1,845 research outputs found
Memory effects and L\'evy walk dynamics in intracellular transport of cargoes
We demonstrate the phenomenon of cumulative inertia in intracellular
transport involving multiple motor proteins in human epithelial cells by
measuring the empirical survival probability of cargoes on the microtubule and
their detachment rates. We found the longer a cargo moves along a microtubule,
the less likely it detaches from it. As a result, the movement of cargoes is
non-Markovian and involves a memory. We observe memory effects on the scale of
up to 2 seconds. We provide a theoretical link between the measured detachment
rate and the super-diffusive Levy walk-like cargo movement.Comment: 9 pages, 6 figure
Variable-order fractional master equation and clustering of particles: non-uniform lysosome distribution
In this paper, we formulate the space-dependent variable-order fractional
master equation to model clustering of particles, organelles, inside living
cells. We find its solution in the long time limit describing non-uniform
distribution due to a space dependent fractional exponent. In the continuous
space limit, the solution of this fractional master equation is found to be
exactly the same as the space-dependent variable-order fractional diffusion
equation. In addition, we show that the clustering of lysosomes, an essential
organelle for healthy functioning of mammalian cells, exhibit space-dependent
fractional exponents. Furthermore, we demonstrate that the non-uniform
distribution of lysosomes in living cells is accurately described by the
asymptotic solution of the space-dependent variable-order fractional master
equation. Finally, Monte Carlo simulations of the fractional master equation
validate our analytical solution.Comment: arXiv admin note: text overlap with arXiv:1902.0308
Network organisation and the dynamics of tubules in the endoplasmic reticulum
From Springer Nature via Jisc Publications RouterHistory: received 2021-04-26, accepted 2021-06-27, registration 2021-07-19, pub-electronic 2021-08-10, online 2021-08-10, collection 2021-12Publication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; doi: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/H017828/1Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100010269; Grant(s): 215189/Z/19/ZFunder: Engineering and Physical Sciences Research Council; doi: http://dx.doi.org/10.13039/501100000266Abstract: The endoplasmic reticulum (ER) is a eukaryotic subcellular organelle composed of tubules and sheet-like areas of membrane connected at junctions. The tubule network is highly dynamic and undergoes rapid and continual rearrangement. There are currently few tools to evaluate network organisation and dynamics. We quantified ER network organisation in Vero and MRC5 cells, and developed an analysis workflow for dynamics of established tubules in live cells. The persistence length, tubule length, junction coordination number and angles of the network were quantified. Hallmarks of imbalances in ER tension, indications of interactions with microtubules and other subcellular organelles, and active dynamics were observed. Clear differences in dynamic behaviour were observed for established tubules at different positions within the cell using itemset mining. We found that tubules with activity-driven fluctuations were more likely to be located away from the cell periphery and a population of peripheral tubules with no signs of active motion was found
The First Passage Probability of Intracellular Particle Trafficking
The first passage probability (FPP), of trafficked intracellular particles
reaching a displacement L, in a given time t or inverse velocity S = t/L, can
be calculated robustly from measured particle tracks, and gives a measure of
particle movement in which different types of motion, e.g. diffusion, ballistic
motion, and transient run-rest motion, can readily be distinguished in a single
graph, and compared with mathematical models. The FPP is attractive in that it
offers a means of reducing the data in the measured tracks, without making
assumptions about the mechanism of motion: for example, it does not employ
smoothing, segementation or arbitrary thresholds to discriminate between
different types of motion in a particle track. Taking experimental data from
tracked endocytic vesicles, and calculating the FPP, we see how three molecular
treatments affect the trafficking. We show the FPP can quantify complicated
movement which is neither completely random nor completely deterministic,
making it highly applicable to trafficked particles in cell biology.Comment: Article: 13 pages, 8 figure
The riparian reactive interface: a climate-sensitive gatekeeper of global nutrient cycles
Riparian zones are critical interfaces to freshwater systems, acting as gateways for the conveyance and modification of macronutrient fluxes from land to rivers and oceans. In this paper, we propose that certain riparian conditions and processes (conceptually 'Riparian Reactive Interfaces') may be susceptible to environmental change with consequences of accelerating local nutrient cycling cascading to global impacts on the cycles of carbon (C), nitrogen (N), and phosphorus (P). However, we argue that this concept is insufficiently understood and that research has not yet established robust baseline data to predict and measure change at the key riparian ecosystem interface. We suggest one contributing factor as lack of interdisciplinary study of abiotic and biotic processes linking C, N, and P dynamics and another being emphasis on riparian ecology and restoration that limits frameworks for handling and scaling topography-soil-water-climate physical and biogeochemical observations from plot to large catchment scales. Scientific effort is required now to evaluate riparian current and future controls on global nutrient cycles through multi-nutrient (and controlling element) studies, grounded in landscape frameworks for dynamic riparian behaviour variation, facilitating scaling to catchment predictions
Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis
Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases
Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the ARF activator Efa6 in C. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function of Drosophila Efa6 in experimentally and genetically amenable fly neurons. First, we show that Drosophila Efa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT elimination domain/MTED) that binds tubulin and inhibits microtubule growth in vitro and cells. If N-terminal MTED-containing fragments are in the cytoplasm they abolish entire microtubule networks of mouse fibroblasts and whole axons of fly neurons. Full-length Efa6 is membrane-attached, hence primarily blocks MTs in the periphery of fibroblasts, and explorative MTs that have left axonal bundles in neurons. Accordingly, loss of Efa6 causes an increase of explorative MTs: In growth cones they enhance axon growth, in axon shafts they cause excessive branching, as well as atrophy through perturbations of MT bundles. Efa6 over-expression causes the opposite phenotypes. Taken together, our work conceptually links molecular and sub-cellular functions of cortical collapse factors to axon growth regulation and reveals new roles in axon branching and in the prevention of axonal atrophy. Furthermore, the MTED delivers a promising tool that can be used to inhibit MTs in a compartmentalised fashion when fusing it to specifically localising protein domains
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Pan-viral serology implicates enteroviruses in acute flaccid myelitis.
Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM
Maintaining independence in individuals with dementia at home after a fall:a protocol for the UK pilot cluster randomised controlled trial MAINTAIN
Introduction: Individuals with dementia face an increased risk of falls. Falls can cause a decline in the individual’s overall functionality. All types of falls, including those that do not result in injury, can lead to psychosocial consequences, such as diminished confidence and a fear of falling. Projections indicate a rising trend in dementia diagnoses, implying an increase in fall incidents. Yet, there is a lack of evidence to support interventions for people living with dementia who have fallen. Our objective is to test the feasibility of a falls intervention trial for people with dementia. Method and analysis: This is a UK-based two-arm pilot cluster randomised controlled trial. In this study, six collaborating sites, which form the clusters, will be randomly allocated to either the intervention arm or the control arm (receiving treatment as usual) at a 1:1 ratio. During the 6 month recruitment phase, each cluster will enrol 10 dyads, comprising 10 individuals with dementia and their respective carers, leading to a total sample size of 60 dyads. The primary outcomes are the feasibility parameters for a full trial (ie, percentage consented, follow-up rate and cost framework). Secondary outcomes include activities of daily living, quality of life, fall efficacy, mobility, goal attainment, cognitive status, occurrence of falls, carer burden and healthcare service utilisation. Outcome measures will be collected at baseline and 28 weeks, with an additional assessment scheduled at 12 weeks for the healthcare service utilisation questionnaire. An embedded process evaluation, consisting of interviews and observations with participants and healthcare professionals, will explore how the intervention operates and the fidelity of study processes. Ethics and dissemination: The study was approved by the NHS and local authority research governance and research ethics committees (NHS REC reference: 23/WA/0126). The results will be shared at meetings and conferences and will be published in peer-reviewed journals. Trial registration number: ISRCTN16413728
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