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  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • The application of remote ischemic conditioning in cardiac surgery
           [version 1; referees: 3 approved]

    • Authors: Zeljko J. Bosnjak, Zhi-Dong Ge
      Abstract: Perioperative myocardial ischemia and infarction are the leading causes of morbidity and mortality following anesthesia and surgery. The discovery of endogenous cardioprotective mechanisms has led to testing of new methods to protect the human heart. These approaches have included ischemic pre-conditioning, per-conditioning, post-conditioning, and remote conditioning of the myocardium. Pre-conditioning and per-conditioning include brief and repetitive periods of sub-lethal ischemia before and during prolonged ischemia, respectively; and post-conditioning is applied at the onset of reperfusion. Remote ischemic conditioning involves transient, repetitive, non-lethal ischemia and reperfusion in one organ or tissue (remote from the heart) that renders myocardium more resistant to lethal ischemia/reperfusion injury. In healthy, young hearts, many conditioning maneuvers can significantly increase the resistance of the heart against ischemia/reperfusion injury. The large multicenter clinical trials with ischemic remote conditioning have not been proven successful in cardiac surgery thus far. The lack of clinical success is due to underlying risk factors that interfere with remote ischemic conditioning and the use of cardioprotective agents that have activated the endogenous cardioprotective mechanisms prior to remote ischemic conditioning. Future preclinical research using remote ischemic conditioning will need to be conducted using comorbid models.
      PubDate: 2017-06-16T14:30:28Z
      DOI: 10.12688/f1000research.11018.1
      Issue No: Vol. 6 (2017)
  • Noise-induced and age-related hearing loss:  new perspectives and
           potential therapies [version 1; referees: 4 approved]

    • Authors: M Charles Liberman
      Abstract: The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.
      PubDate: 2017-06-16T13:49:49Z
      Issue No: Vol. 6 (2017)
  • Dietary assessment methods in epidemiological research: current state of
           the art and future prospects [version 1; referees: 3 approved]

    • Authors: Androniki Naska, Areti Lagiou, Pagona Lagiou
      Abstract: Self-reported dietary intake is assessed by methods of real-time recording (food diaries and the duplicate portion method) and methods of recall (dietary histories, food frequency questionnaires, and 24-hour dietary recalls). Being less labor intensive, recall methods are more frequently employed in nutritional epidemiological investigations. However, sources of error, which include the participants’ inability to fully and accurately recall their intakes as well as limitations inherent in the food composition databases applied to convert the reported food consumption to energy and nutrient intakes, may limit the validity of the generated information. The use of dietary biomarkers is often recommended to overcome such errors and better capture intra-individual variability in intake; nevertheless, it has its own challenges. To address measurement error associated with dietary questionnaires, large epidemiological investigations often integrate sub-studies for the validation and calibration of the questionnaires and/or administer a combination of different assessment methods (e.g. administration of different questionnaires and assessment of biomarker levels). Recent advances in the omics field could enrich the list of reliable nutrition biomarkers, whereas new approaches employing web-based and smart phone applications could reduce respondent burden and, possibly, reporting bias. Novel technologies are increasingly integrated with traditional methods, but some sources of error still remain. In the analyses, food and nutrient intakes always need to be adjusted for total daily energy intake to account for errors related to reporting.
      PubDate: 2017-06-16T13:14:55Z
      DOI: 10.12688/f1000research.10703.1
      Issue No: Vol. 6 (2017)
  • A putative antiviral role of plant cytidine deaminases [version 2;
           referees: 2 approved]

    • Authors: Susana Martín, José M. Cuevas, Ana Grande-Pérez, Santiago F. Elena
      Abstract: Background: A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade.  Host cytidine deaminases (e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis.  By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity.  To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation.  The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases (AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. Methods: Here we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thaliana AtCDA genes in Nicotiana bigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions.  Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes.  This and control plants were then infected with CaMV.  Virus accumulation and mutational spectra where characterized in both types of plants. Results:  We have shown that the A. thaliana AtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated.  Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant. Conclusions: Our results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants.
      PubDate: 2017-06-15T13:32:58Z
      DOI: 10.12688/f1000research.11111.2
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding maternal perinatal mood disorders
           [version 1; referees: 2 approved]

    • Authors: Thalia Robakis, Eugenia Jernick, Katherine Williams
      Abstract: The study of perinatal mental health (mental health during pregnancy and postpartum) is a complex field of study that is of major importance both for the mental and physical health of new mothers and for the neurobehavioral development and long-term functioning of the children they bear. In this review, we cover the most recent additions to this rapidly evolving field. Notable advances include further illumination of the epidemiological patterns and clinical manifestations of perinatal mood disruption; new efficacy data on treatment and prevention; clarifications of the respective contributions of maternal mental illness and psychotropic medication to outcomes of pregnancy, birth, and child development; and updated expert guidelines for screening.
      PubDate: 2017-06-15T09:45:45Z
      DOI: 10.12688/f1000research.10560.1
      Issue No: Vol. 6 (2017)
  • Patient waiting time in the outpatient clinic at a central surgical
           hospital of Vietnam: Implications for resource allocation [version 3;
           referees: 2 approved]

    • Authors: Tho Dinh Tran, Uy Van Nguyen, Vuong Minh Nong, Bach Xuan Tran
      Abstract: Background: Patient waiting time is considered as a crucial parameter in the assessment of healthcare quality and patients’ satisfaction towards healthcare services. Data concerning this has remained limited in Vietnam. Thus, this study aims to assess patient waiting time in the outpatient clinic in Viet Duc Hospital (Hanoi, Vietnam) in order to enable stakeholders to inform evidence-based interventions to improve the quality of healthcare services. Methods: A cross-sectional study was conducted from June 2014 to June 2015 in the outpatient clinic at Viet Duc Hospital. Waiting time stratified by years (2014 and 2015), months of the year, weekdays, and hours of the day were extracted from Hospital Management software and carefully calculated. Stata 12.0 was employed to analyze data, including the average time (M± SD), frequencies and percentage (%). Results: There was a total of 137,881 patients involved in the study. The average waiting time from registration to preliminary diagnosis in 2014 was 50.41 minutes, and in 2015 was 42.05 minutes. A longer waiting time was recorded in the morning and in those having health insurance. Conclusions: Our results provided evidence that despite the decrease of waiting time from 2014 to 2015, waiting time was much higher among patients having health insurance compared to their counterparts. The findings suggest that human resources promotion and distribution should be emphasized in outpatient clinics and health insurance-related administrative procedures should be simplified.
      PubDate: 2017-06-15T08:33:57Z
      DOI: 10.12688/f1000research.11045.3
      Issue No: Vol. 6 (2017)
  • Recent advances in the understanding of renal inflammation and fibrosis in
           lupus nephritis [version 1; referees: 2 approved]

    • Authors: Susan Yung, Desmond YH Yap, Tak Mao Chan
      Abstract: Lupus nephritis is a potentially reversible cause of severe acute kidney injury and is an important cause of end-stage renal failure in Asians and patients of African or Hispanic descent. It is characterized by aberrant exaggerated innate and adaptive immune responses, autoantibody production and their deposition in the kidney parenchyma, triggering complement activation, activation and proliferation of resident renal cells, and expression of pro-inflammatory and chemotactic molecules leading to the influx of inflammatory cells, all of which culminate in destruction of normal nephrons and their replacement by fibrous tissue. Anti-double-stranded DNA (anti-dsDNA) antibody level correlates with disease activity in most patients. There is evidence that apart from mediating pathogenic processes through the formation of immune complexes, pathogenic anti-dsDNA antibodies can bind to resident renal cells and induce downstream pro-apoptotic, pro-inflammatory, or pro-fibrotic processes or a combination of these. Recent data also highlight the critical role of macrophages in acute and chronic kidney injury. Though clinically effective, current treatments for lupus nephritis encompass non-specific immunosuppression and the anti-inflammatory action of high-dose corticosteroids. The clinical and histological impact of novel biologics targeting pro-inflammatory molecules remains to be investigated. Insight into the underlying mechanisms that induce inflammatory and fibrotic processes in the kidney of lupus nephritis could present opportunities for more specific novel treatment options to improve clinical outcomes while minimizing off-target untoward effects. This review discusses recent advances in the understanding of pathogenic mechanisms leading to inflammation and fibrosis of the kidney in lupus nephritis in the context of established standard-of-care and emerging therapies.
      PubDate: 2017-06-13T09:27:34Z
      DOI: 10.12688/f1000research.10445.1
      Issue No: Vol. 6 (2017)
  • Recent advances in hematopoietic stem cell transplantation [version 1;
           referees: 2 approved]

    • Authors: Maxim Norkin, John R Wingard
      Abstract: Hematopoietic cell transplantation (HCT), once used as a last-resort therapy, is now considered a lifesaving procedure for thousands of patients with life-threatening diseases worldwide and is frequently used early in the course of treatment for diseases destined to be uncontrollable by non-HCT therapies. Incremental advances leading to reduction of post-transplant morbidity and mortality by better control of graft versus host disease (GVHD), infections, and regimen-related toxicities, coupled with greater donor options, not only significantly increased the utilization and success of this procedure but also allowed many of these patients to enjoy healthy and productive lives after HCT. Emerging concepts in the field are now focused on the expansion of available donor options, further reduction of transplant-related toxicity, and decrease in post-transplant relapse.
      PubDate: 2017-06-12T13:35:57Z
      DOI: 10.12688/f1000research.11233.1
      Issue No: Vol. 6 (2017)
  • Recent advances in congenital heart disease genomics [version 1; referees:
           2 approved]

    • Authors: Anna Wilsdon, Alejandro Sifrim, Marc-Phillip Hitz, Matthew Hurles, J. David Brook
      Abstract: Congenital heart disease is the most common congenital abnormality, and advances in medical care mean that this population of individuals is surviving for longer than ever before. It represents a significant healthcare challenge, as many patients require life-long care and individuals may ask about the likelihood of their children being affected. Whilst a number of genes have been identified previously from investigation of families with Mendelian inheritance patterns, sequencing the DNA from large cohorts of individuals with congenital heart disease is now providing fresh insights into the genetics of these conditions. This research has enabled novel gene discovery and uncovered the different genetic mechanisms underlying both isolated congenital heart disease and that which occurs in association with other medical problems. This article discusses the most recent advances in this field and the implications for patient care. In addition, we consider the challenges facing researchers in this field and emphasise the need for close working relationships between clinicians and researchers.
      PubDate: 2017-06-12T11:03:36Z
      DOI: 10.12688/f1000research.10113.1
      Issue No: Vol. 6 (2017)
  • Human papillomavirus vaccination: the population impact [version 1;
           referees: 3 approved]

    • Authors: Lai-yang Lee, Suzanne M. Garland
      Abstract: We currently have the knowledge and experience to prevent much of human papillomavirus (HPV)-related disease burden globally. In many countries where prophylactic HPV vaccination programs have been adopted as highly effective public health programs with good vaccine coverage, we are already seeing, in real-world settings, reduction of vaccine-related HPV-type infections, genital warts and cervical pre-cancers with potential reductions in vulvar, vaginal and anal pre-cancers. Moreover, we are seeing a change in cervical screening paradigms, as HPV-based screening programs now have strong evidence to support their use as more sensitive ways to detect underlying cervical abnormalities, as compared with conventional cervical cytology. This article describes the impact of prophylactic vaccination on these outcomes and in settings where these vaccines have been implemented in national immunisation programs. Given the successes seen to date and the availability of essential tools, there has been a global push to ensure that every woman has access to effective cervical screening and every girl has the opportunity for primary prevention through vaccination. A gender-neutral approach by offering vaccination to young boys has also been adopted by some countries and is worthy of consideration given that HPV-related cancers also affect males. Furthermore, vaccination of young boys has the advantage of reducing the risk of HPV transmission to sexual partners, lowering the infectious pool of HPV in the general population and ultimately HPV-related diseases for both genders. Therefore, it is appropriate that all countries consider and promote national guidelines and programs to prevent HPV-related diseases.
      PubDate: 2017-06-12T09:09:13Z
      DOI: 10.12688/f1000research.10691.1
      Issue No: Vol. 6 (2017)
  • Recent advances in the management of chronic obstructive pulmonary disease
           [version 1; referees: 2 approved]

    • Authors: Sharon R Rosenberg, Ravi Kalhan
      Abstract: Novel pharmacotherapies introduce additional options to providers and patients in how to best treat chronic obstructive pulmonary disease (COPD). Emerging data question the role of inhaled corticosteroids in COPD treatment, particularly as combination dual bronchodilator pharmacotherapies demonstrate robust results. For those maximized on pharmacotherapy with continued dyspnea or exacerbations or both, emerging bronchoscopic procedures may offer additional therapy in select patients. This review focuses on data supporting the use of novel ultra bronchodilators, particularly in combination, and on the role for inhaled corticosteroid withdrawal and new bronchoscopic procedures.
      PubDate: 2017-06-09T15:08:39Z
      DOI: 10.12688/f1000research.9819.1
      Issue No: Vol. 6 (2017)
  • Molecular and phenotypic biomarkers of aging [version 1; referees: 3

    • Authors: Xian Xia, Weiyang Chen, Joseph McDermott, Jing-Dong Jackie Han
      Abstract: Individuals of the same age may not age at the same rate. Quantitative biomarkers of aging are valuable tools to measure physiological age, assess the extent of ‘healthy aging’, and potentially predict health span and life span for an individual. Given the complex nature of the aging process, the biomarkers of aging are multilayered and multifaceted. Here, we review the phenotypic and molecular biomarkers of aging. Identifying and using biomarkers of aging to improve human health, prevent age-associated diseases, and extend healthy life span are now facilitated by the fast-growing capacity of multilevel cross-sectional and longitudinal data acquisition, storage, and analysis, particularly for data related to general human populations. Combined with artificial intelligence and machine learning techniques, reliable panels of biomarkers of aging will have tremendous potential to improve human health in aging societies.
      PubDate: 2017-06-09T13:16:45Z
      DOI: 10.12688/f1000research.10692.1
      Issue No: Vol. 6 (2017)
  • New insights into the pathogenesis and prevention of tuberous
           sclerosis-associated neuropsychiatric disorders (TAND) [version 1;
           referees: 3 approved]

    • Authors: Tanjala T. Gipson, Michael V. Johnston
      Abstract: Tuberous sclerosis complex (TSC) is a multi-system disorder resulting from mutations in either the TSC1 or TSC2 genes leading to hyperactivation of mechanistic target of rapamycin (mTOR) signaling. TSC is commonly associated with autism (61%), intellectual disability (45%), and behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties that are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). More than 90% of children with TSC have epilepsy, including infantile spasms, and early onset of seizures, especially infantile spasms, is associated with greater impairment in intellectual development compared with individuals with TSC without seizures. Development of the mTOR inhibitors everolimus and sirolimus has led to considerable progress in the treatment of renal angiomyolipomata, pulmonary lymphangioleiomyomatosis, and subependymal giant cell astrocytomas in the brain. However, similar therapeutic progress is needed in the treatment of TAND.
      PubDate: 2017-06-09T13:14:10Z
      Issue No: Vol. 6 (2017)
  • Screening and identification of novel biologically active natural
           compounds [version 1; referees: 2 approved]

    • Authors: David Newman
      Abstract: With the advent of very rapid and cheap genome analyses and the linkage of these plus microbial metabolomics to potential compound structures came the realization that there was an immense sea of novel agents to be mined and tested. In addition, it is now recognized that there is significant microbial involvement in many natural products isolated from “nominally non-microbial sources”. This short review covers the current screening methods that have evolved and one might even be tempted to say “devolved” in light of the realization that target-based screens had problems when the products entered clinical testing, with off-target effects being the major ones. Modern systems include, but are not limited to, screening in cell lines utilizing very modern techniques (a high content screen) that are designed to show interactions within cells when treated with an “agent”. The underlying principle(s) used in such systems dated back to unpublished attempts in the very early 1980s by the pharmaceutical industry to show toxic interactions within animal cells by using automated light microscopy. Though somewhat successful, the technology was not adequate for any significant commercialization. Somewhat later, mammalian cell lines that were “genetically modified” to alter signal transduction cascades, either up or down, and frequently linked to luciferase readouts, were then employed in a 96-well format. In the case of microbes, specific resistance parameters were induced in isogenic cell lines from approximately the mid-1970s. In the latter two cases, comparisons against parent and sibling cell lines were used in order that a rapid determination of potential natural product “hits” could be made. Obviously, all of these assay systems could also be, and were, used for synthetic molecules. These methods and their results have led to a change in what the term “screening for bioactivity” means. In practice, versions of phenotypic screening are returning, but in a dramatically different scientific environment from the 1970s, as I hope to demonstrate in the short article that follows.
      PubDate: 2017-06-05T14:41:00Z
      DOI: 10.12688/f1000research.11221.1
      Issue No: Vol. 6 (2017)
  • Immunosurveillance by human γδ T lymphocytes: the emerging role of
           butyrophilins [version 1; referees: 2 approved]

    • Authors: Dieter Kabelitz, Marcus Lettau, Ottmar Janssen
      Abstract: In contrast to conventional T lymphocytes, which carry an αβ T-cell receptor and recognize antigens as peptides presented by major histocompatibility complex class I or class II molecules, human γδ T cells recognize different metabolites such as non-peptidic pyrophosphate molecules that are secreted by microbes or overproduced by tumor cells. Hence, γδ T cells play a role in immunosurveillance of infection and cellular transformation. Until recently, it has been unknown how the γδ T-cell receptor senses such pyrophosphates in the absence of known antigen-presenting molecules. Recent studies from several groups have identified a unique role of butyrophilin (BTN) protein family members in this process, notably of BTN3A1. BTNs are a large family of transmembrane proteins with diverse functions in lipid secretion and innate and adaptive immunity. Here we discuss current models of how BTN molecules regulate γδ T-cell activation. We also address the implications of these recent findings on the design of novel immunotherapeutic strategies based on the activation of γδ T cells.
      PubDate: 2017-06-05T10:30:26Z
      DOI: 10.12688/f1000research.11057.1
      Issue No: Vol. 6 (2017)
  • Using spectral decomposition of the signals from laurdan-derived probes to
           evaluate the physical state of membranes in live cells [version 1;
           referees: 2 approved]

    • Authors: Serge Mazeres, Farzad Fereidouni, Etienne Joly
      Abstract: Background: We wanted to investigate the physical state of biological membranes in live cells under the most physiological conditions possible. Methods: For this we have been using laurdan, C-laurdan or M-laurdan to label a variety of cells, and a biphoton microscope equipped with both a thermostatic chamber and a spectral analyser. We also used a flow cytometer to quantify the 450/530 nm ratio of fluorescence emissions by whole cells. Results: We find that using all the information provided by spectral analysis to perform spectral decomposition dramatically improves the imaging resolution compared to using just two channels, as commonly used to calculate generalized polarisation (GP). Coupled to a new plugin called Fraction Mapper, developed to represent the fraction of light intensity in the first component in a stack of two images, we obtain very clear pictures of both the intra-cellular distribution of the probes, and the polarity of the cellular environments where the lipid probes are localised. Our results lead us to conclude that, in live cells kept at 37°C, laurdan, and M-laurdan to a lesser extent, have a strong tendency to accumulate in the very apolar environment of intra-cytoplasmic lipid droplets, but label the plasma membrane (PM) of mammalian cells ineffectively. On the other hand, C-laurdan labels the PM very quickly and effectively, and does not detectably accumulate in lipid droplets. Conclusions: From using these probes on a variety of mammalian cell lines, as well as on cells from Drosophila and Dictyostelium discoideum, we conclude that, apart from the lipid droplets, which are very apolar, probes in intracellular membranes reveal a relatively polar and hydrated environment, suggesting a very marked dominance of liquid disordered states. PMs, on the other hand, are much more apolar, suggesting a strong dominance of liquid ordered state, which fits with their high sterol contents.
      PubDate: 2017-06-01T15:32:54Z
      DOI: 10.12688/f1000research.11577.1
      Issue No: Vol. 6 (2017)
  • Novel approaches to HIV therapy [version 1; referees: 2 approved]

    • Authors: Eric S. Daar
      Abstract: There are approximately 35 million people infected by human immunodeficiency virus (HIV), with an estimated 2 million incident infections annually across the globe. While HIV infection was initially associated with high rates of morbidity and mortality, advances in therapy have transformed it into a chronic and manageable disease. In addition, there is very strong evidence that those on antiretroviral therapy are much less likely to transmit infection to their partners. The success rates for maintaining viral suppression in treated patients has dramatically increased owing to the development of agents that are potent and well tolerated and can often be co-formulated into single pills for simplification. This review will outline advances in treatment over the last several years as well as new strategies that may shift the existing treatment paradigm in the near future.
      PubDate: 2017-05-31T10:26:07Z
      DOI: 10.12688/f1000research.11164.1
      Issue No: Vol. 6 (2017)
  • The use of high-frequency ventilation during general anaesthesia: an
           update [version 1; referees: 3 approved]

    • Authors: Karolina Galmén, Piotr Harbut, Jacob Freedman, Jan G. Jakobsson
      Abstract: Various forms of high-frequency ventilation (HFV) have been described. HFV is broadly defined as artificial ventilation of the lungs with sub-deadspace tidal volumes delivered using supra-physiological frequencies. HFV has been used in anaesthesia and intensive care for special procedures and conditions since the 1960s. Clinical interest in the use and the technical evolution of HFV has developed over time. There is a renewed interest in HFV for avoiding parenchymal movement during stereotactic tumour ablation. The present paper aims to give an overview of the fundamental physiology, technical aspects, and clinical challenges of HFV in ablation procedures during general anaesthesia, where HFV is used to minimise the movements of the ablation target.
      PubDate: 2017-05-30T09:46:08Z
      DOI: 10.12688/f1000research.10823.1
      Issue No: Vol. 6 (2017)
  • Recent advances in microbial fermentation for dairy and health [version 1;
           referees: 3 approved]

    • Authors: Daragh Hill, Ivan Sugrue, Elke Arendt, Colin Hill, Catherine Stanton, R Paul Ross
      Abstract: Microbial fermentation has been used historically for the preservation of foods, the health benefits of which have since come to light. Early dairy fermentations depended on the spontaneous activity of the indigenous microbiota of the milk. Modern fermentations rely on defined starter cultures with desirable characteristics to ensure consistency and commercial viability. The selection of defined starters depends on specific phenotypes that benefit the product by guaranteeing shelf life and ensuring safety, texture, and flavour. Lactic acid bacteria can produce a number of bioactive metabolites during fermentation, such as bacteriocins, biogenic amines, exopolysaccharides, and proteolytically released peptides, among others. Prebiotics are added to food fermentations to improve the performance of probiotics. It has also been found that prebiotics fermented in the gut can have benefits that go beyond helping probiotic growth. Studies are now looking at how the fermentation of prebiotics such as fructo-oligosaccharides can help in the prevention of diseases such as osteoporosis, obesity, and colorectal cancer. The potential to prevent or even treat disease through the fermentation of food is a medically and commercially attractive goal and is showing increasing promise. However, the stringent regulation of probiotics is beginning to detrimentally affect the field and limit their application.
      PubDate: 2017-05-26T15:37:15Z
      DOI: 10.12688/f1000research.10896.1
      Issue No: Vol. 6 (2017)
  • Leishmaniasis: a review [version 1; referees: 2 approved]

    • Authors: Edoardo Torres-Guerrero, Marco Romano Quintanilla-Cedillo, Julieta Ruiz-Esmenjaud, Roberto Arenas
      Abstract: Leishmaniasis is caused by an intracellular parasite transmitted to humans by the bite of a sand fly. It is endemic in Asia, Africa, the Americas, and the Mediterranean region. Worldwide, 1.5 to 2 million new cases occur each year, 350 million are at risk of acquiring the disease, and leishmaniasis causes 70,000 deaths per year. Clinical features depend on the species of Leishmania involved and the immune response of the host. Manifestations range from the localized cutaneous to the visceral form with potentially fatal outcomes. Many drugs are used in its treatment, but the only effective treatment is achieved with current pentavalent antimonials.
      PubDate: 2017-05-26T11:32:32Z
      DOI: 10.12688/f1000research.11120.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding contextual TGFβ signaling [version
           1; referees: 2 approved]

    • Authors: Arshad Ayyaz, Liliana Attisano, Jeffrey L Wrana
      Abstract: The appearance of the first animal species on earth coincides with the emergence of transforming growth factor β (TGFβ) pathways. The evolution of these animals into more complex organisms coincides with a progressively increased TGFβ repertoire through gene duplications and divergence, making secreted TGFβ molecules the largest family of morphogenetic proteins in humans. It is therefore not surprising that TGFβ pathways govern numerous aspects of human biology from early embryonic development to regeneration, hematopoiesis, neurogenesis, and immunity. Such heavy reliance on these pathways is reflected in the susceptibility to minor perturbations in pathway components that can lead to dysregulated signaling and a diverse range of human pathologies such as cancer, fibrosis, and developmental disorders. Attempts to comprehensively resolve these signaling cascades are complicated by the long-recognized paradoxical role the pathway plays in cell biology. Recently, several groups have probed examples of the disparate aspects of TGFβ biology in a variety of animal models and uncovered novel context-dependent regulatory mechanisms. Here, we briefly review recent advancements and discuss their overall impact in directing future TGFβ research.
      PubDate: 2017-05-26T11:27:35Z
      DOI: 10.12688/f1000research.11295.1
      Issue No: Vol. 6 (2017)
  • Effects of physical activity on the link between PGC-1a and FNDC5 in
           muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: A
           systematic review [version 2; referees: 2 approved]

    • Authors: Petros C. Dinas, Ian M. Lahart, James A. Timmons, Per-Arne Svensson, Yiannis Koutedakis, Andreas D. Flouris, George S. Metsios
      Abstract: Background: Exercise may activate a brown adipose-like phenotype in white adipose tissue. The aim of this systematic review was to identify the effects of physical activity on the link between peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and fibronectin type III domain-containing protein 5 (FNDC5) in muscle, circulating Irisin and uncoupling protein one (UCP1) of white adipocytes in humans. Methods: Two databases (PubMed 1966 to 08/2016 and EMBASE 1974 to 08/2016) were searched using an appropriate algorithm. We included articles that examined physical activity and/or exercise in humans that met the following criteria: a) PGC-1a in conjunction with FNDC5 measurements, and b) FNDC5 and/or circulating Irisin and/or UCP1 levels in white adipocytes. Results: We included 51 studies (12 randomised controlled trials) with 2474 participants. Out of the 51 studies, 16 examined PGC-1a and FNDC5 in response to exercise, and only four found increases in both PGC-1a and FNDC5 mRNA and one showed increased FNDC5 mRNA. In total, 22 out of 45 studies that examined circulating Irisin in response to exercise showed increased concentrations when ELISA techniques were used; two studies also revealed increased Irisin levels measured via mass spectrometry. Three studies showed a positive association of circulating Irisin with physical activity levels. One study found no exercise effects on UCP1 mRNA in white adipocytes. Conclusions: The effects of physical activity on the link between PGC-1a, FNDC5 mRNA in muscle and UCP1 in white human adipocytes has attracted little scientific attention. Current methods for Irisin identification lack precision and, therefore, the existing evidence does not allow for conclusions to be made regarding Irisin responses to physical activity. We found a contrast between standardised review methods and accuracy of the measurements used. This should be considered in future systematic reviews.
      PubDate: 2017-05-26T11:12:27Z
      DOI: 10.12688/f1000research.11107.2
      Issue No: Vol. 6 (2017)
  • CyTOF workflow: differential discovery in high-throughput high-dimensional
           cytometry datasets [version 1; referees: 2 approved]

    • Authors: Malgorzata Nowicka, Carsten Krieg, Lukas M. Weber, Felix J. Hartmann, Silvia Guglietta, Burkhard Becher, Mitchell P. Levesque, Mark D. Robinson
      Abstract: High dimensional mass and flow cytometry (HDCyto) experiments have become a method of choice for high throughput interrogation and characterization of cell populations.Here, we present an R-based pipeline for differential analyses of HDCyto data, largely based on Bioconductor packages. We computationally define cell populations using FlowSOM clustering, and facilitate an optional but reproducible strategy for manual merging of algorithm-generated clusters. Our workflow offers different analysis paths, including association of cell type abundance with a phenotype or changes in signaling markers within specific subpopulations, or differential analyses of aggregated signals. Importantly, the differential analyses we show are based on regression frameworks where the HDCyto data is the response; thus, we are able to model arbitrary experimental designs, such as those with batch effects, paired designs and so on. In particular, we apply generalized linear mixed models to analyses of cell population abundance or cell-population-specific analyses of signaling markers, allowing overdispersion in cell count or aggregated signals across samples to be appropriately modeled. To support the formal statistical analyses, we encourage exploratory data analysis at every step, including quality control (e.g. multi-dimensional scaling plots), reporting of clustering results (dimensionality reduction, heatmaps with dendrograms) and differential analyses (e.g. plots of aggregated signals).
      PubDate: 2017-05-26T09:27:36Z
      DOI: 10.12688/f1000research.11622.1
      Issue No: Vol. 6 (2017)
  • Genetic and epigenetic control of gene expression by CRISPR–Cas systems
           [version 1; referees: 3 approved]

    • Authors: Albert Lo, Lei Qi
      Abstract: The discovery and adaption of bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems has revolutionized the way researchers edit genomes. Engineering of catalytically inactivated Cas variants (nuclease-deficient or nuclease-deactivated [dCas]) combined with transcriptional repressors, activators, or epigenetic modifiers enable sequence-specific regulation of gene expression and chromatin state. These CRISPR–Cas-based technologies have contributed to the rapid development of disease models and functional genomics screening approaches, which can facilitate genetic target identification and drug discovery. In this short review, we will cover recent advances of CRISPR–dCas9 systems and their use for transcriptional repression and activation, epigenome editing, and engineered synthetic circuits for complex control of the mammalian genome.
      PubDate: 2017-05-25T11:07:20Z
      DOI: 10.12688/f1000research.11113.1
      Issue No: Vol. 6 (2017)
  • Wnt target genes and where to find them [version 1; referees: 3 approved]

    • Authors: Aravinda-Bharathi Ramakrishnan, Ken M. Cadigan
      Abstract: Wnt/β-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most notably cancer. Wnt stimulation results in stabilization and nuclear import of β-catenin, which then acts as a transcriptional co-activator. Transcription factors of the T-cell family (TCF) are the best-characterized nuclear binding partners of β-catenin and mediators of Wnt gene regulation. This review provides an update on what is known about the transcriptional activation of Wnt target genes, highlighting recent work that modifies the conventional model. Wnt/β-catenin signaling regulates genes in a highly context-dependent manner, and the role of other signaling pathways and TCF co-factors in this process will be discussed. Understanding Wnt gene regulation has served to elucidate many biological roles of the pathway, and we will use examples from stem cell biology, metabolism, and evolution to illustrate some of the rich Wnt biology that has been uncovered.
      PubDate: 2017-05-24T15:57:29Z
      DOI: 10.12688/f1000research.11034.1
      Issue No: Vol. 6 (2017)
  • Nitric oxide signalling and neuronal nitric oxide synthase in the heart
           under stress [version 1; referees: 2 approved]

    • Authors: Yin Hua Zhang
      Abstract: Nitric oxide (NO) is an imperative regulator of the cardiovascular system and is a critical mechanism in preventing the pathogenesis and progression of the diseased heart. The scenario of bioavailable NO in the myocardium is complex: 1) NO is derived from both endogenous NO synthases (endothelial, neuronal, and/or inducible NOSs [eNOS, nNOS, and/or iNOS]) and exogenous sources (entero-salivary NO pathway) and the amount of NO from exogenous sources varies significantly; 2) NOSs are located at discrete compartments of cardiac myocytes and are regulated by distinctive mechanisms under stress; 3) NO regulates diverse target proteins through different modes of post-transcriptional modification (soluble guanylate cyclase [sGC]/cyclic guanosine monophosphate [cGMP]/protein kinase G [PKG]-dependent phosphorylation, S-nitrosylation, and transnitrosylation); 4) the downstream effectors of NO are multidimensional and vary from ion channels in the plasma membrane to signalling proteins and enzymes in the mitochondria, cytosol, nucleus, and myofilament; 5) NOS produces several radicals in addition to NO (e.g. superoxide, hydrogen peroxide, peroxynitrite, and different NO-related derivatives) and triggers redox-dependent responses. However, nNOS inhibits cardiac oxidases to reduce the sources of oxidative stress in diseased hearts. Recent consensus indicates the importance of nNOS protein in cardiac protection under pathological stress. In addition, a dietary regime with high nitrate intake from fruit and vegetables together with unsaturated fatty acids is strongly associated with reduced cardiovascular events. Collectively, NO-dependent mechanisms in healthy and diseased hearts are better understood and shed light on the therapeutic prospects for NO and NOSs in clinical applications for fatal human heart diseases.
      PubDate: 2017-05-23T15:14:26Z
      DOI: 10.12688/f1000research.10128.1
      Issue No: Vol. 6 (2017)
  • Yin and yang of interleukin-17 in host immunity to infection [version 1;
           referees: 2 approved]

    • Authors: Shibali Das, Shabaana Khader
      Abstract: The interleukin-17 (IL-17) family cytokines, such as IL-17A and IL-17F, play important protective roles in host immune response to a variety of infections such as bacterial, fungal, parasitic, and viral. The IL-17R signaling and downstream pathways mediate induction of proinflammatory molecules which participate in control of these pathogens. However, the production of IL-17 can also mediate pathology and inflammation associated with infections. In this review, we will discuss the yin-and-yang roles of IL-17 in host immunity to pathogens.
      PubDate: 2017-05-23T15:12:58Z
      DOI: 10.12688/f1000research.10862.1
      Issue No: Vol. 6 (2017)
  • Pneumocystis jirovecii detection in asymptomatic patients: what does its
           natural history tell us' [version 1; referees: 3 approved]

    • Authors: Alexandre Alanio, Stéphane Bretagne
      Abstract: Pneumocystis jirovecii is an unusual ascomycetous fungus that can be detected in the lungs of healthy individuals. Transmission from human to human is one of its main characteristics in comparison with other fungi responsible for invasive infections. P. jirovecii is transmitted through the air between healthy individuals, who are considered to be the natural reservoir, at least transiently. In immunocompromised patients, P. jirovecii multiplies, leading to subacute infections and acute life-threatening pneumonia, called Pneumocystis pneumonia [PCP]. PCP is caused by genotypically distinct mixtures of organisms in more than 90% of cases, reinforcing the hypothesis that there is constant inhalation of P. jirovecii from different contacts over time, although reactivation of latent organisms from previous exposures may be possible. Detection of P. jirovecii DNA without any symptoms or related radiological signs has been called “colonization”. This situation could be considered as the result of recent exposure to P. jirovecii that could evolve towards PCP, raising the issue of cotrimoxazole prophylaxis for at-risk quantitative polymerase chain reaction (qPCR)-positive immunocompromised patients. The more accurate way to diagnose PCP is the use of real-time quantitative PCR, which prevents amplicon contamination and allows determination of the fungal load that is mandatory to interpret the qPCR results and manage the patient appropriately. The detection of P. jirovecii in respiratory samples of immunocompromised patients should be considered for potential risk of developing PCP. Many challenges still need to be addressed, including a better description of transmission, characterization of organisms present at low level, and prevention of environmental exposure during immunodepression.
      PubDate: 2017-05-23T08:45:37Z
      DOI: 10.12688/f1000research.10619.1
      Issue No: Vol. 6 (2017)
  • Acute mechanical circulatory support for cardiogenic shock: the “door to
           support” time [version 1; referees: 3 approved]

    • Authors: Michele L Esposito, Navin K Kapur
      Abstract: Cardiogenic shock (CS) remains a major cause of in-hospital mortality in the setting of acute myocardial infarction. CS begins as a hemodynamic problem with impaired cardiac output leading to reduced systemic perfusion, increased residual volume within the left and right ventricles, and increased cardiac filling pressures. A critical step towards the development of future algorithms is a clear understanding of the treatment objectives for CS. In this review, we introduce the “door to support” time as an emerging target of therapy to improve outcomes associated with CS, define four key treatment objectives in the management of CS, discuss the importance of early hemodynamic assessment and appropriate selection of acute mechanical circulatory support (AMCS) devices for CS, and introduce a classification scheme that identifies subtypes of CS based on cardiac filling pressures.
      PubDate: 2017-05-22T15:09:45Z
      DOI: 10.12688/f1000research.11150.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding lung function development [version 1;
           referees: 2 approved]

    • Authors: Erik Melén, Stefano Guerra
      Abstract: Recent years have witnessed critical contributions to our understanding of the determinants and long-term implications of lung function development. In this article, we review studies that have contributed to advances in understanding lung function development and its critical importance for lung health into adult life. In particular, we have focused on early life determinants that include genetic factors, perinatal events, environmental exposures, lifestyle, infancy lower respiratory tract infections, and persistent asthma phenotypes. Longitudinal studies have conclusively demonstrated that lung function deficits that are established by school age may track into adult life and increase the risk of adult lung obstructive diseases, such as chronic obstructive pulmonary disease. Furthermore, these contributions have provided initial evidence in support of a direct influence by early life events on an accelerated decline of lung function and an increased susceptibility to its environmental determinants well into adult life. As such, we argue that future health-care programs based on precision medicine approaches that integrate deep phenotyping with tailored medication and advice to patients should also foster optimal lung function growth to be fully effective.
      PubDate: 2017-05-19T14:39:17Z
      DOI: 10.12688/f1000research.11185.1
      Issue No: Vol. 6 (2017)
  • The advantage of channeling nucleotides for very processive functions
           [version 1; referees: 2 approved]

    • Authors: Diana Zala, Uwe Schlattner, Thomas Desvignes, Julien Bobe, Aurélien Roux, Philippe Chavrier, Mathieu Boissan
      Abstract: Nucleoside triphosphate (NTP)s, like ATP (adenosine 5’-triphosphate) and GTP (guanosine 5’-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised ‘microcompartments’, where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.
      PubDate: 2017-05-18T15:20:03Z
      DOI: 10.12688/f1000research.11561.1
      Issue No: Vol. 6 (2017)
  • haploR: an R package for querying web-based annotation tools [version 2;
           referees: 2 approved, 1 approved with reservations]

    • Authors: Ilya Y. Zhbannikov, Konstantin Arbeev, Svetlana Ukraintseva, Anatoliy I. Yashin
      Abstract: We developed haploR, an R package for querying web based genome annotation tools HaploReg and RegulomeDB. haploR gathers information in a data frame which is suitable for downstream bioinformatic analyses. This will facilitate post-genome wide association studies streamline analysis for rapid discovery and interpretation of genetic associations.
      PubDate: 2017-05-15T14:18:42Z
      DOI: 10.12688/f1000research.10742.2
      Issue No: Vol. 6 (2017)
  • Immunoprofiling of human uterine mast cells identifies three phenotypes
           and expression of ERβ and glucocorticoid receptor [version 1; referees: 2

    • Authors: Bianca De Leo, Arantza Esnal-Zufiaurre, Frances Collins, Hilary O.D. Critchley, Philippa T.K. Saunders
      Abstract: Background: Human mast cells (MCs) are long-lived tissue-resident immune cells characterised by granules containing the proteases chymase and/or tryptase. Their phenotype is modulated by their tissue microenvironment. The human uterus has an outer muscular layer (the myometrium) surrounding the endometrium, both of which play an important role in supporting a pregnancy. The endometrium is a sex steroid target tissue consisting of epithelial cells (luminal, glandular) surrounded by a multicellular stroma, with the latter containing an extensive vascular compartment as well as fluctuating populations of immune cells that play an important role in regulating tissue function. The role of MCs in the human uterus is poorly understood with little known about their regulation or the impact of steroids on their differentiation status. The current study had two aims: 1) To investigate the spatial and temporal location of uterine MCs and determine their phenotype; 2) To determine whether MCs express receptors for steroids implicated in uterine function, including oestrogen (ERα, ERβ), progesterone (PR) and glucocorticoids (GR). Methods: Tissue samples from women (n=46) were used for RNA extraction or fixed for immunohistochemistry. Results: Messenger RNAs encoded by TPSAB1 (tryptase) and CMA1 (chymase) were detected in endometrial tissue homogenates. Immunohistochemistry revealed the relative abundance of tryptase MCs was myometrium>basal endometrium>functional endometrium. We show for the first time that uterine MCs are predominantly of the classical MC subtypes: (positive, +; negative, -) tryptase+/chymase- and tryptase+/chymase+, but a third subtype was also identified (tryptase-/chymase+). Tryptase+ MCs were of an ERβ+/ERα-/PR-/GR+ phenotype mirroring other uterine immune cell populations, including natural killer cells. Conclusions: Endometrial tissue resident immune MCs have three protease-specific phenotypes. Expression of both ERβ and GR in MCs mirrors that of other immune cells in the endometrium and suggests that MC function may be altered by the local steroid microenvironment.
      PubDate: 2017-05-12T13:54:39Z
      DOI: 10.12688/f1000research.11432.1
      Issue No: Vol. 6 (2017)
  • On the origin of nonequivalent states: How we can talk about preprints
           [version 1; referees: 2 approved]

    • Authors: Cameron Neylon, Damian Pattinson, Geoffrey Bilder, Jennifer Lin
      Abstract: Increasingly, preprints are at the center of conversations across the research ecosystem. But disagreements remain about the role they play. Do they “count” for research assessment' Is it ok to post preprints in more than one place' In this paper, we argue that these discussions often conflate two separate issues, the history of the manuscript and the status granted it by different communities. In this paper, we propose a new model that distinguishes the characteristics of the object, its “state”, from the subjective “standing” granted to it by different communities. This provides a way to discuss the difference in practices between communities, which will deliver more productive conversations and facilitate negotiation, as well as sharpening our focus on the role of different stakeholders on how to collectively improve the process of scholarly communications not only for preprints, but other forms of scholarly contributions.
      PubDate: 2017-05-02T09:59:13Z
      DOI: 10.12688/f1000research.11408.1
      Issue No: Vol. 6 (2017)
  • Reproducibility2020: Progress and priorities [version 1; referees: 2

    • Authors: Leonard P. Freedman, Gautham Venugopalan, Rosann Wisman
      Abstract: The preclinical research process is a cycle of idea generation, experimentation, and reporting of results. The biomedical research community relies on the reproducibility of published discoveries to create new lines of research and to translate research findings into therapeutic applications. Since 2012, when scientists from Amgen reported that they were able to reproduce only 6 of 53 “landmark” preclinical studies, the biomedical research community began discussing the scale of the reproducibility problem and developing initiatives to address critical challenges. Global Biological Standards Institute (GBSI) released the “Case for Standards” in 2013, one of the first comprehensive reports to address the rising concern of irreproducible biomedical research. Further attention was drawn to issues that limit scientific self-correction, including reporting and publication bias, underpowered studies, lack of open access to methods and data, and lack of clearly defined standards and guidelines in areas such as reagent validation. To evaluate the progress made towards reproducibility since 2013, GBSI identified and examined initiatives designed to advance quality and reproducibility. Through this process, we identified key roles for funders, journals, researchers and other stakeholders and recommended actions for future progress. This paper describes our findings and conclusions.
      PubDate: 2017-05-02T08:31:34Z
      DOI: 10.12688/f1000research.11334.1
      Issue No: Vol. 6 (2017)
  • Evidence of disease control: a realistic concept beyond NEDA in the
           treatment of multiple sclerosis [version 1; referees: 2 approved]

    • Authors: Ana C. Londoño, Carlos A. Mora
      Abstract: Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached.
      PubDate: 2017-04-25T15:55:52Z
      DOI: 10.12688/f1000research.11349.1
      Issue No: Vol. 6 (2017)
  • Case Report: Novel mutations in TBC1D24 are associated with autosomal
           dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism,
           psychosis, and intellectual disability [version 1; referees: 2 approved]

    • Authors: Erika Banuelos, Keri Ramsey, Newell Belnap, Malavika Krishnan, Chris Balak, Szabolcs Szelinger, Ashley L. Siniard, Megan Russell, Ryan Richholt, Matt De Both, Ignazio Piras, Marcus Naymik, Ana M. Claasen, Sampathkumar Rangasamy, Matthew J. Huentelman, David W. Craig, Philippe M. Campeau, Vinodh Narayanan, Isabelle Schrauwen
      Abstract: Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy
      PubDate: 2017-04-24T14:32:36Z
      DOI: 10.12688/f1000research.10588.1
      Issue No: Vol. 6 (2017)
  • The internet trade of counterfeit spirits in Russia – an emerging
           problem undermining alcohol, public health and youth protection
           policies' [version 1; referees: 2 approved]

    • Authors: Maria Neufeld, Dirk W. Lachenmeier, Stephan G. Walch, Jürgen Rehm
      Abstract: Counterfeit alcohol belongs to the category of unrecorded alcohol not reflected in official statistics. The internet trade of alcoholic beverages has been prohibited by the Russian Federation since 2007, but various sellers still offer counterfeit spirits (i.e., forged brand spirits) over the internet to Russian consumers, mostly in a non-deceptive fashion at prices up to 15 times lower than in regular sale. The public health issues arising from this unregulated trade include potential harm to underage drinkers, hazards due to toxic ingredients such as methanol, but most importantly alcohol harms due to potentially increased drinking volumes due to low prices and high availability on the internet. The internet sale also undermines existing alcohol policies such as restrictions of sale locations, sale times and minimum pricing. The need to enforce measures against counterfeiting of spirits, but specifically their internet trade should be implemented as key elements of alcohol policies to reduce unrecorded alcohol consumption, which is currently about 33 % of total consumption in Russia.
      PubDate: 2017-04-20T10:02:49Z
      DOI: 10.12688/f1000research.11418.1
      Issue No: Vol. 6 (2017)
  • Case Report: Making a diagnosis of familial renal disease – clinical and
           patient perspectives [version 1; referees: 2 approved]

    • Authors: Zahra Iqbal, John A. Sayer
      Abstract: Background: A precise molecular genetic diagnosis has become the gold standard for the correct identification and management of many inherited renal diseases. Methods: Here we describe a family with familial focal segmental glomerulosclerosis, and include a clinical and patient perspective on the diagnostic workup and relaying of genetic results following whole exome sequencing. Results: Through next generation sequencing approaches, we identified a pathogenic mutation in TRPC6, the underlying cause of the phenotype. The identification of this mutation had important clinical consequences for the family, including allowing a living-unrelated kidney transplant to proceed in the index case. There are also wider ranging social and ethical dilemmas presented when reaching a genetic diagnosis like this one, which are explored here by both physicians and the index case. Conclusions: Through physician and patient perspectives in a family with inherited renal failure we explore the implications and the magnitude of a molecular genetic diagnosis.
      PubDate: 2017-04-12T15:27:17Z
      DOI: 10.12688/f1000research.11316.1
      Issue No: Vol. 6 (2017)
  • Early fruiting in Synsepalum dulcificum (Schumach. & Thonn.) Daniell
           juveniles induced by water and inorganic nutrient management [version 1;
           referees: 2 approved]

    • Authors: Dèdéou Apocalypse Tchokponhoué, Sognigbé N'Danikou, Iago Hale, Allen Van Deynze, Enoch Gbènato Achigan-Dako
      Abstract: Background. The miracle plant, Synsepalum dulcificum (Schumach. & Thonn.) Daniell is a native African orphan crop species that has recently received increased attention due to its promise as a sweetener and source of antioxidants in both the food and pharmaceutical industries. However, a major obstacle to the species’ widespread utilization is its relatively slow growth rate and prolonged juvenile period. Method. In this study, we tested twelve treatments made up of various watering regimes and exogenous nutrient application (nitrogen, phosphorus and potassium, at varying dosages) on the relative survival, growth, and reproductive development of 15-months-old S. dulcificum juveniles. Results. While the plants survived under most tested growing conditions, nitrogen application at doses higher than 1.5 g [seedling]-1 was found to be highly detrimental, reducing survival to 0%. The treatment was found to affect all growth traits, and juveniles that received a combination of nitrogen, phosphorus, and potassium (each at a rate of 1.5 g [seedling]-1), in addition to daily watering, exhibited the most vegetative growth. The simple daily provision of adequate water was found to greatly accelerate the transition to reproductive maturity in the species (from >36 months to an average of 23 months), whereas nutrient application affected the length of the reproductive phase within a season, as well as the fruiting intensity. Conclusions. This study highlights the beneficial effect of water supply and fertilization on both vegetative and reproductive growth in S. dulcificum. Water supply appeared to be the most important factor unlocking flowering in the species, while the combination of nitrogen, phosphorus and potassium at the dose of 1.5 g (for all) consistently exhibited the highest performance for all growth and yield traits. These findings will help intensify S. dulcificum’s breeding and horticultural development.
      PubDate: 2017-03-30T14:01:58Z
      DOI: 10.12688/f1000research.11091.1
      Issue No: Vol. 6 (2017)
  • Improving agricultural knowledge management: The AgTrials experience
           [version 1; referees: 2 approved]

    • Authors: Glenn Hyman, Herlin Espinosa, Paola Camargo, David Abreu, Medha Devare, Elizabeth Arnaud, Cheryl Porter, Leroy Mwanzia, Kai Sonder, Sibiry Traore
      Abstract: Background: Opportunities to use data and information to address challenges in international agricultural research and development are expanding rapidly. The use of agricultural trial and evaluation data has enormous potential to improve crops and management practices. However, for a number of reasons, this potential has yet to be realized. This paper reports on the experience of the AgTrials initiative, an effort to build an online database of agricultural trials applying principles of interoperability and open access. Methods: Our analysis evaluates what worked and what did not work in the development of the AgTrials information resource. We analyzed data on our users and their interaction with the platform. We also surveyed our users to gauge their perceptions of the utility of the online database. Results: The study revealed barriers to participation and impediments to interaction, opportunities for improving agricultural knowledge management and a large potential for the use of trial and evaluation data. Conclusions: Technical and logistical mechanisms for developing interoperable online databases are well advanced.  More effort will be needed to advance organizational and institutional work for these types of databases to realize their potential.
      PubDate: 2017-03-24T13:56:19Z
      DOI: 10.12688/f1000research.11179.1
      Issue No: Vol. 6 (2017)
  • Questions on unusual Mimivirus-like structures observed in human cells
           [version 1; referees: 2 approved]

    • Authors: Elena Angela Lusi, Dan Maloney, Federico Caicci, Paolo Guarascio
      Abstract: Background: Mimiviruses or giant viruses that infect amoebas have the ability to retain the Gram stain, which is usually used to colour bacteria. There is some evidence suggesting that Mimiviruses can also infect human cells. Guided by these premises, we performed a routine Gram stain on a variety of human specimens to see if we could detect the same Gram positive blue granules that identify Mimiviruses in the amoebas. Methods: We analysed 24 different human specimens (liver, brain, kidney, lymph node and ovary) using Gram stain histochemistry, electron microscopy immunogold, high resolution mass spectrometry and protein identification. Results: We detected in the human cells Gram positive granules that were distinct from bacteria. The fine blue granules displayed the same pattern of the Gram positive granules that diagnose Mimiviruses in the cytoplasm of the amoebas. Electron microscopy confirmed the presence of human Mimiviruses-like structures and mass spectrometry identified histone H4 peptides, which had the same footprints as giant viruses. However, some differences were noted: the Mimivirus-like structures identified in the human cells were ubiquitous and manifested a distinct mammalian retroviral antigenicity. Conclusions: Our main hypotheses are that the structures could be either giant viruses having a retroviral antigenicity or ancestral cellular components having a viral origin. However, other possible alternatives have been proposed to explain the nature and function of the newly identified structures.
      PubDate: 2017-03-14T10:07:21Z
      DOI: 10.12688/f1000research.11007.1
      Issue No: Vol. 6 (2017)
  • The impact factor of an open access journal does not contribute to an
           article’s citations [version 1; referees: 2 approved]

    • Authors: SK Chua, Ahmad M Qureshi, Vijay Krishnan, Dinker R Pai, Laila B Kamal, Sharmilla Gunasegaran, MZ Afzal, Lahiru Ambawatta, JY Gan, PY Kew, Than Winn, Suneet Sood
      Abstract: Background Citations of papers are positively influenced by the journal’s impact factor (IF). For non-open access (non-OA) journals, this influence may be due to the fact that high-IF journals are more often purchased by libraries, and are therefore more often available to researchers, than low-IF journals. This positive influence has not, however, been shown specifically for papers published in open access (OA) journals, which are universally accessible, and do not need library purchase. It is therefore important to ascertain if the IF influences citations in OA journals too. Methods 203 randomized controlled trials (102 OA and 101 non-OA) published in January 2011 were included in the study. Five-year citations for papers published in OA journals were compared to those for non-OA journals. Source papers were derived from PubMed. Citations were retrieved from Web of Science, Scopus, and Google Scholar databases. The Thompson-Reuter’s IF was used. Results OA journals were found to have significantly more citations overall compared to non-OA journals (median 15.5 vs 12, p=0.039). The IF did not correlate with citations for OA journals (Spearman’s rho =0.187, p=0.60). The increase in the citations with increasing IF was minimal for OA journals (beta coefficient = 3.346, 95% CI -0.464, 7.156, p=0.084). In contrast, the IF did show moderate correlation with citations for articles published in non-OA journals (Spearman’s rho=0.514, p
      PubDate: 2017-03-02T09:57:03Z
      DOI: 10.12688/f1000research.10892.1
      Issue No: Vol. 6 (2017)
  • ELIXIR pilot action: Marine metagenomics – towards a domain specific set
           of sustainable services [version 1; referees: 1 approved, 2 approved with

    • Authors: Espen Mikal Robertsen, Hubert Denise, Alex Mitchell, Robert D. Finn, Lars Ailo Bongo, Nils Peder Willassen
      Abstract: Metagenomics, the study of genetic material recovered directly from environmental samples, has the potential to provide insight into the structure and function of heterogeneous microbial communities.  There has been an increased use of metagenomics to discover and understand the diverse biosynthetic capacities of marine microbes, thereby allowing them to be exploited for industrial, food, and health care products. This ELIXIR pilot action was motivated by the need to establish dedicated data resources and harmonized metagenomics pipelines for the marine domain, in order to enhance the exploration and exploitation of marine genetic resources. In this paper, we summarize some of the results from the ELIXIR pilot action “Marine metagenomics – towards user centric services”.
      PubDate: 2017-01-23T16:02:56Z
      DOI: 10.12688/f1000research.10443.1
      Issue No: Vol. 6 (2017)
  • Early embryo mortality in natural human reproduction: What the data say
           [version 2; referees: 1 approved, 2 approved with reservations]

    • Authors: Gavin E. Jarvis
      Abstract: How many human embryos die between fertilisation and birth under natural conditions' It is widely accepted that natural human embryo mortality is high, particularly during the first weeks after fertilisation, with total prenatal losses of 70% and higher frequently claimed. However, the first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period, and establishing the fate of embryos before this is challenging. Calculations are additionally hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are used to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet  is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data concluded that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, natural human embryo mortality is lower than often claimed and widely accepted. Estimates for total prenatal mortality of 70% or higher are exaggerated and not supported by the available data.
      PubDate: 2017-06-07T13:05:15Z
      DOI: 10.12688/f1000research.8937.2
      Issue No: Vol. 5 (2017)
  • Predicting Outcomes of Hormone and Chemotherapy in the Molecular Taxonomy
           of Breast Cancer International Consortium (METABRIC) Study by

    • Authors: Eliseos J. Mucaki, Katherina Baranova, Huy Q. Pham, Iman Rezaeian, Dimo Angelov, Alioune Ngom, Luis Rueda, Peter K. Rogan
      Abstract: Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients; was also used to derive gene signatures of other HT  (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5-fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing genes ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, and TUBB4B was 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival ≥ 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches was also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of genes BCL2L1, BBC3, FGF2, FN1, and TWIST1 was 81.1% accurate in 53 CT patients. In addition, a random forest (RF) classifier using a gene signature (ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2,SLCO1B3, TUBB1, TUBB4A, and TUBB4B) predicted >3-year survival with 85.5% accuracy in 420 HT patients. A similar RF gene signature showed 82.7% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies.
      PubDate: 2017-05-12T13:57:11Z
      DOI: 10.12688/f1000research.9417.3
      Issue No: Vol. 5 (2017)
  • The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a
           mature rat [version 2; referees: 1 approved, 2 approved with reservations]

    • Authors: Mary R. Hannaman, Douglas A. Fitts, Rose M. Doss, David E. Weinstein, Joseph L. Bryant
      Abstract: Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats’ responses to known analgesics and a targeted biologic.   Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site.   Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain.   Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents.
      PubDate: 2017-05-04T14:05:57Z
      DOI: 10.12688/f1000research.9544.2
      Issue No: Vol. 5 (2017)
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Heriot-Watt University
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