British influence in Brussels had been far greater than recognised

Britain had far greater influence in Brussels since 1973 than has been recognised. For decades the UK was a driving and liberalising force when it came to the Single Market, enlargement, competition and trade, as well as foreign policy. Jonathan Faull (Kings College London), Piers Ludlow (LSE), and Laurent Warlouzet (Université du Littoral Côte d'Opale) outline the story of this significant and widespread British sway over the EU

New birds from Costa Rica

5 p. ; 24 cm.Includes bibliographical references

Hydrogen Generation via Novel Supercritical Water Reformation Technology

Track II: Transportation and BiofuelsIncludes audio file (18 min.)A novel, robust, fuel reformation technology has been developed for portable, mobile, stationary, and on-site generation of hydrogen from a variety of feedstocks involving both renewable and nonrenewable resources. Unlike conventional steam methane reforming (SMR), this novel reforming process is carried out non-catalytically in supercritical water, where supercritical water acts both as a highly-energized reforming agent and as an extraordinary homogenizing solvent. The unparalleled merits of this technology, as demonstrated in an experimental prototype system, are quite numerous, including: (a) catalyst-free reactions; (b) capability of handling high sulfur-containing liquid fuels; (c) high once-through conversion; (d) lower temperature operation and higher energy efficiency than conventional steam reforming technology; (e) alleviation and control of coking; (f) use of unpurified, locally available water; (g) compact size and minimal space requirements; (h) great flexibility in feedstock variety; and (h) near-zero discharge. The process technology is superbly applicable to the U.S. military's need for mobile electric power (MEP) generation based on integrated fuel reformation-fuel cell systems, for purposes of stealth (reduced noise and thermal signature), increased mission endurance (higher efficiency), and reduced logistical burden (overall lower fuel consumption). The process technology is also eminently suitable for on-site hydrogen generation via energy-efficient conversion of ethanol crude beer into hydrogen, thus providing a means of seamless integration between the Hydrogen Economy and the Ethanol Economy. Scientific and technological details of the supercritical water reformation (SWR) process will be discussed, with a particular emphasis placed on process chemistry, process engineering, energy materials, and prototype design

Visual stress, its treatment with spectral filters, and its relationship to visually induced motion sickness

We review the concept of visual stress and its relation to neurological disease. Visual stress can occur from the observation of images with unnatural spatial structure and an excess of contrast energy at spatial frequencies to which the visual system is generally most sensitive. Visual stress can often be reduced using spectral filters, provided the colour is selected with precision to suit each individual. The use of such filters and their effects on reading speed are reviewed. The filters have been shown to benefit patients with a variety of neurological conditions other than reading difficulty, all associated with an increased risk of seizures. © 2009 Elsevier Ltd

Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counsellin

Presentism remains

Here I examine some recent attempts to provide a new way of thinking about the philosophy of time that question the central role of ‘presentness’ within the definition of presentism. The central concern raised by these critics turns on the intelligibility and theoretical usefulness of the term ‘is present’ (cf. Correia and Rosenkrantz in Thought 4:19–27, 2015; Deasy in Nous, 2017. https://doi.org/10.1111/nous.12109; Williamson in Modal logic as metaphysics, OUP, Oxford, 2013). My overarching aim is to at least challenge such concerns. I begin with arguments due to Deasy (Nous, 2017. https://doi.org/10.1111/nous.12109). Deasy develops a view that he calls ‘transientism’ and that he takes to be a well-motivated version of presentism. I show that both this way of thinking about presentism and the argument supposedly motivating it all fail. I then move to an argument due to Correia and Rosenkrantz (Thought 4:19–27, 2015). Correia and Rosenkrantz purport to show that presentism can be salvaged without making recourse to the term ‘is present’. I demonstrate that their arguments fail. I then move on to a view, proposed and defended by Merricks (Truth and ontology, OUP, Oxford, 2007), Tallant (Erkenntnis 79:479–501, 2014), and Zimmerman (Philos Pap 25:115–126, 1996), and show that it has the wherewithal to meet the challenges raised by Williamson (Modal logic as metaphysics, OUP, Oxford, 2013) who, as noted above, raises genuine concerns about our capacity to define presentism

Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression

Bicistronic Lentiviruses Containing a Viral 2A Cleavage Sequence Reliably Co-Express Two Proteins and Restore Vision to an Animal Model of LCA1

The disease processes underlying inherited retinal disease are complex and are not completely understood. Many of the corrective gene therapies designed to treat diseases linked to mutations in genes specifically expressed in photoreceptor cells restore function to these cells but fail to stop progression of the disease. There is growing consensus that effective treatments for these diseases will require delivery of multiple therapeutic proteins that will be selected to treat specific aspects of the disease process. The purpose of this study was to design a lentiviral transgene that reliably expresses all of the proteins it encodes and does so in a consistent manner among infected cells. We show, using both in vitro and in vivo analyses, that bicistronic lentiviral transgenes encoding two fluorescent proteins fused to a viral 2A-like cleavage peptide meet these expression criteria. To determine if this transgene design is suitable for therapeutic applications, we replaced one of the fluorescent protein genes with the gene encoding guanylate cyclase -1 (GC1) and delivered lentivirus carrying this transgene to the retinas of the GUCY1*B avian model of Leber congenital amaurosis – 1 (LCA1). GUCY1*B chickens carry a null mutation in the GC1 gene that disrupts photoreceptor function and causes blindness at hatching, a phenotype that closely matches that observed in humans with LCA1. We found that treatment of these animals with the 2A lentivector encoding GC1 restored vision to these animals as evidenced by the presence of optokinetic reflexes. We conclude that 2A-like peptides, with proper optimization, can be successfully incorporated into therapeutic vectors designed to deliver multiple proteins to neural retinal. These results highlight the potential of this vector design to serve as a platform for the development of combination therapies designed to enhance or prolong the benefits of corrective gene therapies