Evidence for a novel feedback loop in the Hedgehog pathway involving the seven transmembranedomain protein Smoothened and the kinase Fused.

International audienceHedgehog (HH) is a major secreted morphogen involved in development, stem cell maintenance and oncogenesis[1, 2].In Drosophila wing imaginal discs, HH produced in the posterior compartment diffuses into the anterior compartment to control target gene transcription via the transcription factor Cubitus interruptus (CI). The first steps in reception and transduction of the HH signal are mediated by its receptor Patched (PTC)[3] and the seven-transmembranedomain protein Smoothened (SMO) [4, 5]. PTC and HH control SMOby regulating its stability, trafficking and phosphorylation (for review see [6]). SMO interacts directly with the Ser-Thr protein kinase Fused (FU) and the kinesin-related protein Costal2 (COS2), which interact with each other and with CI in an intracellular “Hedgehog transducing complex”[7-9].We show here that HH induces FUtargeting to the plasma membrane in a SMO-dependent fashion and that,reciprocally,FUcontrols SMO stability and phosphorylation. FUanchorage to the membrane is sufficient to make it a potent SMO-dependent, PTC-resistant, activator of the pathway. These findings reveal a novel positive-feedback loop in HH transduction and are consistent with a model in which FU and SMO, by mutually enhancing each other's activities, sustain high levels of signalingand render the pathway robust to PTClevel fluctuations

An investigation of data compression techniques for hyperspectral core imager data

We investigate algorithms for tractable analysis of real hyperspectral image data from core samples provided by AngloGold Ashanti. In particular, we investigate feature extraction, non-linear dimension reduction using diffusion maps and wavelet approximation methods on our data

Hedgehog signal transduction proteins: contacts of the Fused kinase and Ci transcription factor with the Kinesin-related protein Costal2

BACKGROUND: Hedgehog signaling proteins play important roles in development by controlling growth and patterning in various animals including Drosophila and mammals. Hedgehog signaling triggers changes in responsive cells through a novel transduction mechanism that ultimately controls the transcription of specific target genes via the activity of zinc finger transcription factors of the Cubitus interruptus /GLI family. In flies, key Hedgehog signal transduction components have been identified including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused. These proteins control Cubitus interruptus cleavage, nucleo-cytoplasmic localization and activation. In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner. RESULTS: Here we identified and mapped direct interactions between Cos2, Fu, and Ci using an in vitro affinity assay and the yeast two-hybrid system. CONCLUSIONS: Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction

Unusual Presentation of Pulmonary Hydatidosis Mimicking Thoracic Malignancy in a Paediatric South African Patient

In this case report, an illustrative case of pulmonary hydatidosis in a young South African girl is presented. The acute symptomatology, rapidly worsening clinical condition and the extremely atypical appearance of the hydatid cysts on imaging were initially misleading and raised suspicion for malignant disease

Intramedullary spinal masses : a pictorial essay

CITATION: Bezuidenhout, A.F., Lipsitz, J.M., Du Plessis, A. 2014. Intramedullary spinal masses: a pictorial essay. South African Journal of Radiology, 18(1):1-7, doi: 10.4102/sajr.v18i1.602.The original publication is available at http://www.sajr.org.za/index.php/sajrThis pictorial essay provides a classification system for the most common intramedullary spinal masses and describes distinguishing imaging features that will aid the radiologist in providing a relevant differential diagnosis to guide further management.http://www.sajr.org.za/index.php/sajr/article/view/602Publisher's versio

Submesoscale Fronts in the Antarctic Marginal Ice Zone and Their Response to Wind Forcing

Submesoscale flows in the ocean are energetic motions, O(1–10 km), that influence stratification and the distributions of properties, such as heat and carbon. They are believed to play an important role in sea‐ice‐impacted oceans by modulating air‐sea‐ice fluxes and sea‐ice extent. The intensity of these flows and their response to wind forcing are unobserved in the sea‐ice regions of the Southern Ocean. We present the first submesoscale‐resolving observations in the Antarctic marginal ice zone (MIZ) collected by surface and underwater autonomous vehicles, for >3 months in austral summer. We observe salinity‐dominated lateral density fronts occurring at sub‐kilometer scales. Surface winds are shown to modify the magnitude of the mixed‐layer density fronts, revealing strongly coupled atmosphere‐ocean processes. We posture that these wind‐front interactions occur as a continuous interplay between front slumping and vertical mixing, which leads to the dispersion of submesoscale fronts. Such processes are expected to be ubiquitous in the Southern Ocean MIZ

Submesoscale Fronts in the Antarctic Marginal Ice Zone and Their Response to Wind Forcing

Submesoscale flows in the ocean are energetic motions, O(1–10 km), that influence stratification and the distributions of properties, such as heat and carbon. They are believed to play an important role in sea‐ice‐impacted oceans by modulating air‐sea‐ice fluxes and sea‐ice extent. The intensity of these flows and their response to wind forcing are unobserved in the sea‐ice regions of the Southern Ocean. We present the first submesoscale‐resolving observations in the Antarctic marginal ice zone (MIZ) collected by surface and underwater autonomous vehicles, for >3 months in austral summer. We observe salinity‐dominated lateral density fronts occurring at sub‐kilometer scales. Surface winds are shown to modify the magnitude of the mixed‐layer density fronts, revealing strongly coupled atmosphere‐ocean processes. We posture that these wind‐front interactions occur as a continuous interplay between front slumping and vertical mixing, which leads to the dispersion of submesoscale fronts. Such processes are expected to be ubiquitous in the Southern Ocean MIZ

The use of confocal microscopy in quantifying changes in membrane potential

Monitoring the plasma membrane potential and its changes can be a time consuming and challenging task especially when conventional electrophysiological techniques are used. The use of potentiometric fluorophores, namely tetramethylrhodamine methylester (TMRM), and digital imaging devices (laser scanning confocal microscopy) provides reliable and time efficient method. Two scorpion pore-forming peptides, namely PP and OP1, were used as a tool to induce depolarization of the plasma membrane potential of neuroblastoma cell line and cardiac myocytes. Alternative methods for the neuroblastoma cells and cardiac myocytes were used. Depolarization of the neuroblastoma cells was calibrated with 140 mM KCl solution with 1 µM valinomycin, after which intensity readers were substituted in the Nernst equation for quantification. Calibration of the alternative method used of the cardiac myocytes' plasma membrane potential changes was calibrated with the use of 5, 20, 40, and 80 mM KCl solutions with 1 µM valinomycin. A calibration curve was then constructed from which plasma membrane potential could be calculated

Meningitis-associated pneumococcal serotype 8, ST 53, strain is hypervirulent in a rat model and has non-haemolytic pneumolysin which can be attenuated by liposomes

Introduction: Streptococcus pneumoniae bacteria cause life-threatening invasive pneumococcal disease (IPD), including meningitis. Pneumococci are classified into serotypes, determined by differences in capsular polysaccharide and both serotype and pneumolysin toxin are associated with disease severity. Strains of serotype 8, ST 53, are increasing in prevalence in IPD in several countries. Methods: Here we tested the virulence of such an isolate in a rat model of meningitis in comparison with a serotype 15B and a serotype 14 isolate. All three were isolated from meningitis patients in South Africa in 2019, where serotype 8 is currently the most common serotype in IPD. Results and Discussion: Only the serotype 8 isolate was hypervirulent causing brain injury and a high mortality rate. It induced a greater inflammatory cytokine response than either the serotype 15B or 14 strain in the rat model and from primary mixed-glia cells isolated from mouse brains. It had the thickest capsule of the three strains and produced non-haemolytic pneumolysin. Pneumolysin-sequestering liposomes reduced the neuroinflammatory cytokine response in vitro indicating that liposomes have the potential to be an effective adjuvant therapy even for hypervirulent pneumococcal strains with non-haemolytic pneumolysin