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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]
  • The emerging role of PET imaging in dementia [version 1; referees: 3

    • Authors: Leonardo Iaccarino, Arianna Sala, Silvia Paola Caminiti, Daniela Perani
      Abstract: A compelling need in the field of neurodegenerative diseases is the development and validation of biomarkers for early identification and differential diagnosis. The availability of positron emission tomography (PET) neuroimaging tools for the assessment of molecular biology and neuropathology has opened new venues in the diagnostic design and the conduction of new clinical trials. PET techniques, allowing the in vivo assessment of brain function and pathology changes, are increasingly showing great potential in supporting clinical diagnosis also in the early and even preclinical phases of dementia. This review will summarize the most recent evidence on fluorine-18 fluorodeoxyglucose-, amyloid -, tau -, and neuroinflammation - PET tools, highlighting strengths and limitations and possible new perspectives in research and clinical applications. Appropriate use of PET tools is crucial for a prompt diagnosis and target evaluation of new developed drugs aimed at slowing or preventing dementia.
      PubDate: 2017-10-12T13:28:49Z
      DOI: 10.12688/f1000research.11603.1
      Issue No: Vol. 6 (2017)
  • Resolving the clinico-radiological paradox in multiple sclerosis [version
           1; referees: 3 approved]

    • Authors: Declan Chard, S Anand Trip
      Abstract: Understanding the clinico-radiological paradox is important in the search for more sensitive and specific surrogates of relapses and disability progression (such that they can be used to inform treatment choices in individual people with multiple sclerosis) and to gain a better understanding of the pathophysiological basis of disability in multiple sclerosis (to identify and assess key therapeutic targets). In this brief review, we will consider themes and issues underlying the clinico-radiological paradox and recent advances in its resolution.
      PubDate: 2017-10-12T09:29:08Z
      DOI: 10.12688/f1000research.11932.1
      Issue No: Vol. 6 (2017)
  • Logarithmic distributions prove that intrinsic learning is Hebbian
           [version 2; referees: 2 approved]

    • Authors: Gabriele Scheler
      Abstract: In this paper, we present data for the lognormal distributions of spike rates, synaptic weights and intrinsic excitability (gain) for neurons in various brain areas, such as auditory or visual cortex, hippocampus, cerebellum, striatum, midbrain nuclei. We find a remarkable consistency of heavy-tailed, specifically lognormal, distributions for rates, weights and gains in all brain areas examined. The difference between strongly recurrent and feed-forward connectivity (cortex vs. striatum and cerebellum), neurotransmitter (GABA (striatum) or glutamate (cortex)) or the level of activation (low in cortex, high in Purkinje cells and midbrain nuclei) turns out to be irrelevant for this feature. Logarithmic scale distribution of weights and gains appears to be a general, functional property in all cases analyzed. We then created a generic neural model to investigate adaptive learning rules that create and maintain lognormal distributions. We conclusively demonstrate that not only weights, but also intrinsic gains, need to have strong Hebbian learning in order to produce and maintain the experimentally attested distributions. This provides a solution to the long-standing question about the type of plasticity exhibited by intrinsic excitability.
      PubDate: 2017-10-11T15:33:05Z
      DOI: 10.12688/f1000research.12130.2
      Issue No: Vol. 6 (2017)
  • Recent Advances in Understanding Cholangiocarcinoma [version 1; referees:
           2 approved]

    • Authors: Lindsey Kennedy, Laura Hargrove, Jennifer Demieville, Nicole Francis, Rowan Seils, Sara Villamaria, Heather Francis
      Abstract: Cholangiocarcinoma (CCA) is an aggressive malignancy that arises from damaged epithelial cells, cholangiocytes, and possibly de-differentiated hepatocytes. CCA has a poor overall survival rate and limited therapeutic options. Based on this data, it is imperative that new diagnostic and therapeutic interventions be developed. Recent work has attempted to understand the pathological mechanisms driving CCA progression. Specifically, recent publications have delved into the role of cancer stem cells (CSCs), mesenchymal stem cells (MSCs), and microRNAs (miRNAs) during CCA pathology. CSCs are a specific subset of cells within the tumor environment that are derived from a cell with stem-like properties and have been shown to influence recurrence and chemoresistance during CCA. MSCs are known for their anti-inflammatory activity and have been postulated to influence malignancy during CCA, but little is known about their exact functions. miRNAs exert various functions via gene regulation at both the transcriptional and the translational levels, giving miRNAs diverse roles in CCA progression. Additionally, current miRNA-based therapeutic approaches are in clinical trials for various liver diseases, giving hope for similar approaches for CCA. However, the interactions among these three factors in the context of CCA are unknown. In this review, we focus on recently published data (within the last 3 years) that discuss the role of CSCs, MSCs, and miRNAs and their possible interactions during CCA pathogenesis.
      PubDate: 2017-10-09T13:27:05Z
      DOI: 10.12688/f1000research.12118.1
      Issue No: Vol. 6 (2017)
  • Renal impairment in stroke patients: A comparison between the haemorrhagic
           and ischemic variants [version 2; referees: 2 approved, 1 not approved]

    • Authors: Pratyush Shrestha, Shalima Thapa, Shikher Shrestha, Subash Lohani, Suresh BK, Oscar MacCormac, Lekhjung Thapa, Upendra Prasad Devkota
      Abstract: Background: Renal impairment is regularly seen in hospitalized stroke patients, affecting the outcome of patients, as well as causing difficulties in their management. A prospective cohort study was conducted to assess the trend of renal function in hospitalized ischemic and haemorrhagic stroke patients. The incidence of renal impairment in these subgroups, the contributing factors and the need for renal replacement in renal impaired patients was evaluated. Methods: Alternate day renal function testing was performed in hospitalized stroke patients. Estimated glomerular filtration rate (e-GFR) was calculated and the trend of renal function in the two stroke subgroups (haemorrhagic and ischemic) was assessed, with renal impairment defined as e-GFR < 60mL/ minute per 1.73m2. Results: Among 52 patients, 25 had haemorrhagic stroke (mean age 59.81 ± 14.67) and 27 had ischemic stroke (mean age 56.12 ± 13.08). The mean e-GFR (mL/minute per 1.732m2) at admission in the haemorrhagic stroke subgroup was 64.79 ± 25.85 compared to 86.04 ± 26.09 in the ischemic stroke subgroup (p=0.005). Sixteen out of 25 (64%) patients in the haemorrhagic stroke subgroup and 9 out of 27 (33.3%) patients in the ischemic subgroup developed renal impairment (p=0.027). The location of the bleed (p=0.8), volume of hematoma (p=0.966) and surgical intervention (p=0.4) did not predispose the patients to renal impairment. One out of 16 patients with haemorrhagic stroke (who eventually died), and 2 out of 9 patients with ischemic stroke required renal replacement. Conclusion: Renal impairment is commonly seen in stroke patients, more so in patients who suffered haemorrhagic strokes.  The impairment, however, is transient and rarely requires renal replacement therapy.
      PubDate: 2017-10-06T15:23:03Z
      DOI: 10.12688/f1000research.12117.2
      Issue No: Vol. 6 (2017)
  • Effects of phospho- and calciotropic hormones on electrolyte transport in
           the proximal tubule [version 1; referees: 2 approved]

    • Authors: Justin J. Lee, Allein Plain, Megan R. Beggs, Henrik Dimke, R. Todd Alexander
      Abstract: Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D3, and fibroblast growth factor 23 (FGF23). The organs central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.
      PubDate: 2017-10-03T14:47:08Z
      DOI: 10.12688/f1000research.12097.1
      Issue No: Vol. 6 (2017)
  • Recent advances in rhythm control for atrial fibrillation [version 1;
           referees: 2 approved]

    • Authors: Richard Bond, Brian Olshansky, Paulus Kirchhof
      Abstract: Atrial fibrillation (AF) remains a difficult management problem. The restoration and maintenance of sinus rhythm—rhythm control therapy—can markedly improve symptoms and haemodynamics for patients who have paroxysmal or persistent AF, but some patients fare well with rate control alone. Sinus rhythm can be achieved with anti-arrhythmic drugs or electrical cardioversion, but the maintenance of sinus rhythm without recurrence is more challenging. Catheter ablation of the AF triggers is more effective than anti-arrhythmic drugs at maintaining sinus rhythm. Whilst pulmonary vein isolation is an effective strategy, other ablation targets are being evaluated to improve sinus rhythm maintenance, especially in patients with chronic forms of AF. Previously extensive ablation strategies have been used for patients with persistent AF, but a recent trial has shown that pulmonary vein isolation without additional ablation lesions is associated with outcomes similar to those of more extensive ablation. This has led to an increase in catheter-based technology to achieve durable pulmonary vein isolation. Furthermore, a combination of anti-arrhythmic drugs and catheter ablation seems useful to improve the effectiveness of rhythm control therapy. Two large ongoing trials evaluate whether a modern rhythm control therapy can improve prognosis in patients with AF.
      PubDate: 2017-10-03T14:39:46Z
      DOI: 10.12688/f1000research.11061.1
      Issue No: Vol. 6 (2017)
  • MicroRNAs in the development and neoplasia of the mammary gland [version
           2; referees: 1 approved, 2 approved with reservations]

    • Authors: Manoj Kumar Jena
      Abstract: Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes. Oncogenic miRs like miR-21, miR-221, and miR-210 are overexpressed in triple negative breast cancer cases which can be diagnostic biomarker for this subtype of cancer.  This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us to understand the molecular details of mammary gland biology, as well as miRs that could be therapeutic targets of breast cancer.
      PubDate: 2017-10-03T11:42:37Z
      DOI: 10.12688/f1000research.12005.2
      Issue No: Vol. 6 (2017)
  • Acute Coronary Syndromes in the Elderly [version 1; referees: 3 approved]

    • Authors: Niels Engberding, Nanette K. Wenger
      Abstract: The clinical evidence for treatment of acute coronary syndrome (ACS) in the elderly is less robust than in patients younger than 75 years. The elderly have the highest incidence of cardiovascular disease and frequently present with ACS. This number can be expected to increase over time because society is aging. Older adults often sustain unfavorable outcomes from ACS because of atypical presentation and delay in recognition. In addition, elderly patients commonly do not receive optimal guideline-directed ACS treatment. Owing to their high baseline risk of ischemic complications, the elderly also fare worse even with optimal ACS treatment as they frequently have more complex coronary disease, more comorbidities, less cardiovascular reserve, and a higher risk of treatment complications. They are also subjected to a broader range of pharmacologic treatment. Treatment complications can be mitigated to some extent by meticulous dose adjustment of antithrombotic and adjunctive therapies. While careful transitions of care and appropriate utilization of post-discharge secondary preventive measures are important in ACS patients of all ages, the elderly are more vulnerable to system errors and thus deserve special attention from the clinician.
      PubDate: 2017-10-02T15:29:39Z
      DOI: 10.12688/f1000research.11064.1
      Issue No: Vol. 6 (2017)
  • A GAP that Divides [version 1; referees: 3 approved]

    • Authors: Angika Basant, Michael Glotzer
      Abstract: Cytokinesis in metazoan cells is mediated by an actomyosin-based contractile ring that assembles in response to activation of the small GTPase RhoA. The guanine nucleotide exchange factor that activates RhoA during cytokinesis, ECT-2, is highly regulated. In most metazoan cells, with the notable exception of the early Caenorhabditis elegans embryo, RhoA activation and furrow ingression require the centralspindlin complex. This exception is due to the existence of a parallel pathway for RhoA activation in C. elegans. Centralspindlin contains CYK-4 which contains a predicted Rho family GTPase-activating protein (GAP) domain. The function of this domain has been the subject of considerable debate. Some publications suggest that the GAP domain promotes RhoA activation (for example, Zhang and Glotzer, 2015; Loria, Longhini and Glotzer, 2012), whereas others suggest that it functions to inactivate the GTPase Rac1 (for example, Zhuravlev et al., 2017). Here, we review the mechanisms underlying RhoA activation during cytokinesis, primarily focusing on data in C. elegans. We highlight the importance of considering the parallel pathway for RhoA activation and detailed analyses of cyk-4 mutant phenotypes when evaluating the role of the GAP domain of CYK-4.
      PubDate: 2017-10-02T10:43:09Z
      DOI: 10.12688/f1000research.12064.1
      Issue No: Vol. 6 (2017)
  • Recent Advances in Understanding Werner Syndrome [version 1; referees: 3

    • Authors: Raghavendra A. Shamanna, Deborah L. Croteau, Jong-Hyuk Lee, Vilhelm A. Bohr
      Abstract: Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.
      PubDate: 2017-09-28T13:38:14Z
      Issue No: Vol. 6 (2017)
  • The management of functional dyspepsia in clinical practice: what lessons
           can be learnt from recent literature' [version 1; referees: 2

    • Authors: Maura Corsetti, Mark Fox
      Abstract: Functional dyspepsia is a prevalent functional gastrointestinal disorder that can significantly erode the quality of life of sufferers and places a major cost burden on healthcare services. In this article, we review the recent literature, selecting the information we consider relevant since it has changed our clinical management of patients with functional dyspepsia.
      PubDate: 2017-09-28T13:23:20Z
      DOI: 10.12688/f1000research.12089.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding autoimmune thyroid disease: the tallest
           tree in the forest of polyautoimmunity [version 1; referees: 2 approved]

    • Authors: Sofie Bliddal, Claus Henrik Nielsen, Ulla Feldt-Rasmussen
      Abstract: Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has led to the hypothesis that the affected patients suffer from a generalized dysregulation of their immune system. The present review summarizes recent discoveries unravelling the immunological mechanisms involved in autoimmunity, ranging from natural autoimmunity to disease-specific autoimmunity. Furthermore, the clinical grounds for considering AITD in a setting of polyautoimmunity are explored. A better understanding of these may pave the way for designing new treatment modalities targeting the underlying immune dysregulation when AITD appears in the context of polyautoimmunity.
      PubDate: 2017-09-28T12:50:28Z
      DOI: 10.12688/f1000research.11535.1
      Issue No: Vol. 6 (2017)
  • Recent advances in eosinophilic esophagitis [version 1; referees: 3

    • Authors: Sandy Durrani, Marc Rothenberg
      Abstract: Eosinophilic esophagitis is a chronic, antigen-driven, eosinophil-predominant inflammatory disease of the esophagus and affects both children and adults. Cutting-edge technologies, such as genome-wide association studies, have advanced our understanding of the disease pathogenesis at a remarkable rate. Recent insights from genetic and mechanistic studies have concluded that a complex interplay between genetic and environmental risk factors, allergic sensitization, and esophageal-specific pathways leads to disease pathogenesis. Importantly, recent epidemiologic studies have found that the incidence and prevalence of eosinophilic esophagitis continue to rise. New guidelines have advocated the elimination of the term proton pump inhibitor (PPI)–responsive esophageal eosinophilia and have recommended using PPIs as a first-line treatment modality. Systemic reviews and meta-analyses confirm the efficacy of PPIs, topical corticosteroids, and empiric food elimination diets. Unmet needs include the development of birth cohort studies, validated diagnostic scoring systems, minimally invasive disease-monitoring methods, and the development of new therapies.
      PubDate: 2017-09-28T10:26:03Z
      DOI: 10.12688/f1000research.11798.1
      Issue No: Vol. 6 (2017)
  • Predator and prey functional traits: understanding the adaptive machinery
           driving predator–prey interactions [version 1; referees: 2 approved]

    • Authors: Oswald Schmitz
      Abstract: Predator–prey relationships are a central component of community dynamics. Classic approaches have tried to understand and predict these relationships in terms of consumptive interactions between predator and prey species, but characterizing the interaction this way is insufficient to predict the complexity and context dependency inherent in predator–prey relationships. Recent approaches have begun to explore predator–prey relationships in terms of an evolutionary-ecological game in which predator and prey adapt to each other through reciprocal interactions involving context-dependent expression of functional traits that influence their biomechanics. Functional traits are defined as any morphological, behavioral, or physiological trait of an organism associated with a biotic interaction. Such traits include predator and prey body size, predator and prey personality, predator hunting mode, prey mobility, prey anti-predator behavior, and prey physiological stress. Here, I discuss recent advances in this functional trait approach. Evidence shows that the nature and strength of many interactions are dependent upon the relative magnitude of predator and prey functional traits. Moreover, trait responses can be triggered by non-consumptive predator–prey interactions elicited by responses of prey to risk of predation. These interactions in turn can have dynamic feedbacks that can change the context of the predator–prey interaction, causing predator and prey to adapt their traits—through phenotypically plastic or rapid evolutionary responses—and the nature of their interaction. Research shows that examining predator–prey interactions through the lens of an adaptive evolutionary-ecological game offers a foundation to explain variety in the nature and strength of predator–prey interactions observed in different ecological contexts.
      PubDate: 2017-09-27T14:23:25Z
      DOI: 10.12688/f1000research.11813.1
      Issue No: Vol. 6 (2017)
  • Recent advances in the management of peptic ulcer bleeding [version 1;
           referees: 2 approved]

    • Authors: Ian Beales
      Abstract: Acute upper gastrointestinal haemorrhage due to peptic ulcer bleeding remains an important cause of emergency presentation and hospital admission. Despite advances in many aspects of management, peptic ulcer bleeding is still associated with significant morbidity, mortality, and healthcare costs. Comprehensive international guidelines have been published, but advances as well as controversies continue to evolve. Important recent advances include the evidence supporting a more restrictive transfusion strategy aiming for a target haemoglobin of 70–90 g/l. Comparative studies have confirmed that the Glasgow–Blatchford score remains the most useful score for predicting the need for intervention as well as for identifying the lowest-risk patients suitable for outpatient management. New scores, including the AIMS65 and Progetto Nazionale Emorragia Digestiva score, may be more accurate in predicting mortality. Pre-endoscopy erythromycin appears to improve outcomes and is probably underused. High-dose oral proton pump inhibition (PPI) for 11 days after PPI infusion is advantageous in those with a Rockall score of 6 or more. Oral is as effective as parenteral iron at restoring haemoglobin levels after a peptic ulcer bleed and both are superior to placebo in this respect. Within endoscopic techniques, haemostatic powders and over-the-scope clips can be used when other methods have failed. A disposable Doppler probe appears to provide more accurate determination of both rebleeding risk and the success of endoscopic therapy than purely visual guidance. Non-Helicobacter pylori, non-aspirin/non-steroidal anti-inflammatory drug ulcers contribute an increasing percentage of bleeding peptic ulcers and are associated with a poor prognosis and high rebleeding rate. The optimal management of these ulcers remains to be determined.
      PubDate: 2017-09-27T12:15:45Z
      DOI: 10.12688/f1000research.11286.1
      Issue No: Vol. 6 (2017)
  • Bacterial vaginosis [version 1; referees: 2 approved]

    • Authors: Phillip Hay
      Abstract: Bacterial vaginosis is the most prevalent cause of abnormal vaginal discharge in women of childbearing age. It can have a major impact on quality of life and psychological wellbeing if frequently recurrent and strongly symptomatic. The use of molecular techniques to study the vaginal microbiome is increasing our understanding of the dynamic changes in flora that occur in health and disease. It might soon be possible to separate Gardnerella into different pathogenic and non-pathogenic species. Many groups are studying compounds that can disrupt the biofilm which is dominated by Gardnerella and Atopobium vaginae. Several studies in the last decade support the concept of bacterial vaginosis as a sexually transmitted infection.
      PubDate: 2017-09-27T10:53:04Z
      DOI: 10.12688/f1000research.11417.1
      Issue No: Vol. 6 (2017)
  • Recent advances in the understanding and management of Klebsiella
           pneumoniae [version 1; referees: 2 approved]

    • Authors: David P. Calfee
      Abstract: Klebsiella pneumoniae, a gram-negative bacillus of the Enterobacteriaceae family, is a component of the normal human microbiota and a common cause of community- and healthcare-associated infections. The increasing prevalence of antimicrobial resistance among K. pneumoniae isolates, particularly among those causing healthcare-associated infections, is an important public health concern. Infections caused by these multidrug-resistant organisms, for which safe and effective antimicrobial therapy options are extremely limited, are associated with poor outcomes for patients. The optimal approach to the treatment of infections caused by these multidrug-resistant strains remains undefined, and treatment decisions for an individual patient should be based on a number of organism- (for example, minimum inhibitory concentration) and patient-specific (for example, site of infection) factors. The emergence of pandrug-resistant strains of K. pneumoniae highlights the critical need for consistent implementation of effective strategies for prevention of transmission and infection and for the development of new antimicrobials with activity against these emerging pathogens.
      PubDate: 2017-09-27T10:27:56Z
      DOI: 10.12688/f1000research.11532.1
      Issue No: Vol. 6 (2017)
  • Meta-fibrosis links positive energy balance and mitochondrial metabolism
           to insulin resistance [version 1; referees: 3 approved]

    • Authors: Daniel S. Lark, David H. Wasserman
      Abstract: Obesity and insulin resistance often emerge from positive energy balance and generally are linked to low-grade inflammation. This low-grade inflammation has been called “meta-inflammation” because it is a consequence of the metabolic dysregulation that can accompany overnutrition. One means by which meta-inflammation is linked to insulin resistance is extracellular matrix expansion secondary to meta-inflammation, which we define here as “meta-fibrosis”. The significance of meta-fibrosis is that it reflects a situation in which the extracellular matrix functions as a multi-level integrator of local (for example, mitochondrial reactive oxygen species production) and systemic (for example, inflammation) inputs that couple to cellular processes creating insulin resistance. While adipose tissue extracellular matrix remodeling has received considerable attention, it is becoming increasingly apparent that liver and skeletal muscle extracellular matrix remodeling also contributes to insulin resistance. In this review, we address recent advances in our understanding of energy balance, mitochondrial energetics, meta-inflammation, and meta-fibrosis in the development of insulin resistance.
      PubDate: 2017-09-27T09:48:55Z
      DOI: 10.12688/f1000research.11653.1
      Issue No: Vol. 6 (2017)
  • More than meets the IR: the expanding roles of variant Ionotropic
           Glutamate Receptors in sensing odor, taste, temperature and moisture
           [version 1; referees: 2 approved]

    • Authors: Lena van Giesen, Paul A. Garrity
      Abstract: The ionotropic receptors (IRs) are a branch of the ionotropic glutamate receptor family and serve as important mediators of sensory transduction in invertebrates. Recent work shows that, though initially studied as olfactory receptors, the IRs also mediate the detection of taste, temperature, and humidity. Here, we summarize recent insights into IR evolution and its potential ecological significance as well as recent advances in our understanding of how IRs contribute to diverse sensory modalities.
      PubDate: 2017-09-26T15:15:01Z
      DOI: 10.12688/f1000research.12013.1
      Issue No: Vol. 6 (2017)
  • Giving eyespots a shiner: Pharmacologic manipulation of the Io moth wing
           pattern [version 2; referees: 2 approved]

    • Authors: Andrei Sourakov
      Abstract: Our knowledge of wing pattern formation in Lepidoptera has advanced significantly in recent years due to the careful examination of several groups of butterflies. The eyespot is a prominent feature of Lepidoptera wing pattern, especially in the family Saturniidae. The present study examined how sulfated polysaccharides affected the wing pattern formation of the Io moth, Automeris io (Saturniidae).  Prepupae and pupae of this species were subjected to injections of heparin and cold shock. While the cold shock had little to no effect on wing pattern, the aberrations resulting from heparin injections were moderate to profound and depended on the dose and the stage at which injection was made. The changes consisted of expansion of the black ring around the dorsal hindwing eyespots and distortion of discal spots on both dorsal and ventral sides of forewings, suggesting a possible link between genetic controls of these elements. Several different types of scales form the normal color pattern of Automeris io, and heparin-induced changes correspond to changes in shape of scales. The resulting aberrations are dubbed ‘Black Eye’ and ‘Comet Eye.’ Other known aberrations of Automeris io eyespots are summarized, illustrated, and named.
      PubDate: 2017-09-26T08:40:21Z
      DOI: 10.12688/f1000research.12258.2
      Issue No: Vol. 6 (2017)
  • Emerging dilemmas in the diagnosis and management of gastroesophageal
           reflux disease [version 1; referees: 2 approved]

    • Authors: Peter Kahrilas, Rena Yadlapati, Sabine Roman
      Abstract: Gastroesophageal reflux disease (GERD) is common, but less so than widely reported because of inconsistencies in definition. In clinical practice, the diagnosis is usually based on a symptom assessment without testing, and the extent of diagnostic testing pursued should be limited to that which guides management or which protects the patient from the risks of a potentially morbid treatment or an undetected early (or imminent) esophageal adenocarcinoma or which does both. When testing is pursued, upper gastrointestinal endoscopy is the most useful initial diagnostic test because it evaluates for the major potential morbidities (Barrett’s, stricture, and cancer) associated with GERD and facilitates the identification of some alternative diagnostic possibilities such as eosinophilic esophagitis. However, endoscopy is insensitive for diagnosing GERD because most patients with GERD have non-erosive reflux disease, a persistent diagnostic dilemma. Although many studies have tried to objectify the diagnosis of GERD with improved technology, this is ultimately a pragmatic diagnosis based on response to proton pump inhibitor (PPI) therapy, and, in the end, response to PPI therapy becomes the major indication for continued PPI therapy. Conversely, in the absence of objective criteria for GERD and the absence of apparent clinical benefit, PPI therapy is not indicated and should be discontinued. PPIs are well tolerated and safe, but nothing is perfectly safe, and in the absence of measurable benefit, even a miniscule risk dominates the risk-benefit assessment.
      PubDate: 2017-09-25T14:39:52Z
      DOI: 10.12688/f1000research.11918.1
      Issue No: Vol. 6 (2017)
  • Recent advances in managing chronic prostatitis/chronic pelvic pain
           syndrome [version 1; referees: 2 approved]

    • Authors: Jaspreet Sandhu, Hin Yu Vincent TU
      Abstract: Chronic prostatitis/chronic pelvic pain syndrome is a common disorder seen in men under the age of 50 and has a considerable negative impact on quality of life; it is a complex and difficult condition to treat, owing to its wide symptomatology. In order to effectively treat this condition, the UPOINT system was developed: it allows clinical profiling of a patient’s symptoms into six broad categories (urinary symptoms, psychological dysfunction, organ-specific symptoms, infectious causes, neurologic dysfunction, and tenderness of the pelvic floor muscles) to allow individualized and multimodal therapy. In this review, we present the most recent advancements in the treatment of chronic prostatitis/chronic pelvic pain syndrome from the past few years.
      PubDate: 2017-09-25T13:28:26Z
      DOI: 10.12688/f1000research.10558.1
      Issue No: Vol. 6 (2017)
  • Spironolactone in cardiovascular disease: an expanding universe'
           [version 1; referees: 2 approved]

    • Authors: John W. Funder
      Abstract: Spironolactone has been marketed for over half a century as a ‘potassium-sparing diuretic’, used primarily in patients with ascites. With the realization that primary aldosteronism is the most common (5-13%) form of secondary hypertension, it has become widely used as a mineralocorticoid receptor antagonist. More recently, in the wake of the RALES trial, spironolactone in addition to standard therapy has been shown to be very beneficial in heart failure with a reduced ejection fraction. Despite the failure of the TOPCAT trial, spironolactone is being increasingly used in diastolic heart failure (i.e. with a preserved ejection fraction). The third currently accepted role for spironolactone is in hypertension resistant to three conventional antihypertensives including a diuretic, where it has been proven to be effective, in contra-distinction to renal artery denervation. Finally, brief consideration will be given to ‘areas in waiting’ – pulmonary hypertension/fibrosis, cancer – where spironolactone may play very useful roles.
      PubDate: 2017-09-22T15:41:14Z
      DOI: 10.12688/f1000research.11887.1
      Issue No: Vol. 6 (2017)
  • How do you recognize and reconstitute a synaptic vesicle after fusion'
           [version 1; referees: 3 approved]

    • Authors: Natali L. Chanaday, Ege T. Kavalali
      Abstract: Synaptic vesicle recycling is essential for sustained and reliable neurotransmission. A key component of synaptic vesicle recycling is the synaptic vesicle biogenesis process that is observed in synapses and that maintains the molecular identity of synaptic vesicles. However, the mechanisms by which synaptic vesicles are retrieved and reconstituted after fusion remain unclear. The complex molecular composition of synaptic vesicles renders their rapid biogenesis a daunting task. Therefore, in this context, kiss-and-run type transient fusion of synaptic vesicles with the plasma membrane without loss of their membrane composition and molecular identity remains a viable hypothesis that can account for the fidelity of the synaptic vesicle cycle. In this article, we discuss the biological implications of this problem as well as its possible molecular solutions.
      PubDate: 2017-09-22T14:53:50Z
      DOI: 10.12688/f1000research.12072.1
      Issue No: Vol. 6 (2017)
  • AMP-activated protein kinase – not just an energy sensor [version 1;
           referees: 3 approved]

    • Authors: David Grahame Hardie, Sheng-Cai Lin
      Abstract: Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy. In this article, we discuss a few interesting recent developments in the AMPK field. Firstly, we review recent findings on the canonical pathway by which AMPK is regulated by adenine nucleotides. Secondly, AMPK is now known to be activated in mammalian cells by glucose starvation by a mechanism that occurs in the absence of changes in adenine nucleotides, involving the formation of complexes with Axin and LKB1 on the surface of the lysosome. Thirdly, in addition to containing the nucleotide-binding sites on the γ subunits, AMPK heterotrimers contain a site for binding of allosteric activators termed the allosteric drug and metabolite (ADaM) site. A large number of synthetic activators, some of which show promise as hypoglycaemic agents in pre-clinical studies, have now been shown to bind there. Fourthly, some kinase inhibitors paradoxically activate AMPK, including one (SU6656) that binds in the catalytic site. Finally, although downstream targets originally identified for AMPK were mainly concerned with metabolism, recently identified targets have roles in such diverse areas as mitochondrial fission, integrity of epithelial cell layers, and angiogenesis.
      PubDate: 2017-09-22T10:11:39Z
      DOI: 10.12688/f1000research.11960.1
      Issue No: Vol. 6 (2017)
  • Protein unfolding mechanisms and their effects on folding experiments
           [version 1; referees: 2 approved]

    • Authors: Lisa J Lapidus
      Abstract: In this review, I discuss the various methods researchers use to unfold proteins in the lab in order to understand protein folding both in vitro and in vivo. The four main techniques, chemical-, heat-, pressure- and force-denaturation, produce distinctly different unfolded conformational ensembles. Recent measurements have revealed different folding kinetics from different unfolding mechanisms. Thus, comparing these distinct unfolded ensembles sheds light on the underlying free energy landscape of folding.
      PubDate: 2017-09-22T10:03:55Z
      DOI: 10.12688/f1000research.12070.1
      Issue No: Vol. 6 (2017)
  • Ketamine for pain [version 1; referees: 2 approved]

    • Authors: Kelly Jonkman, Albert Dahan, Tine van de Donk, Leon Aarts, Marieke Niesters, Monique van Velzen
      Abstract: The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.
      PubDate: 2017-09-20T09:13:41Z
      DOI: 10.12688/f1000research.11372.1
      Issue No: Vol. 6 (2017)
  • Professional medical writing support and the reporting quality of
           randomized controlled trial abstracts among high-impact general medical
           journals [version 2; referees: 2 approved]

    • Authors: Ira Mills, Catherine Sheard, Meredith Hays, Kevin Douglas, Christopher C. Winchester, William T. Gattrell
      Abstract: Background: In articles reporting randomized controlled trials, professional medical writing support is associated with increased adherence to Consolidated Standards of Reporting Trials (CONSORT). We set out to determine whether professional medical writing support was also associated with improved adherence to CONSORT for Abstracts. Methods: Using data from a previously published cross-sectional study of 463 articles reporting randomized controlled trials published between 2011 and 2014 in five top medical journals, we determined the association between professional medical writing support and CONSORT for Abstracts items using a Wilcoxon rank-sum test. Results: The mean proportion of adherence to CONSORT for Abstracts items reported was similar with and without professional medical writing support (64.3% vs 66.5%, respectively; p=0.30). Professional medical writing support was associated with lower adherence to reporting study setting (relative risk [RR]; 0.40; 95% confidence interval [CI], 0.23–0.70), and higher adherence to disclosing harms/side effects (RR 2.04; 95% CI, 1.37–3.03) and funding source (RR 1.75; 95% CI, 1.18–2.60). Conclusions: Although professional medical writing support was not associated with increased overall adherence to CONSORT for Abstracts, important aspects were improved with professional medical writing support, including reporting of adverse events and funding source. This study identifies areas to consider for improvement.
      PubDate: 2017-09-14T13:40:11Z
      DOI: 10.12688/f1000research.12268.2
      Issue No: Vol. 6 (2017)
  • Transcriptomic analysis of Saccharomyces cerevisiae x Saccharomyces
           kudriavzevii hybrids during low temperature winemaking [version 3;
           referees: 2 approved]

    • Authors: Jordi Tronchoni, Estéfani García-Ríos, Jose Manuel Guillamón, Amparo Querol, Roberto Pérez-Torrado
      Abstract: Background: Although Saccharomyces cerevisiae is the most frequently isolated species in wine fermentation, and the most studied species, other species and interspecific hybrids have greatly attracted the interest of researchers in this field in the last few years, given their potential to solve new winemaking industry challenges. S. cerevisiae x S. kudriavzevii hybrids exhibit good fermentative capabilities at low temperatures, and produce wines with smaller alcohol quantities and larger glycerol quantities, which can be very useful to solve challenges in the winemaking industry such as the necessity to enhance the aroma profile. Methods: In this study, we performed a transcriptomic study of S. cerevisiae x S. kudriavzevii hybrids in low temperature winemaking conditions. Results: The results revealed that the hybrids have acquired both fermentative abilities and cold adaptation abilities, attributed to S. cerevisiae and S. kudriavzevii parental species, respectively, showcasing their industrially relevant characteristics. For several key genes, we also studied the contribution to gene expression of each of the alleles of S. cerevisiae and S. kudriavzevii in the S. cerevisiae x S. kudriavzevii hybrids. From the results, it is not clear how important the differential expression of the specific parental alleles is to the phenotype of the hybrids. Conclusions: This study shows that the fermentative abilities of S. cerevisiae x S. kudriavzevii hybrids at low temperatures do not seem to result from differential expression of specific parental alleles of the key genes involved in this phenotype.
      PubDate: 2017-09-12T14:44:18Z
      DOI: 10.12688/f1000research.11550.3
      Issue No: Vol. 6 (2017)
  • Saccharomyces cerevisiae show low levels of traversal across human
           endothelial barrier in vitro [version 2; referees: 2 approved]

    • Authors: Roberto Pérez-Torrado, Amparo Querol
      Abstract: Background:  Saccharomyces cerevisiae is generally considered safe, and is involved in the production of many types of foods and dietary supplements. However, some isolates, which are genetically related to strains used in brewing and baking, have shown virulent traits, being able to produce infections in humans, mainly in immunodeficient patients. This can lead to systemic infections in humans. Methods: In this work, we studied S. cerevisiae isolates in an in vitro human endothelial barrier model, comparing their behaviour with that of several strains of the related pathogens Candida glabrata and Candida albicans. Results: The results showed that this food related yeast is able to cross the endothelial barrier in vitro. However, in contrast to C. glabrata and C. albicans, S. cerevisiae showed very low levels of traversal. Conclusions: We conclude that using an in vitro human endothelial barrier model with S. cerevisiae can be useful to evaluate the safety of S. cerevisiae strains isolated from foods.
      PubDate: 2017-09-12T14:42:15Z
      DOI: 10.12688/f1000research.11782.2
      Issue No: Vol. 6 (2017)
  • Single-incision laparoscopic surgery in gynecologic surgery: a
           single-institutional experience from Saudi Arabia [version 1; referees: 2

    • Authors: Kareemah Salamah, Mohammed Abuzaid, Ahmed Abu-Zaid
      Abstract: Background: Laparoscopy is rapidly replacing laparotomy in the field of gynecologic surgery. Generally, there are limited data concerning the utility of single-incision laparoscopic surgery (SILS) in gynecologic surgery. Specifically, in Saudi Arabia, a third-world country, data are further limited; only one related study has been conducted so far. The purpose of this study is to retrospectively report our single-institutional experience of SILS in terms of feasibility, safety and perioperative outcomes in the management of various gynecologic conditions. Methods: The study took place at the Women’s Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. From January 2012 to May 2016, all gynecologic patients who underwent SILS procedures were analyzed for pre-, intra- and post-operative details. SILS was performed using a single multi-port trocar and standard laparoscopic instruments. Results: A total of 54 patients underwent 66 SILS procedures. The median age and body mass index (BMI) were 36 years and 28.2 kg/m2, respectively. Fourteen patients (26%) had ≥ 1 previous abdominal and/or pelvic surgeries. Twenty-four patients (44.4%) were nulliparous. The three most commonly performed SILS procedures were unilateral salpingo-oophorectomy (45.5%) and unilateral ovarian cystectomy (27.3%) and adhesiolysis (6.1%). The median operative time, estimated blood loss and hospital stay were 74 min, 50 ml and 1 day, respectively. Three patients required conversion to laparotomy, as follows: unidentified non-stopping bleeding source (n=1) and endometriosis stage IV resulting in difficult dissection (n=2). One patient developed post-operative incisional hernia that was treated surgically. The median patients’ post-operative pain (according to Wong-Baker FACES Foundation pain rating scale) within 4 hours was 2. At 4-week post-operatively, the median wound scar length (measured at outpatient clinic) was 2 cm. Conclusions: SILS is feasible, safe and associated with acceptable clinical and surgical outcomes.
      PubDate: 2017-09-07T14:04:30Z
      DOI: 10.12688/f1000research.12545.1
      Issue No: Vol. 6 (2017)
  • The future of metabolomics in ELIXIR [version 1; referees: 2 approved, 1
           approved with reservations]

    • Authors: Merlijn van Rijswijk, Charlie Beirnaert, Christophe Caron, Marta Cascante, Victoria Dominguez, Warwick B. Dunn, Timothy M. D. Ebbels, Franck Giacomoni, Alejandra Gonzalez-Beltran, Thomas Hankemeier, Kenneth Haug, Jose L. Izquierdo-Garcia, Rafael C. Jimenez, Fabien Jourdan, Namrata Kale, Maria I. Klapa, Oliver Kohlbacher, Kairi Koort, Kim Kultima, Gildas Le Corguillé, Nicholas K. Moschonas, Steffen Neumann, Claire O’Donovan, Martin Reczko, Philippe Rocca-Serra, Antonio Rosato, Reza M. Salek, Susanna-Assunta Sansone, Venkata Satagopam, Daniel Schober, Ruth Shimmo, Rachel A. Spicer, Ola Spjuth, Etienne A. Thévenot, Mark R. Viant, Ralf J. M. Weber, Egon L. Willighagen, Gianluigi Zanetti, Christoph Steinbeck
      Abstract: Metabolomics, the youngest of the major omics technologies, is supported by an active community of researchers and infrastructure developers across Europe. To coordinate and focus efforts around infrastructure building for metabolomics within Europe, a workshop on the “Future of metabolomics in ELIXIR” was organised at Frankfurt Airport in Germany. This one-day strategic workshop involved representatives of ELIXIR Nodes, members of the PhenoMeNal consortium developing an e-infrastructure that supports workflow-based metabolomics analysis pipelines, and experts from the international metabolomics community. The workshop established metabolite identification as the critical area, where a maximal impact of computational metabolomics and data management on other fields could be achieved. In particular, the existing four ELIXIR Use Cases, where the metabolomics community - both industry and academia - would benefit most, and which could be exhaustively mapped onto the current five ELIXIR Platforms were discussed. This opinion article is a call for support for a new ELIXIR metabolomics Use Case, which aligns with and complements the existing and planned ELIXIR Platforms and Use Cases.
      PubDate: 2017-09-06T11:23:49Z
      DOI: 10.12688/f1000research.12342.1
      Issue No: Vol. 6 (2017)
  • A case series report of cancer patients undergoing group body
           psychotherapy [version 1; referees: 2 approved]

    • Authors: Astrid Grossert, Gunther Meinlschmidt, Rainer Schaefert
      Abstract: Background: Disturbances in bodily wellbeing represent a key source of psychosocial suffering and impairment related to cancer. Therefore, interventions to improve bodily wellbeing in post-treatment cancer patients are of paramount importance. Notably, body psychotherapy (BPT) has been shown to improve bodily wellbeing in subjects suffering from a variety of mental disorders. However, how post-treatment cancer patients perceive and subjectively react to group BPT aiming at improving bodily disturbances has, to the best of our knowledge, not yet been described. Methods: We report on six patients undergoing outpatient group BPT that followed oncological treatment for malignant neoplasms. The BPT consisted of six sessions based on a scientific embodiment approach, integrating body-oriented techniques to improve patients’ awareness, perception, acceptance, and expression regarding their body. Results: The BPT was well accepted by all patients. Despite having undergone different types of oncological treatment for different cancer types and locations, all subjects reported having appreciated BPT and improved how they perceived their bodies. However, individual descriptions of improvements showed substantial heterogeneity across subjects. Notably, most patients indicated that sensations, perceptions, and other mental activities related to their own body intensified when proceeding through the group BPT sessions. Conclusion: The findings from this case series encourage and inform future studies examining whether group BPT is efficacious in post-treatment cancer patients and investigating the related mechanisms of action. The observed heterogeneity in individual descriptions of perceived treatment effects point to the need for selecting comprehensive indicators of changes in disturbances of bodily wellbeing as the primary patient-reported outcome in future clinical trials. While increases in mental activities related to their own body are commonly interpreted as important mechanisms of therapeutic action in BPT, follow-up assessments are needed to evaluate intended and unintended consequences of these changes in cancer patients.
      PubDate: 2017-09-05T15:49:15Z
      DOI: 10.12688/f1000research.12262.1
      Issue No: Vol. 6 (2017)
  • Functional characterizations of rare UBA1 variants in X-linked Spinal
           Muscular Atrophy [version 1; referees: 2 approved]

    • Authors: Chris D. Balak, Jesse M. Hunter, Mary E. Ahearn, David Wiley, Gennaro D'urso, Lisa Baumbach-Reardon
      Abstract: Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). Methods: In this study, our group characterized the three known missense variants in vitro. Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants. Results: Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1’s enzymatic activity with Ubiquitin, to other roles such as altering UBA1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners.  These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations’ biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.
      PubDate: 2017-09-04T13:27:17Z
      DOI: 10.12688/f1000research.11878.1
      Issue No: Vol. 6 (2017)
  • Gender differences in the prevalence of nonalcoholic fatty liver disease
           in the Northeast of Thailand: A population-based cross-sectional study
           [version 1; referees: 2 approved, 1 not approved]

    • Authors: Ueamporn Summart, Bandit Thinkhamrop, Nittaya Chamadol, Narong Khuntikeo, Metha Songthamwat, Christina Sunyoung Kim
      Abstract: Background. Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. A large number of studies have strongly described larger proportions of men being afflicted with NAFLD than women; however, recent studies investigating the role of gender and NAFLD have exposed the contrary. Methods. This cross-sectional study utilized data from the baseline survey of an ongoing cohort study called the Cholangiocarcinoma Screening and Care Program (CASCAP), conducted in the northeastern region of Thailand between March 2013 and September 2015. Information regarding socio-demographic, including gender, was collected using a standardized self-administered questionnaire. NAFLD was diagnosed with ultrasonography by board-certified radiologists. A binomial regression was used for estimating the prevalence differences, odds ratios (OR) and the 95% confidence intervals (CI) of NAFLD between men and women. Results. A total of 34,709 participants (27,073 females and 7,636 males) were recruited. The prevalence of NAFLD in women was 22.9% (95% CI: 22.5 to 23.5), whereas it was only 18.3% (95% CI: 17.4 to 19.2) in men. After adjusting for age and presence of diabetes mellitus and other underlying diseases, the prevalence was significantly higher in women, with adjusted prevalence difference of 4.2% (95% CI: 3.2 to 5.2) and adjusted OR of 1.3 (95% CI: 1.2 to 1.4). Women had a higher prevalence of NAFLD than men in all age groups and the largest difference was found in those aged 56-60 years (prevalence = 27.4% versus 21.2%; adjusted prevalence difference = 9.4%; 95% CI: 7.9 to 10.9; adjusted OR = 1.8; 95% CI: 1.8 to 2.0). Conclusion. NAFLD is more likely to affect women more than men, in particular, among the population 56-60 years of age, which is the post-menopausal transitional period. Therefore, post-menopausal women should be the target for interventions or further investigation for NAFLD.
      PubDate: 2017-09-04T09:18:18Z
      DOI: 10.12688/f1000research.12417.1
      Issue No: Vol. 6 (2017)
  • Structural brain abnormalities in 12 persons with aniridia [version 2;
           referees: 2 approved]

    • Authors: Madison K. Grant, Anastasia M. Bobilev, Jordan E. Pierce, Jon DeWitte, James D. Lauderdale
      Abstract: Background: Aniridia is a disorder predominately caused by heterozygous loss-of-function mutations of the PAX6 gene, which is a transcriptional regulator necessary for normal eye and brain development.  The ocular abnormalities of aniridia have been well characterized, but mounting evidence has implicated brain-related phenotypes as a prominent feature of this disorder as well.  Investigations using neuroimaging in aniridia patients have shown reductions in discrete brain structures and changes in global grey and white matter.  However, limited sample sizes and substantive heterogeneity of structural phenotypes in the brain remain a challenge.  Methods: Here, we examined brain structure in a new population sample in an effort to add to the collective understanding of anatomical abnormalities in aniridia.  The current study used 3T magnetic resonance imaging to acquire high-resolution structural data in 12 persons with aniridia and 12 healthy demographically matched comparison subjects.  Results: We examined five major structures: the anterior commissure, the posterior commissure, the pineal gland, the corpus callosum, and the optic chiasm.  The most consistent reductions were found in the anterior commissure and the pineal gland; however, abnormalities in all of the other structures examined were present in at least one individual.  Conclusions: Our results indicate that the anatomical abnormalities in aniridia are variable and largely individual-specific.  These findings suggest that future studies investigate this heterogeneity further, and that normal population variation should be considered when evaluating structural abnormalities.
      PubDate: 2017-09-01T09:44:34Z
      DOI: 10.12688/f1000research.11063.2
      Issue No: Vol. 6 (2017)
  • recount workflow: Accessing over 70,000 human RNA-seq samples with
           Bioconductor [version 1; referees: 1 approved, 2 approved with

    • Authors: Leonardo Collado-Torres, Abhinav Nellore, Andrew E. Jaffe
      Abstract: The recount2 resource is composed of over 70,000 uniformly processed human RNA-seq samples spanning TCGA and SRA, including GTEx. The processed data can be accessed via the recount2 website and the recount Bioconductor package. This workflow explains in detail how to use the recount package and how to integrate it with other Bioconductor packages for several analyses that can be carried out with the recount2 resource. In particular, we describe how the coverage count matrices were computed in recount2 as well as different ways of obtaining public metadata, which can facilitate downstream analyses. Step-by-step directions show how to do a gene-level differential expression analysis, visualize base-level genome coverage data, and perform an analyses at multiple feature levels. This workflow thus provides further information to understand the data in recount2 and a compendium of R code to use the data.
      PubDate: 2017-08-24T15:44:21Z
      DOI: 10.12688/f1000research.12223.1
      Issue No: Vol. 6 (2017)
  • A survey of working conditions within biomedical research in the United
           Kingdom [version 3; referees: 2 approved]

    • Authors: Nick Riddiford
      Abstract: Background: Recent articles have presented a bleak view of career prospects in biomedical research in the US. Too many PhDs and postdocs are trained for too few research positions, creating a “holding-tank” of experienced senior postdocs who are unable to get a permanent position. Coupled with relatively low salaries and high levels of pressure to publish in top-tier academic journals, this has created a toxic environment that is perhaps responsible for a recently observed decline in biomedical postdocs in the US, the so-called “postdocalypse”. Methods: To address the gulf of information relating to working habits and attitudes of UK-based academic biomedical researchers, a link to an online survey was included in an article published in the Guardian newspaper. Survey data were collected between 21st March 2016 and 6th November 2016 and analysed to examine discrete profiles for three major career stages: PhD, postdoc and principal investigator. Results: Overall, the data presented here echo trends observed in the US: The 520 UK-based biomedical researchers responding to the survey reported feeling disillusioned with academic research, due to the low chance of getting a permanent position and the long hours required at the bench. Also like the US, large numbers of researchers at each distinct career stage are considering leaving biomedical research altogether. Conclusions: There are several systemic flaws in the academic scientific research machine – for example the continual overproduction of PhDs and the lack of stability in the early-mid stages of a research career - that are slowly being addressed in countries such as the US and Germany. These data suggest that similar flaws also exist in the UK, with a large proportion of respondents concerned about their future in research. To avoid lasting damage to the biomedical research agenda in the UK, addressing such concerns should be a major priority.
      PubDate: 2017-08-16T12:48:30Z
      DOI: 10.12688/f1000research.11029.3
      Issue No: Vol. 6 (2017)
  • Tourette syndrome research highlights from 2016 [version 1; referees: 2
           approved, 1 approved with reservations]

    • Authors: Kevin J. Black
      Abstract: This article presents highlights chosen from research that appeared during 2016 on Tourette syndrome and other tic disorders. Selected articles felt to represent meaningful advances in the field are briefly summarized.
      PubDate: 2017-08-11T12:59:04Z
      DOI: 10.12688/f1000research.12330.1
      Issue No: Vol. 6 (2017)
  • cophesim: a comprehensive phenotype simulator for testing novel
           association methods [version 1; referees: 2 approved]

    • Authors: Ilya Y. Zhbannikov, Konstantin G. Arbeev, Anatoliy I. Yashin
      Abstract: Simulation is important in evaluating novel methods when input data is not easily obtainable or specific assumptions are needed. We present cophesim, a software to add the phenotype to generated genotype data prepared with a genetic simulator. The output of cophesim can be used as a direct input for different genome wide association study tools. cophesim is available from
      PubDate: 2017-08-01T15:28:06Z
      DOI: 10.12688/f1000research.11968.1
      Issue No: Vol. 6 (2017)
  • CNS cell-type localization and LPS response of TLR signaling pathways
           [version 1; referees: 2 approved]

    • Authors: Gizelle M. McCarthy, Courtney R. Bridges, Yuri A. Blednov, R. Adron Harris
      Abstract: Background: Innate immune signaling in the brain has emerged as a contributor to many central nervous system (CNS) pathologies, including mood disorders, neurodegenerative disorders, neurodevelopmental disorders, and addiction. Toll-like receptors (TLRs), a key component of the innate immune response, are particularly implicated in neuroimmune dysfunction. However, most of our understanding about TLR signaling comes from the peripheral immune response, and it is becoming clear that the CNS immune response is unique. One controversial aspect of neuroimmune signaling is which CNS cell types are involved. While microglia are the CNS cell-type derived from a myeloid lineage, studies suggest that other glial cell types and even neurons express TLRs, although this idea is controversial. Furthermore, recent work suggests a discrepancy between RNA and protein expression within the CNS. Methods: To elucidate the CNS cell-type localization of TLRs and their downstream signaling molecules, we isolated microglia and astrocytes from the brain of adult mice treated with saline or the TLR4 ligand lipopolysaccharide (LPS). Glial mRNA and protein expression was compared to a cellular-admixture to determine cell-type enrichment. Results: Enrichment analysis revealed that most of the TLR pathway genes are localized in microglia and changed in microglia following immune challenge. However, expression of Tlr3 was enriched in astrocytes, where it increased in response to LPS. Furthermore, attempts to determine protein cell-type localization revealed that many antibodies are non-specific and that antibody differences are contributing to conflicting localization results. Conclusions: Together these results highlight the cell types that should be looked at when studying TLR signaling gene expression and suggest that non-antibody approaches need to be used to accurately evaluate protein expression.
      PubDate: 2017-07-19T08:32:33Z
      DOI: 10.12688/f1000research.12036.1
      Issue No: Vol. 6 (2017)
  • Sanger sequencing as a first-line approach for molecular diagnosis of
           Andersen-Tawil syndrome [version 1; referees: 2 approved]

    • Authors: Armando Totomoch-Serra, Manlio F. Marquez, David E. Cervantes-Barragán
      Abstract: In 1977, Frederick Sanger developed a new method for DNA sequencing based on the chain termination method, now known as the Sanger sequencing method (SSM).  Recently, massive parallel sequencing, better known as next-generation sequencing (NGS),  is replacing the SSM for detecting mutations in cardiovascular diseases with a genetic background. The present opinion article wants to remark that “targeted” SSM is still effective as a first-line approach for the molecular diagnosis of some specific conditions, as is the case for Andersen-Tawil syndrome (ATS). ATS is described as a rare multisystemic autosomal dominant channelopathy syndrome caused mainly by a heterozygous mutation in the KCNJ2 gene. KCJN2 has particular characteristics that make it attractive for “directed” SSM. KCNJ2 has a sequence of 17,510 base pairs (bp), and a short coding region with two exons (exon 1=166 bp and exon 2=5220 bp), half of the mutations are located in the C-terminal cytosolic domain, a mutational hotspot has been described in residue Arg218, and this gene explains the phenotype in 60% of ATS cases that fulfill all the clinical criteria of the disease. In order to increase the diagnosis of ATS we urge cardiologists to search for facial and muscular abnormalities in subjects with frequent ventricular arrhythmias (especially bigeminy) and prominent U waves on the electrocardiogram.
      PubDate: 2017-06-28T10:41:53Z
      Issue No: Vol. 6 (2017)
  • Accessibility to health services among migrant workers in the Northeast of
           Thailand [version 1; referees: 2 approved]

    • Authors: Suprawee Khongthanachayopit, Wongsa Laohasiriwong
      Abstract: Background. There is an increasing trend of trans-border migration from neighboring countries to Thailand. According to human rights laws, everyone must have access to health services, even if they are from other nationalities.  However, a small minority of health personnel in Thailand discriminate against immigrant workers, as they are from a lower financial bracket. Methods. This cross-sectional study aims to determine the prevalence of accessibility to health services and factors associated with access to health services among migrant workers who work along the Northeast border of Thailand. A total of 621 legal migrant workers were randomly selected to respond to a structured questionnaire about the satisfaction of health services, using the 5As of health services: availability; accessibility; accommodation; affordability; acceptability.  Associations between independent variables and access to health services were analysed   using multiple logistic regression analysis. Results. The results indicated that the majority of these registered migrant workers were female (63.9%) with an average age of 29± 8.61 years old, and were married (54.3%). Most of the workers worked at restaurants (80%), whereas only 20% were in agricultural sectors. Only 14% (95% CI: 11-17%) of migrant workers had access to health services. The factors that were significantly associated with accessibility to health service experienced ill health during the past one year (OR = 2.48; 95%CI; 1.54–3.97; p-value
      PubDate: 2017-06-22T13:46:22Z
      DOI: 10.12688/f1000research.11651.1
      Issue No: Vol. 6 (2017)
  • Case report: Percutaneous electrical neural field stimulation in two cases
           of sympathetically-mediated pain [version 1; referees: 1 approved, 2
           approved with reservations]

    • Authors: Lynn Fraser, Anna Woodbury
      Abstract: Background: Fibromyalgia and complex regional pain syndrome (CRPS) are both chronic pain syndromes with pathophysiologic mechanisms related to autonomic nervous system dysregulation and central sensitization.  Both syndromes are considered difficult to treat with conventional pain therapies. Case presentations: Here we describe a female veteran with fibromyalgia and a male veteran with CRPS, both of whom failed multiple pharmacologic, physical and psychological therapies for pain, but responded to percutaneous electrical neural field stimulation (PENFS) targeted at the auricular branches of the cranial nerves. Discussion: While PENFS applied to the body has been previously described for treatment of localized pain, PENFS effects on cranial nerve branches of the ear is not well-known, particularly when used for regional and full-body pain syndromes such as those described here. PENFS of the ear is a minimally-invasive, non-pharmacologic therapy that could lead to improved quality of life and decreased reliance on medication. However, further research is needed to guide clinical application, particularly in complex pain patients.
      PubDate: 2017-06-15T14:09:28Z
      DOI: 10.12688/f1000research.11494.1
      Issue No: Vol. 6 (2017)
  • Viewing RNA-seq data on the entire human genome [version 1; referees: 3

    • Authors: Eric M. Weitz, Lorena Pantano, Jingzhi Zhu, Bennett Upton, Ben Busby
      Abstract: RNA-Seq Viewer is a web application that enables users to visualize genome-wide expression data from NCBI’s Sequence Read Archive (SRA) and Gene Expression Omnibus (GEO) databases. The application prototype was created by a small team during a three-day hackathon facilitated by NCBI at Brandeis University. The backend data pipeline was developed and deployed on a shared AWS EC2 instance. Source code is available at
      PubDate: 2017-04-28T14:09:22Z
      DOI: 10.12688/f1000research.9762.1
      Issue No: Vol. 6 (2017)
  • Case Report: Whole exome sequencing identifies variation c.2308G>A p.E770K
           in RAG1 associated with B- T- NK+ severe combined immunodeficiency
           [version 2; referees: 2 approved, 1 not approved]

    • Authors: Geeta Madathil Govindaraj, Shamsudheen Karuthedath Vellarikkal, Rijith Jayarajan, Rowmika Ravi, Ankit Verma, Krishnan Chakkiyar, Machinari Puthenpurayil Jayakrishnan, Riyaz Arakkal, Revathi Raj, Rajeevan Kunnaruvath, Sridhar Sivasubbu, Vinod Scaria
      Abstract: Severe combined immunodeficiency is a large clinically heterogeneous group of disorders caused by a defect in the development of humoral or cellular immune responses. At least 13 genes are known to be involved in the pathophysiology of the disease and the mutation spectrum in SCID has been well documented. Mutations of the recombination-activating genes RAG 1 and RAG 2 are associated with a range of clinical presentations including, severe combined immunodeficiency and autoimmunity. Recently, our understanding of the molecular basis of immune dysfunction in RAG deficiency has improved tremendously with newer insights into the ultrastructure of the RAG complex. In this report, we describe the application of whole exome sequencing for arriving at a molecular diagnosis in a child suffering from B- T- NK+ severe combined immunodeficiency. Apart from making the accurate molecular diagnosis, we also add a genetic variation c.2308G>A p.E770K to the compendium of variations associated with the disease.
      PubDate: 2017-10-02T08:48:00Z
      DOI: 10.12688/f1000research.9473.2
      Issue No: Vol. 5 (2017)
  • Case Report: Application of whole exome sequencing for accurate diagnosis
           of rare syndromes of mineralocorticoid excess [version 2; referees: 2

    • Authors: Ranjit Narayanan, Shamsudheen Karuthedath Vellarikkal, Rijith Jayarajan, Ankit Verma, Vishal Dixit, Vinod Scaria, Sridhar Sivasubbu
      Abstract: Syndromes of mineralocorticoid excess (SME) are closely related clinical manifestations occurring within a specific set of diseases. Overlapping clinical manifestations of such syndromes often create a dilemma in accurate diagnosis, which is crucial for disease surveillance and management especially in rare genetic disorders. Here we demonstrate the use of whole exome sequencing (WES) for accurate diagnosis of rare SME and report that p.R337C variation in the HSD11B2 gene causes progressive apparent mineralocorticoid excess (AME) syndrome in a South Indian family of Mappila origin.
      PubDate: 2017-09-04T11:47:47Z
      DOI: 10.12688/f1000research.8779.2
      Issue No: Vol. 5 (2017)
  • Null hypothesis significance testing: a guide to commonly misunderstood
           concepts and recommendations for good practice [version 5; referees: 2
           approved, 2 not approved]

    • Authors: Cyril Pernet
      Abstract: Although thoroughly criticized, null hypothesis significance testing (NHST) remains the statistical method of choice used to provide evidence for an effect, in biological, biomedical and social sciences. In this short guide, I first summarize the concepts behind the method, distinguishing test of significance (Fisher) and test of acceptance (Newman-Pearson) and point to common interpretation errors regarding the p-value. I then present the related concepts of confidence intervals and again point to common interpretation errors. Finally, I discuss what should be reported in which context. The goal is to clarify concepts to avoid interpretation errors and propose simple reporting practices.
      PubDate: 2017-10-12T13:25:47Z
      DOI: 10.12688/f1000research.6963.5
      Issue No: Vol. 4 (2017)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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