Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Ferlins are an ancient family of Ca2+-binding, multi-C2 domain vesicle fusion proteins. Of the six human ferlins, mutations in dysferlin cause muscular dystrophy and otoferlin cause deafness. We detail the tissue-distribution, subcellular localization and endocytic trafficking of the human ferlins. Dysferlin and myoferlin, type-I ferlins, localize to the plasma membrane and late endosomes, which display potential for occasional recycling. Otoferlin and Fer1L6, type-II ferlins, localize to dedicated recycling subcompartments of the trans-Golgi network. We establish that type-I and type-II ferlins segregate into late-endosomal and recycling trans-Golgi compartments. Ferlins are a family of transmembrane-anchored vesicle fusion proteins uniquely characterized by 5-7 tandem cytoplasmic C2 domains, Ca2+-regulated phospholipid-binding domains that regulate vesicle fusion in the synaptotagmin family. In humans, dysferlin mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) due to defective Ca2+-dependent, vesicle-mediated membrane repair and otoferlin mutations cause non-syndromic deafness due to defective Ca2+-triggered auditory neurotransmission. In this study, we describe the tissue-specific expression, subcellular localization and endocytic trafficking of the ferlin family. Studies of endosomal transit together with 3D-structured illumination microscopy reveals dysferlin and myoferlin are abundantly expressed at the PM and cycle to Rab7-positive late endosomes, supporting potential roles in the late-endosomal pathway. In contrast, Fer1L6 shows concentrated localization to a specific compartment of the trans-Golgi/recycling endosome, cycling rapidly between this compartment and the PM via Rab11 recycling endosomes. Otoferlin also shows trans-Golgi to PM cycling, with very low levels of PM otoferlin suggesting either brief PM residence, or rare incorporation of otoferlin molecules into the PM. Thus, type-I and type-II ferlins segregate as PM/late-endosomal or trans-Golgi/recycling ferlins, consistent with different ferlins mediating vesicle fusion events in specific subcellular locations

Group Analysis of Variable Coefficient Diffusion-Convection Equations. I. Enhanced Group Classification

We discuss the classical statement of group classification problem and some its extensions in the general case. After that, we carry out the complete extended group classification for a class of (1+1)-dimensional nonlinear diffusion--convection equations with coefficients depending on the space variable. At first, we construct the usual equivalence group and the extended one including transformations which are nonlocal with respect to arbitrary elements. The extended equivalence group has interesting structure since it contains a non-trivial subgroup of non-local gauge equivalence transformations. The complete group classification of the class under consideration is carried out with respect to the extended equivalence group and with respect to the set of all point transformations. Usage of extended equivalence and correct choice of gauges of arbitrary elements play the major role for simple and clear formulation of the final results. The set of admissible transformations of this class is preliminary investigated.Comment: 25 page

A parametric model for the changes in the complex valued conductivity of a lung during tidal breathing

Classical homogenization theory based on the Hashin-Shtrikman coated ellipsoids is used to model the changes in the complex valued conductivity (or admittivity) of a lung during tidal breathing. Here, the lung is modeled as a two-phase composite material where the alveolar air-filling corresponds to the inclusion phase. The theory predicts a linear relationship between the real and the imaginary parts of the change in the complex valued conductivity of a lung during tidal breathing, and where the loss cotangent of the change is approximately the same as of the effective background conductivity and hence easy to estimate. The theory is illustrated with numerical examples, as well as by using reconstructed Electrical Impedance Tomography (EIT) images based on clinical data from an ongoing study within the EU-funded CRADL project. The theory may be potentially useful for improving the imaging algorithms and clinical evaluations in connection with lung EIT for respiratory management and monitoring in neonatal intensive care units

New results on group classification of nonlinear diffusion-convection equations

Using a new method and additional (conditional and partial) equivalence transformations, we performed group classification in a class of variable coefficient $(1+1)$-dimensional nonlinear diffusion-convection equations of the general form $f(x)u_t=(D(u)u_x)_x+K(u)u_x.$ We obtain new interesting cases of such equations with the density $f$ localized in space, which have large invariance algebra. Exact solutions of these equations are constructed. We also consider the problem of investigation of the possible local trasformations for an arbitrary pair of equations from the class under consideration, i.e. of describing all the possible partial equivalence transformations in this class.Comment: LaTeX2e, 19 page

Clinical performance of a novel textile interface for neonatal chest electrical impedance tomography

Objective: Critically ill neonates and infants might particularly benefit from continuous chest electrical impedance tomography (EIT) monitoring at the bedside. In this study a textile 32-electrode interface for neonatal EIT examination has been developed and tested to validate its clinical performance. The objectives were to assess ease of use in a clinical setting, stability of contact impedance at the electrode–skin interface and possible adverse effects. Approach: Thirty preterm infants (gestational age: 30.3 ± 3.9 week (mean ± SD), postnatal age: 13.8 ± 28.2 d, body weight at inclusion: 1727 ± 869 g) were included in this multicentre study. The electrode–skin contact impedances were measured continuously for up to 3 d and analysed during the initial 20-min phase after fastening the belt and during a 10 h measurement interval without any clinical interventions. The skin condition was assessed by attending clinicians. Main results: Our findings imply that the textile electrode interface is suitable for long-term neonatal chest EIT imaging. It does not cause any distress for the preterm infants or discomfort. Stable contact impedance of about 300 Ohm was observed immediately after fastening the electrode belt and during the subsequent 20 min period. A slight increase in contact impedance was observed over time. Tidal variation of contact impedance was less than 5 Ohm. Significance: The availability of a textile 32-electrode belt for neonatal EIT imaging with simple, fast, accurate and reproducible placement on the chest strengthens the potential of EIT to be used for regional lung monitoring in critically ill neonates and infants

Isolating the Effect of Arch Architecture on Aortic Hemodynamics Late After Coarctation Repair: A Computational Study

OBJECTIVES: Effective management of aortic coarctation (CoA) affects long-term cardiovascular outcomes. Full appreciation of CoA hemodynamics is important. This study aimed to analyze the relationship between aortic shape and hemodynamic parameters by means of computational simulations, purposely isolating the morphological variable. METHODS: Computational simulations were run in three aortic models. MRI-derived aortic geometries were generated using a statistical shape modeling methodology. Starting from n = 108 patients, the mean aortic configuration was derived in patients without CoA (n = 37, “no-CoA”), with surgically repaired CoA (n = 58, “r-CoA”) and with unrepaired CoA (n = 13, “CoA”). As such, the aortic models represented average configurations for each scenario. Key hemodynamic parameters (i.e., pressure drop, aortic velocity, vorticity, wall shear stress WSS, and length and number of strong flow separations in the descending aorta) were measured in the three models at three time points (peak systole, end systole, end diastole). RESULTS: Comparing no-CoA and CoA revealed substantial differences in all hemodynamic parameters. However, simulations revealed significant increases in vorticity at the site of CoA repair, higher WSS in the descending aorta and a 12% increase in power loss, in r-CoA compared to no-CoA, despite no clinically significant narrowing (CoA index >0.8) in the r-CoA model. CONCLUSIONS: Small alterations in aortic morphology impact on key hemodynamic indices. This may contribute to explaining phenomena such as persistent hypertension in the absence of any clinically significant narrowing. Whilst cardiovascular events in these patients may be related to hypertension, the role of arch geometry may be a contributory factor

Optimized breath detection algorithm in electrical impedance tomography

This paper defines a method for optimizing the breath delineation algorithms used in Electrical Impedance Tomography (EIT). In lung EIT the identification of the breath phases is central for generating tidal impedance variation images, subsequent data analysis and clinical evaluation. The optimisation of these algorithms is particularly important in neonatal care since the existing breath detectors developed for adults may give insufficient reliability in neonates due to their very irregular breathing pattern. Our approach is generic in the sense that it relies on the definition of a gold standard and the associated definition of detector sensitivity and specificity, an optimisation criterion and a set of detector parameters to be investigated. The gold standard has been defined by 11 clinicians with previous experience with EIT and the performance of our approach is described and validated using a neonatal EIT dataset acquired within the EU-funded CRADL project. Three different algorithms are proposed that are improving the breath detector performance by adding conditions on 1) maximum tidal breath rate obtained from zero-crossings of the EIT breathing signal, 2) minimum tidal impedance amplitude and 3) minimum tidal breath rate obtained from Time-Frequency (TF) analysis. As a baseline the zero crossing algorithm has been used with some default parameters based on the Swisstom EIT device. Based on the gold standard, the most crucial parameters of the proposed algorithms are optimised by using a simple exhaustive search and a weighted metric defined in connection with the Receiver Operating Characterics (ROC). This provides a practical way to achieve any desirable trade-off between the sensitivity and the specificity of the detectors. [Abstract copyright: © 2018 Institute of Physics and Engineering in Medicine.

Effect of routine suction on lung aeration in critically ill neonates and young infants measured with electrical impedance tomography

oai:repository.mdx.ac.uk:y1752Endotracheal suctioning is a widely used procedure to remove secretions from the airways of ventilated patients. Despite its prevalence, regional effects of this maneuver have seldom been studied. In this study, we explore its effects on regional lung aeration in neonates and young infants using electrical impedance tomography (EIT) as part of the large EU-funded multicenter observational study CRADL. 200 neonates and young infants in intensive care units were monitored with EIT for up to 72 h. EIT parameters were calculated to detect changes in ventilation distribution, ventilation inhomogeneity and ventilation quantity on a breath-by-breath level 5–10 min before and after suctioning. The intratidal change in aeration over time was investigated by means of regional expiratory time constants calculated from all respiratory cycles using an innovative procedure and visualized by 2D maps of the thoracic cross-section. 344 tracheal suctioning events from 51 patients could be analyzed. They showed no or very small changes of EIT parameters, with a dorsal shift of the center of ventilation by 0.5% of the chest diameter and a 7% decrease of tidal impedance variation after suctioning. Regional time constants did not change significantly. Routine suctioning led to EIT- detectable but merely small changes of the ventilation distribution in this study population. While still a measure requiring further study, the time constant maps may help clinicians interpret ventilationmechanics in specific cases

Model selection based algorithm in neonatal Chest EIT

This paper presents a new method for selecting a patient specific forward model to compensate for anatomical variations in electrical impedance tomography (EIT) monitoring of neonates. The method uses a combination of shape sensors and absolute reconstruction. It takes advantage of a probabilistic approach which automatically selects the best estimated forward model fit from pre-stored library models. Absolute/static image reconstruction is performed as the core of the posterior probability calculations. The validity and reliability of the algorithm in detecting a suitable model in the presence of measurement noise is studied with simulated and measured data from 11 patients. The paper also demonstrates the potential improvements on the clinical parameters extracted from EIT images by considering a unique case study with a neonate patient undergoing computed tomography imaging as clinical indication prior to EIT monitoring. Two well-known image reconstruction techniques, namely GREIT and tSVD, are implemented to create the final tidal images. The impacts of appropriate model selection on the clinical extracted parameters such as center of ventilation and silent spaces are investigated. The results show significant improvements to the final reconstructed images and more importantly to the clinical EIT parameters extracted from the images that are crucial for decision-making and further interventions