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

Dispersion insensitive, high-speed optical clock recovery based on a mode-locked laser diode

An investigation into the effects of varying levels of chromatic dispersion on a mode- locked laser diode optical clock recovery process is presented. Results demonstrate that this technique is invariant to input dispersion varying between +75 ps/nm

Glyph visualization: A fail-safe design scheme based on quasi-hamming distances

© 1981-2012 IEEE. In many spatial and temporal visualization applications, glyphs provide an effective means for encoding multivariate data. However, because glyphs are typically small, they are vulnerable to various perceptual errors. This article introduces the concept of a quasi-Hamming distance in the context of glyph design and examines the feasibility of estimating the quasi-Hamming distance between a pair of glyphs and the minimal Hamming distance for a glyph set. The authors demonstrate the design concept by developing a file-system event visualization that can depict the activities of multiple users

Investigating the influence of the sulfur oxidation state on solid state conformation

Design, synthesis and structural characterization of a series of diphenylacetylene derivatives bearing organosulfur, amide and amine moieties has been achieved in which the molecular conformation is controlled through variation of the hydrogen bond properties on alteration of the oxidisation level of sulfur

The impact of storage conditions upon gentamicin coated antimicrobial implants

A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 °C, 75% relative humidity or exposure to light. The effect of γ-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography–mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities

Herschel limits on far-infrared emission from circumstellar dust around nearby Type Ia supernovae

We report upper limits on dust emission at far-infrared (IR) wavelengths from three nearby Type Ia supernovae: SNe 2011by, 2011fe and 2012cg. Observations were carried out at 70 um and 160 um with the Photodetector Array Camera and Spectrometer (PACS) on board the Herschel Space Observatory. None of the supernovae were detected in the far-IR, allowing us to place upper limits on the amount of pre-existing dust in the circumstellar environment. Due to its proximity, SN 2011fe provides the tightest constraints, M_dust < 7 * 10^-3 M_sun at a 3 sigma-level for dust temperatures T_dust ~500 K assuming silicate or graphite dust grains of size a = 0.1 um. For SNe 2011by and 2012cg the corresponding upper limits are less stringent, with M_dust < 0.1 M_sun for the same assumptions.Comment: 6 pages, 3 figures, 1 table. Accepted for publication in MNRA

E-cadherin can limit the transforming properties of activating β-catenin mutations

Wnt pathway deregulation is a common characteristic of many cancers. But only Colorectal Cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve a Wnt deregulation and acquire a crypt-progenitor-cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with significantly higher expression of the β-catenin binding partner E-cadherin. This increased expression is associated with a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction of E-cadherin synergised with an activating mutation of β-catenin so there was now a rapid CPC phenotype within the colon and SI. Thus there is a threshold of β-catenin that is required to drive transformation and E-cadherin can act as a buffer to prevent β-catenin accumulation

Please mind the gap: students’ perspectives of the transition in academic skills between A-level and degree level geography

This paper explores first-year undergraduates’ perceptions of the transition from studying geography at pre-university level to studying for a degree. This move is the largest step students make in their education, and the debate about it in the UK has been reignited due to the government’s planned changes to A-level geography. However, missing from most of this debate is an appreciation of the way in which geography students themselves perceive their transition to university. This paper begins to rectify this absence. Using student insights, we show that their main concern is acquiring the higher level skills required for university learning

A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and, in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targeting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed, an agenda for drug repurposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methods aimed at discovering novel chemical and biological means of targeting a short list of host and viral entities which should extend the arsenal of anti-SARS-CoV-2 agents. This longer term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.Welcome Trust 107715/Z/15/

W(h)ither the academy? An exploration of the role of university social work in shaping the future of social work in Europe

A controversial proposal to pilot the training of child protection social workers through an intensive work-based route in England is being supported and funded by the UK Government. Frontline, the brainchild of a former teacher, locates social work training within local authorities (‘the agency’) rather than university social work departments (‘the academy’) and has stimulated debate amongst social work academics about their role in shaping the direction of the profession. As a contribution to this debate, this paper explores the duality of social work education, which derives its knowledge from both the academic social sciences and the experience of practice within social work agencies. While social work education has traditionally been delivered by the academy, this paper also explores whether the delivery of training in the allied professions of probation and nursing by ‘the agency’ is equally effective. Finally, this paper explores the Helsinki model which achieves a synergy of ‘academy’ and ‘agency’. It suggests that there are alternative models of social work education, practice and research which avoid dichotomies between the ‘academy’ and the ‘agency’ and enable the profession to be shaped by both social work academics and practitioners