Structural Reorganization of Parallel Actin Bundles by Crosslinking Proteins: Incommensurate States of Twist

We construct a coarse-grained model of parallel actin bundles crosslinked by compact, globular bundling proteins, such as fascin and espin, necessary components of filapodial and mechanosensory bundles. Consistent with structural observations of bundles, we find that the optimal geometry for crosslinking is overtwisted, requiring a coherent structural change of the helical geometry of the filaments. We study the linker-dependent thermodynamic transition of bundled actin filaments from their native state to the overtwisted state and map out the "twist-state'' phase diagram in terms of the availability as well as the flexibility of crosslinker proteins. We predict that the transition from the uncrosslinked to fully-crosslinked state is highly sensitive to linker flexibility: flexible crosslinking smoothly distorts the twist-state of bundled filaments, while rigidly crosslinked bundles undergo a phase transition, rapidly overtwisting filaments over a narrow range of free crosslinker concentrations. Additionally, we predict a rich spectrum of intermediate structures, composed of alternating domains of sparsely-bound (untwisted) and strongly-bound (overtwisted) filaments. This model reveals that subtle differences in crosslinking agents themselves modify not only the detailed structure of parallel actin bundles, but also the thermodynamic pathway by which they form.Comment: Main Text (25 pages, 7 figures) with supporting material (12 pages, 9 figures, 2 tables

Does the process map influence the outcome of quality improvement work? A comparison of a sequential flow diagram and a hierarchical task analysis diagram

Background: Many quality and safety improvement methods in healthcare rely on a complete and accurate map of the process. Process mapping in healthcare is often achieved using a sequential flow diagram, but there is little guidance available in the literature about the most effective type of process map to use. Moreover there is evidence that the organisation of information in an external representation affects reasoning and decision making. This exploratory study examined whether the type of process map - sequential or hierarchical - affects healthcare practitioners' judgments.Methods: A sequential and a hierarchical process map of a community-based anti coagulation clinic were produced based on data obtained from interviews, talk-throughs, attendance at a training session and examination of protocols and policies. Clinic practitioners were asked to specify the parts of the process that they judged to contain quality and safety concerns. The process maps were then shown to them in counter-balanced order and they were asked to circle on the diagrams the parts of the process where they had the greatest quality and safety concerns. A structured interview was then conducted, in which they were asked about various aspects of the diagrams.Results: Quality and safety concerns cited by practitioners differed depending on whether they were or were not looking at a process map, and whether they were looking at a sequential diagram or a hierarchical diagram. More concerns were identified using the hierarchical diagram compared with the sequential diagram and more concerns were identified in relation to clinical work than administrative work. Participants' preference for the sequential or hierarchical diagram depended on the context in which they would be using it. The difficulties of determining the boundaries for the analysis and the granularity required were highlighted.Conclusions: The results indicated that the layout of a process map does influence perceptions of quality and safety problems in a process. In quality improvement work it is important to carefully consider the type of process map to be used and to consider using more than one map to ensure that different aspects of the process are captured

Islands of conformational stability for Filopodia

Filopodia are long, thin protrusions formed when bundles of fibers grow outwardly from a cell surface while remaining closed in a membrane tube. We study the subtle issue of the mechanical stability of such filopodia and how this depends on the deformation of the membrane that arises when the fiber bundle adopts a helical configuration. We calculate the ground state conformation of such filopodia, taking into account the steric interaction between the membrane and the enclosed semiflexible fiber bundle. For typical filopodia we find that a minimum number of fibers is required for filopodium stability. Our calculation elucidates how experimentally observed filopodia can obviate the classical Euler buckling condition and remain stable up to several tens of . We briefly discuss how experimental observation of the results obtained in this work for the helical-like deformations of enclosing membrane tubes in filopodia could possibly be observed in the acrosomal reactions of the sea cucumber Thyone, and the horseshoe crab Limulus. Any realistic future theories for filopodium stability are likely to rely on an accurate treatment of such steric effects, as analysed in this work

Altitude Acclimatization Alleviates the Hypoxia-Induced Suppression of Exogenous Glucose Oxidation During Steady-State Aerobic Exercise

This study investigated how high-altitude (HA, 4300 m) acclimatization affected exogenous glucose oxidation during aerobic exercise. Sea-level (SL) residents (n = 14 men) performed 80-min, metabolically matched exercise (V˙O2 ∼ 1.7 L/min) at SL and at HA < 5 h after arrival (acute HA, AHA) and following 22-d of HA acclimatization (chronic HA, CHA). During HA acclimatization, participants sustained a controlled negative energy balance (-40%) to simulate the “real world” conditions that lowlanders typically experience during HA sojourns. During exercise, participants consumed carbohydrate (CHO, n = 8, 65.25 g fructose + 79.75 g glucose, 1.8 g carbohydrate/min) or placebo (PLA, n = 6). Total carbohydrate oxidation was determined by indirect calorimetry and exogenous glucose oxidation by tracer technique with 13C. Participants lost (P ≤ 0.05, mean ± SD) 7.9 ± 1.9 kg body mass during the HA acclimatization and energy deficit period. In CHO, total exogenous glucose oxidized during the final 40 min of exercise was lower (P < 0.01) at AHA (7.4 ± 3.7 g) than SL (15.3 ± 2.2 g) and CHA (12.4 ± 2.3 g), but there were no differences between SL and CHA. Blood glucose and insulin increased (P ≤ 0.05) during the first 20 min of exercise in CHO, but not PLA. In CHO, glucose declined to pre-exercise concentrations as exercise continued at SL, but remained elevated (P ≤ 0.05) throughout exercise at AHA and CHA. Insulin increased during exercise in CHO, but the increase was greater (P ≤ 0.05) at AHA than at SL and CHA, which did not differ. Thus, while acute hypoxia suppressed exogenous glucose oxidation during steady-state aerobic exercise, that hypoxic suppression is alleviated following altitude acclimatization and concomitant negative energy balance

Eisosome proteins assemble into a membrane scaffold

Membrane organization by eisosomes is mediated by self-assembly of its main components into a membrane-bound protein scaffold with lipid-binding specificity