Planar cell polarity signalling couples cell division and morphogenesis during neurulation

Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births. Mouse and frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling might control neurulation by promoting the convergence of neural progenitors to the midline. Here we show a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a function for PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previously unrecognized mechanism that might underlie NTDs.     

Fracture behavior and microstructure analysis of Al2O3–MgO–CaO castables for steel-ladle purging plugs

Three different castables based on the Al₂O₃–MgO–CaO system were prepared as steel-ladle purging plug refractories: corundum- based low-cement castable (C-LCC), corundum-spinel-based low-cement castable (C-S-LCC), and corundum-spinel no-cement castable (C-S-NCC) (hydratable alumina (ρ-Al₂O₃) bonded). The fracture behavior at room temperature was tested by the method of “wedge-splitting” on samples pre-fired at different temperatures; the specific fracture energy G′_f and notched tensile strength σ_NT were obtained from these tests. In addition, the Young’s modulus E was measured by the method of resonance frequency of damping analysis (RFDA). The thermal stress resistance parameter R′′′′ calculated using the values of G′_f, σ_NT, and E was used to evaluate the thermal shock resistance of the materials. According to the microstructure analysis results, the sintering effect and the bonding type of the matrix material were different among these three castables, which explains their different fracture behaviors.     

Recognizing Treelike k-Dissimilarities

A k-dissimilarity D on a finite set X, |X|????k, is a map from the set of size k subsets of X to the real numbers. Such maps naturally arise from edgeweighted trees T with leaf-set X: Given a subset Y of X of size k, D(Y ) is defined to be the total length of the smallest subtree of T with leaf-set Y . In case k?=?2, it is well-known that 2-dissimilarities arising in this way can be characterized by the so-called ??4-point condition??. However, in case k?>?2 Pachter and Speyer (2004) recently posed the following question: Given an arbitrary k-dissimilarity, how do we test whether this map comes from a tree? In this paper, we provide an answer to this question, showing that for k????3 a k-dissimilarity on a set X arises from a tree if and only if its restriction to every 2?k-element subset of X arises from some tree, and that 2?k is the least possible subset size to ensure that this is the case. As a corollary, we show that there exists a polynomial-time algorithm to determine when a k-dissimilarity arises from a tree. We also give a 6-point condition for determining when a 3-dissimilarity arises from a tree, that is similar to the aforementioned 4-point condition.     

Reversal of pathological pain through specific spinal GABAA receptor subtypes

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.     

Facing glycosphingolipid–Shiga toxin interaction: dire straits for endothelial cells of the human vasculature

The two major Shiga toxin (Stx) types, Stx1 and Stx2, produced by enterohemorrhagic Escherichia coli (EHEC) in particular injure renal and cerebral microvascular endothelial cells after transfer from the human intestine into the circulation. Stxs are AB₅ toxins composed of an enzymatically active A subunit and the pentameric B subunit, which preferentially binds to the glycosphingolipid globotriaosylceramide (Gb3Cer/CD77). This review summarizes the current knowledge on Stx-caused cellular injury and the structural diversity of Stx receptors as well as the initial molecular interaction of Stxs with the human endothelium of different vascular beds. The varying lipoforms of Stx receptors and their spatial organization in lipid rafts suggest a central role in different modes of receptor-mediated endocytosis and intracellular destiny of the toxins. The design and development of tailored Stx neutralizers targeting the oligosaccharide–toxin recognition event has become a very real prospect to ameliorate or prevent life-threatening renal and neurological complications.