Demonstration of the Zero-Crossing Phasemeter with a LISA Test-bed Interferometer

The Laser Interferometer Space Antenna (LISA) is being designed to detect and study in detail gravitational waves from sources throughout the Universe such as massive black hole binaries. The conceptual formulation of the LISA space-borne gravitational wave detector is now well developed. The interferometric measurements between the sciencecraft remain one of the most important technological and scientific design areas for the mission. Our work has concentrated on developing the interferometric technologies to create a LISA-like optical signal and to measure the phase of that signal using commercially available instruments. One of the most important goals of this research is to demonstrate the LISA phase timing and phase reconstruction for a LISA-like fringe signal, in the case of a high fringe rate and a low signal level. We present current results of a test-bed interferometer designed to produce an optical LISA-like fringe signal previously discussed in the literature.Comment: find minor corrections in the CQG versio

Optimizing the Earth-LISA "rendez-vous"

We present a general survey of heliocentric LISA orbits, hoping it might help in the exercise of rescoping the mission. We try to semi-analytically optimize the orbital parameters in order to minimize the disturbances coming from the Earth-LISA interaction. In a set of numerical simulations we include nonautonomous perturbations and provide an estimate of Doppler shift and breathing as a function of the trailing angle.Comment: 18 pages, 16 figures. Submitted on CQ

Technology requirements of exploration beyond Neptune by solar sail propulsion

This paper provides a set of requirements for the technology development of a solar sail propelled Interstellar Heliopause Probe mission. The mission is placed in the context of other outer solar systems missions, ranging from a Kuiper Belt mission through to an Oort cloud mission. Mission requirements are defined and a detailed parametric trajectory analysis and launch date scan performed. Through analysis of the complete mission trade space a set of critical technology development requirements are identified which include an advanced lightweight composite High-Gain Antenna, a high-efficiency Ka-band travelling-wave tube amplifier and a radioisotope thermoelectric generator with power density of approximately 12 W/kg. It is also shown that the Interstellar Heliopause Probe mission necessitates the use of a spinning sail, limiting the direct application of current hardware development activities. A Kuiper Belt mission is then considered as a pre-curser to the Interstellar Heliopause Probe, while it is also shown through study of an Oort cloud mission that the Interstellar Heliopause Probe mission is the likely end-goal of any future solar sail technology development program. As such, the technology requirements identified to enable the Interstellar Heliopause Probe must be enabled through all prior missions, with each mission acting as an enabling facilitator towards the next

A genome-wide DNA methylation signature for SETD1B-related syndrome

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfeld, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript.info:eu-repo/semantics/publishedVersio

Two analogy strategies: The cases of mind metaphors and introspection

Analogical reasoning is often employed in problem-solving and metaphor interpretation. This paper submits that, as a default, analogical reasoning addressing these different tasks employs different mapping strategies: In problem-solving, it employs analogy-maximising strategies (like structure mapping, Gentner & Markman 1997); in metaphor interpretation, analogy-minimising strategies (like ATT-Meta, Barnden 2015). The two strategies interact in analogical reasoning with conceptual metaphors. This interaction leads to predictable fallacies. The paper supports these hypotheses through case-studies on ‘mind’-metaphors from ordinary discourse, and abstract problem-solving in the philosophy of mind, respectively: It shows that (1) default metaphorical interpretations for vision- and space-cognition metaphors can be derived with a variant of the analogy-minimising ATT-Meta approach, (2) philosophically influential introspective conceptions of the mind can be derived with conceptual metaphors only through an analogy-maximising strategy, and (3) the interaction of these strategies leads to hitherto unrecognised fallacies in analogical reasoning with metaphors. This yields a debunking explanation of introspective conceptions

A genome-wide DNA methylation signature for SETD1B-related syndrome

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients

Less is more: possibility and necessity as centres of gravity in a usage-based classification of core modals in Polish

In this paper we present the results of an empirical study into the cognitive reality of existing classifications of modality using Polish data. We analyzed random samples of 250 independent observations for the 7 most frequent modal words (móc, można, musieć, należy, powinien, trzeba, wolno), extracted from the Polish national corpus. Observations were annotated for modal type according to a number of classifications, including van der Auwera and Plungian (1998), as well as for morphological, syntactic and semantic properties using the Behavioral Profiling approach (Divjak and Gries 2006). Multiple correspondence analysis and (polytomous) regression models were used to determine how well modal type and usage align. These corpus-based findings were validated experimentally. In a forced choice task, naive native speakers were exposed to definitions and prototypical examples of modal types or functions, then labeled a number of authentic corpus sentences accordingly. In the sorting task, naive native speakers sorted authentic corpus sentences into semantically coherent groups. We discuss the results of our empirical study as well as the issues involved in building usage-based accounts on traditional linguistic classifications

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).clinical trial, phase iiicomparative studyjournal articlemulticenter studyrandomized controlled trialresearch support, non-u.s. gov't2012 Sep 20importedErratum in : N Engl J Med. 2012 Oct 25;367(17):1673

Identification of a Dual-Specific T Cell Epitope of the Hemagglutinin Antigen of an H5 Avian Influenza Virus in Chickens

Avian influenza viruses (AIV) of the H5N1 subtype have caused morbidity and mortality in humans. Although some migratory birds constitute the natural reservoir for this virus, chickens may play a role in transmission of the virus to humans. Despite the importance of avian species in transmission of AIV H5N1 to humans, very little is known about host immune system interactions with this virus in these species. The objective of the present study was to identify putative T cell epitopes of the hemagglutinin (HA) antigen of an H5 AIV in chickens. Using an overlapping peptide library covering the HA protein, we identified a 15-mer peptide, H5246–260, within the HA1 domain which induced activation of T cells in chickens immunized against the HA antigen of an H5 virus. Furthermore, H5246–260 epitope was found to be presented by both major histocompatibility complex (MHC) class I and II molecules, leading to activation of CD4+ and CD8+ T cell subsets, marked by proliferation and expression of interferon (IFN)-γ by both of these cell subsets as well as the expression of granzyme A by CD8+ T cells. This is the first report of a T cell epitope of AIV recognized by chicken T cells. Furthermore, this study extends the previous finding of the existence of dual-specific epitopes in other species to chickens. Taken together, these results elucidate some of the mechanisms of immune response to AIV in chickens and provide a platform for creation of rational vaccines against AIV in this species