Sulf1 influences the Shh morphogen gradient during the dorsal ventral patterning of the neural tube in Xenopus tropicalis

AbstractGenetic studies have established that heparan sulphate proteoglycans (HSPGs) are required for signalling by key developmental regulators, including Hedgehog, Wnt/Wg, FGF, and BMP/Dpp. Post-synthetic remodelling of heparan sulphate (HS) by Sulf1 has been shown to modulate these same signalling pathways. Sulf1 codes for an N-acetylglucosamine 6-O-endosulfatase, an enzyme that specifically removes the 6-O sulphate group from glucosamine in highly sulfated regions of HS chains. One striking aspect of Sulf1 expression in all vertebrates is its co-localisation with that of Sonic hedgehog in the floor plate of the neural tube. We show here that Sulf1 is required for normal specification of neural progenitors in the ventral neural tube, a process known to require a gradient of Shh activity. We use single-cell injection of mRNA coding for GFP-tagged Shh in early Xenopus embryos and find that Sulf1 restricts ligand diffusion. Moreover, we find that the endogenous distribution of Shh protein in Sulf1 knockdown embryos is altered, where a less steep ventral to dorsal gradient forms in the absence of Sulf1, resulting in more a diffuse distribution of Shh. These data point to an important role for Sulf1 in the ventral neural tube, and suggests a mechanism whereby Sulf1 activity shapes the Shh morphogen gradient by promoting ventral accumulation of high levels of Shh protein

Computational approaches for understanding the diagnosis and treatment of Parkinson's disease

This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson’s disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson’s by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way

Towards OPM-MEG in a virtual reality environment

Virtual reality (VR) provides an immersive environment in which a participant can experience a feeling of presence in a virtual world. Such environments generate strong emotional and physical responses and have been used for wide-ranging applications. The ability to collect functional neuroimaging data whilst a participant is immersed in VR would represent a step change for experimental paradigms; unfortunately, traditional brain imaging requires participants to remain still, limiting the scope of naturalistic interaction within VR. Recently however, a new type of magnetoencephalography (MEG) device has been developed, that employs scalp-mounted optically-pumped magnetometers (OPMs) to measure brain electrophysiology. Lightweight OPMs, coupled with precise control of the background magnetic field, enables participant movement during data acquisition. Here, we exploit this technology to acquire MEG data whilst a participant uses a virtual reality head-mounted display (VRHMD). We show that, despite increased magnetic interference from the VRHMD, we were able to measure modulation of alpha-band oscillations, and the visual evoked field. Moreover, in a VR experiment in which a participant had to move their head to look around a virtual wall and view a visual stimulus, we showed that the measured MEG signals map spatially in accordance with the known organisation of primary visual cortex. This technique could transform the type of neuroscientific experiment that can be undertaken using functional neuroimaging

Real-Time Detection and Rapid Multiwavelength Follow-up Observations of a Highly Subluminous Type II-P Supernova from the Palomar Transient Factory Survey

The Palomar Transient Factory (PTF) is an optical wide-field variability survey carried out using a camera with a 7.8 square degree field of view mounted on the 48-in Oschin Schmidt telescope at Palomar Observatory. One of the key goals of this survey is to conduct high-cadence monitoring of the sky in order to detect optical transient sources shortly after they occur. Here, we describe the real-time capabilities of the PTF and our related rapid multiwavelength follow-up programs, extending from the radio to the gamma-ray bands. We present as a case study observations of the optical transient PTF10vdl (SN 2010id), revealed to be a very young core-collapse (Type II-P) supernova having a remarkably low luminosity. Our results demonstrate that the PTF now provides for optical transients the real-time discovery and rapid-response follow-up capabilities previously reserved only for high-energy transients like gamma-ray bursts.Comment: ApJ, in press; all spectroscopic data available from the Weizmann Institute of Science Experimental Astrophysics Spectroscopy System (WISEASS; http://www.weizmann.ac.il/astrophysics/wiseass/

Longer-term oral antiplatelet use in stable post-myocardial infarction patients: Insights from the long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) observational study.

OBJECTIVE: To describe contemporary patient characteristics and treatment patterns, including antithrombotic management, of post-myocardial infarction (MI) stable coronary artery disease (CAD) patients at high atherothrombotic risk from different geographical regions. METHODS: Patients ≥50years with prior MI 1-3years ago and ≥1 risk factor (age ≥65years, diabetes, 2nd prior MI >1yr ago, multivessel CAD, creatinine clearance 15-1year was highest (39%) in Asia-Pacific and lowest (12%) in Europe. CONCLUSIONS: Despite guideline recommendations, 1 in 4 post-MI patients did not receive DAPT for ~1year. In contrast to guideline recommendations supporting newer ADPris, clopidogrel was mainly prescribed. Prior to recent RCT data supporting DAPT >1year post-MI/PCI, >1 in 4 patients have continued on DAPT, though with substantial international variability

Measuring nickel masses in Type Ia supernovae using cobalt emission in nebular phase spectra

The light curves of Type Ia supernovae (SNe Ia) are powered by the radioactive decay of $^{56}$Ni to $^{56}$Co at early times, and the decay of $^{56}$Co to $^{56}$Fe from ~60 days after explosion. We examine the evolution of the [Co III] 5892 A emission complex during the nebular phase for SNe Ia with multiple nebular spectra and show that the line flux follows the square of the mass of $^{56}$Co as a function of time. This result indicates both efficient local energy deposition from positrons produced in $^{56}$Co decay, and long-term stability of the ionization state of the nebula. We compile 77 nebular spectra of 25 SN Ia from the literature and present 17 new nebular spectra of 7 SNe Ia, including SN2014J. From these we measure the flux in the [Co III] 5892 A line and remove its well-behaved time dependence to infer the initial mass of $^{56}$Ni ($M_{Ni}$) produced in the explosion. We then examine $^{56}$Ni yields for different SN Ia ejected masses ($M_{ej}$ - calculated using the relation between light curve width and ejected mass) and find the $^{56}$Ni masses of SNe Ia fall into two regimes: for narrow light curves (low stretch s~0.7-0.9), $M_{Ni}$ is clustered near $M_{Ni}$ ~ 0.4$M_\odot$ and shows a shallow increase as $M_{ej}$ increases from ~1-1.4$M_\odot$; at high stretch, $M_{ej}$ clusters at the Chandrasekhar mass (1.4$M_\odot$) while $M_{Ni}$ spans a broad range from 0.6-1.2$M_\odot$. This could constitute evidence for two distinct SN Ia explosion mechanisms.Comment: 16 pages, 12 figures (main text), plus data tables in appendix. Spectra released on WISeREP. Submitted to MNRAS, comments welcom

Upper limits for undetected trace species in the stratosphere of Titan

In this paper we describe a first quantitative search for several molecules in Titan's stratosphere in Cassini CIRS infrared spectra. These are: ammonia (NH3), methanol (CH3OH), formaldehyde (H2CO), and acetonitrile (CH3CN), all of which are predicted by photochemical models but only the last of which observed, and not in the infrared. We find non-detections in all cases, but derive upper limits on the abundances from low-noise observations at 25{\deg}S and 75{\deg}N. Comparing these constraints to model predictions, we conclude that CIRS is highly unlikely to see NH3 or CH3OH emissions. However, CH3CN and H2CO are closer to CIRS detectability, and we suggest ways in which the sensitivity threshold may be lowered towards this goal.Comment: 11 pages plus 6 figure file

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan.Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30 mg/kg), or MM07 (10 mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment.Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4 weeks of treatment.Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.The Wellcome Trust 107715/Z/15/Z

The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo

Signaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of bioavailability, proteolytic instability and susceptibility to renal clearance. CMF-019, a small molecule apelin agonist that displays strong bias towards G protein signaling over β-arrestin (∼400 fold), may be more suitable. This study demonstrates that in addition to being a positive inotrope, CMF-019 caused dose-dependent vasodilatation in vivo (50 nmol 4.16 ± 1.18 mmHg, **p < 0.01; 500 nmol 6.62 ± 1.85 mmHg, **p < 0.01), without receptor desensitization. Furthermore, CMF-019 rescues human pulmonary artery endothelial cells from apoptosis induced by tumor necrosis factor α and cycloheximide (5.66 ± 0.97%, **p < 0.01) by approximately 50% of that observable with rhVEGF (11.59 ± 1.85%, **p < 0.01), suggesting it has disease-modifying potential in vitro. CMF-019 displays remarkable bias at the apelin receptor for a small molecule and importantly recapitulates all aspects of the cardiovascular responses to the endogenous ligand, [Pyr1]apelin-13, in vivo. Additionally, it is able to protect human pulmonary artery endothelial cells from apoptosis, suggesting that the beneficial effects observed with apelin agonists extend beyond hemodynamic alleviation and address disease etiology itself. These findings support CMF-019 as a G protein biased small molecule apelin agonist in vitro and in vivo that could form the basis for the design of novel therapeutic agents in chronic diseases, such as, pulmonary arterial hypertension