Non-affine mechanics of entangled networks inspired by intermediate filaments

Inspired by massive intermediate filament (IF) reorganization in superstretched epithelia, we examine computationally the principles controlling the mechanics of a set of entangled filaments whose ends slide on the cell boundary. We identify an entanglement metric and threshold beyond which random loose networks respond non-affinely and nonlinearly to stretch by self-organizing into structurally optimal star-shaped configurations. A simple model connecting cellular and filament strains links emergent mechanics to cell geometry, network topology, and filament mechanics. We identify a safety net mechanism in IF networks and provide a framework to harness entanglement in soft fibrous materials.Comment: 23 pages, 16 figures; expanded discussion of non-affinity, added supplementary data on interaction with frictional background at fast loading rates, modified title, results unchange

Losing Sight of Land: Tales of Dyslexia and Dyspraxia in Psychophysical Actor Training

This article reports on the findings of a research project into the impact of psychophysical actor training methods on neurodiverse students. It illustrates how the application of a Social Theory of Learning Difference reveals the mechanisms whereby these training methods dysconsciously discriminate against those students who are dyslexic and/or dyspraxic learners. The research findings recognise the inherent value of psychophysical methods in the training of actors but suggests that there is a need to move away from a singular Psycho-Medical Theory of Learning Difference and to adopt a framework of learning difference based on the Social Model of (dis)ability, which requires institutions to adapt their provision to better meet a diverse range of needs. A revision of psychophysical approaches is proposed, which draws on a neuroscientific theory of experiential practice and a psychological framework of actor engagement. This new approach seeks to enhance the effective communication of embodied knowledge and skills in diverse actor training contexts and to allow students who are dyslexic and/or dyspraxic learners equal access to that learning

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice

BACKGROUND: It is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response. RESULTS: We have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A) was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP), and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden) in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens. CONCLUSION: These results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects

Challenging the in-vivo assessment of biomechanical properties of the uterine cervix: A critical analysis of ultrasound based quasi-static procedures

Measuring the stiffness of the uterine cervix might be useful in the prediction of preterm delivery, a still unsolved health issue of global dimensions. Recently, a number of clinical studies have addressed this topic, proposing quantitative methods for the assessment of the mechanical properties of the cervix. Quasi-static elastography, maximum compressibility using ultrasound and aspiration tests have been applied for this purpose. The results obtained with the different methods seem to provide contradictory information about the physiologic development of cervical stiffness during pregnancy. Simulations and experiments were performed in order to rationalize the findings obtained with ultrasound based, quasi-static procedures. The experimental and computational results clearly illustrate that standardization of quasi-static elastography leads to repeatable strain values, but for different loading forces. Since force cannot be controlled, this current approach does not allow the distinction between a globally soft and stiff cervix. It is further shown that introducing a reference elastomer into the elastography measurement might overcome the problem of force standardization, but a careful mechanical analysis is required to obtain reliable stiffness values for cervical tissue. In contrast, the maximum compressibility procedure leads to a repeatable, semi-quantitative assessment of cervical consistency, due to the nonlinear nature of the mechanical behavior of cervical tissue. The evolution of cervical stiffness in pregnancy obtained with this procedure is in line with data from aspiration tests

How cosmetic tightening products modulate the biomechanics and morphology of human skin

The active and passive mechanical behavior of a cosmetic tightening product for skin anti-aging is investigated based on a wide range of in vivo and in vitro measurements. The experimental data are used to inform a numerical model of the attained cosmetic effect, which is then implemented in a commercial finite-element framework and used to analyze the mechanisms that regulate the biomechanical interaction between the native tissue and the tightening film. Such a film reduces wrinkles and enhances skin consistency by increasing its stiffness by 48-107% and reducing inelastic, non-recoverable deformations (−47%). The substrate deformability influences both the extent of tightening and the reduction of wrinkle amplitude. The present findings allow, for the first time, to rationalize the mechanisms of action of cosmetic products with a tightening action and provide quantitative evidence for further optimization of this fascinating class of biomaterials.ISSN:1742-7061ISSN:1878-756