Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy

GSK (ClinicalTrials.gov identifier NCT01573767

A small S-MIF signal in Martian regolith pyrite: Implications for the atmosphere

keywords: Sulfur, sulfate, Mars, S-MIF, regolith, atmosphereThe past Martian atmosphere is often compared to the Archean Earth’s as both were dominated by CO2-rich and O2-poor chemistries. Archean Earth rocks preserve mass-independently fractionated sulfur isotopes (S-MIF; non-zero Δ33S and Δ36S), originating from photochemistry in an anoxic atmosphere. Thus, Martian crustal rocks might also be expected to preserve a S-MIF signature, providing insights into past atmospheric chemistry. We have used secondary ion mass spectrometry (SIMS) to investigate in situ, the sulfur isotope systematics of NWA 8171 (paired to NWA 7034), a Martian polymict breccia containing pyrite that formed through hydrothermal sulfur addition in a near-surface regolith setting. In this meteorite, pyrite grains have a weighted mean of Δ33S of -0.14 ± 0.08 ‰ and Δ36S = -0.70 ± 0.40 ‰ (2 s.e.m.), so the S-MIF signature is subtle. Sulfur isotope data for four additional shergottites yield Δ33S values that are not resolvable from zero, as in previous studies of shergottites. At first glance the result for the polymict breccia might seem surprising, but no Martian meteorite yet has yielded a S-MIF signature akin to the large deviations seen on Earth. We suggest that S-MIF-bearing aerosols (H2SO4 and S8) were produced when volcanic activity pushed a typically oxidising Martian atmosphere into a reduced state. After rain-out of these aerosols, S8 would tend to be oxidised by chlorate, dampening the S-MIF signal, which might be somewhat retained in the more abundant photolytic sulfate. Then in the regolith, mixing of aqueous surface-derived sulfate with igneous sulfide (the latter with zero MIF), to form the abundant pyrite seen in NWA 8171, would further dampen the S-MIF signal. Nonetheless, the small negative Δ33S anomalies seen in Martian meteorites imply that volcanic activity was sufficient to produce a reducing atmosphere at times. This volcanically-driven atmospheric evolution would tend to produce high levels of carbonyl sulfide (OCS). Given that OCS is a relatively long-lived strong greenhouse gas, the S-MIF signal implies that volcanism periodically generated warmer conditions, perhaps offering an evidence-based solution to the young wet Mars paradox

Detection of structural mosaicism from targeted and whole-genome sequencing data.

Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements

PINOT: an intuitive resource for integrating protein-protein interactions

The past decade has seen the rise of omics data, for the understanding of biological systems in health and disease. This wealth of data includes protein-protein interaction (PPI) derived from both low and high-throughput assays, which is curated into multiple databases that capture the extent of available information from the peer-reviewed literature. Although these curation efforts are extremely useful, reliably downloading and integrating PPI data from the variety of available repositories is challenging and time consuming. We here present a novel user-friendly web-resource called PINOT (Protein Interaction Network Online Tool; available at http://www.reading.ac.uk/bioinf/PINOT/PINOT_form.html) to optimise the collection and processing of PPI data from the IMEx consortium associated repositories (members and observers) and from WormBase for constructing, respectively, human and C. elegans PPI networks. Users submit a query containing a list of proteins of interest for which PINOT will mine PPIs. PPI data is downloaded, merged, quality checked, and confidence scored based on the number of distinct methods and publications in which each interaction has been reported. Examples of PINOT applications are provided to highlight the performance, the ease of use and the potential applications of this tool. PINOT is a tool that allows users to survey the literature, extracting PPI data for a list of proteins of interest. The comparison with analogous tools showed that PINOT was able to extract similar numbers of PPIs while incorporating a set of innovative features. PINOT processes both small and large queries, it downloads PPIs live through PSICQUIC and it applies quality control filters on the downloaded PPI annotations (i.e. removing the need of manual inspection by the user). PINOT provides the user with information on detection methods and publication history for each of the downloaded interaction data entry and provides results in a table format that can be easily further customised and/or directly uploaded in a network visualization software

A simple and versatile 2-dimensional platform to study plant germination and growth under controlled humidity

We describe a simple, inexpensive, but remarkably versatile and controlled growth environment for the observation of plant germination and seedling root growth on a flat, horizontal surface over periods of weeks. The setup provides to each plant a controlled humidity (between 56% and 91% RH), and contact with both nutrients and atmosphere. The flat and horizontal geometry of the surface supporting the roots eliminates the gravitropic bias on their development and facilitates the imaging of the entire root system. Experiments can be setup under sterile conditions and then transferred to a non-sterile environment. The system can be assembled in 1-2 minutes, costs approximately 8.78$per plant, is almost entirely reusable (0.43$ per experiment in disposables), and is easily scalable to a variety of plants. We demonstrate the performance of the system by germinating, growing, and imaging Wheat (Triticum aestivum), Corn (Zea mays), and Wisconsin Fast Plants (Brassica rapa). Germination rates were close to those expected for optimal conditions

Doyne lecture 2016:intraocular health and the many faces of inflammation

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Sharp truth: health care workers remain at risk of bloodborne infection.

BACKGROUND: In 2013, new regulations for the prevention of sharps injuries were introduced in the UK. All health care employers are required to provide the safest possible working environment by preventing or controlling the risk of sharps injuries. AIMS: To analyse data on significant occupational sharps injuries among health care workers in England, Wales and Northern Ireland before the introduction of the 2013 regulations and to assess bloodborne virus seroconversions among health care workers sustaining a blood or body fluid exposure. METHODS: Analysis of 10 years of information on percutaneous and mucocutaneous exposures to blood or other body fluids from source patients infected with a bloodborne virus, collected in England, Wales and Northern Ireland through routine surveillance of health care workers reported for the period 2002-11. RESULTS: A total of 2947 sharps injuries involving a source patient infected with a bloodborne virus were reported by health care workers. Significant sharps injuries were 67% higher in 2011 compared with 2002. Sharps injuries involving an HIV-, hepatitis B virus- or hepatitis C virus (HCV)-infected source patient increased by 107, 69 and 60%, respectively, between 2002 and 2011. During the study period, 14 health care workers acquired HCV following a sharps injury. CONCLUSIONS: Our data show that during a 10-year period prior to the introduction of new regulations in 2013, health care workers were at risk of occupationally acquired bloodborne virus infection. To prevent sharps injuries, health care service employers should adopt safety-engineered devices, institute safe systems of work and promote adherence to standard infection control procedures

Universal treatment success among healthcare workers diagnosed with occupationally acquired acute hepatitis C.

Healthcare workers (HCWs) are at risk of occupationally acquired hepatitis C. In the UK, 17 HCWs were diagnosed with occupationally acquired acute hepatitis C between 2002 and 2011. All 17 cases involved percutaneous injuries from hollowbore needles, 16 known to be contaminated with blood. Of these 17 HCWs, 15 received antiviral therapy and 14 are known to have achieved viral clearance. Treatment success was irrespective of genotype. The successful treatment of HCWs emphasizes the need for UK guidelines on the management of occupationally acquired acute hepatitis C