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

The evolution of future Antarctic surface melt using PISM-dEBM-simple

&amp;lt;p&amp;gt;With a volume of 58 m sea-level equivalent, the Antarctic Ice Sheet represents the largest potential source of future sea-level rise under global warming. While the ice sheet gains mass through snowfall at the surface, it loses mass through dynamic discharge and iceberg calving into the ocean, as well as by melting at the surface and underneath its floating ice shelves.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Already today, Antarctica is contributing to sea-level rise. So far, this contribution has been comparatively modest, but is expected to increase in the future. Most of the current mass losses are concentrated in the West Antarctic Ice Sheet, mainly caused by sub-shelf melting and ice discharge. Because air temperatures are low and thus surface melt rates are small, any significant melting at the surface is restricted to the low-elevation coastal zones. At the same time, most of the mass loss is offset by snowfall, which is projected to further increase in a warming atmosphere.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;As warming progresses over the coming centuries, the question arises as to how long the mass losses on the one side will be compensated by the gains on the other. In 21st-century projections, increasing surface mass balance is outweighing increased discharge even under strong warming scenarios. However, in long-term (multi-century to millennium scale) warming simulations the positive surface mass balance trend shows a peak and subsequent reversal. Owing to positive feedbacks, like the surface-elevation or the ice-albedo feedback, this effect can be enhanced once a surface lowering is triggered or the surface reflectivity is lowered by initial melt.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Here, we implement a simplified version of the diurnal Energy Balance Model (dEBM-simple) as a surface module in the Parallel Ice Sheet Model (PISM), which extends the conventional positive-degree-day (PDD) approach to include the influence of solar radiation and parameterizes the ice albedo as a function of melting, implicitly accounting for the ice-albedo feedback.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Using a model sensitivity ensemble, we analyze the range of possible surface mass balance evolutions over the 21st century as well as in long-term simulations based on extended end-of-century climatological conditions with the coupled model. The comparison with the PDD approach hints to a strong overestimation of surface melt rates of the latter, even under present day conditions. The dEBM-simple further allows us to disentangle the respective contributions of temperature- and insolation-driven surface melt to future sea level rise.&amp;lt;/p&amp;gt;</jats:p

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

INTERNAÇÕES HOSPITALARES POR TRANSTORNOS MENTAIS DEVIDO AO USO DE ÁLCOOL E SUBSTÂNCIAS PSICOATIVAS: UMA AVALIAÇÃO DE 2018 A 2023

&nbsp; Brazil has the highest rates of anxiety disorders and is fifth in cases of depression, which drives individuals to use alcohol and psychoactive substances as a mechanism to alleviate mental suffering. This study aims to analyze the clinical and epidemiological landscape of dengue cases in the Southeast region of Brazil from 2014 to 2023. It is a descriptive, quantitative, and retrospective study based on data obtained from the Hospital Morbidity System (SIH) at the Department of Informatics of the Unified Health System (DATASUS). The total number of hospitalizations for mental disorders associated with the use of alcohol and psychoactive substances in Brazil between 2018 and 2023 was 435,923. The South region had the highest number of cases (n=181,455), with the state of Rio Grande do Sul accounting for over 54.69% of these hospitalizations. The age group with the highest frequency of cases was 30 to 39 years, corresponding to 26.89% (n=117,234) of the cases. The sample was predominantly composed of male individuals, accounting for 81.15% (n=353,754) of the total. The most frequent race/color in the analyzed sample was white, representing 45.88% (n=200,010) of the cases. Most of the care provided was in an emergency setting, corresponding to 84.61% of the cases. The average length of stay was 20.4 days. During the analyzed period, there were 2,472 deaths, with the majority occurring in individuals aged 50 to 59 years, representing 24.91% of the total. The study revealed a growing trend in the number of cases, particularly among the younger population, which may lead to severe chemical dependency.O Brasil é o país que apresenta as maiores taxas de transtornos de ansiedade e o quinto em casos de depressão, o que leva os indivíduos a buscar o uso de álcool e substâncias psicoativas como mecanismo para aliviar o sofrimento mental. O presente trabalho tem o objetivo de analisar o panorama clínico e epidemiológico dos casos de por transtorno mental associado ao uso de álcool e substâncias psicoativas no Brasil, entre 2018 e 2023. Trata-se de um estudo descritivo, quantitativo e retrospectivo, com base em dados obtidos através do Sistema de Morbidade Hospitalar (SIH) no Departamento de Informática do Sistema Único de Saúde (DATASUS). O total de internações por transtorno mental associado ao uso de álcool e substâncias psicoativas no Brasil, entre 2018 e 2023, foi de 435.923. A região Sul apresentou o maior número de casos (n=181.455), sendo o Rio Grande do Sul o estado responsável por mais de 54,69% dessas internações. A faixa etária com maior frequência de casos foi a de 30 a 39 anos, correspondendo a 26,89% (n=117.234) dos casos. A amostra foi, em sua maioria, composta por indivíduos do sexo masculino, correspondendo a 81,15% (n=353.754) do total. A cor/raça mais frequente na amostra analisada foi a branca, correspondendo a 45,88% (n=200.010) dos casos. A maioria dos atendimentos foi feita em caráter de urgência, correspondendo a 84,61% dos casos. A média de permanência foi de 20,4 dias de internação. Durante o período analisado, houve 2.472 óbitos, dos quais a maior parte eram indivíduos entre 50 e 59 anos, representando 24,91% do total. O estudo evidenciou um padrão de crescimento no número de casos, principalmente entre a população mais jovem, o que pode levar a uma grave dependência química.  

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