Ligation of α-Dystroglycan on Podocytes Induces Intracellular Signaling: A New Mechanism for Podocyte Effacement?

Contains fulltext : 79974.pdf (publisher's version ) (Open Access)BACKGROUND: Alpha-dystroglycan is a negatively charged glycoprotein that covers the apical and basolateral membrane of the podocyte. Its transmembrane binding to the cytoskeleton is regulated via tyrosine phosphorylation (pY892) of beta-dystroglycan. At the basolateral side alpha-dystroglycan binds the glomerular basement membrane. At the apical membrane, it plays a role in the maintenance of the filtration slit. In this study, we evaluated whether ligation of alpha-dystroglycan with specific antibodies or natural ligands induces intracellular signaling, and whether there is an effect on podocyte architecture. METHODOLOGY/PRINCIPAL FINDINGS: Conditionally immortalized podocytes were exposed in vitro to antibodies to alpha-dystroglycan, and to fibronectin, biglycan, laminin and agrin. Intracellular calcium fluxes, phosphorylation of beta-dystroglycan and podocyte architecture were studied. Antibodies to alpha-dystroglycan could specifically induce calcium signaling. Fibronectin also induced calcium signaling, and led to dephosphorylation of pY892 in beta-dystroglycan. Ligation of alpha-dystroglycan resulted in an altered actin architecture, a decreased number of podocyte pedicles and a more flattened appearance of the podocyte. CONCLUSIONS/SIGNIFICANCE: We conclude that ligation of alpha-dystroglycan on podocytes induces intracellular calcium signaling, which leads to an altered cytoskeleton architecture akin to the situation of foot process effacement. In particular the ability of fibronectin to induce intracellular signaling events is of interest, since the expression and excretion of this protein is upregulated in several proteinuric diseases. Therefore, fibronectin-induced signaling via dystroglycan may be a novel mechanism for foot process effacement in proteinuric diseases

Benchmarking of electro-optic monitors for femtosecond electron bunches

The longitudinal profiles of ultrashort relativistic electron bunches at the soft x-ray free-electron laser FLASH have been investigated using two single-shot detection schemes: an electro-optic (EO) detector measuring the Coulomb field of the bunch and a radio-frequency structure transforming the charge distribution into a transverse streak. A comparison permits an absolute calibration of the EO technique. EO signals as short as 60 fs (rms) have been observed, which is a new record in the EO detection of single electron bunches and close to the limit given by the EO material properties

Electro-optic time profile monitors for femtosecond electron bunches at the soft x-ray free-electron laser FLASH

Precise measurements of the temporal profile of ultrashort electron bunches are of high interest for the optimization and operation of ultraviolet and x-ray free-electron lasers. The electro-optic (EO) technique has been applied for a single-shot direct visualization of the time profile of individual electron bunches at FLASH. This paper presents a thorough description of the experimental setup and the results. An absolute calibration of the EO technique has been performed utilizing simultaneous measurements with a transverse-deflecting radio-frequency structure that transforms the longitudinal bunch charge distribution into a transverse streak. EO signals as short as 60 fs (rms) have been observed using a gallium-phosphide (GaP) crystal, which is a new record in the EO detection of single electron bunches and close to the physical limit imposed by the EO material properties. The data are in quantitative agreement with a numerical simulation of the EO detection process

Single-shot longitudinal bunch profile measurements at FLASH using electro-optic detection:experiment, simulation, and validation

At the superconducting linac of FLASH at DESY, we have installed an electro-optic (EO) experiment for single- shot, non-destructive measurements of the longitudinal electric charge distribution of individual electron bunches. The time profile of the electric bunch field is electro- optically encoded onto a chirped titanium-sapphire laser pulse. In the decoding step, the profile is retrieved either from a cross-correlation of the encoded pulse with a 30 fs laser pulse, obtained from the same laser (electro- optic temporal decoding, EOTD), or from the spectral intensity of the transmitted probe pulse (electro-optic spectral decoding, EOSD). At FLASH, the longitudinally compressed electron bunches have been measured during FEL operation with a resolution of better than 50 fs. The electro-optic process in gallium phosphide was numerically simulated using as input data the bunch shapes determined with a transverse-deflecting RF structure. In this contribution, we present electro-optically measured bunch profiles and compare them with the simulation

A calibration method for broad-bandwidth cavity enhanced absorption spectroscopy performed with supercontinuum radiation

An efficient calibration method has been developed for broad-bandwidth cavity enhanced absorption spectroscopy. The calibration is performed using phase shift cavity ring-down spectroscopy, which is conveniently implemented through use of an acousto-optic tunable filter (AOTF). The AOTF permits a narrowband portion of the SC spectrum to be scanned over the full high-reflectivity bandwidth of the cavity mirrors. After calibration the AOTF is switched off and broad-bandwidth CEAS can be performed with the same light source without any loss of alignment to the set-up. We demonstrate the merits of the method by probing transitions of oxygen molecules O-2 and collisional pairs of oxygen molecules (O-2)(2) in the visible spectral range

Supporting parents of youths with intellectual disabilities and psychopathology

Background: Parents of children and adolescents with both intellectual disabilities (ID) and psychopathology often experience high levels of parenting stress. To support these parents, information is required regarding the types of support they need and whether their needs are met. Method: In a sample of 745 youths (aged 10-24 years) with moderate to borderline ID, 289 parents perceived emotional and/or behavioural problems in their child. They were asked about their needs for support and whether these needs were met. Logistic regression analysis revealed the variables associated with both needing and receiving specific types of support. In addition, we asked those parents who had refrained from seeking support about their reasons. Results: Most parents (88.2%) needed some supports, especially a friendly ear, respite care, child mental health care and information. Parents who perceived both emotional and behavioural problems in their child needed support the most. In addition, parents whose child had any of these problems before the past year, who worried most about their child and suffered from psychopathology themselves, more often needed support. Parents of children with moderate ID or physical problems especially needed 'relief care', that is, respite care, activities for the child and practical/material help. The need for a friendly ear was met most often (75.3%), whereas the need for parental counselling was met least often (35.5%). Not receiving support despite having a need for it was primarily related to the level of need. Parents who indicated to have a stronger need for support received support more often than parents who had a relatively low need for support. The parents' main reasons for not seeking support concerned their evaluation of their child's problems (not so serious or temporary), not knowing where to find support or wanting to solve the problems themselves first. Conclusions: Most parents had various support needs that were frequently unmet. Service providers should especially aim at providing information, activities, child mental health care and parental counselling. Furthermore, parents need to be informed about where and how they can obtain what kind of support. A case manager can be of help in this