New insights into the molecular mechanisms specifying neuronal polarity in vivo

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Important progress has been made towards the identification of the molecular mechanisms regulating neuronal polarization using primarily in vitro approaches such as dissociated culture of rodent hippocampal neurons. The predominant view emerging from this paradigm is that neuronal polarization is initiated by intrinsic activation of signaling pathways underlying the initial break in neuronal symmetry that precedes the future asymmetric growth of the axon. Recent evidence shows that (i) axon-dendrite polarization is specified when neurons engage migration in vivo, (ii) a kinase pathway defined by LKB1and SAD-kinases (Par4/Par1 dyad) is required for proper neuronal polarization in vivo and that (iii) extracellular cues can play an instructive role during neuronal polarization. Here, we review some of these recent results and highlight future challenges in the field including the determination of how extracellular cues control intracellular responses underlying neuronal polarization in vivo

1-(5-Chloro-2,4-dihydroxy­phen­yl)-2-(4-ethoxy­phen­yl)ethanone

The structure of the title compound, C16H15ClO4, contains aryl rings which are inclined by 75.6 (1)° to each other. It displays intra­molecular O—H⋯O hydrogen bonding between the 2-hydr­oxy and carbonyl groups, forming a six-membered ring. Furthermore, the 4-hydr­oxy group, acting as a hydrogen-bond donor, is bound to the O atom of the 2-hydr­oxy group of another mol­ecule

Chiral Extrapolations and Exotic Meson Spectrum

We examine the chiral corrections to exotic meson masses calculated in lattice QCD. In particular, we ask whether the non-linear chiral behavior at small quark masses, which has been found in other hadronic systems, could lead to large corrections to the predictions of exotic meson masses based on linear extrapolations to the chiral limit. We find that our present understanding of exotic meson decay dynamics suggests that open channels may not make a significant contribution to such non-linearities whereas the virtual, closed channels may be important.Comment: 13 pagers, 2 figure

‘I’d be proud to spend the sacred foreign aid budget on our poor pensioners’: Representations of macro aid resourcing in the Irish, UK and US print-media during the economic crisis, 2008–2011

The news-media has been identified as an influence on donor nations’ overseas aid allocations, acting as a site where decisions are justified to ‘domestic constituencies’ and through which resistance is mobilised. Mediated pressures on aid allocations amplified between 2008 and 2011 in three donor countries experiencing domestic economic difficulties: Ireland, the UK and the US. This study suggests that each country’s print-media positioned the macro resourcing of aid primarily as an inward concern, neglected recipient country needs, and made weak connections to international policy frameworks to benchmark, contextualise and rationalise aid allocations. The research suggests that the explanatory limitations of the countries’ news-models in communicating the processes and rationales underpinning macro aid resourcing may be a factor in sustaining a knowledge and legitimacy deficit among domestic publics for international aid agreements

An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors

<p>Abstract</p> <p>Background</p> <p>CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no <it>in vitro </it>models that reproduce these features of myelination failure.</p> <p>Results</p> <p>Forebrain coronal slices from postnatal day (P) 0.5/1 rat pups were cultured for 1, 5, or 9 days <it>in vitro </it>(DIV). Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA), an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2⁺OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα⁺and PDGFRα⁺/Ki67⁺OPCs were significantly elevated compared to 0 DIV (<it>P </it>< 0.01). Despite this proliferative response, at 9 DIV ~60% of white matter OLs were late progenitors (preOLs), compared to ~7% in the postnatal day 10 rat (<it>P </it>< 0.0001), consistent with preOL maturation arrest. Addition of HA to slices significantly decreased the density of MBP⁺OLs at 9 DIV compared to controls (217 ± 16 <it>vs. </it>328 ± 17 cells/mm², respectively; <it>P </it>= 0.0003), supporting an inhibitory role of HA in OL lineage progression in chronic lesions.</p> <p>Conclusions</p> <p>Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation.</p

Respiratory pathogen colonisation of dental plaque, the lower airways and endotracheal tube biofilms during mechanical ventilation

Purpose In mechanically ventilated patients, the endotracheal tube is an essential interface between the patient and ventilator, but inadvertently, it also facilitates the development of ventilator-associated pneumonia (VAP) by subverting pulmonary host defenses. A number of investigations suggest that bacteria colonizing the oral cavity may be important in the etiology of VAP. The present study evaluated microbial changes that occurred in dental plaque and lower airways of 107 critically ill mechanically ventilated patients. Materials and Methods Dental plaque and lower airways fluid was collected during the course of mechanical ventilation, with additional samples of dental plaque obtained during the entirety of patients' hospital stay. Results A “microbial shift” occurred in dental plaque, with colonization by potential VAP pathogens, namely, Staphylococcus aureus and Pseudomonas aeruginosa in 35 patients. Post-extubation analyses revealed that 70% and 55% of patients whose dental plaque included S aureus and P aeruginosa, respectively, reverted back to having a predominantly normal oral microbiota. Respiratory pathogens were also isolated from the lower airways and within the endotracheal tube biofilms. Conclusions To the best of our knowledge, this is the largest study to date exploring oral microbial changes during both mechanical ventilation and after recovery from critical illness. Based on these findings, it was apparent that during mechanical ventilation, dental plaque represents a source of potential VAP pathogens

[12CII] and [13CII] 158 mum emission from NGC 2024: Large column densities of ionized carbon

Context: We analyze the NGC 2024 HII region and molecular cloud interface using [12CII] and [13CII] observations. Aims: We attempt to gain insight into the physical structure of the interface layer between the molecular cloud and the HII region. Methods. Observations of [12CII] and [13CII] emission at 158 {\mu}m with high spatial and spectral resolution allow us to study the detailed structure of the ionization front and estimate the column densities and temperatures of the ionized carbon layer in the PDR. Results: The [12CII] emission closely follows the distribution of the 8 mum continuum. Across most of the source, the spectral lines have two velocity peaks similar to lines of rare CO isotopes. The [13CII] emission is detected near the edge-on ionization front. It has only a single velocity component, which implies that the [12CII] line shape is caused by self-absorption. An anomalous hyperfine line-intensity ratio observed in [13CII] cannot yet be explained. Conclusions: Our analysis of the two isotopes results in a total column density of N(H)~1.6\times10^23 cm^-2 in the gas emitting the [CII] line. A large fraction of this gas has to be at a temperature of several hundred K. The self-absorption is caused by a cooler (T<=100 K) foreground component containing a column density of N(H)~10^22 cm^-2

LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. We show here that the serine/threonine kinase LKB1, previously implicated in the establishment of epithelial polarity and control of cell growth, is required for axon specification during neuronal polarization in the mammalian cerebral cortex. LKB1 polarizing activity requires its association with the pseudokinase Stradalpha and phosphorylation by kinases such as PKA and p90RSK, which transduce neurite outgrowth-promoting cues. Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex. SAD kinases, in turn, phosphorylate effectors such as microtubule-associated proteins that implement polarization. Thus, we provide evidence in vivo and in vitro for a multikinase pathway that links extracellular signals to the intracellular machinery required for axon specification

TGF-β Signaling Specifies Axons during Brain Development

In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown. Here, we report that transforming growth factor-β (TGF-β) initiates signaling pathways both in vivo and in vitro to fate naïve neurites into axons. Neocortical neurons lacking the type II TGF-β receptor (TβR2) fail to initiate axons during development. Exogenous TGF-β is sufficient to direct the rapid growth and differentiation of an axon, and genetic enhancement of receptor activity promotes the formation of multiple axons. Finally, we show that the bulk of these TGF-β-dependent events are mediated by site-specific phosphorylation of Par6. These results define an extrinsic cue for neuronal polarity in vivo that patterns neural circuits in the developing brain