PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors have been characterised over the years, including formation of signalling-competent ligand-receptor complexes, their endocytosis and trafficking. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors are still elusive. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of brain-derived neurotrophic factor (BDNF) -activated TrkB and p75NTR in motor neurons. Here, using a proteomic approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1 knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors

A Disease With Many Faces

Can you diagnose this man with progressively worsening shortness of breath, mucous productive cough, weight loss, fatigue and a history of suspected pulmonary tuberculosis? http://bit.ly/2VUdnTr.info:eu-repo/semantics/publishedVersio

Asymptotic analysis of an elastic rod with rounded ends

We derive a one-dimensional model for an elastic shuttle, that is, a thin rod with rounded ends and small fixed terminals, by means of an asymptotic procedure of dimension reduction. In the model, deformation of the shuttle is described by a system of ordinary differential equations with variable degenerating coefficients, and the number of the required boundary conditions at the end points of the one-dimensional image of the rod depends on the roundness exponent m is an element of(0,1). Error estimates are obtained in the case m is an element of(0,1/4) by using an anisotropic weighted Korn inequality, which was derived in an earlier paper by the authors. We also briefly discuss boundary layer effects, which can be neglected in the case m is an element of(0,1/4) but play a crucial role in the formulation of the limit problem for m >= 1/4.Peer reviewe

Towards the use of hydrogels in the treatment of limbal stem cell deficiency

Corneal blindness caused by limbal stem cell deficiency (LSCD) is a prevailing disorder worldwide. Clinical outcomes for LSCD therapy using amniotic membrane (AM) are unpredictable. Hydrogels can eliminate limitations of standard therapy for LSCD, because they present all the advantages of AM (i.e. biocompatibility, inertness and a biodegradable structure) but unlike AM, they are structurally uniform and can be easily manipulated to alter mechanical and physical properties. Hydrogels can be delivered with minimum trauma to the ocular surface and do not require extensive serological screening before clinical application. The hydrogel structure is also amenable to modifications which direct stem cell fate. In this focussed review we highlight hydrogels as biomaterial substrates which may replace and/or complement AM in the treatment of LSCD

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Lepton Number Violation from Colored States at the LHC

The possibility to search for lepton number violating signals at the Large Hadron Collider (LHC) in the colored seesaw scenario is investigated. In this context the fields that generate neutrino masses at the one-loop level are scalar and Majorana fermionic color-octets of SU(3). Due to the QCD strong interaction these states may be produced at the LHC with a favorable rate. We study the production mechanisms and decays relevant to search for lepton number violation signals in the channels with same-sign dileptons. In the simplest case when the two fermionic color-octets are degenerate in mass, one could use their decays to distinguish between the neutrino spectra. We find that for fermionic octets with mass up to about 1 TeV the number of same-sign dilepton events is larger than the standard model background indicating a promising signal for new physics.Comment: minor corrections, added reference