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Journal Cover F1000Research
  [SJR: 0.56]   [H-I: 9]   [4 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • Dysfunctional adipose tissue and low-grade inflammation in the management
           of the metabolic syndrome: current practices and future advances [version
           1; referees: 2 approved]

    • Authors: Marleen M. J. van Greevenbroek, Casper G. Schalkwijk, Coen D.A. Stehouwer
      Abstract: The ongoing worldwide obesity epidemic makes the metabolic syndrome an increasingly important entity. In this review, we provide a short background on the metabolic syndrome, we discuss recent developments in the three main options that have been identified for intervention in the metabolic syndrome, i.e. lifestyle and surgical and pharmacological interventions, and we focus on different views in the literature and also include our own viewpoints on the metabolic syndrome. In addition, we discuss some emerging treatment targets for adipose tissue dysfunction and low-grade inflammation, i.e. activation of the inflammasome and the complement system, and consider some selected opportunities for intervention in these processes.
      PubDate: 2016-10-13T12:06:09Z
      DOI: 10.12688/f1000research.8971.1
      Issue No: Vol. 5 (2016)
  • Muddled mechanisms: recent progress towards antimalarial target
           identification [version 1; referees: 2 approved]

    • Authors: Rachel L. Edwards, Audrey R. Odom John
      Abstract: In the past decade, malaria rates have plummeted as a result of aggressive infection control measures and the adoption of artemisinin-based combination therapies (ACTs). However, a potential crisis looms ahead. Treatment failures to standard antimalarial regimens have been reported in Southeast Asia, and devastating consequences are expected if resistance spreads to the African continent. To prevent a potential public health emergency, the antimalarial arsenal must contain therapeutics with novel mechanisms of action (MOA). An impressive number of high-throughput screening (HTS) campaigns have since been launched, identifying thousands of compounds with activity against one of the causative agents of malaria, Plasmodium falciparum. Now begins the difficult task of target identification, for which studies are often tedious, labor intensive, and difficult to interpret. In this review, we highlight approaches that have been instrumental in tackling the challenges of target assignment and elucidation of the MOA for hit compounds. Studies that apply these innovative techniques to antimalarial target identification are described, as well as the impact of the data in the field.
      PubDate: 2016-10-13T11:56:44Z
      DOI: 10.12688/f1000research.9477.1
      Issue No: Vol. 5 (2016)
  • Perioperative regional anaesthesia and postoperative longer-term outcomes
           [version 1; referees: 3 approved]

    • Authors: Jan Jakobsson, Mark Z. Johnson
      Abstract: Regional anaesthesia provides effective anaesthesia and analgesia in the perioperative setting. Central neuraxial blocks—that is, spinal and epidural blocks—are well established as an alternative or adjunct to general anaesthesia. Peripheral blocks may be used as part of multimodal anaesthesia/analgesia in perioperative practice, reducing the need for opioid analgesics and enhancing early recovery. Furthermore, regional anaesthesia has increased in popularity and may be done with improved ease and safety with the introduction of ultrasound-guided techniques. The effects of local anaesthetics and regional anaesthesia on long-term outcomes such as morbidity, mortality, the quality of recovery beyond the duration of analgesia, and whether it can expedite the resumption of activities of daily living are less clear. It has also been suggested that regional anaesthesia may impact the risk of metastasis after cancer surgery. This article provides an overview of current evidence around quality of recovery, risk for delirium, long-term effects, and possible impact on cancer disease progression associated with the clinical use of local and regional anaesthetic techniques. In summary, there is still a lack of robust data that regional anaesthesia has a clinical impact beyond its well-acknowledged beneficial effects of reducing pain, reduced opioid consumption, and improved quality of early recovery. Further high-quality prospective studies on long-term outcomes are warranted.
      PubDate: 2016-10-11T15:56:36Z
      DOI: 10.12688/f1000research.9100.1
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding hepatic drug transport [version 1;
           referees: 2 approved]

    • Authors: Bruno Stieger, Bruno Hagenbuch
      Abstract: Cells need to strictly control their internal milieu, a function which is performed by the plasma membrane. Selective passage of molecules across the plasma membrane is controlled by transport proteins. As the liver is the central organ for drug metabolism, hepatocytes are equipped with numerous drug transporters expressed at the plasma membrane. Drug disposition includes absorption, distribution, metabolism, and elimination of a drug and hence multiple passages of drugs and their metabolites across membranes. Consequently, understanding the exact mechanisms of drug transporters is essential both in drug development and in drug therapy. While many drug transporters are expressed in hepatocytes, and some of them are well characterized, several transporters have only recently been identified as new drug transporters. Novel powerful tools to deorphanize (drug) transporters are being applied and show promising results. Although a large set of tools are available for studying transport in vitro and in isolated cells, tools for studying transport in living organisms, including humans, are evolving now and rely predominantly on imaging techniques, e.g. positron emission tomography. Imaging is an area which, certainly in the near future, will provide important insights into "transporters at work" in vivo.
      PubDate: 2016-10-06T13:12:26Z
      DOI: 10.12688/f1000research.9466.1
      Issue No: Vol. 5 (2016)
  • Using diverse U.S. beef cattle genomes to identify missense mutations in
           EPAS1, a gene associated with pulmonary hypertension [version 2; referees:
           2 approved]

    • Authors: Michael P. Heaton, Timothy P.L. Smith, Jacky K. Carnahan, Veronica Basnayake, Jiansheng Qiu, Barry Simpson, Theodore S. Kalbfleisch
      Abstract: The availability of whole genome sequence (WGS) data has made it possible to discover protein variants in silico. However, existing bovine WGS databases do not show data in a form conducive to protein variant analysis, and tend to under represent the breadth of genetic diversity in global beef cattle. Thus, our first aim was to use 96 beef sires, sharing minimal pedigree relationships, to create a searchable and publicly viewable set of mapped genomes relevant for 19 popular breeds of U.S. cattle. Our second aim was to identify protein variants encoded by the bovine endothelial PAS domain-containing protein 1 gene (EPAS1), a gene associated with pulmonary hypertension in Angus cattle. The identity and quality of genomic sequences were verified by comparing WGS genotypes to those derived from other methods. The average read depth, genotype scoring rate, and genotype accuracy exceeded 14, 99%, and 99%, respectively. The 96 genomes were used to discover four amino acid variants encoded by EPAS1 (E270Q, P362L, A671G, and L701F) and confirm two variants previously associated with disease (A606T and G610S). The six EPAS1 missense mutations were verified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays, and their frequencies were estimated in a separate collection of 1154 U.S. cattle representing 46 breeds. A rooted phylogenetic tree of eight polypeptide sequences provided a framework for evaluating the likely order of mutations and potential impact of EPAS1 alleles on the adaptive response to chronic hypoxia in U.S. cattle. This public, whole genome resource facilitates in silico identification of protein variants in diverse types of U.S. beef cattle, and provides a means of translating WGS data into a practical biological and evolutionary context for generating and testing hypotheses.
      PubDate: 2016-10-05T15:46:27Z
      DOI: 10.12688/f1000research.9254.2
      Issue No: Vol. 5 (2016)
  • Recent progress and future challenges in algal biofuel production [version
           1; referees: 4 approved]

    • Authors: Jonathan B. Shurin, Michael D. Burkart, Stephen P. Mayfield, Val H. Smith
      Abstract: Modern society is fueled by fossil energy produced millions of years ago by photosynthetic organisms. Cultivating contemporary photosynthetic producers to generate energy and capture carbon from the atmosphere is one potential approach to sustaining society without disrupting the climate. Algae, photosynthetic aquatic microorganisms, are the fastest growing primary producers in the world and can therefore produce more energy with less land, water, and nutrients than terrestrial plant crops. We review recent progress and challenges in developing bioenergy technology based on algae. A variety of high-value products in addition to biofuels can be harvested from algal biomass, and these may be key to developing algal biotechnology and realizing the commercial potential of these organisms. Aspects of algal biology that differentiate them from plants demand an integrative approach based on genetics, cell biology, ecology, and evolution. We call for a systems approach to research on algal biotechnology rooted in understanding their biology, from the level of genes to ecosystems, and integrating perspectives from physical, chemical, and social sciences to solve one of the most critical outstanding technological problems.
      PubDate: 2016-10-04T10:58:30Z
      DOI: 10.12688/f1000research.9217.1
      Issue No: Vol. 5 (2016)
  • Biology and structure of leukocyte β2 integrins and their role in
           inflammation [version 1; referees: 3 approved]

    • Authors: M. Amin Arnaout
      Abstract: Integrins comprise a large family of αβ heterodimeric cell adhesion receptors that are expressed on all cells except red blood cells and that play essential roles in the regulation of cell growth and function. The leukocyte integrins, which include members of the β1, β2, β3, and β7 integrin family, are critical for innate and adaptive immune responses but also can contribute to many inflammatory and autoimmune diseases when dysregulated. This review focuses on the β2 integrins, the principal integrins expressed on leukocytes. We review their discovery and role in host defense, the structural basis for their ligand recognition and activation, and their potential as therapeutic targets.
      PubDate: 2016-10-04T09:59:16Z
      DOI: 10.12688/f1000research.9415.1
      Issue No: Vol. 5 (2016)
  • Factors affecting stone free rate of primary percutaneous nephrolithotomy
           on staghorn calculi: a single center experience of 15 years [version 2;
           referees: 2 approved]

    • Authors: Widi Atmoko, Ponco Birowo, Nur Rasyid
      Abstract: Objectives: Percutaneous nephrolithotomy on staghorn calculi is challenging for urologists because it is difficult to remove all of the stones. The purpose of this study was to evaluate the associated factors of stone-free rate after primary percutaneous nephrolithotomy on staghorn calculi in a large series of patients at a single, tertiary referral, endourologic stone center. Methods: We collected data from medical record between January 2000 and December 2015. A total of 345 primary percutaneous nephrolithotomy procedures were performed for patients with staghorn calculi. This study included both and made no distinction between partial and complete staghorn calculi. Stone-free is defined as the absence of residual stones after undergoing percutaneous nephrolithotomy for the first time. Significant factors from univariate analysis that correlated with stone-free rate after primary percutaneous nephrolithotomy of staghorn stone were further analyzed using multivariate regression analysis. Results: The mean patient age was 52.23±10.38 years. The stone-free rate of percutaneous nephrolithotomy monotherapy was 62.6%. The mean operating time was 79.55±34.46 minutes. The mean length of stay in hospital was 4.29±3.00 days. Using the chi-square test, history of ipsilateral open renal stone surgery (p = 0.01), stone burden (p = < 0.001), and type of anesthesia (p = 0.04) had a significant impact on the stone-free. From multivariate analysis, the history of ipsilateral open renal stone surgery [OR 0.48; 95% CI 0.28-0.81; p 0.01] and the stone burden [OR 0.28; 95% CI 0.18-0.45; p 0.00] were significant independent risk factors for stone-free.
      PubDate: 2016-09-30T16:31:52Z
      DOI: 10.12688/f1000research.9509.2
      Issue No: Vol. 5 (2016)
  • Whose sample is it anyway? Widespread misannotation of samples in
           transcriptomics studies [version 2; referees: 2 approved]

    • Authors: Lilah Toker, Min Feng, Paul Pavlidis
      Abstract: Concern about the reproducibility and reliability of biomedical research has been rising. An understudied issue is the prevalence of sample mislabeling, one impact of which would be invalid comparisons. We studied this issue in a corpus of human transcriptomics studies by comparing the provided annotations of sex to the expression levels of sex-specific genes. We identified apparent mislabeled samples in 46% of the datasets studied, yielding a 99% confidence lower-bound estimate for all studies of 33%. In a separate analysis of a set of datasets concerning a single cohort of subjects, 2/4 had mislabeled samples, indicating laboratory mix-ups rather than data recording errors. While the number of mixed-up samples per study was generally small, because our method can only identify a subset of potential mix-ups, our estimate is conservative for the breadth of the problem. Our findings emphasize the need for more stringent sample tracking, and that re-users of published data must be alert to the possibility of annotation and labelling errors.
      PubDate: 2016-09-30T15:40:19Z
      DOI: 10.12688/f1000research.9471.2
      Issue No: Vol. 5 (2016)
  • Current status and future prospects for enabling chemistry technology in
           the drug discovery process [version 1; referees: 2 approved]

    • Authors: Stevan W. Djuric, Charles W. Hutchins, Nari N. Talaty
      Abstract: This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of “dangerous” reagents. Also featured are advances in the “computer-assisted drug design” area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities.
      PubDate: 2016-09-30T15:17:19Z
      DOI: 10.12688/f1000research.9515.1
      Issue No: Vol. 5 (2016)
  • Contemporary views on inflammatory pain mechanisms: TRPing over innate and
           microglial pathways [version 1; referees: 3 approved]

    • Authors: Zhonghui Guan, Judith Hellman, Mark Schumacher
      Abstract: Tissue injury, whether by trauma, surgical intervention, metabolic dysfunction, ischemia, or infection, evokes a complex cellular response (inflammation) that is associated with painful hyperalgesic states. Although in the acute stages it is necessary for protective reflexes and wound healing, inflammation may persist well beyond the need for tissue repair or survival. Prolonged inflammation may well represent the greatest challenge mammalian organisms face, as it can lead to chronic painful conditions, organ dysfunction, morbidity, and death. The complexity of the inflammatory response reflects not only the inciting event (infection, trauma, surgery, cancer, or autoimmune) but also the involvement of heterogeneous cell types including neuronal (primary afferents, sensory ganglion, and spinal cord), non-neuronal (endothelial, keratinocytes, epithelial, and fibroblasts), and immune cells. In this commentary, we will examine 1.) the expression and regulation of two members of the transient receptor potential family in primary afferent nociceptors and their activation/regulation by products of inflammation, 2.) the role of innate immune pathways that drive inflammation, and 3.) the central nervous system’s response to injury with a focus on the activation of spinal microglia driving painful hyperalgesic states.
      PubDate: 2016-09-30T15:13:00Z
      Issue No: Vol. 5 (2016)
  • Gut chemosensing: implications for disease pathogenesis [version 1;
           referees: 2 approved]

    • Authors: Christopher J. Berg, Jonathan D. Kaunitz
      Abstract: The ability of humans to sense chemical signals in ingested substances is implicit in the ability to detect the five basic tastes; sweet, sour, bitter, salty, and umami. Of these, sweet, bitter, and umami tastes are detected by lingual G-protein-coupled receptors (GPCRs). Recently, these receptors were also localized to the gut mucosa. In this review, we will emphasize recent advances in the understanding of the mechanisms and consequences of foregut luminal chemosensing, with special emphasis on cell surface GPCRs such as the sweet and proteinaceous taste receptors (TASRs), short- and long-chain fatty acid (FA) receptors, and bile acid receptors. The majority of these luminal chemosensors are expressed on enteroendocrine cells (EECs), which are specialized endocrine cells in the intestine and pancreas that release gut hormones with ligand activation. These gut hormones are responsible for a wide variety of physiologic and homeostatic mechanisms, including glycemic control, appetite stimulation and suppression, regulation of gastric emptying, and trophic effects on the intestinal epithelium. Released from the EECs, the gut peptides have paracrine, autocrine, and endocrine effects. Additionally, EECs have unique direct connections to the enteric nervous system enabling precise transmission of sensory data to and communication with the central nervous system. We will also describe how gut sensors are implicated in gut hormone release, followed by examples of how altered gut chemosensing has been implicated in pathological conditions such as metabolic diseases including diabetes and obesity, functional dyspepsia, helminthic infections, colitis, gastric bypass surgery, and gastric inflammation and cancer.
      PubDate: 2016-09-30T15:09:24Z
      DOI: 10.12688/f1000research.9208.1
      Issue No: Vol. 5 (2016)
  • The mesh controversy [version 1; referees: 2 approved]

    • Authors: Joshua A. Cohn, Elizabeth Timbrook Brown, Casey G. Kowalik, Melissa R. Kaufmann, Roger R. Dmochowski, W. Stuart Reynolds
      Abstract: Pelvic organ prolapse and stress urinary incontinence are common conditions for which approximately 11% of women will undergo surgical intervention in their lifetime. The use of vaginal mesh for pelvic organ prolapse and stress urinary incontinence rose rapidly in the early 2000s as over 100 mesh products were introduced into the clinical armamentarium with little regulatory oversight for their use. US Food and Drug Administration Public Health Notifications in 2008 and 2011, as well as reclassification of transvaginal mesh for prolapse to class III in early 2016, were a response to debilitating complications associated with transvaginal mesh placement in many women. The midurethral sling has not been subject to the same reclassification and continues to be endorsed as the “gold standard” for surgical management of stress urinary incontinence by subspecialty societies. However, litigators have not differentiated between mesh for prolapse and mesh for incontinence. As such, all mesh, including that placed for stress urinary incontinence, faces continued controversy amidst an uncertain future. In this article, we review the background of the mesh controversy, recent developments, and the anticipated role of mesh in surgery for prolapse and stress urinary incontinence going forward.
      PubDate: 2016-09-30T14:29:08Z
      DOI: 10.12688/f1000research.9229.1
      Issue No: Vol. 5 (2016)
  • A fully featured COMBINE archive of a simulation study on syncytial
           mitotic cycles in Drosophila embryos [version 1; referees: 1 approved, 2
           approved with reservations]

    • Authors: Martin Scharm, Dagmar Waltemath
      Abstract: COMBINE archives are standardised containers for data files related to a simulation study in computational biology. This manuscript describes a fully featured archive of a previously published simulation study, including (i) the original publication, (ii) the model, (iii) the analyses, and (iv) metadata describing the files and their origin. With the archived data at hand, it is possible to reproduce the results of the original work. The archive can be used for both, educational and research purposes. Anyone may reuse, extend and update the archive to make it a valuable resource for the scientific community.
      PubDate: 2016-09-29T14:38:20Z
      DOI: 10.12688/f1000research.9379.1
      Issue No: Vol. 5 (2016)
  • Pattern of triple negative epithelial ovarian cancer in indigenous African
           women [version 1; referees: 2 approved]

    • Authors: Mustapha Akanji Ajani, Ayodeji Akeem Salami, Olutosin Alaba Awolude, Abideen Olayiwola Oluwasola
      Abstract: Background: Triple negative epithelial ovarian cancer (TNEOC)  refers to ovarian carcinomas that do not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor- type 2 (HER-2/neu).  The aim of this study is to determine the pattern of triple negative epithelial ovarian cancer in indigenous African women. Methods: We performed a retrospective review of ER, PR and HER-2/neu expression in 90 Nigerian patients with histologically diagnosed epithelial ovarian cancer. Lack of expression of ER, PR and HER2/neu antigens was used to determine carcinomas that are among the TNEOC. We also compared the clinicopathological parameters (age, International Federation of Gynaecology and Obstetrics (FIGO) stage, grade and histological subtype) in patients with TNEOC and non- TNEOC . Results: Thirty-eight (42.2%) of the 90 tumours diagnosed as EOC were negative for ER, PR and HER2/neu expression. There was no significant association between TNEOC with other parameters such as age, FIGO stage and histological grade. Sixteen (66.7%) of the 24 mucinous carcinomas were triple negative, while only 21 (33.3%) of the 63 serous carcinomas were triple-negative and one (50%) of the two endometrioid carcinomas was triple negative. There was a significant association between triple-negative tumours and histological subtypes of EOC (p = 0.034). Conclusions: A subtype of epithelial ovarian cancer that is negative for ER, PR and HER-2/neu has been discovered in indigenous African women. TNEOC expression is high and is comparable to the triple negative breast cancer subtype seen in people of African ancestry. Future study of TNEOC in a large sample size should be considered.
      PubDate: 2016-09-28T10:09:56Z
      DOI: 10.12688/f1000research.9632.1
      Issue No: Vol. 5 (2016)
  • Advances in understanding COPD [version 1; referees: 3 approved]

    • Authors: Gary P. Anderson
      Abstract: In recent years, thousands of publications on chronic obstructive pulmonary disease (COPD) and its related biology have entered the world literature, reflecting the increasing scientific and medical interest in this devastating condition. This article is a selective review of several important emerging themes that offer the hope of creating new classes of COPD medicines. Whereas basic science is parsing molecular pathways in COPD, its comorbidities, and asthma COPD overlap syndrome (ACOS) with unprecedented sophistication, clinical translation is disappointingly slow. The article therefore also considers solutions to current difficulties that are impeding progress in translating insights from basic science into clinically useful treatments.
      PubDate: 2016-09-27T14:53:50Z
      DOI: 10.12688/f1000research.7018.1
      Issue No: Vol. 5 (2016)
  • Proximal hypospadias: we aren’t always keeping our promises [version
           1; referees: 2 approved]

    • Authors: Christopher J. Long, Douglas A. Canning
      Abstract: Hypospadias surgery is a humbling art form. The evolution of surgical techniques has made distal hypospadias outcomes favorable, but recent publications suggest that our complication rates for proximal hypospadias are much higher than previously reported. To explain these shortcomings, we examine the literature and focus on the lack of standardized documentation, the subsequent inability to objectify the severity of the phenotype, and the underestimation of complications due to lack of long-term follow up. The variability in surgical technique and the fact that the literature abounds with small case series from single institutions also limits our ability to compare outcomes. We believe that the use of standardized and scored phenotype assessments from diagnosis through the extended postoperative period will allow for improved scientific assessment of outcomes. This will facilitate multi-institution collaboration and tabulation of outcomes, allowing rapid data accumulation and assessment for this rare disorder. As surgeons, we must follow boys through puberty into adulthood and must honestly report our results in order to advance our surgical approach to this complicated problem.
      PubDate: 2016-09-26T15:28:34Z
      DOI: 10.12688/f1000research.9230.1
      Issue No: Vol. 5 (2016)
  • Recent advances in the surgical management of rhinosinusitis [version 1;
           referees: 4 approved]

    • Authors: Alexandria F. Jaksha, Erik K. Weitzel, Adrienne M. Laury
      Abstract: Rhinosinusitis affects a significant portion of the US population, and its management imposes a substantial burden on the healthcare system. The treatment of chronic rhinosinusitis includes initial medical management prior to consideration of surgical intervention. However, if surgery does become necessary, several factors must be considered in order to optimize outcomes. This review evaluates surgical patient selection, perioperative medical management, and the extent of operative intervention, with the goal of improving surgical results, decreasing the need for revision surgery, and enhancing the patient’s quality of life. Specific variations in patient genotypes and phenotypes will be further explored with regard to their implications on surgical outcomes. Additionally, the evidence behind pre- and post-operative antibiotic and steroid use will be evaluated. Finally, we will review evolving surgical tools and techniques that are currently being utilized for the treatment of specific subsets of rhinosinusitis.
      PubDate: 2016-09-26T15:01:15Z
      DOI: 10.12688/f1000research.9163.1
      Issue No: Vol. 5 (2016)
  • Getting to S: CDK functions and targets on the path to cell-cycle
           commitment [version 1; referees: 2 approved]

    • Authors: Robert P. Fisher
      Abstract: How and when eukaryotic cells make the irrevocable commitment to divide remain central questions in the cell-cycle field. Parallel studies in yeast and mammalian cells seemed to suggest analogous control mechanisms operating during the G1 phase—at Start or the restriction (R) point, respectively—to integrate nutritional and developmental signals and decide between distinct cell fates: cell-cycle arrest or exit versus irreversible commitment to a round of division. Recent work has revealed molecular mechanisms underlying this decision-making process in both yeast and mammalian cells but also cast doubt on the nature and timing of cell-cycle commitment in multicellular organisms. These studies suggest an expanded temporal window of mitogen sensing under certain growth conditions, illuminate unexpected obstacles and exit ramps on the path to full cell-cycle commitment, and raise new questions regarding the functions of cyclin-dependent kinases (CDKs) that drive G1 progression and S-phase entry.
      PubDate: 2016-09-26T14:02:53Z
      DOI: 10.12688/f1000research.9463.1
      Issue No: Vol. 5 (2016)
  • Robotics in Colorectal Surgery [version 1; referees: 2 approved]

    • Authors: Allison Weaver, Scott Steele
      Abstract: Over the past few decades, robotic surgery has developed from a futuristic dream to a real, widely used technology. Today, robotic platforms are used for a range of procedures and have added a new facet to the development and implementation of minimally invasive surgeries. The potential advantages are enormous, but the current progress is impeded by high costs and limited technology. However, recent advances in haptic feedback systems and single-port surgical techniques demonstrate a clear role for robotics and are likely to improve surgical outcomes. Although robotic surgeries have become the gold standard for a number of procedures, the research in colorectal surgery is not definitive and more work needs to be done to prove its safety and efficacy to both surgeons and patients.
      PubDate: 2016-09-26T13:54:17Z
      DOI: 10.12688/f1000research.9389.1
      Issue No: Vol. 5 (2016)
  • ­­­­­­Recent advances in managing Peyronie’s disease [version 1;
           referees: 2 approved]

    • Authors: Oliver Kayes, Rauf Khadr
      Abstract: Peyronie’s disease remains an under-reported and debilitating problem which can result in significant physical and psychological symptoms for some men. The classic symptom complex includes penile curvature, penile plaque, and penile pain. Men can also present with erectile dysfunction, penile instability, and penile shortening, alongside feelings of low mood/libido, dysmorphobia, and low self-esteem. This review highlights the current key publications in the medical literature and provides updates on new clinical therapies whilst postulating about potential future treatments on the horizon.
      PubDate: 2016-09-26T13:47:59Z
      DOI: 10.12688/f1000research.9041.1
      Issue No: Vol. 5 (2016)
  • Terrestrial Carbon Cycle Variability [version 1; referees: 2 approved]

    • Authors: Dennis Baldocchi, Youngryel Ryu, Trevor Keenan
      Abstract: A growing literature is reporting on how the terrestrial carbon cycle is experiencing year-to-year variability because of climate anomalies and trends caused by global change. As CO2 concentration records in the atmosphere exceed 50 years and as satellite records reach over 30 years in length, we are becoming better able to address carbon cycle variability and trends. Here we review how variable the carbon cycle is, how large the trends in its gross and net fluxes are, and how well the signal can be separated from noise. We explore mechanisms that explain year-to-year variability and trends by deconstructing the global carbon budget. The CO2 concentration record is detecting a significant increase in the seasonal amplitude between 1958 and now. Inferential methods provide a variety of explanations for this result, but a conclusive attribution remains elusive. Scientists have reported that this trend is a consequence of the greening of the biosphere, stronger northern latitude photosynthesis, more photosynthesis by semi-arid ecosystems, agriculture and the green revolution, tropical temperature anomalies, or increased winter respiration. At the global scale, variability in the terrestrial carbon cycle can be due to changes in constituent fluxes, gross primary productivity, plant respiration and heterotrophic (microbial) respiration, and losses due to fire, land use change, soil erosion, or harvesting. It remains controversial whether or not there is a significant trend in global primary productivity (due to rising CO2, temperature, nitrogen deposition, changing land use, and preponderance of wet and dry regions). The degree to which year-to-year variability in temperature and precipitation anomalies affect global primary productivity also remains uncertain. For perspective, interannual variability in global gross primary productivity is relatively small (on the order of 2 Pg-C y-1) with respect to a large and uncertain background (123 +/- 4 Pg-C y-1), and detected trends in global primary productivity are even smaller (33 Tg-C y-2). Yet residual carbon balance methods infer that the terrestrial biosphere is experiencing a significant and growing carbon sink. Possible explanations for this large and growing net land sink include roles of land use change and greening of the land, regional enhancement of photosynthesis, and down regulation of plant and soil respiration with warming temperatures. Longer time series of variables needed to provide top-down and bottom-up assessments of the carbon cycle are needed to resolve these pressing and unresolved issues regarding how, why, and at what rates gross and net carbon fluxes are changing.
      PubDate: 2016-09-26T12:57:26Z
      DOI: 10.12688/f1000research.8962.1
      Issue No: Vol. 5 (2016)
  • Group B Streptococcus vaccine development: present status and future
           considerations, with emphasis on perspectives for low and middle income
           countries [version 1; referees: 2 approved]

    • Authors: Miwako Kobayashi, Johan Vekemans, Carol J. Baker, Adam J. Ratner, Kirsty Le Doare, Stephanie J. Schrag
      Abstract: Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations.
      PubDate: 2016-09-22T09:13:39Z
      DOI: 10.12688/f1000research.9363.1
      Issue No: Vol. 5 (2016)
  • Plasticity of the Leishmania genome leading to gene copy number variations
           and drug resistance [version 1; referees: 5 approved]

    • Authors: Marie-Claude N. Laffitte, Philippe Leprohon, Barbara Papadopoulou, Marc Ouellette
      Abstract: Leishmania has a plastic genome, and drug pressure can select for gene copy number variation (CNV). CNVs can apply either to whole chromosomes, leading to aneuploidy, or to specific genomic regions. For the latter, the amplification of chromosomal regions occurs at the level of homologous direct or inverted repeated sequences leading to extrachromosomal circular or linear amplified DNAs. This ability of Leishmania to respond to drug pressure by CNVs has led to the development of genomic screens such as Cos-Seq, which has the potential of expediting the discovery of drug targets for novel promising drug candidates.
      PubDate: 2016-09-20T13:27:05Z
      DOI: 10.12688/f1000research.9218.1
      Issue No: Vol. 5 (2016)
  • Recent advances in T-cell engineering for use in immunotherapy [version 1;
           referees: 3 approved]

    • Authors: Preeti Sharma, David M. Kranz
      Abstract: Adoptive T-cell therapies have shown exceptional promise in the treatment of cancer, especially B-cell malignancies. Two distinct strategies have been used to redirect the activity of ex vivo engineered T cells. In one case, the well-known ability of the T-cell receptor (TCR) to recognize a specific peptide bound to a major histocompatibility complex molecule has been exploited by introducing a TCR against a cancer-associated peptide/human leukocyte antigen complex. In the other strategy, synthetic constructs called chimeric antigen receptors (CARs) that contain antibody variable domains (single-chain fragments variable) and signaling domains have been introduced into T cells. Whereas many reviews have described these two approaches, this review focuses on a few recent advances of significant interest. The early success of CARs has been followed by questions about optimal configurations of these synthetic constructs, especially for efficacy against solid tumors. Among the many features that are important, the dimensions and stoichiometries of CAR/antigen complexes at the synapse have recently begun to be appreciated. In TCR-mediated approaches, recent evidence that mutated peptides (neoantigens) serve as targets for endogenous T-cell responses suggests that these neoantigens may also provide new opportunities for adoptive T-cell therapies with TCRs.
      PubDate: 2016-09-19T12:58:26Z
      DOI: 10.12688/f1000research.9073.1
      Issue No: Vol. 5 (2016)
  • Applying a complex adaptive system's understanding of health to primary
           care [version 2; referees: 2 approved]

    • Authors: Johannes Bircher, Eckhart G. Hahn
      Abstract: This paper explores the diagnostic and therapeutic potential of a new concept of health. Investigations into the nature of health have led to a new definition that explains health as a complex adaptive system (CAS) and is based on five components (a-e). Humans like all biological creatures must satisfactorily respond to (a) the demands of life. For this purpose they need (b) a biologically given potential (BGP) and (c) a personally acquired potential (PAP). These properties of individuals are embedded within (d) social and (e) environmental determinants of health. Between these five components of health there are 10 complex interactions that justify viewing health as a CAS. In each patient, the current state of health as a CAS evolved from the past, will move forward to a new future, and has to be analyzed and treated as an autonomous whole. A diagnostic procedure is suggested as follows: together with the patient, the five components and 10 complex interactions are assessed. This may help patients to better understand their situations and to recognize possible next steps that may be useful in order to evolve toward better health by themselves. In this process mutual trust in the patient-physician interaction is critical. The described approach offers new possibilities for helping patients improve their health prospects.
      PubDate: 2016-09-16T14:22:00Z
      DOI: 10.12688/f1000research.9042.2
      Issue No: Vol. 5 (2016)
  • Development and interval testing of a naturalistic driving methodology to
           evaluate driving behavior in clinical research [version 2; referees: 2

    • Authors: Ganesh M. Babulal, Aaron Addison, Nupur Ghoshal, Sarah H. Stout, Elizabeth K. Vernon, Mark Sellan, Catherine M. Roe
      Abstract: Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer’s disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD.  Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval. Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation. Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction.  However, these devices require strict protocols and controlled testing for adoption into research paradigms.  After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD.  Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.
      PubDate: 2016-09-15T15:04:37Z
      DOI: 10.12688/f1000research.9150.2
      Issue No: Vol. 5 (2016)
  • An annotation of cuts, depicted locations, and temporal progression in the
           motion picture "Forrest Gump" [version 1; referees: 2 approved]

    • Authors: Christian O. Häusler, Michael Hanke
      Abstract: Here we present an annotation of locations and temporal progression depicted in the movie “Forrest Gump”, as an addition to a large public functional brain imaging dataset ( The annotation provides information about the exact timing of each of the 870 shots, and the depicted location after every cut with a high, medium, and low level of abstraction. Additionally, four classes are used to distinguish the differences of the depicted time between shots. Each shot is also annotated regarding the type of location (interior/exterior) and time of day. This annotation enables further studies of visual perception, memory of locations, and the perception of time under conditions of real-life complexity using the studyforrest dataset.
      PubDate: 2016-09-08T13:57:34Z
      DOI: 10.12688/f1000research.9536.1
      Issue No: Vol. 5 (2016)
  • Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett
           syndrome mouse model [version 1; referees: 2 approved]

    • Authors: Sampathkumar Rangasamy, Shannon Olfers, Brittany Gerald, Alex Hilbert, Sean Svejda, Vinodh Narayanan
      Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant) expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant (Mecp2A140V/y) and wild type (Mecp2+/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele) and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”).
      PubDate: 2016-09-08T09:16:11Z
      DOI: 10.12688/f1000research.8156.1
      Issue No: Vol. 5 (2016)
  • Deep brain stimulation in Gilles de la Tourette syndrome: killing several
           birds with one stone' [version 1; referees: 2 approved]

    • Authors: Andreas Hartmann
      Abstract: In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients’ ailments but as a stepping stone to improved holistic care made possible by tic reduction.
      PubDate: 2016-09-07T11:24:20Z
      DOI: 10.12688/f1000research.9521.1
      Issue No: Vol. 5 (2016)
  • Clonal selection versus clonal cooperation: the integrated perception of
           immune objects [version 1; referees: 2 approved]

    • Authors: Serge Nataf
      Abstract: Analogies between the immune and nervous systems were first envisioned by the immunologist Niels Jerne who introduced the concepts of antigen "recognition" and immune "memory". However, since then, it appears that only the cognitive immunology paradigm proposed by Irun Cohen, attempted to further theorize the immune system functions through the prism of neurosciences. The present paper is aimed at revisiting this analogy-based reasoning. In particular, a parallel is drawn between the brain pathways of visual perception and the processes allowing the global perception of an "immune object". Thus, in the visual system, distinct features of a visual object (shape, color, motion) are perceived separately by distinct neuronal populations during a primary perception task. The output signals generated during this first step instruct then an integrated perception task performed by other neuronal networks. Such a higher order perception step is by essence a cooperative task that is mandatory for the global perception of visual objects. Based on a re-interpretation of recent experimental data, it is suggested that similar general principles drive the integrated perception of immune objects in secondary lymphoid organs (SLOs). In this scheme, the four main categories of signals characterizing an immune object (antigenic, contextual, temporal and localization signals) are first perceived separately by distinct networks of immunocompetent cells.  Then, in a multitude of SLO niches, the output signals generated during this primary perception step are integrated by TH-cells at the single cell level. This process eventually generates a multitude of T-cell and B-cell clones that perform, at the scale of SLOs, an integrated perception of immune objects. Overall, this new framework proposes that integrated immune perception and, consequently, integrated immune responses, rely essentially on clonal cooperation rather than clonal selection.
      PubDate: 2016-09-05T13:34:02Z
      DOI: 10.12688/f1000research.9386.1
      Issue No: Vol. 5 (2016)
  • Opportunities and considerations for visualising neuroimaging data on very
           large displays [version 1; referees: 2 approved]

    • Authors: Matthew B. Wall, David Birch, May Y. Yong
      Abstract: Neuroimaging experiments can generate impressive volumes of data and many images of the results. This is particularly true of multi-modal imaging studies that use more than one imaging technique, or when imaging is combined with other assessments. A challenge for these studies is appropriate visualisation of results in order to drive insights and guide accurate interpretations. Next-generation visualisation technology therefore has much to offer the neuroimaging community. One example is the Imperial College London Data Observatory; a high-resolution (132 megapixel) arrangement of 64 monitors, arranged in a 313 degree arc, with a 6 metre diameter, powered by 32 rendering nodes. This system has the potential for high-resolution, large-scale display of disparate data types in a space designed to promote collaborative discussion by multiple researchers and/or clinicians. Opportunities for the use of the Data Observatory are discussed, with particular reference to applications in Multiple Sclerosis (MS) research and clinical practice. Technical issues and current work designed to optimise the use of the Data Observatory for neuroimaging are also discussed, as well as possible future research that could be enabled by the use of the system in combination with eye-tracking technology.
      PubDate: 2016-09-02T14:04:54Z
      DOI: 10.12688/f1000research.9522.1
      Issue No: Vol. 5 (2016)
  • Analysis of morphine responses in mice reveals a QTL on Chromosome 7
           [version 1; referees: 2 approved]

    • Authors: Wim E. Crusio, Esha Dhawan, Elissa J. Chesler, Anna Delprato
      Abstract: In this study we identified a quantitative trait locus (QTL) on mouse Chromosome 7 associated with locomotor activity and rearing post morphine treatment. This QTL was revealed after correcting for the effects of another QTL peak on Chromosome 10 using composite interval mapping. The positional candidate genes are Syt9 and Ppfibp2. Several other genes within the interval are linked to neural processes, locomotor activity, and the defensive response to harmful stimuli.
      PubDate: 2016-09-02T14:01:52Z
      DOI: 10.12688/f1000research.9484.1
      Issue No: Vol. 5 (2016)
  • Illustrating and homology modeling the proteins of the Zika virus [version
           2; referees: 2 approved]

    • Authors: Sean Ekins, John Liebler, Bruno J. Neves, Warren G. Lewis, Megan Coffee, Rachelle Bienstock, Christopher Southan, Carolina H. Andrade
      Abstract: The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.
      PubDate: 2016-09-01T09:10:25Z
      DOI: 10.12688/f1000research.8213.2
      Issue No: Vol. 5 (2016)
  • Plant expression systems, a budding way to confront chikungunya and Zika
           in developing countries' [version 1; referees: 2 approved]

    • Authors: Jaime A. Cardona-Ospina, Juan C. Sepúlveda-Arias, L. Mancilla, Luis G. Gutierrez-López
      Abstract: Plant expression systems could be used as biofactories of heterologous proteins that have the potential to be used with biopharmaceutical aims and vaccine design. This technology is scalable, safe and cost-effective and it has been previously proposed as an option for vaccine and protein pharmaceutical development in developing countries. Here we present a proposal of how plant expression systems could be used to address Zika and chikungunya outbreaks through development of vaccines and rapid diagnostic kits.
      PubDate: 2016-08-31T14:50:40Z
      DOI: 10.12688/f1000research.9502.1
      Issue No: Vol. 5 (2016)
  • Changes in labial capillary density on ascent to and descent from high
           altitude [version 1; referees: 2 approved]

    • Authors: Edward Gilbert-Kawai, Jonny Coppel, Hennis Phillip, Michael Grocott, Can Ince, Daniel Martin
      Abstract: Present knowledge of how the microcirculation is altered by prolonged exposure to hypoxia at high altitude is incomplete and modification of existing analytical techniques may improve our knowledge considerably. We set out to use a novel simplified method of measuring in vivo capillary density during an expedition to high altitude using a CytoCam incident dark field imaging video-microscope. The simplified method of data capture involved recording one-second images of the mucosal surface of the inner lip to reveal data about microvasculature density in ten individuals. This was done on ascent to, and descent from, high altitude. Analysis was conducted offline by two independent investigators blinded to the participant identity, testing conditions and the imaging site.  Additionally we monitored haemoglobin concentration and haematocrit data to see if we could support or refute mechanisms of altered density relating to vessel recruitment. Repeated sets of paired values were compared using Kruskall Wallis Analysis of Variance tests, whilst comparisons of values between sites was by related samples Wilcoxon Signed Rank Test. Correlation between different variables was performed using Spearman’s rank correlation coefficient, and concordance between analysing investigators using intra-class correlation coefficient. There was a significant increase in capillary density from London on ascent to high altitude; median capillaries per field of view area increased from 22.8 to 25.3 (p=0.021). There was a further increase in vessel density during the six weeks spent at altitude (25.3 to 32.5, p=0.017). Moreover, vessel density remained high on descent to Kathmandu (31.0 capillaries per field of view area), despite a significant decrease in haemoglobin concentration and haematocrit. Using a simplified technique, we have demonstrated an increase in capillary density on early and sustained exposure to hypobaric hypoxia at thigh altitude, and that this remains elevated on descent to normoxia. The technique is simple, reliable and reproducible.
      PubDate: 2016-08-30T15:23:14Z
      DOI: 10.12688/f1000research.7649.1
      Issue No: Vol. 5 (2016)
  • Estimating limits for natural human embryo mortality [version 1; referees:
           2 approved]

    • Authors: Gavin E. Jarvis
      Abstract: Natural human embryonic mortality is generally considered to be high. Values of 70% and higher are widely cited. However, it is difficult to determine accurately owing to an absence of direct data quantifying embryo loss between fertilisation and implantation. The best available data for quantifying pregnancy loss come from three published prospective studies (Wilcox, Zinaman and Wang) with daily cycle by cycle monitoring of human chorionic gonadotrophin (hCG) in women attempting to conceive. Declining conception rates cycle by cycle in these studies indicate that a proportion of the study participants were sub-fertile. Hence, estimates of fecundability and pre-implantation embryo mortality obtained from the whole study cohort will inevitably be biased. This new re-analysis of aggregate data from these studies confirms the impression that discrete fertile and sub-fertile sub-cohorts were present. The proportion of sub-fertile women in the three studies was estimated as 28.1% (Wilcox), 22.8% (Zinaman) and 6.0% (Wang). The probability of conceiving an hCG pregnancy (indicating embryo implantation) was, respectively, 43.2%, 38.1% and 46.2% among normally fertile women, and 7.6%, 2.5% and 4.7% among sub-fertile women. Pre-implantation loss is impossible to calculate directly from available data although plausible limits can be estimated. Based on this new analysis and a model for evaluating reproductive success and failure it is proposed that a plausible range for normal human embryo and fetal mortality from fertilisation to birth is 40-60%.
      PubDate: 2016-08-26T15:34:44Z
      DOI: 10.12688/f1000research.9479.1
      Issue No: Vol. 5 (2016)
  • Invariant death [version 1; referees: 2 approved]

    • Authors: Steven A. Frank
      Abstract: In nematodes, environmental or physiological perturbations alter death’s scaling of time. In human cancer, genetic perturbations alter death’s curvature of time. Those changes in scale and curvature follow the constraining contours of death’s invariant geometry. I show that the constraints arise from a fundamental extension to the theories of randomness, invariance and scale. A generalized Gompertz law follows. The constraints imposed by the invariant Gompertz geometry explain the tendency of perturbations to stretch or bend death’s scaling of time. Variability in death rate arises from a combination of constraining universal laws and particular biological processes.
      PubDate: 2016-08-25T13:35:19Z
      DOI: 10.12688/f1000research.9456.1
      Issue No: Vol. 5 (2016)
  • A real-world intention-to-treat analysis of a decade’s experience of
           treatment of hepatitis C with interferon-based therapies [version 1;
           referees: 2 approved]

    • Authors: Nowlan Selvapatt, Ashley Brown
      Abstract: Objectives: To assess the uptake of pegylated interferon (PegIFN) plus ribavirin (RBV)-based regimens in patients with hepatitis C virus (HCV) in a large, single-centre, real-world setting over 10 years. Methods: This was a single centre, retrospective analysis of data from patients who attended their first appointment for treatment of HCV genotype 1–3 between 2003 and 2013. Patients were stratified by HCV genotype. The total number of patients who attended their first appointment, incidence of patients who did not proceed to treatment and associated reasons, and incidence of patients treated were analysed. Sustained virological response (SVR) rates were also reported for all patient populations. Results: Overall, 1,132 patients attended their first appointment; 47.8% were included in the genotype 1 group (genotype 1a: 22.2%, genotype 1b: 13.3%, genotype 1 other: 12.3%), 7.7% in the genotype 2 group and 44.5% in the genotype 3 group. A greater proportion of patients received treatment versus those who did not receive treatment (84.4% vs 15.6%, respectively). Reasons for declining treatment included: patient declined treatment with PegIFN plus RBV: 35.0%, medical contraindications: 20.3% and mental health-related contraindications: 13.6%. An SVR was achieved in 52.6% of patients who attended their first appointment and 62.3% of patients who received treatment. Conclusions: Approximately half of the patients included in this study achieved an SVR. A noteworthy proportion of patients did not receive treatment due to a reluctance to receive PegIFN plus RBV or contraindications to therapy. Results suggest an ongoing need for improvement in the treatment uptake and overall outcomes – particularly for genotype 2 and 3 patients for whom availability of interferon-free regimens is limited. The introduction of more tolerable direct-acting antiviral regimes may help overcome barriers to uptake demonstrated within this cohort.
      PubDate: 2016-08-24T12:51:04Z
      DOI: 10.12688/f1000research.9114.1
      Issue No: Vol. 5 (2016)
  • A reanalysis of “Two types of asynchronous activity in networks of
           excitatory and inhibitory spiking neurons” [version 1; referees: 2

    • Authors: Rainer Engelken, Farzad Farkhooi, David Hansel, Carl van Vreeswijk, Fred Wolf
      Abstract: Neuronal activity in the central nervous system varies strongly in time and across neuronal populations. It is a longstanding proposal that such fluctuations generically arise from chaotic network dynamics. Various theoretical studies predict that the rich dynamics of rate models operating in the chaotic regime can subserve circuit computation and learning. Neurons in the brain, however, communicate via spikes and it is a theoretical challenge to obtain similar rate fluctuations in networks of spiking neuron models. A recent study investigated spiking balanced networks of leaky integrate and fire (LIF) neurons and compared their dynamics to a matched rate network with identical topology, where single unit input-output functions were chosen from isolated LIF neurons receiving Gaussian white noise input. A mathematical analogy between the chaotic instability in networks of rate units and the spiking network dynamics was proposed. Here we revisit the behavior of the spiking LIF networks and these matched rate networks. We find expected hallmarks of a chaotic instability in the rate network: For supercritical coupling strength near the transition point, the autocorrelation time diverges. For subcritical coupling strengths, we observe critical slowing down in response to small external perturbations. In the spiking network, we found in contrast that the timescale of the autocorrelations is insensitive to the coupling strength and that rate deviations resulting from small input perturbations rapidly decay. The decay speed even accelerates for increasing coupling strength. In conclusion, our reanalysis demonstrates fundamental differences between the behavior of pulse-coupled spiking LIF networks and rate networks with matched topology and input-output function. In particular there is no indication of a corresponding chaotic instability in the spiking network.
      PubDate: 2016-08-22T13:42:33Z
      DOI: 10.12688/f1000research.9144.1
      Issue No: Vol. 5 (2016)
  • Neck keloids: evaluation of risk factors and recommendation for keloid
           staging system [version 2; referees: 2 approved]

    • Authors: Michael H. Tirgan
      Abstract: Importance: Health care providers have long struggled with recurrent and hard to treat keloids. Advancing our understanding of natural history and risk factors for development of large, very large and massive neck keloids can lead to improved treatment outcomes. Clinical staging system for the categorization of keloid lesions, as well as grouping of keloid patients according to the extent of skin involvement is both fundamental for design and delivery of proper plan of care and an absolute necessity for methodical trial design and interpretation of the results thereof. Objective: To review clinical presentation and natural history of neck keloids; to explore risk factors for development of large, very large and massive neck keloids; and to propose a clinical staging system that allows for categorization of keloid lesions by their size and grouping of keloid patients by the extent of their skin involvement.  Setting: This is a retrospective analysis of 82 consecutive patients with neck keloids who were seen by the author in his keloid specialty medical practice.    Intervention: Non-surgical treatment was offered to all patients.  Results: Neck-area keloids were found to have several unique characteristics. All 65 African Americans in this study had keloidal lesions elsewhere on their skin. Very large and massive neck keloids appear to be race-specific and almost exclusively seen among African Americans. Submandibular and submental skin was the most commonly involved area of the neck. Keloid removal surgery was found to be the main risk factor for development of very large and massive neck keloids.  Conclusions and relevance: Surgical removal of neck keloids results in wounding of the skin and triggering a pathological wound-healing response that often leads to formation of a much larger keloid.  Given the potential for greater harm from surgery, the author proposes non-surgical approach for treatment of all primary neck keloids. Author’s attempts to properly categorize keloid lesions and to group the study subjects was hampered by the lack of a previously defined methodology. A clinical staging system is proposed to address the deficiency in grouping of keloid patients according to the size and extent of skin involvement with keloid lesions.
      PubDate: 2016-08-19T13:19:35Z
      DOI: 10.12688/f1000research.9086.2
      Issue No: Vol. 5 (2016)
  • Rapid and high throughput molecular identification of diverse mosquito
           species by high resolution melting analysis [version 1; referees: 2

    • Authors: Yvonne Ukamaka Ajamma, Enock Mararo, David Omondi, Thomas Onchuru, Anne W. T. Muigai, Daniel Masiga, Jandouwe Villinger
      Abstract: Mosquitoes are a diverse group of invertebrates, with members that are among the most important vectors of diseases. The correct identification of mosquitoes is paramount to the control of the diseases that they transmit. However, morphological techniques depend on the quality of the specimen and often unavailable taxonomic expertise, which may still not be able to distinguish mosquitoes among species complexes (sibling and cryptic species). High resolution melting (HRM) analyses, a closed-tube, post-polymerase chain reaction (PCR) method used to identify variations in nucleic acid sequences, has been used to differentiate species within the Anopheles gambiae and Culex pipiens complexes. We validated the use of PCR-HRM analyses to differentiate species within Anopheles and within each of six genera of culicine mosquitoes, comparing primers targeting cytochrome b (cyt b), NADH dehydrogenase subunit 1 (ND1), intergenic spacer region (IGS) and cytochrome c oxidase subunit 1 (COI) gene regions. HRM analyses of amplicons from all the six primer pairs successfully differentiated two or more mosquito species within one or more genera (Aedes (Ae. vittatus from Ae. metallicus), Culex (Cx. tenagius from Cx. antennatus, Cx. neavei from Cx. duttoni, cryptic Cx. pipiens species), Anopheles (An. gambiae s.s. from An. arabiensis) and Mansonia (Ma. africana from Ma. uniformis)) based on their HRM profiles. However, PCR-HRM could not distinguish between species within Aedeomyia (Ad. africana and Ad. furfurea), Mimomyia (Mi. hispida and Mi. splendens) and Coquillettidia (Cq. aurites, Cq. chrysosoma, Cq. fuscopennata, Cq. metallica, Cq. microannulatus, Cq. pseudoconopas and Cq. versicolor) genera using any of the primers. The IGS and COI barcode region primers gave the best and most definitive separation of mosquito species among anopheline and culicine mosquito genera, respectively, while the other markers may serve to confirm identifications of closely related sub-species. This approach can be employed for rapid identification of mosquitoes.
      PubDate: 2016-08-11T10:10:08Z
      DOI: 10.12688/f1000research.9224.1
      Issue No: Vol. 5 (2016)
  • Ability of device to collect bacteria from cough aerosols generated by
           adults with cystic fibrosis [version 1; referees: 2 approved]

    • Authors: David N. Ku, Sarah K. Ku, Beth Helfman, Nael A. McCarty, Bernard J. Wolff, Jonas M. Winchell, Larry J. Anderson
      Abstract: Background: Identifying lung pathogens and acute spikes in lung counts remain a challenge in the treatment of patients with cystic fibrosis (CF). Bacteria from the deep lung may be sampled from aerosols produced during coughing. Methods: A new device was used to collect and measure bacteria levels from cough aerosols of patients with CF. Sputum and oral specimens were also collected and measured for comparison. Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus mitis were detected in specimens using Real-Time Polymerase Chain Reaction (RT-PCR) molecular assays. Results: Twenty adult patients with CF and 10 healthy controls participated. CF related bacteria (CFRB) were detected in 13/20 (65%) cough specimens versus 15/15 (100%) sputum specimens. Commensal S. mitis was present in 0/17 (0%, p=0.0002) cough specimens and 13/14 (93%) sputum samples. In normal controls, no bacteria were collected in cough specimens but 4/10 (40%) oral specimens were positive for CFRB. Conclusions: Non-invasive cough aerosol collection may detect lower respiratory pathogens in CF patients, with similar specificity and sensitivity to rates detected by BAL, without contamination by oral CFRB or commensal bacteria.
      PubDate: 2016-08-05T09:39:49Z
      DOI: 10.12688/f1000research.9251.1
      Issue No: Vol. 5 (2016)
  • Navigating the Zika panic [version 1; referees: 2 approved]

    • Authors: Nathan D. Grubaugh, Kristian G. Andersen
      Abstract: The epidemics of Ebola virus in West Africa and Zika virus in America highlight how viruses can explosively emerge into new territories. These epidemics also exposed how unprepared we are to handle infectious disease emergencies. This is also true when we consider hypothesized new clinical features of infection, such as the associations between Zika virus infection and severe neurological disease, including microcephaly and Guillain-Barré syndrome. On the surface, these pathologies appear to be new features of Zika virus infection, however, causal relationships have not yet been established. Decades of limited Zika virus research are making us scramble to determine the true drivers behind the epidemic, often at the expense of over-speculation without credible evidence. Here we review the literature and find no conclusive evidence at this time for significant biological differences between the American Zika virus strains and those circulating elsewhere. Rather, the epidemic scale in the Americas may be facilitated by an abnormally warm climate, dense human and mosquito populations, and previous exposure to other viruses. Severe disease associated with Zika virus may therefore not be a new trait for the virus, rather it may have been overlooked due to previously small outbreaks. Much of the recent panic regarding Zika virus has been about the Olympics in Brazil. We do not find any substantial evidence that the Olympics will result in a significant number of new Zika virus infections (~10 predicted) or that the Olympics will promote further epidemic spread over what is already expected. The Zika virus epidemic in the Americas is a serious situation and decisions based on solid scientific evidence - not hyped media speculations - are required for effective outbreak response.
      PubDate: 2016-08-04T09:54:54Z
      DOI: 10.12688/f1000research.9370.1
      Issue No: Vol. 5 (2016)
  • Automated analysis of retinal imaging using machine learning techniques
           for computer vision [version 1; referees: 2 approved]

    • Authors: Jeffrey De Fauw, Pearse Keane, Nenad Tomasev, Daniel Visentin, George van den Driessche, Mike Johnson, Cian O Hughes, Carlton Chu, Joseph Ledsam, Trevor Back, Tunde Peto, Geraint Rees, Hugh Montgomery, Rosalind Raine, Olaf Ronneberger, Julien Cornebise
      Abstract: There are almost two million people in the United Kingdom living with sight loss, including around 360,000 people who are registered as blind or partially sighted. Sight threatening diseases, such as diabetic retinopathy and age related macular degeneration have contributed to the 40% increase in outpatient attendances in the last decade but are amenable to early detection and monitoring. With early and appropriate intervention, blindness may be prevented in many cases.   Ophthalmic imaging provides a way to diagnose and objectively assess the progression of a number of pathologies including neovascular (“wet”) age-related macular degeneration (wet AMD) and diabetic retinopathy. Two methods of imaging are commonly used: digital photographs of the fundus (the ‘back’ of the eye) and Optical Coherence Tomography (OCT, a modality that uses light waves in a similar way to how ultrasound uses sound waves). Changes in population demographics and expectations and the changing pattern of chronic diseases creates a rising demand for such imaging. Meanwhile, interrogation of such images is time consuming, costly, and prone to human error. The application of novel analysis methods may provide a solution to these challenges.   This research will focus on applying novel machine learning algorithms to automatic analysis of both digital fundus photographs and OCT in Moorfields Eye Hospital NHS Foundation Trust patients.   Through analysis of the images used in ophthalmology, along with relevant clinical and demographic information, Google DeepMind Health will investigate the feasibility of automated grading of digital fundus photographs and OCT and provide novel quantitative measures for specific disease features and for monitoring the therapeutic success.
      PubDate: 2016-07-05T07:30:26Z
      DOI: 10.12688/f1000research.8996.1
      Issue No: Vol. 5 (2016)
  • IncucyteDRC: An R package for the dose response analysis of live cell
           imaging data [version 1; referees: 2 approved]

    • Authors: Philip J. Chapman, Dominic I. James, Amanda J. Watson, Gemma V. Hopkins, Ian D. Waddell, Donald J. Ogilvie
      Abstract: We present IncucyteDRC, an R package for the analysis of data from live cell imaging cell proliferation experiments carried out on the Essen Biosciences IncuCyte ZOOM instrument. The package provides a simple workflow for summarising data into a form that can be used to calculate dose response curves and EC50 values for small molecule inhibitors. Data from different cell lines, or cell lines grown under different conditions, can be normalised as to their doubling time. A simple graphical web interface, implemented using shiny, is provided for the benefit of non-R users. The software is potentially useful to any research group studying the impact of small molecule inhibitors on cell proliferation using the IncuCyte ZOOM.
      PubDate: 2016-05-23T13:59:01Z
      DOI: 10.12688/f1000research.8694.1
      Issue No: Vol. 5 (2016)
  • Report on noninvasive prenatal testing: classical and
           alternative approaches [version 1; referees: 2 approved]

    • Authors: Kateryna S. Pantiukh, Nikolay N. Chekanov, Igor V. Zaigrin, Alexei M. Zotov, Alexander M. Mazur, Egor B. Prokhortchouk
      Abstract: Concerns of traditional prenatal aneuploidy testing methods, such as low accuracy of noninvasive and health risks associated with invasive procedures, were overcome with the introduction of novel noninvasive methods based on genetics (NIPT). These were rapidly adopted into clinical practice in many countries after a series of successful trials of various independent submethods. Here we present results of own NIPT trial carried out in Moscow, Russia. 1012 samples were subjected to the method aimed at measuring chromosome coverage by massive parallel sequencing. Two alternative approaches are ascertained: one based on maternal/fetal differential methylation and another based on allelic difference. While the former failed to provide stable results, the latter was found to be promising and worthy of conducting a large-scale trial. One critical point in any NIPT approach is the determination of fetal cell-free DNA fraction, which dictates the reliability of obtained results for a given sample. We show that two different chromosome Y representation measures—by real-time PCR and by whole-genome massive parallel sequencing—are practically interchangeable (r=0.94). We also propose a novel method based on maternal/fetal allelic difference which is applicable in pregnancies with fetuses of either sex. Even in its pilot form it correlates well with chromosome Y coverage estimates (r=0.74) and can be further improved by increasing the number of polymorphisms.
      PubDate: 2016-04-22T09:28:47Z
      DOI: 10.12688/f1000research.8243.1
      Issue No: Vol. 5 (2016)
  • Finding the shortest path with PesCa: a tool for network reconstruction
           [version 2; referees: 2 approved, 2 approved with reservations]

    • Authors: Giovanni Scardoni, Gabriele Tosadori, Sakshi Pratap, Fausto Spoto, Carlo Laudanna
      Abstract: Network analysis is of growing interest in several fields ranging from economics to biology. Several methods have been developed to investigate different properties of physical networks abstracted as graphs, including quantification of specific topological properties, contextual data enrichment, simulation of pathway dynamics and visual representation. In this context, the PesCa app for the Cytoscape network analysis environment is specifically designed to help researchers infer and manipulate networks based on the shortest path principle. PesCa offers different algorithms allowing network reconstruction and analysis starting from a list of genes, proteins and in general a set of interconnected nodes. The app is useful in the early stage of network analysis, i.e. to create networks or generate clusters based on shortest path computation, but can also help further investigations and, in general, it is suitable for every situation requiring the connection of a set of nodes that apparently do not share links, such as isolated nodes in sub-networks. Overall, the plugin enhances the ability of discovering interesting and not obvious relations between high dimensional sets of interacting objects.
      PubDate: 2016-04-07T11:23:46Z
      DOI: 10.12688/f1000research.6769.2
      Issue No: Vol. 4 (2016)
  • Evolution of bright colours in animals: worlds of prohibition and oblivion
           [version 2; referees: 1 approved, 2 approved with reservations]

    • Authors: Wladimir J. Alonso
      Abstract: Because the ability to hide in plain sight provides a major selective advantage to both prey and predator species, the emergence of the striking colouration of some animal species (such as many coral reef fish) represents an evolutionary conundrum that remains unsolved to date. Here I propose a framework by which conspicuous colours can emerge when the selective pressures for camouflage are relaxed (1) because camouflage is not essential under specific prey/predator conditions or (2) due to the impossibility of reducing the signal-to-background noise in the environment. The first case is found among non-predator-species that possess effective defences against predators (hence a “Carefree World”), such as the strong macaws’ beaks and the flight abilities of hummingbirds. The second case is found in diurnal mobile fish of coral reef communities, which swim in clear waters against highly contrasting and unpredictable background (hence an "Hyper-Visible World”). In those contexts the selective pressures that usually come secondary to camouflage (such as sexual, warning, species recognition or territorial display) are free to drive the evolution of brilliant and diverse colouration. This theoretical framework can also be useful for studying the conditions that allow for conspicuousness in other sensory contexts (acoustic, chemical, electrical, etc.).
      PubDate: 2016-03-22T15:11:25Z
      DOI: 10.12688/f1000research.6493.2
      Issue No: Vol. 4 (2016)
  • wigExplorer, a BioJS component to visualise wig data [version 3; referees:
           1 approved, 2 approved with reservations, 1 not approved]

    • Authors: Anil S. Thanki, Rafael C. Jimenez, Gemy G. Kaithakottil, Manuel Corpas, Robert P. Davey
      Abstract: Summary: wigExplorer is a BioJS component whose main purpose is to provide a platform for visualisation of wig-formatted data. Wig files are extensively used by genome browsers such as the UCSC Genome Browser. wigExplorer follows the BioJS standard specification, requiring a simple configuration and installation. wigExplorer provides an easy way to navigate the visible region of the canvas and allows interaction with other components via predefined events. Availability:;
      PubDate: 2016-08-09T10:45:36Z
      DOI: 10.12688/f1000research.3-53.v3
      Issue No: Vol. 3 (2016)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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