Feedback Mechanism for Microtubule Length Regulation by Stathmin Gradients

We formulate and analyze a theoretical model for the regulation of microtubule (MT) polymerization dynamics by the signaling proteins Rac1 and stathmin. In cells, the MT growth rate is inhibited by cytosolic stathmin, which, in turn, is inactivated by Rac1. Growing MTs activate Rac1 at the cell edge, which closes a positive feedback loop. We investigate both tubulin sequestering and catastrophe promotion as mechanisms for MT growth inhibition by stathmin. For a homogeneous stathmin concentration in the absence of Rac1, we find a switch-like regulation of the MT mean length by stathmin. For constitutively active Rac1 at the cell edge, stathmin is deactivated locally, which establishes a spatial gradient of active stathmin. In this gradient, we find a stationary bimodal MT length distributions for both mechanisms of MT growth inhibition by stathmin. One subpopulation of the bimodal length distribution can be identified with fast growing and long pioneering MTs in the region near the cell edge, which have been observed experimentally. The feedback loop is closed through Rac1 activation by MTs. For tubulin sequestering by stathmin, this establishes a bistable switch with two stable states: one stable state corresponds to upregulated MT mean length and bimodal MT length distributions, i.e., pioneering MTs; the other stable state corresponds to an interrupted feedback with short MTs. Stochastic effects as well as external perturbations can trigger switching events. For catastrophe promoting stathmin we do not find bistability

Active Brownian particles moving in a random Lorentz gas

Biological microswimmers often inhabit a porous or crowded environment such as soil. In order to understand how such a complex environment influences their spreading, we numerically study non-interacting active Brownian particles (ABPs) in a two-dimensional random Lorentz gas. Close to the percolation transition in the Lorentz gas, they perform the same subdiffusive motion as ballistic and diffusive particles. However, due to their persistent motion they reach their long-time dynamics faster than passive particles and also show superdiffusive motion at intermediate times. While above the critical obstacle density ηcthe ABPs are trapped, their long-time diffusion belowηcis strongly influenced by the propulsion speed v0. With increasing v0, ABPs are stuck at the obstacles for longer times. Thus, for large propulsion speed, the long-time diffusion constant decreases more strongly in a denser obstacle environment than for passive particles. This agrees with the behavior of an effective swimming velocity and persistence time, which we extract from the velocity autocorrelation function

Reversibility of Red blood Cell deformation

The ability of cells to undergo reversible shape changes is often crucial to their survival. For Red Blood Cells (RBCs), irreversible alteration of the cell shape and flexibility often causes anemia. Here we show theoretically that RBCs may react irreversibly to mechanical perturbations because of tensile stress in their cytoskeleton. The transient polymerization of protein fibers inside the cell seen in sickle cell anemia or a transient external force can trigger the formation of a cytoskeleton-free membrane protrusion of micrometer dimensions. The complex relaxation kinetics of the cell shape is shown to be responsible for selecting the final state once the perturbation is removed, thereby controlling the reversibility of the deformation. In some case, tubular protrusion are expected to relax via a peculiar "pearling instability".Comment: 4 pages, 3 figure

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1

Background: Spinocerebellar ataxia type 1 (SCA-ATXN1) is an inherited progressive ataxia disorder characterized by an adult-onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described. Objectives: To describe a retinal phenotype and its functional relevance in SCA-ATXN1. Methods: We applied optical coherence tomography (OCT) in 20 index cases with SCA-ATXN1 and 22 healthy controls (HCs), investigating qualitative changes and quantifying the peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIP) volume as markers of optic atrophy and outer retinal layers as markers of maculopathy. Visual function was assessed by high- (HC-VA) and low-contrast visual acuity (LC-VA) and the Hardy-Rand-Rittler pseudoisochromatic test for color vision. Results: Five patients (25%) showed distinct maculopathies in the ellipsoid zone (EZ). Furthermore, pRNFL (P < 0.001) and GCIP (P = 0.002) were reduced in patients (pRNFL, 80.86 ± 9.49 μm; GCIP, 1.84 ± 0.16 mm3) compared with HCs (pRNFL, 97.02 ± 8.34 μm; GCIP, 1.98 ± 0.12 mm3). Outer macular layers were similar between groups, but reduced in patients with maculopathies. HC-VA (P = 0.002) and LC-VA (P < 0.001) were reduced in patients (HC-VA [logMAR]: 0.01 ± 010; LC-VA [logMAR]: 0.44 ± 0.16) compared with HCs (HC-VA [logMAR]: –0.12 ± 0.08; LC-VA [logMAR]: 0.25 ± 0.05). Color vision was abnormal in 2 patients with maculopathies. Conclusions: A distinct maculopathy, termed EZ disruption, as well as optic atrophy add to the known nonataxia features in SCA-ATXN1. Whereas optic atrophy may be understood as part of a widespread neurodegeneration, EZ disruption may be explained by effects of ataxin-1 gene or protein on photoreceptors. Our findings extend the spectrum of nonataxia signs in SCA-ATXN1 with potential relevance for diagnosis and monitoring

Disease-causing mutations in BEST1 gene are associated with altered sorting of bestrophin-1 protein

Doumanov, Jordan A. et al.Mutations in BEST1 gene, encoding the bestrophin-1 (Best1) protein are associated with macular dystrophies. Best1 is predominantly expressed in the retinal pigment epithelium (RPE), and is inserted in its basolateral membrane. We investigated the cellular localization in polarized MDCKII cells of disease-associated Best1 mutant proteins to study specific sorting motifs of Best1. Real-time PCR and western blots for endogenous expression of BEST1 in MDCK cells were performed. Best1 mutant constructs were generated using site-directed mutagenesis and transfected in MDCK cells. For protein sorting, confocal microscopy studies, biotinylation assays and statistical methods for quantification of mislocalization were used. Analysis of endogenous expression of BEST1 in MDCK cells revealed the presence of BEST1 transcript but no protein. Confocal microscopy and quantitative analyses indicate that transfected normal human Best1 displays a basolateral localization in MDCK cells, while cell sorting of several Best1 mutants (Y85H, Q96R, L100R, Y227N, Y227E) was altered. In contrast to constitutively active Y227E, constitutively inactive Y227F Best1 mutant localized basolaterally similar to the normal Best1 protein. Our data suggest that at least three basolateral sorting motifs might be implicated in proper Best1 basolateral localization. In addition, non-phosphorylated tyrosine 227 could play a role for basolateral delivery. © 2013 by the authors; licensee MDPI, Basel, Switzerland.This work was supported by Agence Nationale de la Recherche (Chaire d’Excellence to Shomi S. Bhattacharya), Fondation Voir et Entendre (Young Investigator Grants to Christina Zeitz and Emeline F. Nandrot), Centre National de la Recherche Scientifique (CNRS) and Fondation Bettencourt Schueller (to Emeline F. Nandrot), Université Pierre et Marie Curie-Paris6 (Bonus Qualité Recherche to Christina Zeitz), Foundation Fighting Blindness (grant number CD-CL-0808-0466-CHNO to Isabelle Audo), Centre d’Investigation Clinique 503 recognized as a Foundation Fighting Blindness Center (grant number C-CMM-0907-0428-INSERM04), Fundacion Progreso y Salud (to Shomi S. Bhattacharya, Maria Luz Bellido Diaz, Abhay Krishna and Paloma Dominguez Gimenez), Instituto de Salud Carlos III (grant number CM06/00183 to Maria Luz Bellido Diaz) and Bulgarian National Science Fund (grant number DDVU 02/10). Additionally, the Institut de la Vision is funded by Institut National de la Santé et de la Recherche Médicale, Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique and Départment de Paris.Peer Reviewe

Hantavirus Infection in Anajatuba, Maranhão, Brazil

In 2000, the first outbreak of hantavirus pulmonary syndrome was recognized in the Brazilian Amazon (Maranhão State). An epidemiologic study identified a 13.3% prevalence of hantavirus-specific immunoglobulin G. The analysis of risk factors suggests that persons are occupationally exposed to infected rodents in the crop fields

Assessment of Night Vision Problems in Patients with Congenital Stationary Night Blindness

Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the ‘‘Light Lab’’. In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the ‘‘2D Light Lab’’ showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling

Sensitivity of ice loss to uncertainty in flow law parameters in an idealized one-dimensional geometry

Acceleration of the flow of ice drives mass losses in both the Antarctic and the Greenland Ice Sheet. The projections of possible future sea-level rise rely on numerical ice-sheet models, which solve the physics of ice flow, melt, and calving. While major advancements have been made by the ice-sheet modeling community in addressing several of the related uncertainties, the flow law, which is at the center of most process-based ice-sheet models, is not in the focus of the current scientific debate. However, recent studies show that the flow law parameters are highly uncertain and might be different from the widely accepted standard values. Here, we use an idealized flow-line setup to investigate how these uncertainties in the flow law translate into uncertainties in flow-driven mass loss. In order to disentangle the effect of future warming on the ice flow from other effects, we perform a suite of experiments with the Parallel Ice Sheet Model (PISM), deliberately excluding changes in the surface mass balance. We find that changes in the flow parameters within the observed range can lead up to a doubling of the flow-driven mass loss within the first centuries of warming, compared to standard parameters. The spread of ice loss due to the uncertainty in flow parameters is on the same order of magnitude as the increase in mass loss due to surface warming. While this study focuses on an idealized flow-line geometry, it is likely that this uncertainty carries over to realistic three-dimensional simulations of Greenland and Antarctica