The Role of Vascular Endothelial Growth Factor in Systemic Sclerosis

The pathological hallmarks of Systemic sclerosis (SSc) constitute an inter-related triad of autoimmunity, vasculopathy and tissue remodeling. Many signaling mediators have been implicated in SSc pathology; most focusing on individual components of this pathogenic triad and current treatment paradigms tend to approach management of such as distinct entities. The present review shall examine the role of vascular endothelial growth factor (VEGF) in SSc pathogenesis. We shall outline potential mechanisms whereby differential vascular endothelial growth factor-A (VEGF-A) isoform expression (through conventional and alternative VEGF-A splicing,) may influence the relevant burden of vasculopathy and fibrosis offering novel insight into clinical heterogeneity and disease progression in SSc. Emerging therapeutic approaches targeting VEGF signaling pathways might play an important role in the management of SSc, and differential VEGF-A splice isoform expression may provide a tool for personalized medicine approaches to disease management.</p

High frequency ultrasound assessment of systemic sclerosis skin involvement:intra-observer repeatability and relationship with clinician assessment and dermal collagen content

OBJECTIVE: The modified Rodnan skin score (mRSS) remains the preferred method for skin assessment in systemic sclerosis (SSc). There are concerns regarding high inter-observer variability of mRSS and negative clinical trials utilising mRSS as the primary endpoint. High frequency ultrasound (HFUS) allows objective assessment of cutaneous fibrosis in SSc. We investigated the relationship between HFUS with both mRSS and dermal collagen.METHODS: Skin thickness (ST), echogenicity and novel Shear wave elastography (SWE) were assessed in 53 SSc patients and 15 healthy controls (HC) at the finger, hand, forearm and abdomen. The relationship between HFUS parameters with mRSS (n=53) and dermal collagen (10 SSc patients and 10 HC) was investigated. Intra-observer repeatability of HFUS was calculated using intra-class correlation coefficients (ICCs).RESULTS: HFUS assessment of ST (hand/forearm) and SWE (finger/hand) correlated with local mRSS at some sites. Subclinical abnormalities in ST, echogenicity and SWE were present in clinically uninvolved SSc skin. Additionally, changes in echogenicity and SWE were sometimes apparent despite objectively normal ST on HFUS. ST, SWE and local mRSS correlated strongly with collagen quantification (rho 0.697, 0.709, 0.649 respectively). Intra-observer repeatability was high for all HFUS parameters (ICCs for ST 0.946-0.978, echogenicity 0.648- 0.865 and SWE 0.953-0.973).CONCLUSION: Our data demonstrates excellent reproducibility and reassuring convergent validity with dermal collagen content. Detection of subclinical abnormalities is an additional benefit of HFUS. The observed correlations with collagen quantification support further investigation of HFUS as an alternative to mRSS in clinical trial settings.</p

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease

An astrophysical interpretation of the remarkable g-mode frequency groups of the rapidly rotating γ Dor star, KIC 5608334

The Fourier spectrum of the γ-Dor variable KIC 5608334 shows remarkable frequency groups at ∼3, ∼6, ∼9, and 11–12 d−1. We explain the four frequency groups as prograde sectoral g modes in a rapidly rotating star. Frequencies of intermediate-to-high radial order prograde sectoral g modes in a rapidly rotating star are proportional to |m| (i.e. ν∝|m|) in the corotating frame as well as in the inertial frame. This property is consistent with the frequency groups of KIC 5608334 as well as the period versus period-spacing relation present within each frequency group, if we assume a rotation frequency of 2.2 d−1, and that each frequency group consists of prograde sectoral g modes of |m| = 1, 2, 3, and 4, respectively. In addition, these modes naturally satisfy near-resonance conditions νi ≈ νj + νk with mi = mj + mk. We even find exact resonance frequency conditions (within the precise measurement uncertainties) in many cases, which correspond to combination frequencies

Reading during the composition of multi-sentence texts: an eye-movement study

Writers composing multi-sentence texts have immediate access to a visual representation of what they have written. Little is known about the detail of writers’ eye movements within this text during production. We describe two experiments in which competent adult writers’ eye-movements were tracked while performing short expository writing tasks. These are contrasted with conditions in which participants read and evaluated researcher-provided texts. Writers spent a mean of around 13% of their time looking back into their text. Initiation of these look-back sequences was strongly predicted by linguistically important boundaries in their ongoing production (e.g., writers were much more likely to look back immediately prior to starting a new sentence). 36% of look-back sequences were associated with sustained reading and the remainder with less patterned forward and backward saccades between words ("hopping"). Fixation and gaze durations and the presence of word-length effects suggested lexical processing of fixated words in both reading and hopping sequences. Word frequency effects were not present when writers read their own text. Findings demonstrate the technical possibility and potential value of examining writers’ fixations within their just-written text. We suggest that these fixations do not serve solely, or even primarily, in monitoring for error, but play an important role in planning ongoing production

MHC Class I Bound to an Immunodominant Theileria parva Epitope Demonstrates Unconventional Presentation to T Cell Receptors

T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1214–224 epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design

Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years. Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice. Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003). During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4% in lcSSc, p = 0.002). As previously observed, the rate of development of SRC was highest in the first 3 years of disease- 10% in dcSSc and 3% in lcSSc. All incidences of clinically important cardiac disease developed in the first 5 years from disease onset (7% in dcSSc v 1% in lcSSc, p < 0.001) and remained unchanged at 10 years. As expected, 10-year survival among lcSSc subjects was significantly higher (81%) compared to that of dcSSc patients (70%, p = 0.006). Interestingly, although over the first 5 years the death rate was much higher in the dcSSc cohort (16% v 6% in lcSSc), over the following years it became very similar for both subsets (14% and 13% between years 5 and 10, and 18% and 17% between years 10 and 15 for dcSSc and lcSSc respectively). Conclusions: Even though dcSSc patients have higher incidence for most organ complications compared to lcSSc subjects, the worse survival among them is mainly due to higher early mortality rate. Mortality rate after first 5 years of disease becomes comparable in the two disease subsets. Disclosure statement: The authors have declared no conflicts of interes

The RESET project: constructing a European tephra lattice for refined synchronisation of environmental and archaeological events during the last c. 100 ka

This paper introduces the aims and scope of the RESET project (. RESponse of humans to abrupt Environmental Transitions), a programme of research funded by the Natural Environment Research Council (UK) between 2008 and 2013; it also provides the context and rationale for papers included in a special volume of Quaternary Science Reviews that report some of the project's findings. RESET examined the chronological and correlation methods employed to establish causal links between the timing of abrupt environmental transitions (AETs) on the one hand, and of human dispersal and development on the other, with a focus on the Middle and Upper Palaeolithic periods. The period of interest is the Last Glacial cycle and the early Holocene (c. 100-8 ka), during which time a number of pronounced AETs occurred. A long-running topic of debate is the degree to which human history in Europe and the Mediterranean region during the Palaeolithic was shaped by these AETs, but this has proved difficult to assess because of poor dating control. In an attempt to move the science forward, RESET examined the potential that tephra isochrons, and in particular non-visible ash layers (cryptotephras), might offer for synchronising palaeo-records with a greater degree of finesse. New tephrostratigraphical data generated by the project augment previously-established tephra frameworks for the region, and underpin a more evolved tephra 'lattice' that links palaeo-records between Greenland, the European mainland, sub-marine sequences in the Mediterranean and North Africa. The paper also outlines the significance of other contributions to this special volume: collectively, these illustrate how the lattice was constructed, how it links with cognate tephra research in Europe and elsewhere, and how the evidence of tephra isochrons is beginning to challenge long-held views about the impacts of environmental change on humans during the Palaeolithic. © 2015 Elsevier Ltd.RESET was funded through Consortium Grants awarded by the Natural Environment Research Council, UK, to a collaborating team drawn from four institutions: Royal Holloway University of London (grant reference NE/E015905/1), the Natural History Museum, London (NE/E015913/1), Oxford University (NE/E015670/1) and the University of Southampton, including the National Oceanography Centre (NE/01531X/1). The authors also wish to record their deep gratitude to four members of the scientific community who formed a consultative advisory panel during the lifetime of the RESET project: Professor Barbara Wohlfarth (Stockholm University), Professor Jørgen Peder Steffensen (Niels Bohr Institute, Copenhagen), Dr. Martin Street (Romisch-Germanisches Zentralmuseum, Neuwied) and Professor Clive Oppenheimer (Cambridge University). They provided excellent advice at key stages of the work, which we greatly valued. We also thank Jenny Kynaston (Geography Department, Royal Holloway) for construction of several of the figures in this paper, and Debbie Barrett (Elsevier) and Colin Murray Wallace (Editor-in-Chief, QSR) for their considerable assistance in the production of this special volume.Peer Reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead