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

Linear response of a grafted semiflexible polymer to a uniform force field

We use the worm-like chain model to analytically calculate the linear response of a grafted semiflexible polymer to a uniform force field. The result is a function of the bending stiffness, the temperature, the total contour length, and the orientation of the field with respect to that of the grafted end. We also study the linear response of a worm-like chain with a periodic alternating sequence of positive and negative charges. This can be considered as a model for a polyampholyte with intrinsic bending siffness and negligible intramolecular interactions. We show how the finite intrinsic persistence length affects the linear response to the external field.Comment: 6 pages, 3 figure

Semantic memory is impaired in both dementia with Lewy Bodies (DLB) and dementia of Alzheimer's type (DAT): a comparative neuropsychological study and literature review

OBJECTIVE---To test the hypothesis that semantic impairment is present in both patients with dementia with Lewy bodies (DLB) and those with dementia of Alzheimer's type (DAT). METHODS---A comprehensive battery of neuropsychological tasks designed to assess semantic memory, visuoperceptual function, verbal fluency, and recognition memory was given to groups of patients with DLB (n=10), DAT (n=10) matched pairwise for age and mini mental state examination (MMSE), and age matched normal controls (n=15). RESULTS---Both DLB and DAT groups exhibited impaired performance across the range of tasks designed to assess semantic memory. Whereas patients with DAT showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words. As in previous studies, patients with DLB but not those with DAT were found to have impaired visuoperceptual functioning. Letter and category fluency were equally reduced for the patients with DLB whereas performance on letter fluency was significantly better in the DAT group. Recognition memory for faces and words was impaired in both groups. CONCLUSIONS---Semantic impairment is not limited to patients with DAT. Patients with DLB exhibit particular problems when required to access meaning from pictures that is most likely to arise from a combination of semantic and visuoperceptual impairments

Persistence of a pinch in a pipe

The response of low-dimensional solid objects combines geometry and physics in unusual ways, exemplified in structures of great utility such as a thin-walled tube that is ubiquitous in nature and technology. Here we provide a particularly surprising consequence of this confluence of geometry and physics in tubular structures: the anomalously large persistence of a localized pinch in an elastic pipe whose effect decays very slowly as an oscillatory exponential with a persistence length that diverges as the thickness of the tube vanishes, which we confirm experimentally. The result is more a consequence of geometry than material properties, and is thus equally applicable to carbon nanotubes as it is to oil pipelines.Comment: 6 pages, 3 figure

Force generation in small ensembles of Brownian motors

The motility of certain gram-negative bacteria is mediated by retraction of type IV pili surface filaments, which are essential for infectivity. The retraction is powered by a strong molecular motor protein, PilT, producing very high forces that can exceed 150 pN. The molecular details of the motor mechanism are still largely unknown, while other features have been identified, such as the ring-shaped protein structure of the PilT motor. The surprisingly high forces generated by the PilT system motivate a model investigation of the generation of large forces in molecular motors. We propose a simple model, involving a small ensemble of motor subunits interacting through the deformations on a circular backbone with finite stiffness. The model describes the motor subunits in terms of diffusing particles in an asymmetric, time-dependent binding potential (flashing ratchet potential), roughly corresponding to the ATP hydrolysis cycle. We compute force-velocity relations in a subset of the parameter space and explore how the maximum force (stall force) is determined by stiffness, binding strength, ensemble size, and degree of asymmetry. We identify two qualitatively different regimes of operation depending on the relation between ensemble size and asymmetry. In the transition between these two regimes, the stall force depends nonlinearly on the number of motor subunits. Compared to its constituents without interactions, we find higher efficiency and qualitatively different force-velocity relations. The model captures several of the qualitative features obtained in experiments on pilus retraction forces, such as roughly constant velocity at low applied forces and insensitivity in the stall force to changes in the ATP concentration.Comment: RevTex 9 pages, 4 figures. Revised version, new subsections in Sec. III, removed typo

Deciphering the mechanisms of phonological therapy in jargon aphasia

Background: Severe word production difficulties remain one of the most challenging clinical symptoms to treat in individuals with jargon aphasia. Clinically, it is important to determine why some individuals with jargon aphasia improve following therapy when others do not. We report a therapy study with AM, an individual with severe neologistic jargon aphasia, and provide a subsequent comparison to previous cases, with the purpose of informing both our theoretical and clinical understanding of jargon aphasia. Aims: This research aimed to investigate AM’s locus of word production deficit and determine the effectiveness of Phonological Component Analysis (PCA) therapy, a phonological cueing therapy, in the re-learning and generalization of naming responses for words. In addition, AM’s performance in therapy, linguistic profile, and ability to engage with therapy/cues were compared in a retrospective analysis with the background linguistic and therapy data of two other individuals with jargon aphasia (P9, Leonard et al., 2008; FF, Bose, 2013), who responded differentially to PCA. This was undertake to explore possible prognostic indicators of phonological therapy for jargon aphasia. Methods and Procedures: A battery of linguistic and neuropsychological tests was used to identify AM’s word production deficit. A single-subject multiple probe design across behaviours was employed to evaluate the effects of PCA therapy on the re-learning and generalization of naming responses. In the retrospective analysis of AM, P9 and FF, we compared differences and similarities in performance on various linguistic tasks, the ability to engage in therapy (i.e., ability to generate and utilize the cues), as well as to retain and maintain cues. Outcomes and Results: AM’s locus of deficit was identified in the mapping between semantics and phonology. PCA was found to be effective in improving naming in two of the three treated word lists during the treatment phase; however, these gains were not maintained. Generalization to untreated picture names was not observed. Findings from the retrospective analysis illustrated that oral reading skills, ability to segment phonological information from words and active engagement with provided cues are likely prerequisites for obtaining robust and long-term gains. Conclusions and Implications: We demonstrated that phonological therapy could be beneficial for the remediation of naming abilities at least in the re-learning phase; however, maintenance and generalization of these gains were limited. This research helps to elucidate the considerations and evaluations necessary for the appropriateness of phonological therapy and candidacy of individuals with jargon aphasia for this treatment approach