by disparate and often polarised viewpoints from engaged stakeholders. At the current stage, Open Access has become such a global issue that it is critical for all involved in scholarly publishing, including policymakers, publishers, research funders, governments, learned societies, librarians, and academic communities, to be well-informed on the history, benefits, and pitfalls of Open Access. In spite of this, there is a general lack of consensus regarding the advantages or disadvantages of Open Access at multiple levels. This review aims to to be a resource for current knowledge on the impacts of Open Access by synthesizing important research in three major areas of impact: academic, economic and societal. While there is clearly much scope for additional research, several key trends are identified, including a broad citation advantage for researchers who publish openly, as well as additional benefits to the non-academic dissemination of their work. The economic case for Open Access is less well-understood, although it is clear that access to the research literature is key for innovative enterprises, and a range of governmental and non-governmental services. Furthermore, Open Access has the potential to save publishers and research funders considerable amounts of financial resources. The social case for Open Access is strong, in particular for advancing citizen science initiatives, and leveling the playing field for researchers in developing countries. Open Access supersedes all potential alternative modes of access to the scholarly literature through enabling unrestricted re-use, and long-term stability independent of financial constraints of traditional publishers that impede knowledge sharing. Open Access remains only one of the multiple challenges that the scholarly publishing system is currently facing. Yet, it provides one foundation for increasing engagement with researchers regarding ethical standards of publishing. We recommend that Open Access supporters focus their efforts on working to establish viable new models and systems of scholarly communication, rather than trying to undermine the existing ones as part of the natural evolution of the scholarly ecosystem. Based on this, future research should investigate the wider impacts of an ecosystem-wide transformation to a system of Open Research.
      PubDate: 2016-04-11T10:51:31Z
      DOI: 10.12688/f1000research.8460.1
      Issue No: Vol. 5 (2016)
  • Advances in understanding – genetic basis of intellectual disability
           [version 1; referees: 2 approved]

    • Authors: Pietro Chiurazzi, Filomena Pirozzi
      Abstract: Intellectual disability is the most common developmental disorder characterized by a congenital limitation in intellectual functioning and adaptive behavior. It often co-occurs with other mental conditions like attention deficit/hyperactivity disorder and autism spectrum disorder, and can be part of a malformation syndrome that affects other organs. Considering the heterogeneity of its causes (environmental and genetic), its frequency worldwide varies greatly. This review focuses on known genes underlying (syndromic and non-syndromic) intellectual disability, it provides a succinct analysis of their Gene Ontology, and it suggests the use of transcriptional profiling for the prioritization of candidate genes.
      PubDate: 2016-04-07T14:57:09Z
      DOI: 10.12688/f1000research.7134.1
      Issue No: Vol. 5 (2016)
  • Activity-relevant similarity values for fingerprints and implications for
           similarity searching [version 1; referees: 3 approved]

    • Abstract: A largely unsolved problem in chemoinformatics is the issue of how calculated compound similarity relates to activity similarity, which is central to many applications. In general, activity relationships are predicted from calculated similarity values. However, there is no solid scientific foundation to bridge between calculated molecular and observed activity similarity. Accordingly, the success rate of identifying new active compounds by similarity searching is limited. Although various attempts have been made to establish relationships between calculated fingerprint similarity values and biological activities, none of these has yielded generally applicable rules for similarity searching. In this study, we have addressed the question of molecular versus activity similarity in a more fundamental way. First, we have evaluated if activity-relevant similarity value ranges could in principle be identified for standard fingerprints and distinguished from similarity resulting from random compound comparisons. Then, we have analyzed if activity-relevant similarity values could be used to guide typical similarity search calculations aiming to identify active compounds in databases. It was found that activity-relevant similarity values can be identified as a characteristic feature of fingerprints. However, it was also shown that such values cannot be reliably used as thresholds for practical similarity search calculations. In addition, the analysis presented herein helped to rationalize differences in fingerprint search performance.
      PubDate: 2016-04-06T16:09:29Z
      DOI: 10.12688/f1000research.8357.1
      Issue No: Vol. 5 (2016)
  • Mapping Zika virus infection using geographical information systems in
           Tolima, Colombia, 2015-2016 [version 1; referees: 2 approved]

    • Abstract: Objective: Geographical information systems (GIS) have been extensively used for the development of epidemiological maps of tropical diseases, however not yet specifically for Zika virus (ZIKV) infection. Methods: Surveillance case data of the ongoing epidemics of ZIKV in the Tolima department, Colombia (2015-2016) were used to estimate cumulative incidence rates (cases/100,000 pop.) to develop the first maps in the department and its municipalities, including detail for the capital, Ibagué. The GIS software used was Kosmo Desktop 3.0RC1®. Two thematic maps were developed according to municipality and communes incidence rates. Results: Up to March 5, 2016, 4,094 cases of ZIKV were reported in Tolima, for cumulated rates of 289.9 cases/100,000 pop. (7.95% of the country). Burden of ZIKV infection has been concentrated in its east area, where municipalities have reported >500 cases/100,000 pop. These municipalities are bordered by two other departments, Cundinamarca (3,778 cases) and Huila (5,338 cases), which also have high incidences of ZIKV infection. Seven municipalities of Tolima ranged from 250-499.99 cases/100,000 pop., of this group five border with high incidence municipalities (>250), including the capital, where almost half of the reported cases of ZIKV in Tolima are concentrated. Conclusions: Use of GIS-based epidemiological maps helps to  guide decisions for the prevention and control of diseases that represent significant issues in the region and the country, but also in emerging conditions such as ZIKV.
      PubDate: 2016-04-05T15:10:48Z
      DOI: 10.12688/f1000research.8436.1
      Issue No: Vol. 5 (2016)
  • The emerging role of phosphoinositide clustering in intracellular
           trafficking and signal transduction [version 1; referees: 4 approved]

    • Authors: Laura Picas, Frederique Gaits-Iacovoni, Bruno Goud
      Abstract: Phosphoinositides are master regulators of multiple cellular processes: from vesicular trafficking to signaling, cytoskeleton dynamics, and cell growth. They are synthesized by the spatiotemporal regulated activity of phosphoinositide-metabolizing enzymes. The recent observation that some protein modules are able to cluster phosphoinositides suggests that alternative or complementary mechanisms might operate to stabilize the different phosphoinositide pools within cellular compartments. Herein, we discuss the different known and potential molecular players that are prone to engage phosphoinositide clustering and elaborate on how such a mechanism might take part in the regulation of intracellular trafficking and signal transduction.
      PubDate: 2016-03-31T16:07:53Z
      DOI: 10.12688/f1000research.7537.1
      Issue No: Vol. 5 (2016)
  • Utilization and control of ecological interactions in polymicrobial
           infections and community-based microbial cell factories [version 1;
           referees: 3 approved]

    • Authors: Vinoth Wigneswaran, Cristina Isabel Amador, Lotte Jelsbak, Claus Sternberg, Lars Jelsbak
      Abstract: Microbial activities are most often shaped by interactions between co-existing microbes within mixed-species communities. Dissection of the molecular mechanisms of species interactions within communities is a central issue in microbial ecology, and our ability to engineer and control microbial communities depends, to a large extent, on our knowledge of these interactions. This review highlights the recent advances regarding molecular characterization of microbe-microbe interactions that modulate community structure, activity, and stability, and aims to illustrate how these findings have helped us reach an engineering-level understanding of microbial communities in relation to both human health and industrial biotechnology.
      PubDate: 2016-03-31T15:40:26Z
      DOI: 10.12688/f1000research.7876.1
      Issue No: Vol. 5 (2016)
  • Recent advances in central cardiovascular control: sex, ROS, gas and
           inflammation [version 1; referees: 2 approved]

    • Authors: Pauline M. Smith, Alastair V. Ferguson
      Abstract: The central nervous system (CNS) in concert with the heart and vasculature is essential to maintaining cardiovascular (CV) homeostasis. In recent years, our understanding of CNS control of blood pressure regulation (and dysregulation leading to hypertension) has evolved substantially to include (i) the actions of signaling molecules that are not classically viewed as CV signaling molecules, some of which exert effects at CNS targets in a non-traditional manner, and (ii) CNS locations not traditionally viewed as central autonomic cardiovascular centers. This review summarizes recent work implicating immune signals and reproductive hormones, as well as gasotransmitters and reactive oxygen species in the pathogenesis of hypertension at traditional CV control centers. Additionally, recent work implicating non-conventional CNS structures in CV regulation is discussed.
      PubDate: 2016-03-31T11:10:39Z
      DOI: 10.12688/f1000research.7987.1
      Issue No: Vol. 5 (2016)
  • Technical advances in proteomics: new developments in data-independent
           acquisition [version 1; referees: 3 approved]

    • Authors: Alex Hu, William S. Noble, Alejandro Wolf-Yadlin
      Abstract: The ultimate aim of proteomics is to fully identify and quantify the entire complement of proteins and post-translational modifications in biological samples of interest. For the last 15 years, liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-dependent acquisition (DDA) mode has been the standard for proteomics when sampling breadth and discovery were the main objectives; multiple reaction monitoring (MRM) LC-MS/MS has been the standard for targeted proteomics when precise quantification, reproducibility, and validation were the main objectives. Recently, improvements in mass spectrometer design and bioinformatics algorithms have resulted in the rediscovery and development of another sampling method: data-independent acquisition (DIA). DIA comprehensively and repeatedly samples every peptide in a protein digest, producing a complex set of mass spectra that is difficult to interpret without external spectral libraries. Currently, DIA approaches the identification breadth of DDA while achieving the reproducible quantification characteristic of MRM or its newest version, parallel reaction monitoring (PRM). In comparative de novo identification and quantification studies in human cell lysates, DIA identified up to 89% of the proteins detected in a comparable DDA experiment while providing reproducible quantification of over 85% of them. DIA analysis aided by spectral libraries derived from prior DIA experiments or auxiliary DDA data produces identification and quantification as reproducible and precise as that achieved by MRM/PRM, except on low‑abundance peptides that are obscured by stronger signals. DIA is still a work in progress toward the goal of sensitive, reproducible, and precise quantification without external spectral libraries. New software tools applied to DIA analysis have to deal with deconvolution of complex spectra as well as proper filtering of false positives and false negatives. However, the future outlook is positive, and various researchers are working on novel bioinformatics techniques to address these issues and increase the reproducibility, fidelity, and identification breadth of DIA.
      PubDate: 2016-03-31T10:41:08Z
      DOI: 10.12688/f1000research.7042.1
      Issue No: Vol. 5 (2016)
  • Concerning immune synapses: a spatiotemporal timeline [version 1;
           referees: 2 approved]

    • Authors: Alvaro Ortega-Carrion, Miguel Vicente-Manzanares
      Abstract: The term “immune synapse” was originally coined to highlight the similarities between the synaptic contacts between neurons in the central nervous system and the cognate, antigen-dependent interactions between T cells and antigen-presenting cells. Here, instead of offering a comprehensive molecular catalogue of molecules involved in the establishment, stabilization, function, and resolution of the immune synapse, we follow a spatiotemporal timeline that begins at the initiation of exploratory contacts between the T cell and the antigen-presenting cell and ends with the termination of the contact. We focus on specific aspects that distinguish synapses established by cytotoxic and T helper cells as well as unresolved issues and controversies regarding the formation of this intercellular structure.
      PubDate: 2016-03-31T09:49:23Z
      DOI: 10.12688/f1000research.7796.1
      Issue No: Vol. 5 (2016)
  • Monoclonal antibodies against muscle actin isoforms: epitope
           identification and analysis of isoform expression by immunoblot and
           immunostaining in normal and regenerating skeletal muscle [version 1;
           referees: 2 approved, 1 approved with reservations]

    • Authors: Christine Chaponnier, Giulio Gabbiani
      Abstract: Higher vertebrates express six different highly conserved actin isoforms that can be classified in three subgroups: 1) sarcomeric actins, α-skeletal (α-SKA) and α-cardiac (α-CAA), 2) smooth muscle actins (SMAs), α-SMA and γ-SMA, and 3) cytoplasmic actins (CYAs), β-CYA and γ-CYA. The variations among isoactins, in each subgroup, are due to 3-4 amino acid differences located in their acetylated N-decapeptide sequence. The first monoclonal antibody (mAb) against an actin isoform (α-SMA) was produced and characterized in our laboratory in 1986 (Skalli et al., 1986). We have further obtained mAbs against the 5 other isoforms. In this report, we focus on the mAb anti-α-SKA and anti-α-CAA obtained after immunization of mice with the respective acetylated N-terminal decapeptides using the Repetitive Immunizations at Multiple Sites Strategy (RIMMS). In addition to the identification of their epitope by immunoblotting, we describe the expression of the 2 sarcomeric actins in mature skeletal muscle and during muscle repair after micro-lesions. In particular, we analyze the expression of α-CAA, α-SKA and α-SMA by co-immunostaining in a time course frame during the muscle repair process. Our results indicate that a restricted myocyte population expresses α-CAA and suggest a high capacity of self-renewal in muscle cells. These antibodies may represent a helpful tool for the follow-up of muscle regeneration and pathological changes.
      PubDate: 2016-03-30T16:06:44Z
      DOI: 10.12688/f1000research.8154.1
      Issue No: Vol. 5 (2016)
  • Eph-ephrin signaling in nervous system development [version 1; referees: 2

    • Authors: Karina S. Cramer, Ilona J. Miko
      Abstract: Ephrins and Eph receptors enable contact-mediated interactions between cells at every stage of nervous system development. In spite of their broad binding affinities, Eph proteins facilitate specificity in neuronal migration and axon targeting. This review focuses on recent studies that demonstrate how these proteins interact with each other, and with other signaling pathways, to guide specificity in a diverse set of developmental processes.
      PubDate: 2016-03-30T09:55:55Z
      DOI: 10.12688/f1000research.7417.1
      Issue No: Vol. 5 (2016)
  • Cell biology and genetics of minimal change disease [version 1; referees:
           2 approved]

    • Authors: Moin A. Saleem, Yasuko Kobayashi
      Abstract: Minimal change disease (MCD) is an important cause of nephrotic syndrome and is characterized by massive proteinuria and hypoalbuminemia, resulting in edema and hypercholesterolemia. The podocyte plays a key role in filtration and its disruption results in a dramatic loss of function leading to proteinuria. Immunologic disturbance has been suggested in the pathogenesis of MCD. Because of its clinical features, such as recurrent relapse/remission course, steroid response in most patients, and rare familial cases, a genetic defect has been thought to be less likely in MCD. Recent progress in whole-exome sequencing reveals pathogenic mutations in familial cases in steroid-sensitive nephrotic syndrome (SSNS) and sheds light on possible mechanisms and key molecules in podocytes in MCD. On the other hand, in the majority of cases, the existence of circulating permeability factors has been implicated along with T lymphocyte dysfunction. Observations of benefit with rituximab added B cell involvement to the disease. Animal models are unsatisfactory, and the humanized mouse may be a good model that well reflects MCD pathophysiology to investigate suggested “T cell dysfunction” directly related to podocytes in vivo. Several candidate circulating factors and their effects on podocytes have been proposed but are still not sufficient to explain whole mechanisms and clinical features in MCD. Another circulating factor disease is focal segmental glomerulosclerosis (FSGS), and it is not clear if this is a distinct entity, or on the same spectrum, implicating the same circulating factor(s). These patients are mostly steroid resistant and often have a rapid relapse after transplantation. In clinical practice, predicting relapse or disease activity and response to steroids is important and is an area where novel biomarkers can be developed based on our growing knowledge of podocyte signaling pathways. In this review, we discuss recent findings in genetics and podocyte biology in MCD.
      PubDate: 2016-03-30T09:24:03Z
      DOI: 10.12688/f1000research.7300.1
      Issue No: Vol. 5 (2016)
  • Strategically targeting MYC in cancer [version 1; referees: 2 approved]

    • Authors: Valeriya Posternak, Michael D. Cole
      Abstract: MYC is a major driver of cancer cell growth and mediates a transcriptional program spanning cell growth, the cell cycle, metabolism, and cell survival. Many efforts have been made to deliberately target MYC for cancer therapy. A variety of compounds have been generated to inhibit MYC function or stability, either directly or indirectly. The most direct inhibitors target the interaction between MYC and MAX, which is required for DNA binding. Unfortunately, these compounds do not have the desired pharmacokinetics and pharmacodynamics for in vivo application. Recent studies report the indirect inhibition of MYC through the development of two compounds, JQ1 and THZ1, which target factors involved in unique stages of transcription. These compounds appear to have significant therapeutic value for cancers with high levels of MYC, although some effects are MYC-independent. These approaches serve as a foundation for developing novel compounds to pharmacologically target MYC-driven cancers.
      PubDate: 2016-03-29T15:58:01Z
      DOI: 10.12688/f1000research.7879.1
      Issue No: Vol. 5 (2016)
  • Probiotics in critically ill children [version 1; referees: 2 approved]

    • Authors: Sunit C. Singhi, Suresh Kumar
      Abstract: Gut microflora contribute greatly to immune and nutritive functions and act as a physical barrier against pathogenic organisms across the gut mucosa. Critical illness disrupts the balance between host and gut microflora, facilitating colonization, overgrowth, and translocation of pathogens and microbial products across intestinal mucosal barrier and causing systemic inflammatory response syndrome and sepsis. Commonly used probiotics, which have been developed from organisms that form gut microbiota, singly or in combination, can restore gut microflora and offer the benefits similar to those offered by normal gut flora, namely immune enhancement, improved barrier function of the gastrointestinal tract (GIT), and prevention of bacterial translocation. Enteral supplementation of probiotic strains containing either Lactobacillus alone or in combination with Bifidobacterium reduced the incidence and severity of necrotizing enterocolitis and all-cause mortality in preterm infants. Orally administered Lactobacillus casei subspecies rhamnosus, Lactobacillus reuteri, and Lactobacillus rhamnosus were effective in the prevention of late-onset sepsis and GIT colonization by Candida in preterm very low birth weight infants. In critically ill children, probiotics are effective in the prevention and treatment of antibiotic-associated diarrhea. Oral administration of a mix of probiotics for 1 week to children on broad-spectrum antibiotics in a pediatric intensive care unit decreased GIT colonization by Candida, led to a 50% reduction in candiduria, and showed a trend toward decreased incidence of candidemia. However, routine use of probiotics cannot be supported on the basis of current scientific evidence. Safety of probiotics is also a concern; rarely, probiotics may cause bacteremia, fungemia, and sepsis in immunocompromised critically ill children. More studies are needed to answer questions on the effectiveness of a mix versus single-strain probiotics, optimum dosage regimens and duration of treatment, cost effectiveness, and risk-benefit potential for the prevention and treatment of various critical illnesses.
      PubDate: 2016-03-29T15:45:42Z
      DOI: 10.12688/f1000research.7630.1
      Issue No: Vol. 5 (2016)
  • Finding Ponce de Leon’s Pill: Challenges in Screening for Anti-Aging
           Molecules [version 1; referees: 3 approved]

    • Authors: Surinder Kumar, David B. Lombard
      Abstract: Aging is characterized by the progressive accumulation of degenerative changes, culminating in impaired function and increased probability of death. It is the major risk factor for many human pathologies – including cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases – and consequently exerts an enormous social and economic toll. The major goal of aging research is to develop interventions that can delay the onset of multiple age-related diseases and prolong healthy lifespan (healthspan). The observation that enhanced longevity and health can be achieved in model organisms by dietary restriction or simple genetic manipulations has prompted the hunt for chemical compounds that can increase lifespan. Most of the pathways that modulate the rate of aging in mammals have homologs in yeast, flies, and worms, suggesting that initial screening to identify such pharmacological interventions may be possible using invertebrate models. In recent years, several compounds have been identified that can extend lifespan in invertebrates, and even in rodents. Here, we summarize the strategies employed, and the progress made, in identifying compounds capable of extending lifespan in organisms ranging from invertebrates to mice and discuss the formidable challenges in translating this work to human therapies.
      PubDate: 2016-03-29T15:26:39Z
      DOI: 10.12688/f1000research.7821.1
      Issue No: Vol. 5 (2016)
  • A curated transcriptome dataset collection to investigate the
           immunobiology of HIV infection [version 1; referees: 2 approved]

    • Authors: Jana Blazkova, Sabri Boughorbel, Scott Presnell, Charlie Quinn, Damien Chaussabel
      Abstract: Compendia of large-scale datasets available in public repositories provide an opportunity to identify and fill current gaps in biomedical knowledge. But first, these data need to be readily accessible to research investigators for interpretation. Here, we make available a collection of transcriptome datasets relevant to HIV infection. A total of 2717 unique transcriptional profiles distributed among 34 datasets were identified, retrieved from the NCBI Gene Expression Omnibus (GEO), and loaded in a custom web application, the Gene Expression Browser (GXB), designed for interactive query and visualization of integrated large-scale data. Multiple sample groupings and rank lists were created to facilitate dataset query and interpretation via this interface. Web links to customized graphical views can be generated by users and subsequently inserted in manuscripts reporting novel findings, such as discovery notes. The tool also enables browsing of a single gene across projects, which can provide new perspectives on the role of a given molecule across biological systems. This curated dataset collection is available at:
      PubDate: 2016-03-11T11:04:27Z
      DOI: 10.12688/f1000research.8204.1
      Issue No: Vol. 5 (2016)
  • Surveillance, insecticide resistance and control of an invasive Aedes
           aegypti (Diptera: Culicidae) population in California [version 2;
           referees: 2 approved]

    • Authors: Anthony J. Cornel, Jodi Holeman, Catelyn C. Nieman, Yoosook Lee, Charles Smith, Mark Amorino, Katherine K. Brisco, Roberto Barrera, Gregory C. Lanzaro, F. Stephen Mulligan III
      Abstract: The invasion and subsequent establishment in California of Aedes aegypti in 2013 has created new challenges for local mosquito abatement and vector control districts. Studies were undertaken to identify effective and economical strategies to monitor the abundance and spread of this mosquito species as well as for its control. Overall, BG Sentinel (BGS) traps were found to be the most sensitive trap type to measure abundance and spread into new locations. Autocidal-Gravid-Ovitraps (AGO-B), when placed at a site for a week, performed equally to BGS in detecting the presence of female Ae. aegypti. Considering operational cost and our findings, we recommend use of BGS traps for surveillance in response to service requests especially in locations outside the known infestation area. We recommend AGO-Bs be placed at fixed sites, cleared and processed once a week to monitor mosquito abundance within a known infestation area. Long-term high density placements of AGO-Bs were found to show promise as an environmentally friendly trap-kill control strategy. California Ae. aegypti were found to be homozygous for the V1016I mutation in the voltage gated sodium channel gene, which is implicated to be involved in insecticide resistance. This strain originating from Clovis, California was resistant to some pyrethroids but not to deltamethrin in bottle bio-assays. Sentinel cage ultra-low-volume (ULV) trials using a new formulation of deltamethrin (DeltaGard®) demonstrated that it provided some control (average of 56% death in sentinel cages in a 91.4 m spray swath) after a single truck mounted aerial ULV application in residential areas.
      PubDate: 2016-03-07T14:00:41Z
      DOI: 10.12688/f1000research.8107.2
      Issue No: Vol. 5 (2016)
  • A new hypothesis: some metastases are the result of inflammatory processes
           by adapted cells, especially adapted immune cells at sites of inflammation
           [version 1; referees: 2 approved]

    • Authors: Leili Shahriyari
      Abstract: There is an old hypothesis that metastasis is the result of migration of tumor cells from the tumor to a distant site. In this article, we propose another mechanism for metastasis, for cancers that are initiated at the site of chronic inflammation. We suggest that cells at the site of chronic inflammation might become adapted to the inflammatory process, and these adaptations may lead to the initiation of an inflammatory tumor. For example, in an inflammatory tumor immune cells might be adapted to send signals of proliferation or angiogenesis, and epithelial cells might be adapted to proliferation (like inactivation of tumor suppressor genes). Therefore, we hypothesize that metastasis could be the result of an inflammatory process by adapted cells, especially adapted immune cells at the site of inflammation, as well as the migration of tumor cells with the help of activated platelets, which travel between sites of inflammation.  If this hypothesis is correct, then any treatment causing necrotic cell death may not be a good solution. Because necrotic cells in the tumor micro-environment or anywhere in the body activate the immune system to initiate the inflammatory process, and the involvement of adapted immune cells in the inflammatory processes leads to the formation and progression of tumors. Adapted activated immune cells send more signals of proliferation and/or angiogenesis than normal cells. Moreover, if there were adapted epithelial cells, they would divide at a much higher rate in response to the proliferation signals than normal cells. Thus, not only would the tumor come back after the treatment, but it would also grow more aggressively.
      PubDate: 2016-02-16T10:31:51Z
      DOI: 10.12688/f1000research.8055.1
      Issue No: Vol. 5 (2016)
  • Understanding the nature of health: New perspectives for medicine and
           public health. Improved wellbeing at lower costs [version 1; referees: 2

    • Authors: Johannes Bircher, Eckhart G. Hahn
      Abstract: Background: Current dilemmas of health care systems call for a new look at the nature of health. This is offered by the Meikirch model. We explore its hypothetical benefit for the future of medicine and public health. Meikirch model: It states: “Health is a dynamic state of wellbeing emergent from conducive interactions between individuals’ potentials, life’s demands, and social and environmental determinants.” “Throughout the life course health results when an individuals’ biologically given potential (BGP) and his or her personally acquired potential (PAP), interacting with social and environmental determinants, satisfactorily respond to the demands of life.” Methods: We explored the Meikirch model’s possible applications for personal and public health care. Results: The PAP of each individual is the most modifiable component of the model. It responds to constructive social interactions and to personal growth. If an individual’s PAP is nurtured to develop further, it likely will contribute much more to health than without fostering. It may also compensate for losses of the BGP. An ensuing new culture of health may markedly improve health in the society. The rising costs of health care presumably are due in part to the tragedy of the commons and to moral hazard. Health as a complex adaptive system offers new possibilities for patient care, particularly for general practitioners. Discussion: Analysis of health systems by the Meikirch model reveals that in many areas more can be done to improve people’s health and to reduce health care costs than is done today. The Meikirch model appears promising for individual and public health in low and high income countries. Emphasizing health instead of disease the Meikirch model reinforces article 12 of the International Covenant on Economic, Social and Cultural Rights of the United Nations – that abandons the WHO definition - and thereby may contribute to its reinterpretation.
      PubDate: 2016-02-12T16:14:01Z
      DOI: 10.12688/f1000research.7849.1
      Issue No: Vol. 5 (2016)
  • Patterns of database citation in articles and patents indicate long-term
           scientific and industry value of biological data resources [version 1;
           referees: 2 approved]

    • Authors: David Bousfield, Johanna McEntyre, Sameer Velankar, George Papadatos, Alex Bateman, Guy Cochrane, Jee-Hyub Kim, Florian Graef, Vid Vartak, Blaise Alako, Niklas Blomberg
      Abstract: Data from open access biomolecular data resources, such as the European Nucleotide Archive and the Protein Data Bank are extensively reused within life science research for comparative studies, method development and to derive new scientific insights. Indicators that estimate the extent and utility of such secondary use of research data need to reflect this complex and highly variable data usage. By linking open access scientific literature, via Europe PubMedCentral, to the metadata in biological data resources we separate data citations associated with a deposition statement from citations that capture the subsequent, long-term, reuse of data in academia and industry.  We extend this analysis to begin to investigate citations of biomolecular resources in patent documents. We find citations in more than 8,000 patents from 2014, demonstrating substantial use and an important role for data resources in defining biological concepts in granted patents to both academic and industrial innovators. Combined together our results indicate that the citation patterns in biomedical literature and patents vary, not only due to citation practice but also according to the data resource cited. The results guard against the use of simple metrics such as citation counts and show that indicators of data use must not only take into account citations within the biomedical literature but also include reuse of data in industry and other parts of society by including patents and other scientific and technical documents such as guidelines, reports and grant applications.
      PubDate: 2016-02-11T15:21:30Z
      DOI: 10.12688/f1000research.7911.1
      Issue No: Vol. 5 (2016)
  • Associations between chlorophyll a and various microcystin-LR health
           advisory concentrations [version 1; referees: 1 approved, 2 approved with

    • Authors: Jeffrey W. Hollister, Betty J. Kreakie
      Abstract: Cyanobacteria harmful algal blooms (cHABs) are associated with a wide range of adverse health effects that stem mostly from the presence of cyanotoxins. To help protect against these impacts, several health advisory levels have been set for some toxins. In particular, one of the more common toxins, microcystin-LR, has several advisory levels set for drinking water and recreational use. However, compared to other water quality measures, field measurements of microcystin-LR are not commonly available due to cost and advanced understanding required to interpret results. Addressing these issues will take time and resources. Thus, there is utility in finding indicators of microcystin-LR that are already widely available, can be estimated quickly and in situ, and used as a first defense against high concentrations of microcystin-LR. Chlorophyll a is commonly measured, can be estimated in situ, and has been shown to be positively associated with microcystin-LR. In this paper, we use this association to provide estimates of chlorophyll a concentrations that are indicative of a higher probability of exceeding select health advisory concentrations for microcystin-LR. Using the 2007 National Lakes Assessment and a conditional probability approach, we identify chlorophyll a concentrations that are more likely than not to be associated with an exceedance of a microcystin-LR health advisory level. We look at the recent US EPA health advisories for drinking water as well as the World Health Organization levels for drinking water and recreational use and identify a range of chlorophyll a thresholds. A 50% chance of exceeding one of the microcystin-LR advisory concentrations of 0.3, 1, 1.6, and 2 g/L is associated with chlorophyll a concentration thresholds of 23.4, 67.0, 83.5, and 105.8, respectively. When managing for these various microcystin-LR levels, exceeding these reported chlorophyll a concentrations should be a trigger for further testing and possible management action.
      PubDate: 2016-02-09T11:36:30Z
      DOI: 10.12688/f1000research.7955.1
      Issue No: Vol. 5 (2016)
  • Open drug discovery for the Zika virus [version 1; referees: 3 approved]

    • Authors: Sean Ekins, Daniel Mietchen, Megan Coffee, Thomas P Stratton, Joel S Freundlich, Lucio Freitas-Junior, Eugene Muratov, Jair Siqueira-Neto, Antony J Williams, Carolina Andrade
      Abstract: The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.
      PubDate: 2016-02-09T10:30:45Z
      DOI: 10.12688/f1000research.8013.1
      Issue No: Vol. 5 (2016)
  • Associations between joint effusion in the knee and gene expression levels
           in the circulation: a meta-analysis [version 1; referees: 3 approved]

    • Abstract: Objective: To identify molecular biomarkers for early knee osteoarthritis (OA), we examined whether joint effusion in the knee associated with different gene expression levels in the circulation. Materials and Methods: Joint effusion grades measured with magnetic resonance (MR) imaging and gene expression levels in blood were determined in women of the Rotterdam Study (N=135) and GARP (N=98). Associations were examined using linear regression analyses, adjusted for age, fasting status, RNA quality, technical batch effects, blood cell counts, and BMI. To investigate enriched pathways and protein-protein interactions, we used the DAVID and STRING webtools. Results: In a meta-analysis, we identified 257 probes mapping to 189 unique genes in blood that were nominally significantly associated with joint effusion grades in the knee. Several compelling genes were identified such as C1orf38 and NFATC1. Significantly enriched biological pathways were: response to stress, gene expression, negative regulation of intracellular signal transduction, and antigen processing and presentation of exogenous pathways. Conclusion: Meta-analyses and subsequent enriched biological pathways resulted in interesting candidate genes associated with joint effusion that require further characterization. Associations were not transcriptome-wide significant most likely due to limited power. Additional studies are required to replicate our findings in more samples, which will greatly help in understanding the pathophysiology of OA and its relation to inflammation, and may result in biomarkers urgently needed to diagnose OA at an early stage.
      PubDate: 2016-01-27T11:28:29Z
      DOI: 10.12688/f1000research.7763.1
      Issue No: Vol. 5 (2016)
  • Referencing cross-reactivity of detection antibodies for protein array
           experiments [version 1; referees: 1 approved, 2 approved with

    • Authors: Darragh Lemass, Richard O'Kennedy, Gregor S. Kijanka
      Abstract: Protein arrays are frequently used to profile antibody repertoires in humans and animals. High-throughput protein array characterisation of complex antibody repertoires requires a platform-dependent, lot-to-lot validation of secondary detection antibodies. This article details the validation of an affinity-isolated anti-chicken IgY antibody produced in rabbit and a goat anti-rabbit IgG antibody conjugated with alkaline phosphatase using protein arrays consisting of 7,390 distinct human proteins. Probing protein arrays with secondary antibodies in absence of chicken serum revealed non-specific binding to 61 distinct human proteins. The cross-reactivity of the tested secondary detection antibodies points towards the necessity of platform-specific antibody characterisation studies for all secondary immunoreagents. Secondary antibody characterisation using protein arrays enables generation of reference lists of cross-reactive proteins, which can be then excluded from analysis in follow-up experiments. Furthermore, making such cross-reactivity lists accessible to the wider research community may help to interpret data generated by the same antibodies in applications not related to protein arrays such as immunoprecipitation, Western blots or other immunoassays.
      PubDate: 2016-01-18T14:23:51Z
      DOI: 10.12688/f1000research.7668.1
      Issue No: Vol. 5 (2016)
  • The dream of health information for all [version 1; referees: 3 approved]

    • Abstract: In 2004, an influential report in The Lancet suggested that open health information for all could be achieved by 2015. Unfortunately, this goal has not yet been accomplished. Despite progress in obtaining quality scientific articles in Latin America, it remains difficult to reliably access new and cutting-edge research. As graduating Peruvian medical students, we have confronted many obstacles in obtaining access to quality and up-to-date information and a constant tension between accessing "what is available" rather than "what we need". As we have learned, these limitations affect not only our own education but also the choices we make in the management of our patients. In the following article, we state our point of view regarding limitations in access to scientific articles in Peru and Latin America.
      PubDate: 2016-01-08T12:00:27Z
      DOI: 10.12688/f1000research.6950.1
      Issue No: Vol. 5 (2016)
  • BioTapestry now provides a web application and improved drawing and layout
           tools [version 1; referees: 2 approved]

    • Authors: Suzanne M. Paquette, Kalle Leinonen, William J.R. Longabaugh
      Abstract: Gene regulatory networks (GRNs) control embryonic development, and to understand this process in depth, researchers need to have a detailed understanding of both the network architecture and its dynamic evolution over time and space. Interactive visualization tools better enable researchers to conceptualize, understand, and share GRN models. BioTapestry is an established application designed to fill this role, and recent enhancements released in Versions 6 and 7 have targeted two major facets of the program. First, we introduced significant improvements for network drawing and automatic layout that have now made it much easier for the user to create larger, more organized network drawings. Second, we revised the program architecture so it could continue to support the current Java desktop Editor program, while introducing a new BioTapestry GRN Viewer that runs as a JavaScript web application in a browser. We have deployed a number of GRN models using this new web application. These improvements will ensure that BioTapestry remains viable as a research tool in the face of the continuing evolution of web technologies, and as our understanding of GRN models grows.
      PubDate: 2016-01-08T11:19:48Z
      DOI: 10.12688/f1000research.7620.1
      Issue No: Vol. 5 (2016)
  • Rituximab efficiently depletes B cells in lung tumors and normal lung
           tissue [version 1; referees: 2 approved]

    • Abstract: Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab.
      PubDate: 2016-01-08T10:08:35Z
      DOI: 10.12688/f1000research.7599.1
      Issue No: Vol. 5 (2016)
  • DREAMTools: a Python package for scoring collaborative challenges [version
           2; referees: 1 approved, 2 approved with reservations]

    • Abstract: DREAM challenges are community competitions designed to advance computational methods and address fundamental questions in system biology and translational medicine. Each challenge asks participants to develop and apply computational methods to either predict unobserved outcomes or to identify unknown model parameters given a set of training data. Computational methods are evaluated using an automated scoring metric, scores are posted to a public leaderboard, and methods are published to facilitate community discussions on how to build improved methods. By engaging participants from a wide range of science and engineering backgrounds, DREAM challenges can comparatively evaluate a wide range of statistical, machine learning, and biophysical methods. Here, we describe DREAMTools, a Python package for evaluating DREAM challenge scoring metrics. DREAMTools provides a command line interface that enables researchers to test new methods on past challenges, as well as a framework for scoring new challenges. As of March 2016, DREAMTools includes more than 80% of completed DREAM challenges. DREAMTools complements the data, metadata, and software tools available at the DREAM website and on the Synapse platform at Availability: DREAMTools is a Python package. Releases and documentation are available at The source code is available at
      PubDate: 2016-04-08T10:06:14Z
      DOI: 10.12688/f1000research.7118.2
      Issue No: Vol. 4 (2016)
  • A protocol to examine vision and gait in Parkinson’s disease: impact
           of cognition and response to visual cues [version 2; referees: 2 approved]

    • Authors: Samuel Stuart, Brook Galna, Sue Lord, Lynn Rochester
      Abstract: Background Cognitive and visual impairments are common in Parkinson’s disease (PD) and contribute to gait deficit and falls. To date, cognition and vision in gait in PD have been assessed separately. Impact of both functions (which we term ‘visuo-cognition’) on gait however is likely interactive and can be tested using visual sampling (specifically saccadic eye movements) to provide an online behavioural measure of performance. Although experiments using static paradigms show saccadic impairment in PD, few studies have quantified visual sampling during dynamic motor tasks such as gait. This article describes a protocol developed for testing visuo-cognition during gait in order to examine the: 1) independent roles of cognition and vision in gait in PD, 2) interaction between both functions, and 3) role of visuo-cognition in gait in PD. Methods Two groups of older adults (≥50 years old) were recruited; non-demented people with PD (n=60) and age-matched controls (n=40). Participants attended one session and a sub-group (n=25) attended two further sessions in order to establish mobile eye-tracker reliability. Participants walked in a gait laboratory under different attentional (single and dual task), environmental (walk straight, through a door and turning), and cueing (no visual cues and visual cues) conditions. Visual sampling was recorded using synchronised mobile eye-tracker and electrooculography systems, and gait was measured using 3D motion analysis. Discussion This exploratory study examined visuo-cognitive processes and their impact on gait in PD. Improved understanding of the influence of cognitive and visual functions on visual sampling during gait and gait in PD will assist in development of interventions to improve gait and reduce falls risk. This study will also help establish robust mobile eye-tracking methods in older adults and people with PD.
      PubDate: 2016-03-24T15:59:14Z
      DOI: 10.12688/f1000research.7320.2
      Issue No: Vol. 4 (2016)
  • Signaling mechanism by the Staphylococcus aureus two-component system
           LytSR: role of acetyl phosphate in bypassing the cell membrane electrical
           potential sensor LytS [version 2; referees: 2 approved]

    • Authors: Kevin Patel, Dasantila Golemi-Kotra
      Abstract: The two-component system LytSR has been linked to the signal transduction of cell membrane electrical potential perturbation and is involved in the adaptation of Staphylococcus aureus to cationic antimicrobial peptides. It consists of a membrane-bound histidine kinase, LytS, which belongs to the family of multiple transmembrane-spanning domains receptors, and a response regulator, LytR, which belongs to the novel family of non-helix-turn-helix DNA-binding domain proteins. LytR regulates the expression of cidABC and lrgAB operons, the gene products of which are involved in programmed cell death and lysis. In vivo studies have demonstrated involvement of two overlapping regulatory networks in regulating the lrgAB operon, both depending on LytR. One regulatory network responds to glucose metabolism and the other responds to changes in the cell membrane potential. Herein, we show that LytS has autokinase activity and can catalyze a fast phosphotransfer reaction, with 50% of its phosphoryl group lost within 1 minute of incubation with LytR. LytS has also phosphatase activity. Notably, LytR undergoes phosphorylation by acetyl phosphate at a rate that is 2-fold faster than the phosphorylation by LytS. This observation is significant in lieu of the in vivo observations that regulation of the lrgAB operon is LytR-dependent in the presence of excess glucose in the medium. The latter condition does not lead to perturbation of the cell membrane potential but rather to the accumulation of acetate in the cell. Our study provides insights into the molecular basis for regulation of lrgAB in a LytR-dependent manner under conditions that do not involve sensing by LytS.
      PubDate: 2016-03-22T12:54:59Z
      DOI: 10.12688/f1000research.6213.2
      Issue No: Vol. 4 (2016)
  • Transcription factor motif quality assessment requires systematic
           comparative analysis [version 2; referees: 2 approved]

    • Authors: Caleb Kipkurui Kibet, Philip Machanick
      Abstract: Transcription factor (TF) binding site prediction remains a challenge in gene regulatory research due to degeneracy and potential variability in binding sites in the genome. Dozens of algorithms designed to learn binding models (motifs) have generated many motifs available in research papers with a subset making it to databases like JASPAR, UniPROBE and Transfac. The presence of many versions of motifs from the various databases for a single TF and the lack of a standardized assessment technique makes it difficult for biologists to make an appropriate choice of binding model and for algorithm developers to benchmark, test and improve on their models. In this study, we review and evaluate the approaches in use, highlight differences and demonstrate the difficulty of defining a standardized motif assessment approach. We review scoring functions, motif length, test data and the type of performance metrics used in prior studies as some of the factors that influence the outcome of a motif assessment. We show that the scoring functions and statistics used in motif assessment influence ranking of motifs in a TF-specific manner. We also show that TF binding specificity can vary by source of genomic binding data. We also demonstrate that information content of a motif is not in isolation a measure of motif quality but is influenced by TF binding behaviour. We conclude that there is a need for an easy-to-use tool that presents all available evidence for a comparative analysis.
      PubDate: 2016-03-14T14:05:46Z
      DOI: 10.12688/f1000research.7408.2
      Issue No: Vol. 4 (2016)
  • CRE: a cost effective and rapid approach for PCR-mediated concatenation of
           KRAS and EGFR exons [version 2; referees: 2 approved]

    • Authors: Manoj P. Ramteke, Kuldeep J Patel, Mukul Godbole, Maulik Vyas, Kunal Karve, Anuradha Choughule, Kumar Prabhash, Amit Dutt
      Abstract: Molecular diagnostics has changed the way lung cancer patients are treated worldwide. Of several different testing methods available, PCR followed by directed sequencing and amplification refractory mutation system (ARMS) are the two most commonly used diagnostic methods worldwide to detect mutations at KRAS exon 2 and EGFR kinase domain exons 18-21 in lung cancer. Compared to ARMS, the PCR followed by directed sequencing approach is relatively inexpensive but more cumbersome to perform. Moreover, with a limiting amount of genomic DNA from clinical formalin-fixed, paraffin-embedded (FFPE) specimens or fine biopsies of lung tumors, multiple rounds of PCR and sequencing reactions often get challenging. Here, we report a cost-effective single multiplex-PCR based method, CRE (for Co-amplification of five KRAS and EGFR exons), followed by concatenation of the PCR product as a single linear fragment for direct sequencing. CRE is a robust protocol that can be adapted for routine use in clinical diagnostics with reduced variability, cost and turnaround time requiring a minimal amount of template DNA extracted from FFPE or fresh frozen tumor samples. As a proof of principle, CRE is able to detect the activating EGFR L858R and T790M EGFR mutations in lung cancer cell line and primary tumors.
      PubDate: 2016-03-08T13:59:43Z
      DOI: 10.12688/f1000research.6663.2
      Issue No: Vol. 4 (2016)
  • A paradoxical relationship between Resveratrol and copper (II) with
           respect to degradation of DNA and RNA [version 2; referees: 2 approved]

    • Authors: Siddharth Subramaniam, Iqbal Vohra, Aishwarya Iyer, Naveen K Nair, Indraneel Mittra
      Abstract: Resveratrol (R), a plant polyphenol, is known to reduce Cu (II) to Cu (I) generating reactive oxygen species that can cleave plasmid DNA. Here we report a surprising observation of a paradoxical relationship between R and Cu whereby plasmid DNA cleaving / degrading activity of R-Cu increased progressively as the ratio of R to Cu was increased i.e., the concentration of Cu was successively reduced with respect to a fixed concentration R. Whereas cleavage of plasmid DNA occurred at low molar ratios of R to Cu, at higher ratios, complete degradation of DNA was achieved. By further increasing the ratio, whereby the concentration of Cu was reduced to very low levels, the DNA degrading activity of R-Cu was lost. This paradoxical relationship is also seen with respect to eukaryotic genomic DNA and RNA. Since R-Cu may have anti-cancer and anti-viral activities, our findings may not only help to improve the therapeutic efficacy of R-Cu but also reduce its toxic side effects with the use of low concentration of Cu.
      PubDate: 2016-03-02T15:28:12Z
      DOI: 10.12688/f1000research.7202.2
      Issue No: Vol. 4 (2016)
  • The TOUCH program and natalizumab: Fundamental flaw in patient protection
           [version 2; referees: 2 approved, 1 approved with reservations]

    • Authors: Jagannadha Avasarala
      Abstract: Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program – this strategy helps monitor the disease. Clinical vigilance remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic.  This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met – to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development.
      PubDate: 2016-02-18T16:46:46Z
      DOI: 10.12688/f1000research.7513.2
      Issue No: Vol. 4 (2016)
  • Possible identification of CENP-C in fish and the presence of the CENP-C
           motif in M18BP1 of vertebrates. [version 2; referees: 2 approved]

    • Authors: Leos Kral
      Abstract: The centromeric protein CENP-C is a base component of the kinetochore. This protein, along with CENP-A has been shown to adaptively evolve in a number of animal and plant species. In order to determine if CENP-C also evolves in fish species, I attempted to retrieve fish CENP-C sequences from GenBank. No Teleostei CENP-C sequences were found either by name or by BLASTP searches with the vertebrate CENP-C motif sequence. A number of putative Teleostei protein sequences were identified in GenBank that have homology to the C-terminal cupin domain of vertebrate CENP-C. These proteins only have partial homology to the CENP-C motif, but evidence is presented that makes it likely that these fish proteins are orthologs of CENP-C. Interestingly, it was also discovered that the CENP-C motif sequence is also mostly present in M18BP1 proteins of fish and some other vertebrates but not in mammals. This finding may have implications for CENP-C and M18BP1 assembly in centromeric regions of different vertebrate taxa.
      PubDate: 2016-01-20T10:55:08Z
      DOI: 10.12688/f1000research.6823.2
      Issue No: Vol. 4 (2016)
  • Tetranucleotide usage highlights genomic heterogeneity among
           mycobacteriophages [version 2; referees: 2 approved]

    • Authors: Benjamin Siranosian, Sudheesha Perera, Edward Williams, Chen Ye, Christopher de Graffenried, Peter Shank
      Abstract: Background The genomic sequences of mycobacteriophages, phages infecting mycobacterial hosts, are diverse and mosaic. Mycobacteriophages often share little nucleotide similarity, but most of them have been grouped into lettered clusters and further into subclusters. Traditionally, mycobacteriophage genomes are analyzed based on sequence alignment or knowledge of gene content. However, these approaches are computationally expensive and can be ineffective for significantly diverged sequences. As an alternative to alignment-based genome analysis, we evaluated tetranucleotide usage in mycobacteriophage genomes. These methods make it easier to characterize features of the mycobacteriophage population at many scales. Description We computed tetranucleotide usage deviation (TUD), the ratio of observed counts of 4-mers in a genome to the expected count under a null model. TUD values are comparable between members of a phage subcluster and distinct between subclusters. With few exceptions, neighbor joining phylogenetic trees and hierarchical clustering dendrograms constructed using TUD values place phages in a monophyletic clade with members of the same subcluster. Regions in a genome with exceptional TUD values can point to interesting features of genomic architecture. Finally, we found that subcluster B3 mycobacteriophages contain significantly overrepresented 4-mers and 6-mers that are atypical of phage genomes. Conclusions Statistics based on tetranucleotide usage support established clustering of mycobacteriophages and can uncover interesting relationships within and between sequenced phage genomes. These methods are efficient to compute and do not require sequence alignment or knowledge of gene content. The code to download mycobacteriophage genome sequences and reproduce our analysis is freely available at
      PubDate: 2015-10-30T11:37:03Z
      DOI: 10.12688/f1000research.6077.2
      Issue No: Vol. 4 (2015)
  • ve-SEQ: Robust, unbiased enrichment for streamlined detection and
           whole-genome sequencing of HCV and other highly diverse pathogens [version
           1; referees: 2 approved]

    • Authors: David Bonsall, M. Azim Ansari, Camilla Ip, Amy Trebes, Anthony Brown, Paul Klenerman, David Buck, STOP-HCV Consortium, Paolo Piazza, Eleanor Barnes, Rory Bowden
      Abstract: The routine availability of high-depth virus sequence data would allow the sensitive detection of resistance-associated variants that can jeopardize HIV or hepatitis C virus (HCV) treatment. We introduce ve-SEQ, a high-throughput method for sequence-specific enrichment and characterization of whole-virus genomes at up to 20% divergence from a reference sequence and 1,000-fold greater sensitivity than direct sequencing. The extreme genetic diversity of HCV led us to implement an algorithm for the efficient design of panels of oligonucleotide probes to capture any sequence among a defined set of targets without detectable bias. ve-SEQ enables efficient detection and sequencing of any HCV genome, including mixtures and intra-host variants, in a single experiment, with greater tolerance of sequence diversity than standard amplification methods and greater sensitivity than metagenomic sequencing, features that are directly applicable to other pathogens or arbitrary groups of target organisms, allowing the combination of sensitive detection with sequencing in many settings.
      PubDate: 2015-10-13T14:47:45Z
      DOI: 10.12688/f1000research.7111.1
      Issue No: Vol. 4 (2015)
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