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Journal Cover F1000Research
  [SJR: 0.219]   [H-I: 3]   [4 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • Novel insights into mitotic chromosome condensation [version 1; referees:
           2 approved]

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

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

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

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

    • Authors: Xu Zhang, Wenqian Hu
      Abstract: Mammalian development is under tight control to ensure precise gene expression. Recent studies reveal a new layer of regulation of gene expression mediated by long noncoding RNAs. These transcripts are longer than 200nt that do not have functional protein coding capacity. Interestingly, many of these long noncoding RNAs are expressed with high specificity in different types of cells, tissues, and developmental stages in mammals, suggesting that they may have functional roles in diverse biological processes. Here, we summarize recent findings of long noncoding RNAs in hematopoiesis, which is one of the best-characterized mammalian cell differentiation processes. Then we provide our own perspectives on future studies of long noncoding RNAs in this field.
      PubDate: 2016-07-20T15:37:59Z
      DOI: 10.12688/f1000research.8349.1
      Issue No: Vol. 5 (2016)
  • High quality, small molecule-activity datasets for kinase research
           [version 2; referees: 2 approved]

    • Abstract: Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR) data. Bioactivity databases such as the Kinase Knowledgebase (KKB), WOMBAT, GOSTAR, and ChEMBL provide researchers with quantitative data characterizing the activity of compounds across many biological assays. The KKB, for example, contains over 1.8M kinase structure-activity data points reported in peer-reviewed journals and patents. In the spirit of fostering methods development and validation worldwide, we have extracted and have made available from the KKB 258K structure activity data points and 76K associated unique chemical structures across eight kinase targets. These data are freely available for download within this data note.
      PubDate: 2016-07-20T15:33:39Z
      DOI: 10.12688/f1000research.8950.2
      Issue No: Vol. 5 (2016)
  • Recent advances in understanding cardiac contractility in health and
           disease [version 1; referees: 4 approved]

    • Authors: Ken T. MacLeod
      Abstract: The aim of this review is to provide the reader with a synopsis of some of the emerging ideas and experimental findings in cardiac physiology and pathophysiology that were published in 2015. To provide context for the non-specialist, a brief summary of cardiac contraction and calcium (Ca) regulation in the heart in health and disease is provided. Thereafter, some recently published articles are introduced that indicate the current thinking on (1) the Ca regulatory pathways modulated by Ca/calmodulin-dependent protein kinase II, (2) the potential influences of nitrosylation by nitric oxide or S-nitrosated proteins, (3) newly observed effects of reactive oxygen species (ROS) on contraction and Ca regulation following myocardial infarction and a possible link with changes in mitochondrial Ca, and (4) the effects of some of these signaling pathways on late Na current and pro-arrhythmic afterdepolarizations as well as the effects of transverse tubule disturbances.
      PubDate: 2016-07-20T15:19:56Z
      DOI: 10.12688/f1000research.8661.1
      Issue No: Vol. 5 (2016)
  • search.bioPreprint: a discovery tool for cutting edge, preprint biomedical
           research articles [version 2; referees: 2 approved]

    • Authors: Carrie L. Iwema, John LaDue, Angela Zack, Ansuman Chattopadhyay
      Abstract: The time it takes for a completed manuscript to be published traditionally can be extremely lengthy. Article publication delay, which occurs in part due to constraints associated with peer review, can prevent the timely dissemination of critical and actionable data associated with new information on rare diseases or developing health concerns such as Zika virus. Preprint servers are open access online repositories housing preprint research articles that enable authors (1) to make their research immediately and freely available and (2) to receive commentary and peer review prior to journal submission. There is a growing movement of preprint advocates aiming to change the current journal publication and peer review system, proposing that preprints catalyze biomedical discovery, support career advancement, and improve scientific communication. While the number of articles submitted to and hosted by preprint servers are gradually increasing, there has been no simple way to identify biomedical research published in a preprint format, as they are not typically indexed and are only discoverable by directly searching the specific preprint server websites. To address this issue, we created a search engine that quickly compiles preprints from disparate host repositories and provides a one-stop search solution. Additionally, we developed a web application that bolsters the discovery of preprints by enabling each and every word or phrase appearing on any web site to be integrated with articles from preprint servers. This tool, search.bioPreprint, is publicly available at
      PubDate: 2016-07-20T10:54:27Z
      DOI: 10.12688/f1000research.8798.2
      Issue No: Vol. 5 (2016)
  • Homing in on the hepatic scar: recent advances in cell-specific targeting
           of liver fibrosis [version 1; referees: 3 approved]

    • Authors: Ross Dobie, Neil C. Henderson
      Abstract: Despite the high prevalence of liver disease globally, there are currently no approved anti-fibrotic therapies to treat patients with liver fibrosis. A major goal in anti-fibrotic therapy is the development of drug delivery systems that allow direct targeting of the major pro-scarring cell populations within the liver (hepatic myofibroblasts) whilst not perturbing the homeostatic functions of other mesenchymal cell types present within both the liver and other organ systems. In this review we will outline some of the recent advances in our understanding of myofibroblast biology, discussing both the origin of myofibroblasts and possible myofibroblast fates during hepatic fibrosis progression and resolution. We will then discuss the various strategies currently being employed to increase the precision with which we deliver potential anti-fibrotic therapies to patients with liver fibrosis.
      PubDate: 2016-07-19T15:55:45Z
      DOI: 10.12688/f1000research.8822.1
      Issue No: Vol. 5 (2016)
  • Neurobiology of opioid dependence in creating addiction vulnerability
           [version 1; referees: 3 approved]

    • Authors: Christopher J. Evans, Catherine M. Cahill
      Abstract: Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality — the “drug-dependent” state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to the current opioid epidemic in the USA.
      PubDate: 2016-07-19T15:40:35Z
      DOI: 10.12688/f1000research.8369.1
      Issue No: Vol. 5 (2016)
  • The role of acid inhibition in Helicobacter pylori eradication [version 1;
           referees: 3 approved]

    • Authors: David R. Scott, George Sachs, Elizabeth A. Marcus
      Abstract: Infection of the stomach by the gastric pathogen Helicobacter pylori results in chronic active gastritis and leads to the development of gastric and duodenal ulcer disease and gastric adenocarcinoma. Eradication of H. pylori infection improves or resolves the associated pathology. Current treatments of H. pylori infection rely on acid suppression in combination with at least two antibiotics. The role of acid suppression in eradication therapy has been variously attributed to antibacterial activity of proton pump inhibitors directly or through inhibition of urease activity or increased stability and activity of antibiotics. Here we discuss the effect of acid suppression on enhanced replicative capacity of H. pylori to permit the bactericidal activity of growth-dependent antibiotics. The future of eradication therapy will rely on improvement of acid inhibition along with current antibiotics or the development of novel compounds targeting the organism’s ability to survive in acid.
      PubDate: 2016-07-19T15:30:15Z
      DOI: 10.12688/f1000research.8598.1
      Issue No: Vol. 5 (2016)
  • From hepatoprotection models to new therapeutic modalities for treating
           liver diseases: a personal perspective [version 2; referees: 2 approved]

    • Abstract: A variety of rodent models of hepatoprotection have been developed in which tolerance to acetaminophen-induced hepatotoxicity occurs. Autoprotection/heteroprotection is a phenomenon where prior exposure to a mildly toxic dose of toxicant confers protection against a subsequently administered higher dose of the same toxicant (as in the case of autoprotection) or to a different toxicant (referred to as heteroprotection). Multiple mechanisms regulate this adaptive response, including hepatocellular proliferation, proteostasis, enhanced expression of cytoprotective genes, and altered tissue immune response. In this review, we will discuss recent findings that highlight the complexity of these adaptive mechanisms and we also outline the usefulness of these findings to devise therapeutic and/or diagnostic tools for acetaminophen-induced liver damage in patients.
      PubDate: 2016-07-19T13:51:57Z
      DOI: 10.12688/f1000research.8609.2
      Issue No: Vol. 5 (2016)
  • Transporting mitochondria in neurons [version 1; referees: 2 approved]

    • Authors: Meredith M. Course, Xinnan Wang
      Abstract: Neurons demand vast and vacillating supplies of energy. As the key contributors of this energy, as well as primary pools of calcium and signaling molecules, mitochondria must be where the neuron needs them, when the neuron needs them. The unique architecture and length of neurons, however, make them a complex system for mitochondria to navigate. To add to this difficulty, mitochondria are synthesized mainly in the soma, but must be transported as far as the distant terminals of the neuron. Similarly, damaged mitochondria—which can cause oxidative stress to the neuron—must fuse with healthy mitochondria to repair the damage, return all the way back to the soma for disposal, or be eliminated at the terminals. Increasing evidence suggests that the improper distribution of mitochondria in neurons can lead to neurodegenerative and neuropsychiatric disorders. Here, we will discuss the machinery and regulatory systems used to properly distribute mitochondria in neurons, and how this knowledge has been leveraged to better understand neurological dysfunction.
      PubDate: 2016-07-18T14:50:01Z
      DOI: 10.12688/f1000research.7864.1
      Issue No: Vol. 5 (2016)
  • Genome-edited human stem cell-derived beta cells: a powerful tool for
           drilling down on type 2 diabetes GWAS biology [version 1; referees: 2

    • Authors: Nicola L. Beer, Anna L. Gloyn
      Abstract: Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes. Such models facilitate investigation of diabetes-associated genomic perturbations in a physiologically representative cell context and allow the role of both developmental and adult islet dysfunction in T2D pathogenesis to be investigated. Accordingly, we interrogate the role that patient-derived induced pluripotent stem cell models are playing in understanding cellular dysfunction in monogenic diabetes, and how site-specific nucleases such as the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system are helping to confirm genes crucial to human endocrine pancreas development. We also highlight the novel biology gleaned in the absence of patient lines, including an ability to model the whole phenotypic spectrum of diabetes phenotypes occurring both in utero and in adult cells, interrogating the non-coding ‘islet regulome’ for disease-causing perturbations, and understanding the role of other islet cell types in aberrant glycaemia. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type.
      PubDate: 2016-07-15T09:07:35Z
      DOI: 10.12688/f1000research.8682.1
      Issue No: Vol. 5 (2016)
  • Recent advances in phototherapy for psoriasis [version 1; referees: 2

    • Authors: Mio Nakamura, Benjamin Farahnik, Tina Bhutani
      Abstract: Phototherapy involves repeated exposure of the skin to ultraviolet light to treat various inflammatory skin conditions such as psoriasis. Recent studies have identified specific immunologic effects of phototherapy that may underlie phototherapy efficacy. Furthermore, recent advancements have been made in developing safe and effective targeted phototherapy modalities for difficult-to-treat areas such as scalp psoriasis. Targeted phototherapy in the form of the excimer laser holds potential for more aggressive, effective treatment and long-lasting remission of psoriasis. Phototherapy is now also used successfully with biologic agents as combination therapy to treat recalcitrant psoriasis. Therefore, though one of the oldest therapeutic modalities for psoriasis, phototherapy remains a mainstay treatment with promise for further advancement.
      PubDate: 2016-07-13T11:08:34Z
      DOI: 10.12688/f1000research.8846.1
      Issue No: Vol. 5 (2016)
  • Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1
           antibodies [version 2; referees: 2 approved]

    • Authors: Binh Phong, Lawrence P. Kane
      Abstract: Polymorphisms in the T cell (or transmembrane) immunoglobulin and mucin domain 1 (TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.
      PubDate: 2016-07-08T10:46:14Z
      DOI: 10.12688/f1000research.8132.2
      Issue No: Vol. 5 (2016)
  • Adolescent Klinefelter syndrome: is there an advantage to testis tissue
           harvesting or not' [version 1; referees: 3 approved]

    • Authors: Robert Oates
      Abstract: It is currently unclear whether an adolescent with 47,XXY Klinefelter syndrome will be better off having testicular sperm extraction (TESE) performed in an effort to ‘preserve fertility’ for the future or, alternatively, should be advised to simply wait until adulthood when he and his partner are ready to begin a family. This report will provide data suggesting that there is no obvious ‘preservation’ benefit and that recommending TESE to the 47,XXY boy and his parents may not be as helpful as it might appear and may be overly aggressive.
      PubDate: 2016-07-06T14:57:21Z
      DOI: 10.12688/f1000research.8395.1
      Issue No: Vol. 5 (2016)
  • Emerging concepts for PI3K/mTOR inhibition as a potential treatment for
           osteosarcoma [version 1; referees: 2 approved]

    • Authors: Michael W. Bishop, Katherine A. Janeway
      Abstract: Patients with metastatic and recurrent osteosarcoma fare poorly, and new therapeutic strategies are needed to improve survival. Several recent complementary genomic and pathway analyses of both murine and human osteosarcoma have revealed common aberrations of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway in osteosarcoma. Preclinical data demonstrate that inhibition of PI3K and mTOR with either a combination of single agents or dual inhibiting compounds can decrease cell proliferation and induce cell cycle arrest and apoptosis. With a lack of available clinical agents active in osteosarcoma, PI3K/mTOR inhibition represents a potential vulnerability in osteosarcoma that warrants clinical investigation.
      PubDate: 2016-07-06T11:01:07Z
      DOI: 10.12688/f1000research.8228.1
      Issue No: Vol. 5 (2016)
  • Hospital and patient influencing factors of treatment schemes given to
           type 2 diabetes mellitus inpatients in Inner Mongolia, China [version 1;
           referees: 2 approved]

    • Authors: Nan Zhang, Edward McNeil, Sawitri Assanangkornchai, Yancun Fan
      Abstract: Background: In clinical practice, the physician’s treatment decision making is influenced by many factors besides the patient’s clinical conditions and is the fundamental cause of healthcare inequity and discrimination in healthcare settings. Type 2 diabetes mellitus (T2DM) is a chronic disease with high prevalence, long average length of stay and high hospitalization rate. Although the treatment of T2DM is well guideline driven, there is a large body of evidence showing the existence of treatment disparities. More empirical studies from the provider side are needed to determine if non-clinical factors influence physician’s treatment choices.   Objective: To determine the hospital and patient influencing factors of treatment schemes given to T2DM inpatients in Inner Mongolia, China.   Methods: A cross-sectional, hospital-based survey using a cluster sampling technique was conducted in three tertiary hospitals and three county hospitals in Inner Mongolia, China. Treatment schemes were categorized as lifestyle management, oral therapy or insulin therapy according to the national guideline. Socio-demographic characteristics and variables related to severity of disease at the individual level and hospital level were collected. Weighted multinomial logistic regression models were used to determine influencing factors of treatment schemes.   Results: Regardless of patients’ clinical conditions and health insurance types, both hospital and patient level variables were associated with treatment schemes. Males were more likely to be given oral therapy (RRR=1.72, 95% CI=1.06-2.81) and insulin therapy (RRR=1.94, 95% CI=1.29-2.91) compared to females who were given lifestyle management more frequently. Compared to the western region, hospitals in the central regions of Inner Mongolia were less likely to prescribe T2DM patients oral therapy (RRR = 0.18, 95% CI=0.05-0.61) and insulin therapy (RRR = 0.20, 95% CI=0.06-0.67) than lifestyle management. Compared with non-reformed tertiary hospitals, reformed tertiary hospitals and county hospitals were less likely to give T2DM patients oral therapy (RRR = 0.07 and 0.1 respectively) and insulin therapy (RRR = 0.11 and 0.17 respectively).   Conclusion: Gender was the only socio-demographic factors associated with treatment scheme for T2DM patients. Hospitals from different regions have different T2DM treatment patterns. Implementation of reform was shown to be associated with controlling medication use for T2DM inpatients. Further studies are needed to investigate the causes of unreasonable treatment disparities so that policies can be generated accordingly.
      PubDate: 2016-07-05T15:46:51Z
      DOI: 10.12688/f1000research.9095.1
      Issue No: Vol. 5 (2016)
  • Case Report: Whole exome sequencing reveals a novel frameshift deletion
           mutation p.G2254fs in COL7A1 associated with autosomal recessive
           dystrophic epidermolysis bullosa [version 2; referees: 2 approved, 1
           approved with reservations]

    • Authors: Shamsudheen Karuthedath Vellarikkal, Rijith Jayarajan, Ankit Verma, Sreelata Nair, Rowmika Ravi, Vigneshwar Senthivel, Sridhar Sivasubbu, Vinod Scaria
      Abstract: Dystrophic epidermolysis bullosa simplex (DEB) is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB) is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES). Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.
      PubDate: 2016-07-05T14:14:55Z
      DOI: 10.12688/f1000research.8380.2
      Issue No: Vol. 5 (2016)
  • Plant adaptation to drought stress [version 1; referees: 3 approved]

    • Authors: Supratim Basu, Venkategowda Ramegowda, Anuj Kumar, Andy Pereira
      Abstract: Plants in their natural habitats adapt to drought stress in the environment through a variety of mechanisms, ranging from transient responses to low soil moisture to major survival mechanisms of escape by early flowering in absence of seasonal rainfall. However, crop plants selected by humans to yield products such as grain, vegetable, or fruit in favorable environments with high inputs of water and fertilizer are expected to yield an economic product in response to inputs. Crop plants selected for their economic yield need to survive drought stress through mechanisms that maintain crop yield. Studies on model plants for their survival under stress do not, therefore, always translate to yield of crop plants under stress, and different aspects of drought stress response need to be emphasized. The crop plant model rice (Oryza sativa) is used here as an example to highlight mechanisms and genes for adaptation of crop plants to drought stress.
      PubDate: 2016-06-30T15:23:55Z
      DOI: 10.12688/f1000research.7678.1
      Issue No: Vol. 5 (2016)
  • Recent advances in imaging subcellular processes [version 1; referees: 2

    • Authors: Kenneth A. Myers, Christopher Janetopoulos
      Abstract: Cell biology came about with the ability to first visualize cells. As microscopy techniques advanced, the early microscopists became the first cell biologists to observe the inner workings and subcellular structures that control life. This ability to see organelles within a cell provided scientists with the first understanding of how cells function. The visualization of the dynamic architecture of subcellular structures now often drives questions as researchers seek to understand the intricacies of the cell. With the advent of fluorescent labeling techniques, better and new optical techniques, and more sensitive and faster cameras, a whole array of questions can now be asked. There has been an explosion of new light microscopic techniques, and the race is on to build better and more powerful imaging systems so that we can further our understanding of the spatial and temporal mechanisms controlling molecular cell biology.
      PubDate: 2016-06-30T14:43:09Z
      DOI: 10.12688/f1000research.8399.1
      Issue No: Vol. 5 (2016)
  • Urinary tract infection in the setting of vesicoureteral reflux [version
           1; referees: 2 approved]

    • Authors: Michael L. Garcia-Roig, Andrew J. Kirsch
      Abstract: Vesicoureteral reflux (VUR) is the most common underlying etiology responsible for febrile urinary tract infections (UTIs) or pyelonephritis in children. Along with the morbidity of pyelonephritis, long-term sequelae of recurrent renal infections include renal scarring, proteinuria, and hypertension. Treatment is directed toward the prevention of recurrent infection through use of continuous antibiotic prophylaxis during a period of observation for spontaneous resolution or by surgical correction. In children, bowel and bladder dysfunction (BBD) plays a significant role in the occurrence of UTI and the rate of VUR resolution. Effective treatment of BBD leads to higher rates of spontaneous resolution and decreased risk of UTI.
      PubDate: 2016-06-30T14:42:24Z
      DOI: 10.12688/f1000research.8390.1
      Issue No: Vol. 5 (2016)
  • Blood loss predictive factors and transfusion practice during percutaneous
           nephrolithotomy of kidney stones: a prospective study [version 1;
           referees: 1 approved, 2 approved with reservations]

    • Authors: Firtantyo Adi Syahputra, Ponco Birowo, Nur Rasyid, Faisal Abdi Matondang, Endrika Noviandrini, Maruto Harjanggi Huseini
      Abstract: Objectives Bleeding is the most common complication of percutaneous nephrolithotomy (PCNL). Injudicious transfusion is frequently performed in current practice, even though it is not always needed. This study aimed to identify the predictive factors of blood loss in the PCNL procedure and evaluate the perioperative transfusion practice.   Methods A prospective study of PCNL was randomly performed by two consultants of endo-urology at our institution. The inclusion criteria were adults with kidney pelvic stones >20 mm or stone in inferior calyx >10 mm or staghorn stone. Those with coagulopathy, under anti-coagulant treatment or open conversion were excluded. A full blood count was taken at baseline and during 12, 24, 36, 72-hours post-operatively. Factors such as stone burden, sex, body surface area, shifting of hematocrit level and amount of blood transfused were analyzed statistically using line regression to identify the predictive factors of total blood loss (TBL).   Results Eighty-five patients were enrolled in this study. Mean TBL was 560.92 ± 428.43 mL for both endo-urology surgeons. Stone burden was the most influential factor for TBL (p=0.037). Our results revealed that TBL (mL) = -153.379 + 0.229 × stone burden (mm2) + 0.203 x baseline serum hematocrit (%); thus considerably predicted the need for blood transfusion. A total of 87.1% patients did not receive perioperative transfusion, 3.5% received intra-operative transfusion, 7.1% received post-operative transfusion, 23% had both intra and post-operative transfusion, resulting in a cross-matched transfusion ratio of 7.72. Mean perioperative blood transfused was 356.00 ± 145.88 mL.
      PubDate: 2016-06-30T12:37:23Z
      DOI: 10.12688/f1000research.8993.1
      Issue No: Vol. 5 (2016)
  • Recent Insights into Cell Surface Heparan Sulphate Proteoglycans and
           Cancer [version 1; referees: 3 approved]

    • Authors: John R Couchman, Hinke Multhaupt, Ralph D. Sanderson
      Abstract: A small group of cell surface receptors are proteoglycans, possessing a core protein with one or more covalently attached glycosaminoglycan chains. They are virtually ubiquitous and their chains are major sites at which protein ligands of many types interact. These proteoglycans can signal and regulate important cell processes, such as adhesion, migration, proliferation, and differentiation. Since many protein ligands, such as growth factors, morphogens, and cytokines, are also implicated in tumour progression, it is increasingly apparent that cell surface proteoglycans impact tumour cell behaviour. Here, we review some recent advances, emphasising that many tumour-related functions of proteoglycans are revealed only after their modification in processes subsequent to synthesis and export to the cell surface. These include enzymes that modify heparan sulphate structure, recycling of whole or fragmented proteoglycans into exosomes that can be paracrine effectors or biomarkers, and lateral interactions between some proteoglycans and calcium channels that impact the actin cytoskeleton.
      PubDate: 2016-06-29T11:07:54Z
      DOI: 10.12688/f1000research.8543.1
      Issue No: Vol. 5 (2016)
  • Production of Basal Bodies in bulk for dense multicilia formation [version
           1; referees: 2 approved]

    • Authors: Xiumin Yan, Huijie Zhao, Xueliang Zhu
      Abstract: Centriole number is normally under tight control and is directly linked to ciliogenesis. In cells that use centrosomes as mitotic spindle poles, one pre-existing mother centriole is allowed to duplicate only one daughter centriole per cell cycle. In multiciliated cells, however, many centrioles are generated to serve as basal bodies of the cilia. Although deuterosomes were observed more than 40 years ago using electron microscopy and are believed to produce most of the basal bodies in a mother centriole-independent manner, the underlying molecular mechanisms have remained unknown until recently. From these findings arise more questions and a call for clarifications that will require multidisciplinary efforts.
      PubDate: 2016-06-28T14:51:10Z
      DOI: 10.12688/f1000research.8469.1
      Issue No: Vol. 5 (2016)
  • Recent insights: mesenchymal stromal/stem cell therapy for acute
           respiratory distress syndrome [version 1; referees: 2 approved]

    • Authors: Shahd Horie, John G. Laffey
      Abstract: Acute respiratory distress syndrome (ARDS) causes respiratory failure, which is associated with severe inflammation and lung damage and has a high mortality and for which there is no therapy. Mesenchymal stromal/stem cells (MSCs) are adult multi-progenitor cells that can modulate the immune response and enhance repair of damaged tissue and thus may provide a therapeutic option for ARDS. MSCs demonstrate efficacy in diverse in vivo models of ARDS, decreasing bacterial pneumonia and ischemia-reperfusion-induced injury while enhancing repair following ventilator-induced lung injury. MSCs reduce the pro-inflammatory response to injury while augmenting the host response to bacterial infection. MSCs appear to exert their effects via multiple mechanisms—some are cell interaction dependent whereas others are paracrine dependent resulting from both soluble secreted products and microvesicles/exosomes derived from the cells. Strategies to further enhance the efficacy of MSCs, such as by overexpressing anti-inflammatory or pro-repair molecules, are also being investigated. Encouragingly, early phase clinical trials of MSCs in patients with ARDS are under way, and experience with these cells in trials for other diseases suggests that the cells are well tolerated. Although considerable translational challenges, such as concerns regarding cell manufacture scale-up and issues regarding cell potency and batch variability, must be overcome, MSCs constitute a highly promising potential therapy for ARDS.
      PubDate: 2016-06-28T14:44:14Z
      DOI: 10.12688/f1000research.8217.1
      Issue No: Vol. 5 (2016)
  • Mechanisms of low back pain: a guide for diagnosis and therapy [version 1;
           referees: 3 approved]

    • Authors: Massimo Allegri, Silvana Montella, Fabiana Salici, Adriana Valente, Maurizio Marchesini, Christian Compagnone, Marco Baciarello, Maria Elena Manferdini, Guido Fanelli
      Abstract: Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question “what is the pain generator” among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach.
      PubDate: 2016-06-28T12:45:22Z
      DOI: 10.12688/f1000research.8105.1
      Issue No: Vol. 5 (2016)
  • Recent advances in molecular genetics of melanoma progression:
           implications for diagnosis and treatment [version 1; referees: 3 approved]

    • Authors: Iwei Yeh
      Abstract: According to the multi-step carcinogenesis model of cancer, initiation results in a benign tumor and subsequent genetic alterations lead to tumor progression and the acquisition of the hallmarks of cancer. This article will review recent discoveries in our understanding of initiation and progression in melanocytic neoplasia and the impact on diagnostic dermatopathology.
      PubDate: 2016-06-28T11:25:13Z
      DOI: 10.12688/f1000research.8247.1
      Issue No: Vol. 5 (2016)
  • The regulation of hematopoietic stem cell populations [version 1;
           referees: 2 approved]

    • Authors: Hector Mayani
      Abstract: Evidence presented over the last few years indicates that the hematopoietic stem cell (HSC) compartment comprises not just one but a number of different cell populations. Based on HSCs’ proliferation and engraftment potential, it has been suggested that there are two classes of HSC, with long- and short-term engraftment potential. HSC heterogeneity seems to involve differentiation capacities as well, since it has been shown that some HSC clones are able to give rise to both myeloid and lymphoid progeny, whereas others are lymphoid deficient. It has been recognized that HSC function depends on intrinsic cell regulators, which are modulated by external signals. Among the former, we can include transcription factors and non-coding RNAs as well as epigenetic modifiers. Among the latter, cytokines and extracellular matrix molecules have been implicated. Understanding the elements and mechanisms that regulate HSC populations is of significant relevance both in biological and in clinical terms, and research in this area still has to face several complex and exciting challenges.
      PubDate: 2016-06-28T09:42:35Z
      DOI: 10.12688/f1000research.8532.1
      Issue No: Vol. 5 (2016)
  • Management of postpartum haemorrhage [version 1; referees: 2 approved]

    • Authors: Marie Pierre Bonnet, Dan Benhamou
      Abstract: Postpartum Haemorrhage (PPH) is a major cause of maternal morbidity and mortality. Treatment of acquired coagulopathy observed in severe PPH is an important part of PPH management, but is mainly based on literature in trauma patients, and data thus should be interpreted with caution. This review describes recent advances in transfusion strategy and in the use of tranexamic acid and fibrinogen concentrates in women with PPH.
      PubDate: 2016-06-27T13:11:14Z
      DOI: 10.12688/f1000research.7836.1
      Issue No: Vol. 5 (2016)
  • Pathogenesis of myasthenia gravis: update on disease types, models, and
           mechanisms [version 1; referees: 2 approved]

    • Authors: William D. Phillips, Angela Vincent
      Abstract: Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.
      PubDate: 2016-06-27T11:00:39Z
      DOI: 10.12688/f1000research.8206.1
      Issue No: Vol. 5 (2016)
  • Advances in genetics: widening our understanding of prostate cancer
           [version 1; referees: 2 approved]

    • Authors: Angela C. Pine, Flavia F. Fioretti, Greg N. Brooke, Charlotte L. Bevan
      Abstract: Prostate cancer is a leading cause of cancer-related death in Western men. Our understanding of the genetic alterations associated with disease predisposition, development, progression, and therapy response is rapidly improving, at least in part, owing to the development of next-generation sequencing technologies. Large advances have been made in our understanding of the genetics of prostate cancer through the application of whole-exome sequencing, and this review summarises recent advances in this field and discusses how exome sequencing could be used clinically to promote personalised medicine for prostate cancer patients.
      PubDate: 2016-06-27T09:56:01Z
      DOI: 10.12688/f1000research.8019.1
      Issue No: Vol. 5 (2016)
  • Thirty-five years of research into ribozymes and nucleic acid catalysis:
           where do we stand today' [version 1; referees: 2 approved]

    • Abstract: Since the discovery of the first catalytic RNA in 1981, the field of ribozyme research has developed from the discovery of catalytic RNA motifs in nature and the elucidation of their structures and catalytic mechanisms, into a field of engineering and design towards application in diagnostics, molecular biology and medicine. Owing to the development of powerful protocols for selection of nucleic acid catalysts with a desired functionality from random libraries, the spectrum of nucleic acid supported reactions has greatly enlarged, and importantly, ribozymes have been accompanied by DNAzymes. Current areas of research are the engineering of allosteric ribozymes for artificial regulation of gene expression, the design of ribozymes and DNAzymes for medicinal and environmental diagnostics, and the demonstration of RNA world relevant ribozyme activities. In addition, new catalytic motifs or novel genomic locations of known motifs continue to be discovered in all branches of life by the help of high-throughput bioinformatic approaches. Understanding the biological role of the catalytic RNA motifs widely distributed in diverse genetic contexts belongs to the big challenges of future RNA research.
      PubDate: 2016-06-27T09:52:52Z
      DOI: 10.12688/f1000research.8601.1
      Issue No: Vol. 5 (2016)
  • Extracoporeal photopheresis treatment of acute graft-versus-host disease
           following allogeneic haematopoietic stem cell transplantation [version 1;
           referees: 2 approved]

    • Authors: Aisling M. Flinn, Andrew R. Gennery
      Abstract: Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery.
      PubDate: 2016-06-27T09:21:10Z
      DOI: 10.12688/f1000research.8118.1
      Issue No: Vol. 5 (2016)
  • Tourette syndrome research highlights 2015 [version 1; referees: 3

    • Authors: Cheryl A. Richards, Kevin J. Black
      Abstract: We present selected highlights from research that appeared during 2015 on Tourette syndrome and other tic disorders. Topics include phenomenology, comorbidities, developmental course, genetics, animal models, neuroimaging, electrophysiology, pharmacology, and treatment. We briefly summarize articles whose results we believe may lead to new treatments, additional research or modifications in current models of TS.
      PubDate: 2016-06-24T11:19:15Z
      DOI: 10.12688/f1000research.8769.1
      Issue No: Vol. 5 (2016)
  • Bioconductor workflow for microbiome data analysis: from raw reads to
           community analyses [version 1; referees: 2 approved]

    • Authors: Ben J. Callahan, Kris Sankaran, Julia A. Fukuyama, Paul J. McMurdie, Susan P. Holmes
      Abstract: High-throughput sequencing of PCR-amplified taxonomic markers (like the 16S rRNA gene) has enabled a new level of analysis of complex bacterial communities known as microbiomes. Many tools exist to quantify and compare abundance levels or microbial composition of communities in different conditions. The sequencing reads have to be denoised and assigned to the closest taxa from a reference database. Common approaches use a notion of 97% similarity and normalize the data by subsampling to equalize library sizes. In this paper, we show that statistical models allow more accurate abundance estimates. By providing a complete workflow in R, we enable the user to do sophisticated downstream statistical analyses, including both parameteric and nonparametric methods. We provide examples of using the R packages dada2, phyloseq, DESeq2, ggplot2 and vegan to filter, visualize and test microbiome data. We also provide examples of supervised analyses using random forests, partial least squares and linear models as well as nonparametric testing using community networks and the ggnetwork package.
      PubDate: 2016-06-24T10:43:02Z
      DOI: 10.12688/f1000research.8986.1
      Issue No: Vol. 5 (2016)
  • SNPsplit: Allele-specific splitting of alignments between genomes with
           known SNP genotypes [version 1; referees: 2 approved]

    • Authors: Felix Krueger, Simon R. Andrews
      Abstract: Sequencing reads overlapping polymorphic sites in diploid mammalian genomes may be assigned to one allele or the other. This holds the potential to detect gene expression, chromatin modifications, DNA methylation or nuclear interactions in an allele-specific fashion. SNPsplit is an allele-specific alignment sorter designed to read files in SAM/BAM format and determine the allelic origin of reads or read-pairs that cover known single nucleotide polymorphic (SNP) positions. For this to work libraries must have been aligned to a genome in which all known SNP positions were masked with the ambiguity base ’N’ and aligned using a suitable mapping program such as Bowtie2, TopHat, STAR, HISAT2, HiCUP or Bismark. SNPsplit also provides an automated solution to generate N-masked reference genomes for hybrid mouse strains based on the variant call information provided by the Mouse Genomes Project. The unique ability of SNPsplit to work with various different kinds of sequencing data including RNA-Seq, ChIP-Seq, Bisulfite-Seq or Hi-C opens new avenues for the integrative exploration of allele-specific data.
      PubDate: 2016-06-23T15:55:17Z
      DOI: 10.12688/f1000research.9037.1
      Issue No: Vol. 5 (2016)
  • From reads to genes to pathways: differential expression analysis of
           RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood
           pipeline [version 1; referees: 2 approved]

    • Authors: Yunshun Chen, Aaron T. L. Lun, Gordon K. Smyth
      Abstract: In recent years, RNA sequencing (RNA-seq) has become a very widely used technology for profiling gene expression. One of the most common aims of RNA-seq profiling is to identify genes or molecular pathways that are differentially expressed (DE) between two or more biological conditions. This article demonstrates a computational workflow for the detection of DE genes and pathways from RNA-seq data by providing a complete analysis of an RNA-seq experiment profiling epithelial cell subsets in the mouse mammary gland. The workflow uses R software packages from the open-source Bioconductor project and covers all steps of the analysis pipeline, including alignment of read sequences, data exploration, differential expression analysis, visualization and pathway analysis. Read alignment and count quantification is conducted using the Rsubread package and the statistical analyses are performed using the edgeR package. The differential expression analysis uses the quasi-likelihood functionality of edgeR.
      PubDate: 2016-06-20T13:33:12Z
      DOI: 10.12688/f1000research.8987.1
      Issue No: Vol. 5 (2016)
  • Combining combing and secondary ion mass spectrometry to study DNA on
           chips using 13C and 15N labeling [version 1; referees: 2 approved]

    • Abstract: Dynamic secondary ion mass spectrometry (D-SIMS) imaging of combed DNA – the combing, imaging by SIMS or CIS method – has been developed previously using a standard NanoSIMS 50 to reveal, on the 50 nm scale, individual DNA fibers labeled with different, non-radioactive isotopes in vivo and to quantify these isotopes. This makes CIS especially suitable for determining the times, places and rates of DNA synthesis as well as the detection of the fine-scale re-arrangements of DNA and of molecules associated with combed DNA fibers. Here, we show how CIS may be extended to 13C-labeling via the detection and quantification of the 13C14N- recombinant ion and the use of the 13C:12C ratio, we discuss how CIS might permit three successive labels, and we suggest ideas that might be explored using CIS.
      PubDate: 2016-06-20T11:13:03Z
      DOI: 10.12688/f1000research.8361.1
      Issue No: Vol. 5 (2016)
  • RNA-seq analysis is easy as 1-2-3 with limma, Glimma and edgeR [version 1;
           referees: 3 approved]

    • Authors: Charity W. Law, Monther Alhamdoosh, Shian Su, Gordon K. Smyth, Matthew E. Ritchie
      Abstract: The ability to easily and efficiently analyse RNA-sequencing data is a key strength of the Bioconductor project. Starting with counts summarised at the gene-level, a typical analysis involves pre-processing, exploratory data analysis, differential expression testing and pathway analysis with the results obtained informing future experiments and validation studies. In this workflow article, we analyse RNA-sequencing data from the mouse mammary gland, demonstrating use of the popular edgeR package to import, organise, filter and normalise the data, followed by the limma package with its voom method, linear modelling and empirical Bayes moderation to assess differential expression and perform gene set testing. This pipeline is further enhanced by the Glimma package which enables interactive exploration of the results so that individual samples and genes can be examined by the user. The complete analysis offered by these three packages highlights the ease with which researchers can turn the raw counts from an RNA-sequencing experiment into biological insights using Bioconductor.
      PubDate: 2016-06-17T10:37:09Z
      DOI: 10.12688/f1000research.9005.1
      Issue No: Vol. 5 (2016)
  • Decrease in rate of multiple sclerosis-related hospitalizations in
           Portugal [version 1; referees: 2 approved]

    • Authors: Marta Pereira, Dimitra Lambrelli, Sreeram V. Ramagopalan
      Abstract: We sought to investigate the rate of multiple sclerosis (MS)-related hospitalizations in Portugal and assess whether there have been temporal changes as described in other countries. Using data from the Portuguese National Discharge Registry, we observed that between 2008 and 2013 the rate of MS-related hospitalizations decreased by 44%, from 15.9/100 person-years (95% confidence interval (CI: 14.9-16.9) in 2008 to 8.9/100 person-years (95% CI: 8.2-9.6) in 2013. The change in hospitalization rates is in accordance with what has been observed in other countries, and coincides with the release of new therapies for MS in Portugal.
      PubDate: 2016-06-13T09:38:36Z
      DOI: 10.12688/f1000research.8787.1
      Issue No: Vol. 5 (2016)
  • Whole-genome sequencing of nine esophageal adenocarcinoma cell lines
           [version 1; referees: 2 approved]

    • Authors: Gianmarco Contino, Matthew D. Eldridge, Maria Secrier, Lawrence Bower, Rachael Fels Elliott, Jamie Weaver, Andy G. Lynch, Paul A.W. Edwards, Rebecca C. Fitzgerald
      Abstract: Esophageal adenocarcinoma (EAC) is highly mutated and molecularly heterogeneous. The number of cell lines available for study is limited and their genome has been only partially characterized. The availability of an accurate annotation of their mutational landscape is crucial for accurate experimental design and correct interpretation of genotype-phenotype findings. We performed high coverage, paired end whole genome sequencing on eight EAC cell lines—ESO26, ESO51, FLO-1, JH-EsoAd1, OACM5.1 C, OACP4 C, OE33, SK-GT-4—all verified against original patient material, and one esophageal high grade dysplasia cell line, CP-D. We have made available the aligned sequence data and report single nucleotide variants (SNVs), small insertions and deletions (indels), and copy number alterations, identified by comparison with the human reference genome and known single nucleotide polymorphisms (SNPs). We compare these putative mutations to mutations found in primary tissue EAC samples, to inform the use of these cell lines as a model of EAC.
      PubDate: 2016-06-10T14:58:41Z
      DOI: 10.12688/f1000research.7033.1
      Issue No: Vol. 5 (2016)
  • Early-childhood housing mobility and subsequent PTSD in adolescence: a
           Moving to Opportunity reanalysis [version 1; referees: 2 approved]

    • Authors: David C. Norris, Andrew Wilson
      Abstract: In a 2014 report on adolescent mental health outcomes in the Moving to Opportunity for Fair Housing Demonstration (MTO), Kessler et al. reported that, at 10- to 15-year follow-up, boys from households randomized to an experimental housing voucher intervention experienced 12-month prevalence of post-traumatic stress disorder (PTSD) at several times the rate of boys from control households. We reanalyze this finding here, bringing to light a PTSD outcome imputation procedure used in the original analysis, but not described in the study report. By bootstrapping with repeated draws from the frequentist sampling distribution of the imputation model used by Kessler et al., and by varying two pseudorandom number generator seeds that fed their analysis, we account for several purely statistical components of the uncertainty inherent in their imputation procedure. We also discuss other sources of uncertainty in this procedure that were not accessible to a formal reanalysis.
      PubDate: 2016-05-27T10:52:18Z
      DOI: 10.12688/f1000research.8753.1
      Issue No: Vol. 5 (2016)
  • Identification of selective inhibitors of RET and comparison with current
           clinical candidates through development and validation of a robust
           screening cascade [version 1; referees: 2 approved]

    • Authors: Amanda J. Watson, Gemma V. Hopkins, Samantha Hitchin, Habiba Begum, Stuart Jones, Allan Jordan, Sarah Holt, H. Nikki March, Rebecca Newton, Helen Small, Alex Stowell, Ian D. Waddell, Bohdan Waszkowycz, Donald J. Ogilvie
      Abstract: RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent.   At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments.   In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.
      PubDate: 2016-05-26T09:29:36Z
      DOI: 10.12688/f1000research.8724.1
      Issue No: Vol. 5 (2016)
  • Can free open access resources strengthen knowledge-based emerging public
           health priorities, policies and programs in Africa' [version 1;
           referees: 2 approved]

    • Authors: Ernest Tambo, Ghislaine Madjou, Christopher Khayeka-Wandabwa, Emmanuel N. Tekwu, Oluwasogo A. Olalubi, Nicolas Midzi, Louis Bengyella, Ahmed A. Adedeji, Jeanne Y. Ngogang
      Abstract: Tackling emerging epidemics and infectious diseases burden in Africa requires increasing unrestricted open access and free use or reuse of regional and global policies reforms as well as timely communication capabilities and strategies. Promoting, scaling up data and information sharing between African researchers and international partners are of vital importance in accelerating open access at no cost. Free Open Access (FOA) health data and information acceptability, uptake tactics and sustainable mechanisms are urgently needed. These are critical in establishing real time and effective knowledge or evidence-based translation, proven and validated approaches, strategies and tools to strengthen and revamp health systems.  As such, early and timely access to needed emerging public health information is meant to be instrumental and valuable for policy-makers, implementers, care providers, researchers, health-related institutions and stakeholders including populations when guiding health financing, and planning contextual programs.
      PubDate: 2016-05-09T13:30:27Z
      DOI: 10.12688/f1000research.8662.1
      Issue No: Vol. 5 (2016)
  • Assessment of pharmacogenomic agreement [version 1; referees: 3 approved]

    • Authors: Zhaleh Safikhani, Nehme El-Hachem, Rene Quevedo, Petr Smirnov, Anna Goldenberg, Nicolai Juul Birkbak, Christopher Mason, Christos Hatzis, Leming Shi, Hugo JWL Aerts, John Quackenbush, Benjamin Haibe-Kains
      Abstract: In 2013 we published an analysis demonstrating that drug response data and gene-drug associations reported in two independent large-scale pharmacogenomic screens, Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE), were inconsistent. The GDSC and CCLE investigators recently reported that their respective studies exhibit reasonable agreement and yield similar molecular predictors of drug response, seemingly contradicting our previous findings. Reanalyzing the authors’ published methods and results, we found that their analysis failed to account for variability in the genomic data and more importantly compared different drug sensitivity measures from each study, which substantially deviate from our more stringent consistency assessment. Our comparison of the most updated genomic and pharmacological data from the GDSC and CCLE confirms our published findings that the measures of drug response reported by these two groups are not consistent. We believe that a principled approach to assess the reproducibility of drug sensitivity predictors is necessary before envisioning their translation into clinical settings.
      PubDate: 2016-05-09T11:29:04Z
      DOI: 10.12688/f1000research.8705.1
      Issue No: Vol. 5 (2016)
  • Innovations in scholarly communication - global survey on research tool
           usage [version 1; referees: 2 approved]

    • Authors: Bianca Kramer, Jeroen Bosman
      Abstract: Many new websites and online tools have come into existence to support scholarly communication in all phases of the research workflow. To what extent researchers are using these and more traditional tools has been largely unknown. This 2015-2016 survey aimed to fill that gap. Its results may help decision making by stakeholders supporting researchers and may also help researchers wishing to reflect on their own online workflows. In addition, information on tools usage can inform studies of changing research workflows. The online survey employed an open, non-probability sample. A largely self-selected group of 20663 researchers, librarians, editors, publishers and other groups involved in research took the survey, which was available in seven languages. The survey was open from May 10, 2015 to February 10, 2016. It captured information on tool usage for 17 research activities, stance towards open access and open science, and expectations of the most important development in scholarly communication. Respondents’ demographics included research roles, country of affiliation, research discipline and year of first publication.
      PubDate: 2016-04-18T09:11:24Z
      DOI: 10.12688/f1000research.8414.1
      Issue No: Vol. 5 (2016)
  • Improving quality for maternal care - a case study from Kerala, India
           [version 1; referees: 2 approved]

    • Abstract: Background: The implementation of maternal health guidelines remains unsatisfactory, even for simple, well established interventions. In settings where most births occur in health facilities, as is the case in Kerala, India, preventing maternal mortality is linked to quality of care improvements. Context: Evidence-informed quality standards (QS), including quality statements and measurable structure and process indicators, are one innovative way of tackling the guideline implementation gap. Having adopted a zero tolerance policy to maternal deaths, the Government of Kerala worked in partnership with the Kerala Federation of Obstetricians & Gynaecologists (KFOG) and NICE International to select the clinical topic, develop and initiate implementation of the first clinical QS for reducing maternal mortality in the state. Description of practice: The NICE QS development framework was adapted to the Kerala context, with local ownership being a key principle. Locally generated evidence identified post-partum haemorrhage as the leading cause of maternal death, and as the key priority for the QS. A multidisciplinary group (including policy-makers, gynaecologists and obstetricians, nurses and administrators) was established. Multi-stakeholder workshops convened by the group ensured that the statements, derived from global and local guidelines, and their corresponding indicators were relevant and acceptable to clinicians and policy-makers in Kerala. Furthermore, it helped identify practical methods for implementing the standards and monitoring outcomes. Lessons learned: An independent evaluation of the project highlighted the equal importance of a strong evidence-base and an inclusive development process. There is no one-size-fits-all process for QS development; a principle-based approach might be a better guide for countries to adapt global evidence to their local context.
      PubDate: 2016-02-12T15:28:31Z
      DOI: 10.12688/f1000research.7893.1
      Issue No: Vol. 5 (2016)
  • regionReport: Interactive reports for region-level and feature-level
           genomic analyses [version 2; referees: 2 approved, 1 approved with

    • Authors: Leonardo Collado-Torres, Andrew E. Jaffe, Jeffrey T. Leek
      Abstract: regionReport is an R package for generating detailed interactive reports from region-level genomic analyses as well as feature-level RNA-seq. The report includes quality-control checks, an overview of the results, an interactive table of the genomic regions or features of interest and reproducibility information. regionReport provides specialised reports for exploring DESeq2, edgeR, or derfinder differential expression analyses results. regionReport is also flexible and can easily be expanded with report templates for other analysis pipelines.
      PubDate: 2016-06-29T15:15:53Z
      DOI: 10.12688/f1000research.6379.2
      Issue No: Vol. 4 (2016)
  • DOCLASP - Docking ligands to target proteins using spatial and
           electrostatic congruence extracted from a known holoenzyme and applying
           simple geometrical transformations [version 3; referees: 2 approved]

    • Authors: Sandeep Chakraborty
      Abstract: The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already ’plastic’ binding site. Thus, DOCLASP presents a method for ’soft docking’ ligands to proteins with low computational requirements.
      PubDate: 2016-06-16T10:24:33Z
      DOI: 10.12688/f1000research.5145.3
      Issue No: Vol. 3 (2016)
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