Control of neurite growth and guidance by an inhibitory cell-body signal

The development of a functional nervous system requires tight control of neurite growth and guidance by extracellular chemical cues. Neurite growth is astonishingly sensitive to shallow concentration gradients, but a widely observed feature of both growth and guidance regulation, with important consequences for development and regeneration, is that both are only elicited over the same relatively narrow range of concentrations. Here we show that all these phenomena can be explained within one theoretical framework. We first test long-standing explanations for the suppression of the trophic effects of nerve growth factor at high concentrations, and find they are contradicted by experiment. Instead we propose a new hypothesis involving inhibitory signalling among the cell bodies, and then extend this hypothesis to show how both growth and guidance can be understood in terms of a common underlying signalling mechanism. This new model for the first time unifies several key features of neurite growth regulation, quantitatively explains many aspects of experimental data, and makes new predictions about unknown details of developmental signalling

Global health partnerships: building multi-national collaborations to achieve lasting improvements in maternal and neonatal health

Abstract Background In response to health care challenges worldwide, extensive funding has been channeled to the world’s most vulnerable health systems. Funding alone is not sufficient to address the complex issues and challenges plaguing these health systems. To see lasting improvement in maternal and infant health outcomes in the developing world, a global commitment to the sharing of knowledge and resources through international partnerships is critical. But partnerships that merely introduce western medical techniques and protocols to low resource settings, without heeding the local contexts, are misguided and unsustainable. Forming partnerships with mutual respect, shared vision, and collaborative effort is needed to ensure that all parties, irrespective of whether they belong to resource rich or resource poor settings, learn from each other so that meaningful and sustained system strengthening can take place. Methods In this paper, we describe the partnership building model of an international NGO, Kybele, which is committed to achieving childbirth safety through sustained partnerships in low resource settings. The Kybele model adapts generic stages of successful partnerships documented in the literature to four principles relevant to Kybele’s work. A multiple-case study approach is used to demonstrate how the model is applied in different country settings. Results The four principle of Kybele’s partnership model are robust drivers of successful partnerships in diverse country settings. Conclusions Much has been written about the need for multi-country partnerships to achieve sustainable outcomes in global health, but few papers in the literature describe how this has been achieved in practice. A strong champion, support and engagement of stakeholders, co-creation of solutions with partners, and involvement of partners in the delivery of solutions are all requirements for successful and sustained partnerships

Global health partnerships: building multi-national collaborations to achieve lasting improvements in maternal and neonatal health

Abstract Background In response to health care challenges worldwide, extensive funding has been channeled to the world’s most vulnerable health systems. Funding alone is not sufficient to address the complex issues and challenges plaguing these health systems. To see lasting improvement in maternal and infant health outcomes in the developing world, a global commitment to the sharing of knowledge and resources through international partnerships is critical. But partnerships that merely introduce western medical techniques and protocols to low resource settings, without heeding the local contexts, are misguided and unsustainable. Forming partnerships with mutual respect, shared vision, and collaborative effort is needed to ensure that all parties, irrespective of whether they belong to resource rich or resource poor settings, learn from each other so that meaningful and sustained system strengthening can take place. Methods In this paper, we describe the partnership building model of an international NGO, Kybele, which is committed to achieving childbirth safety through sustained partnerships in low resource settings. The Kybele model adapts generic stages of successful partnerships documented in the literature to four principles relevant to Kybele’s work. A multiple-case study approach is used to demonstrate how the model is applied in different country settings. Results The four principle of Kybele’s partnership model are robust drivers of successful partnerships in diverse country settings. Conclusions Much has been written about the need for multi-country partnerships to achieve sustainable outcomes in global health, but few papers in the literature describe how this has been achieved in practice. A strong champion, support and engagement of stakeholders, co-creation of solutions with partners, and involvement of partners in the delivery of solutions are all requirements for successful and sustained partnerships

Voltammetric monitoring of laccase-catalysed mediated reactions

Six different compounds capable of mediating laccase-catalysed reactions have been tested by cyclic voltammetry. They exhibited quasi-reversible electrodic behaviour with formal redox potentials ranging from 150 to 800 mV (E-0t vs. SCE). The immersion of a laccase-coated glassy carbon electrode (GCE) in mediator solutions generated large cathodic catalytic currents easily recorded by cyclic voltammetry at low-potential scan rates. This current showed two well-defined pH profiles, which correlated with the variation of the mediator redox potentials at the pH range tested. The relevant effect of temperature on the activity of laccase has been assessed here. Likewise, it was shown that the cut-rent record varied with the substrate concentration. This trend fitted Michaelis-Menten kinetics, which allowed us to give an estimation of the affinity of the fungal laccase for the different mediators. (C) 2002 Elsevier Science B.V. All rights reserved

Identification and expression of voltage-gated calcium channel Β subunits in Zebrafish

Voltage-gated calcium channels (VGCC) play important roles in electrically excitable cells and embryonic development. The VGCC Β subunits are essential for membrane localization of the channel and exert modulatory effects on channel functions. In mammals, the VGCC Β subunit gene family contains four members. In zebrafish, there appear to be seven VGCC Β subunits including the previously identified Β1 subunit. cDNAs for six additional VGCC Β subunit homologs were identified in zebrafish, their chromosomal locations determined and their expression patterns characterized during embryonic development. These six genes are primarily expressed in the nervous system with cacnb4a also expressed in the developing heart. Sequence homology, genomic synteny and expression patterns suggest that there are three pairs of duplicate genes for Β2, Β3, and Β4 in zebrafish with distinct expression patterns during embryonic development. Developmental Dynamics 237:3842–3852, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61457/1/21776_ftp.pd

The dynamics of growth cone morphology

Background: Normal brain function depends on the development of appropriate patterns of neural connections. A critical role in guiding axons to their targets during neural development is played by neuronal growth cones. These have a complex and rapidly changing morphology; however, a quantitative understanding of this morphology, its dynamics and how these are related to growth cone movement, is lacking

A requirement for filopodia extension toward Slit during Robo-mediated axon repulsion

Axons navigate long distances through complex 3D environments to interconnect the nervous system during development. Although the precise spatiotemporal effects of most axon guidance cues remain poorly characterized, a prevailing model posits that attractive guidance cues stimulate actin polymerization in neuronal growth cones whereas repulsive cues induce actin disassembly. Contrary to this model, we find that the repulsive guidance cue Slit stimulates the formation and elongation of actin-based filopodia from mouse dorsal root ganglion growth cones. Surprisingly, filopodia form and elongate toward sources of Slit, a response that we find is required for subsequent axonal repulsion away from Slit. Mechanistically, Slit evokes changes in filopodium dynamics by increasing direct binding of its receptor, Robo, to members of the actin-regulatory Ena/VASP family. Perturbing filopodium dynamics pharmacologically or genetically disrupts Slit-mediated repulsion and produces severe axon guidance defects in vivo. Thus, Slit locally stimulates directional filopodial extension, a process that is required for subsequent axonal repulsion downstream of the Robo receptor.National Institutes of Health (U.S.) (Grant F32-CA165700)National Institutes of Health (U.S.) (Grant R01-GM068678)National Institutes of Health (U.S.) (Grant P30-CA014051