84 research outputs 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
Precise Particle Tracking Against a Complicated Background: Polynomial Fitting with Gaussian Weight
We present a new particle tracking software algorithm designed to accurately
track the motion of low-contrast particles against a background with large
variations in light levels. The method is based on a polynomial fit of the
intensity around each feature point, weighted by a Gaussian function of the
distance from the centre, and is especially suitable for tracking endogeneous
particles in the cell, imaged with bright field, phase contrast or fluorescence
optical microscopy. Furthermore, the method can simultaneously track particles
of all different sizes, and allows significant freedom in their shape. The
algorithm is evaluated using the quantitative measures of accuracy and
precision of previous authors, using simulated images at variable
signal-to-noise ratios. To these we add a new test of the error due to a
non-uniform background. Finally the tracking of particles in real cell images
is demonstrated. The method is made freely available for non-commencial use as
a software package with a graphical user-inferface, which can be run within the
Matlab programming environment
Intracellular microrheology of motile Amoeba proteus
The motility of motile Amoeba proteus was examined using the technique of
passive particle tracking microrheology, with the aid of newly-developed
particle tracking software, a fast digital camera and an optical microscope. We
tracked large numbers of endogeneous particles in the amoebae, which displayed
subdiffusive motion at short time scales, corresponding to thermal motion in a
viscoelastic medium, and superdiffusive motion at long time scales due to the
convection of the cytoplasm. Subdiffusive motion was characterised by a
rheological scaling exponent of 3/4 in the cortex, indicative of the
semiflexible dynamics of the actin fibres. We observed shear-thinning in the
flowing endoplasm, where exponents increased with increasing flow rate; i.e.
the endoplasm became more fluid-like. The rheology of the cortex is found to be
isotropic, reflecting an isotropic actin gel. A clear difference was seen
between cortical and endoplasmic layers in terms of both viscoelasticity and
flow velocity, where the profile of the latter is close to a Poiseuille flow
for a Newtonian fluid
Roles of Dynein and Dynactin in Early Endosome Dynamics Revealed Using Automated Tracking and Global Analysis
Microtubule-dependent movement is crucial for the spatial organization of endosomes in most eukaryotes, but as yet there has been no systematic analysis of how a particular microtubule motor contributes to early endosome dynamics. Here we tracked early endosomes labeled with GFP-Rab5 on the nanometer scale, and combined this with global, first passage probability (FPP) analysis to provide an unbiased description of how the minus-end microtubule motor, cytoplasmic dynein, supports endosome motility. Dynein contributes to short-range endosome movement, but in particular drives 85–98% of long, inward translocations. For these, it requires an intact dynactin complex to allow membrane-bound p150Glued to activate dynein, since p50 over-expression, which disrupts the dynactin complex, inhibits inward movement even though dynein and p150Glued remain membrane-bound. Long dynein-dependent movements occur via bursts at up to ∼8 µms−1 that are linked by changes in rate or pauses. These peak speeds during rapid inward endosome movement are still seen when cellular dynein levels are 50-fold reduced by RNAi knock-down of dynein heavy chain, while the number of movements is reduced 5-fold. Altogether, these findings identify how dynein helps define the dynamics of early endosomes
The role of valuation and bargaining in optimising transboundary watercourse treaty regimes
In the face of water scarcity, growing water demands, population increase, ecosystem degradation, climate change, and so on transboundary watercourse states inevitably have to make difficult decisions on how finite quantities of water are distributed. Such waters, and their associated ecosystem services, offer multiple benefits. Valuation and bargaining can play a key role in the sharing of these ecosystems services and their associated benefits across sovereign borders. Ecosystem services in transboundary watercourses essentially constitute a portfolio of assets. Whilst challenging, their commodification, which creates property rights, supports trading. Such trading offers a means by which to resolve conflicts over competing uses and allows states to optimise their ‘portfolios’. However, despite this potential, adoption of appropriate treaty frameworks that might facilitate a market-based approach to the discovery and allocation of water-related ecosystem services at the transboundary level remains both a challenge, and a topic worthy of further study. Drawing upon concepts in law and economics, this paper therefore seeks to advance the study of how treaty frameworks might be developed in a way that supports such a market-based approach to ecosystem services and transboundary waters
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.
Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability
Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.
PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks
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