Travelling Together: A Unifying Pathomechanism for ALS

Axonal transport is critical for neuronal homeostasis and relies on motor complexes bound to cargoes via specific adaptors. However, the mechanisms responsible for the spatiotemporal regulation of axonal transport are not completely understood. A recent study by Liao et al. contributes to filling this gap by reporting that RNA granules ‘hitchhike’ on LAMP1-positive organelles using annexin A11 as a tether

Expanding the Toolkit for In Vivo Imaging of Axonal Transport

Axonal transport maintains neuronal homeostasis by enabling the bidirectional trafficking of diverse organelles and cargoes. Disruptions in axonal transport have devastating consequences for individual neurons and their networks, and contribute to a plethora of neurological disorders. As many of these conditions involve both cell autonomous and non-autonomous mechanisms, and often display a spectrum of pathology across neuronal subtypes, methods to accurately identify and analyze neuronal subsets are imperative. This paper details protocols to assess in vivo axonal transport of signaling endosomes and mitochondria in sciatic nerves of anesthetized mice. Stepwise instructions are provided to 1) distinguish motor from sensory neurons in vivo, in situ, and ex vivo by using mice that selectively express fluorescent proteins within cholinergic motor neurons; and 2) separately or concurrently assess in vivo axonal transport of signaling endosomes and mitochondria. These complementary intravital approaches facilitate the simultaneous imaging of different cargoes in distinct peripheral nerve axons to quantitatively monitor axonal transport in health and disease

Axonal transport and neurological disease

Axonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival. Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease. Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders. However, whether these impairments have a major causative role in, are contributing to or are simply a consequence of neuronal degeneration remains unclear. Therefore, the fundamental relevance of defective trafficking along axons to nerve dysfunction and pathology is often debated. In this article, we review the latest evidence emerging from human and in vivo studies on whether perturbations in axonal transport are indeed integral to the pathogenesis of neurological disease

Fast on-wafer electrical, mechanical, and electromechanical characterization of piezoresistive cantilever force sensors

Validation of a technological process requires an intensive characterization of the performance of the resulting devices, circuits or systems. The technology for the fabrication of Micro and Nanoelectromechanical systems is evolving rapidly, with new kind of device concepts for applications like sensing or harvesting are being proposed and demonstrated. However, the characterization tools and methods for these new devices are still nor fully developed. Here, we present an on-wafer, highly precise and rapid characterization method to measure the mechanical, electrical and electromechanical properties of piezoresistive cantilevers. The set-up is based on a combination of probe-card and atomic force microscopy (AFM) technology, it allows accessing many devices across a wafer and it can be applied to a broad range of MEMS and NEMS. Using this set-up we have characterized the performance of multiple submicron thick piezoresistive cantilever force sensors. For the best design we have obtained a force sensitivity RF=158 uV/nN, a noise of 5.8 uV (1Hz-1kHz) and a minimum detectable force (MDF) of 37 pN with a relative standard deviation of sigma=8%. This small value of sigma, together with a high fabrication yield >95%, validates our fabrication technology. The devices are intended to be used as bio-molecular detectors for the measurement of intermolecular forces between ligand and receptor molecule pairs.This work has been supported by MICINN through projects TEC2011-23600 and NANOSELECT-CSD2007- 00041 (Consolider-Ingenio 2010 Programme).Peer reviewe

The burden of renal cell cancer : A retrospective longitudinal study on occurrence, outcomes and cost using an administrative claims database

Abstract Objective To assess the burden of renal cell carcinoma (RCC) in epidemiologic and economic terms. Methods Retrospective, naturalistic longitudinal study on the occurrence, outcomes and cost of RCC using an administrative database. We selected residents of Friuli-Venezia-Giulia (FVG), a North-eastern Region of Italy, who had a RCC first hospital admission during the period 2000–2004, and we followed them up until: 30th June 2005, death or transfers. Direct medical costs were quantified in the perspective of FVG Regional Health Service. Results We enrolled 1358 patients (63% male), the 18.8% presenting a metastatic-stage, leading to a crude incidence of 23/100.000 person-years. During the follow-up, 76% of the metastatic patients and 21% of the non-metastatic patients died. Total health care costs per-patient over the maximum of follow-up were 16,090€ for the localised stage group and 17,656€ in the metastatic-stage group. Discussion RCC imposes a significant epidemiologic and economic burden to the healthcare-system and the society

The evolution of the axonal transport toolkit

Neurons are highly polarized cells that critically depend on long‐range, bidirectional transport between the cell body and synapse for their function. This continual and highly coordinated trafficking process, which takes place via the axon, has fascinated researchers since the early 20th century. Ramon y Cajal first proposed the existence of axonal trafficking of biological material after observing that dissociation of the axon from the cell body led to neuronal degeneration. Since these first indirect observations, the field has come a long way in its understanding of this fundamental process. However, these advances in our knowledge have been aided by breakthroughs in other scientific disciplines, as well as the parallel development of novel tools, techniques and model systems. In this review, we summarize the evolution of tools used to study axonal transport and discuss how their deployment has refined our understanding of this process. We also highlight innovative tools currently being developed and how their addition to the available axonal transport toolkit might help to address key outstanding questions

Role of Lipophilicity in the Activity of Hexameric Cyclic Peptoid Ion Carriers

Two families of hexameric cyclic peptoids decorated with linear N-alkyl and alternated N-alkyl/N-benzyl side chains (2 a\u2013d and 3 a\u2013c, respectively) were designed and synthesized in order to correlate their logP values (from 2.55 to 6.83) to their ionophoric activities. The present contribution confirms the general ability of hexameric cyclic peptoids to behave as efficient cation carriers, corroborates their preference for Na+ ion, among the tested alkali metals, and suggests a Na+/H+ antiport transport mechanism (rate limited by the transport of the proton) for these new ionophores. Our observations indicate that in order to attain an efficient ionophoric activity, a narrow range of liphophilicity is required (4<5). Moreover, to gain information on the solid state stucture of ionophoric cyclic peptoids with linear N-side chains, X-ray crystallographic studies were performed on exemplar compound 2 a. Crystal structure of compound 2 a confirms the tendency of ionophoric cyclopeptoids with linear N-side chains to form layered assemblies

Synthesis and complexing properties of cyclic benzylopeptoids-a new family of extended macrocyclic peptoids

An efficient protocol for the solid-phase synthesis of six members of a new class of extended macrocyclic peptoids (based on ortho-, meta- and para-N-(methoxyethyl)aminomethyl phenylacetyl units) is described. Theoretical (DFT) and experimental (NMR) studies on the free and Na+-complexed cyclic trimers (3\u20135) and tetramers (6\u20138) demonstrate that annulation of the rigidified peptoids can generate new hosts with the ability to sequestrate one or two sodium cations with the affinities and stoichiometries defined by the macrocycle morphology. Ion transport studies have been also performed in order to better appreciate the factors promoting transmembrane cation translocation