Endothelial PlexinD1 signaling instructs spinal cord vascularization and motor neuron development.

How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we reveal a crosstalk between motor neurons (MNs) and endothelial cells (ECs), necessary for the coordinated development of MNs. By analyzing cell-to-cell interaction profiles of the mouse developing spinal cord, we uncovered semaphorin 3C (Sema3C) and PlexinD1 as a communication axis between MNs and ECs. Using cell-specific knockout mice and in vitro assays, we demonstrate that removal of Sema3C in MNs, or its receptor PlexinD1 in ECs, results in premature and aberrant vascularization of MN columns. Those vascular defects impair MN axon exit from the spinal cord. Impaired PlexinD1 signaling in ECs also causes MN maturation defects at later stages. This study highlights the importance of a timely and spatially controlled communication between MNs and ECs for proper spinal cord development.

Whole-Mount Immunofluorescence Protocol for 3D Imaging, Reconstruction, and Quantification of Fourth Pharyngeal Arch Artery Formation.

Pharyngeal arch arteries (PAA) are formed early during mouse embryogenesis and remodel soon thereafter into the aortic arch arteries. Failure of these vessels to form or remodel results in congenital heart defects. This protocol is designed to study the formation of the PAA using whole-mount immunofluorescence staining, followed by tissue clearing with benzyl alcohol/benzyl benzoate (BAAB) and imaging by confocal microscopy. The fine cellular resolution obtained with this technique allows the embryonic vasculature of the pharyngeal arch artery endothelium to be visualized by surface rendering and quantitatively analyzed by counting the number of endothelial cells in both the PAA and the vascular plexus surrounding them.

PLXNA1 and PLXNA3 cooperate to pattern the nasal axons that guide gonadotropin-releasing hormone neurons.

Gonadotropin-releasing hormone (GnRH) neurons regulate puberty onset and sexual reproduction by secreting GnRH to activate and maintain the hypothalamic-pituitary-gonadal axis. During embryonic development, GnRH neurons migrate along olfactory and vomeronasal axons through the nose into the brain, where they project to the median eminence to release GnRH. The secreted glycoprotein SEMA3A binds its receptors neuropilin (NRP) 1 or NRP2 to position these axons for correct GnRH neuron migration, with an additional role for the NRP co-receptor PLXNA1. Accordingly, mutations in SEMA3A, NRP1, NRP2 and PLXNA1 have been linked to defective GnRH neuron development in mice and inherited GnRH deficiency in humans. Here, we show that only the combined loss of PLXNA1 and PLXNA3 phenocopied the full spectrum of nasal axon and GnRH neuron defects of SEMA3A knockout mice. Together with Plxna1, the human orthologue of Plxna3 should therefore be investigated as a candidate gene for inherited GnRH deficiency.

The long-lived Octodon degus as a rodent drug discovery model for Alzheimer's and other age-related diseases.

Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disease. Despite decades of research, no disease modifying therapy is available and a change of research objectives and/or development of novel research tools may be required. Much AD research has been based on experimental models using animals with a short lifespan that have been extensively genetically manipulated and do not represent the full spectrum of late-onset AD, which make up the majority of cases. The aetiology of AD is heterogeneous and involves multiple factors associated with the late-onset of the disease like disturbances in brain insulin, oxidative stress, neuroinflammation, metabolic syndrome, retinal degeneration and sleep disturbances which are all progressive abnormalities that could account for many molecular, biochemical and histopathological lesions found in brain from patients dying from AD. This review is based on the long-lived rodent Octodon degus (degu) which is a small diurnal rodent native to South America that can spontaneously develop cognitive decline with concomitant phospho-tau, ß-amyloid pathology and neuroinflammation in brain. In addition, the degu can also develop several other conditions like type 2 diabetes, macular and retinal degeneration and atherosclerosis, conditions that are often associated with aging and are often comorbid with AD. Long-lived animals like the degu may provide a more realistic model to study late onset AD.

The impact of delays on maternal and neonatal outcomes in Ugandan public health facilities: the role of absenteeism.

Maternal mortality in low- and middle-income countries continues to remain high. The Ugandan Ministry of Health's Strategic Plan suggests that little, if any, progress has been made in Uganda in terms of improvements in Maternal Health [Millennium Development Goal (MDG) 5] and, more specifically, in reducing maternal mortality. Furthermore, the UNDP report on the MDGs describes Uganda's progress as 'stagnant'. The importance of understanding the impact of delays on maternal and neonatal outcomes in low resource settings has been established for some time. Indeed, the '3-delays' model has exposed the need for holistic multi-disciplinary approaches focused on systems change as much as clinical input. The model exposes the contribution of social factors shaping individual agency and care-seeking behaviour. It also identifies complex access issues which, when combined with the lack of timely and adequate care at referral facilities, contributes to extensive and damaging delays. It would be hard to find a piece of research on this topic that does not reference human resource factors or 'staff shortages' as a key component of this 'puzzle'. Having said that, it is rare indeed to see these human resource factors explored in any detail. In the absence of detailed critique (implicit) 'common sense' presumptions prevail: namely that the economic conditions at national level lead to inadequacies in the supply of suitably qualified health professionals exacerbated by losses to international emigration. Eight years' experience of action-research interventions in Uganda combining a range of methods has lead us to a rather stark conclusion: the single most important factor contributing to delays and associated adverse outcomes for mothers and babies in Uganda is the failure of doctors to be present at work during contracted hours. Failure to acknowledge and respond to this sensitive problem will ultimately undermine all other interventions including professional voluntarism which relies on local 'co-presence' to be effective. Important steps forward could be achieved within the current resource framework, if the political will existed. International NGOs have exacerbated this problem encouraging forms of internal 'brain drain' particularly among doctors. Arguably the system as it is rewards doctors for non-compliance resulting in massive resource inefficiencies.

An in vitro study into the corrosion of intra-oral magnets in the presence of dental amalgam.

The aim of this investigation was to study the corrosion behaviour and products of uncoated neodymium-iron-boron magnets in the presence of dental amalgam. Microcosm plaques were grown on discs of neodymium-iron-boron magnets or amalgam in a constant depth film fermentor. The biofilms were supplied with artificial saliva and growth was determined by viable counting. The results showed that the neodymium-iron-boron magnets corroded with an average daily weight loss of 0.115 +/- 0.032 per cent. However, when the magnets were in close proximity to the amalgam the amount of corrosion was reduced to a daily loss of 0.066 +/- 0.023 per cent. The highest loss of constituent elements from the corrosion products of the magnets was observed for iron. The composition of the microcosm plaques altered markedly between the two materials with less streptococci and more Veillonella spp. present in the biofilms grown on magnets in the presence of amalgam. The corrosion of neodymium-iron-boron magnets is limited and in the presence of amalgam is reduced further. This suggests that amalgam present in the mouth will not cause an increased clinical risk in terms of biocompatibility with neodymium-iron-boron magnets.