Fibroblast Growth Factor 22 Is Not Essential for Skin Development and Repair but Plays a Role in Tumorigenesis

PMCID: PMC3380851This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Bicaudal‐D1 regulates the intracellular sorting and signalling of neurotrophin receptors

We have identified a new function for the dynein adaptor Bicaudal D homolog 1 (BICD1) by screening a siRNA library for genes affecting the dynamics of neurotrophin receptor‐containing endosomes in motor neurons (MNs). Depleting BICD1 increased the intracellular accumulation of brain‐derived neurotrophic factor (BDNF)‐activated TrkB and p75 neurotrophin receptor (p75NTR) by disrupting the endosomal sorting, reducing lysosomal degradation and increasing the co‐localisation of these neurotrophin receptors with retromer‐associated sorting nexin 1. The resulting re‐routing of active receptors increased their recycling to the plasma membrane and altered the repertoire of signalling‐competent TrkB isoforms and p75NTR available for ligand binding on the neuronal surface. This resulted in attenuated, but more sustained, AKT activation in response to BDNF stimulation. These data, together with our observation that Bicd1 expression is restricted to the developing nervous system when neurotrophin receptor expression peaks, indicate that BICD1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand‐activated receptors

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Competition on a divided and ephemeral resource: Testing the assumptions. I. Aggregation

(1) We test the assumptions of the 'aggregation model' of coexistence on a divided and ephemeral resource: (i) that the competing stage is aggregated; (ii) that the distributions of individuals can be represented by a negative binomial distribution; and (iii) that the degree of aggregation can be represented by a constant parameter. The assumption of no association between species is tested in a following paper. (2) Tests are made on 360 datasets representing distributions of Diptera, particularly drosophilids, on a total of 7638 resource patches. Results indicate that for this data: (i) competing stages are strongly aggregated; (ii) the negative binomial is not an exact description but may be adequate; and (iii) aggregation varies with density. (3) We relax the assumption of constant aggregation and develop a model of two-species competition where aggregation varies with density. We show that, with observed estimates of parameters for drosophilids, coexistence between pairs of species with no resource partitioning remains likely despite strong local competition

Building bridges : some lessons from the Middle Ages on the long-term economic impact of bridges over the Thames

This study was inspired by the proposed Thames Gateway Bridge between Beckton and Woolwich and addresses the problem of calculating the long term economic impact of major capital projects, such as bridges. The study of medieval crossings of the Thames reveals that of 18 medieval bridges, only one was allowed to fall into neglect and disappear; the others, once built, remained, and were improved and enlarged and in most cases they or their successors are still present. The conclusion is that in the long term, perhaps the very long term, such capital projects rarely fail to be economically advantageous