Ultrastructural defects in stereocilia and tectorial membrane in aging mouse and human cochleae

The aging cochlea is subjected to a number of pathological changes to play a role in the onset of age-related hearing loss (ARHL). Although ARHL has often been thought of as the result of the loss of hair cells, it is in fact a disorder with a complex etiology, arising from the changes to both the organ of Corti and its supporting structures. In this study, we examine two aging pathologies that have not been studied in detail despite their apparent prevalence; the fusion, elongation, and engulfment of cochlear inner hair cell stereocilia, and the changes that occur to the tectorial membrane (TM), a structure overlying the organ of Corti that modulates its physical properties in response to sound. Our work demonstrates that similar pathological changes occur in these two structures in the aging cochleae of both mice and humans, examines the ultrastructural changes that underlie stereocilial fusion, and identifies the lost TM components that lead to changes in membrane structure. We place these changes into the context of the wider pathology of the aging cochlea, and identify how they may be important in particular for understanding the more subtle hearing pathologies that precede auditory threshold loss in ARHL

Collaborative Gaze Channelling for Improved Cooperation During Robotic Assisted Surgery

The use of multiple robots for performing complex tasks is becoming a common practice for many robot applications. When different operators are involved, effective cooperation with anticipated manoeuvres is important for seamless, synergistic control of all the end-effectors. In this paper, the concept of Collaborative Gaze Channelling (CGC) is presented for improved control of surgical robots for a shared task. Through eye tracking, the fixations of each operator are monitored and presented in a shared surgical workspace. CGC permits remote or physically separated collaborators to share their intention by visualising the eye gaze of their counterparts, and thus recovers, to a certain extent, the information of mutual intent that we rely upon in a vis-à-vis working setting. In this study, the efficiency of surgical manipulation with and without CGC for controlling a pair of bimanual surgical robots is evaluated by analysing the level of coordination of two independent operators. Fitts' law is used to compare the quality of movement with or without CGC. A total of 40 subjects have been recruited for this study and the results show that the proposed CGC framework exhibits significant improvement (p<0.05) on all the motion indices used for quality assessment. This study demonstrates that visual guidance is an implicit yet effective way of communication during collaborative tasks for robotic surgery. Detailed experimental validation results demonstrate the potential clinical value of the proposed CGC framework. © 2012 Biomedical Engineering Society.link_to_subscribed_fulltex

Nonlinear optics: Nonlinear virtues of multimode fibre

Supercontinuum generation — the extreme spectral broadening of laser light (a span from the ultraviolet to the mid-infrared is possible) — is a fascinating process that takes place in a dispersive and strongly nonlinear optical medium

Millimeter-wave Dual-Function Hollow Metal Waveguide to Microstrip Transition and Bandpass Filter based on ENZ Metamaterial

This paper presents a novel design of a millimeterwave dual-function in-plane hollow metal waveguide to microstrip transition and bandpass filter based on epsilon-near-zero (ENZ) metamaterial. A hollow metallic rectangular waveguide (HMRW) that operates near its cut-off frequency of the fundamental TE 10 mode is used to mimic the ENZ metamaterial, allowing the wave to tunnel through the waveguide with an effectively infinite phase-velocity. As a waveguide transition, the ENZ waveguide directly interconnects HMRW and microstrip in the same plane with a minimum insertion loss of 0.7 dB at the 33.06 GHz, overcoming the significant impedance mismatch and geometry difference between HMRW and Microstrip. As a bandpass filter, the design has a near-flat passband with the minimum insertion loss of 0.7 dB and a bandwidth of 1.31 GHz centered at 32.96 GHz, which leads to a Q-factor of 25.17. The work offers a step towards a novel dual-function waveguide transition and bandpass filter that can be used in a variety of functional components for millimeter-wave multichip modules and hybrid integrated circuits

Juxtaposition of system dynamics and agent-based simulation for a case study in immunosenescence

Advances in healthcare and in the quality of life significantly increase human life expectancy. With the aging of populations, new un-faced challenges are brought to science. The human body is naturally selected to be well-functioning until the age of reproduction to keep the species alive. However, as the lifespan extends, unseen problems due to the body deterioration emerge. There are several age-related diseases with no appropriate treatment; therefore, the complex aging phenomena needs further understanding. It is known that immunosenescence is highly correlated to the negative effects of aging. In this work we advocate the use of simulation as a tool to assist the understanding of immune aging phenomena. In particular, we are comparing system dynamics modelling and simulation (SDMS) and agent-based modelling and simulation (ABMS) for the case of age-related depletion of naive T cells in the organism. We address the following research questions: Which simulation approach is more suitable for this problem? Can these approaches be employed interchangeably? Is there any benefit of using one approach compared to the other? Results show that both simulation outcomes closely fit the observed data and existing mathematical model; and the likely contribution of each of the naive T cell repertoire maintenance method can therefore be estimated. The differences observed in the outcomes of both approaches are due to the probabilistic character of ABMS contrasted to SDMS. However, they do not interfere in the overall expected dynamics of the populations. In this case, therefore, they can be employed interchangeably, with SDMS being simpler to implement and taking less computational resources

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

Isolation of human monoclonal autoantibodies derived from pancreatic lymph node and peripheral blood B cells of islet autoantibody-positive patients

Aims/hypothesis Autoantibodies against pancreatic islets and infections by enteroviruses are associated with type 1 diabetes, but the specificity of immune responses within the type 1 diabetic pancreas is poorly characterised. We investigated whether pancreatic lymph nodes could provide a source of antigen-specific B cells for analysis of immune responses within the (pre)diabetic pancreas. Methods Human IgG antibodies were cloned from single B lymphocytes sorted from pancreatic lymph node cells of three organ donors positive for islet autoantibodies, and from the peripheral blood of a patient with type 1 diabetes. Antibodies to insulinoma-associated antigen 2 (IA-2), GAD65, zinc trans- porter 8 (ZnT8) and Coxsackie B virus proteins were assayed by immunoprecipitation and by immunofluorescence on pan- creatic sections. Results Human IgG antibodies (863) were successfully cloned and produced from 4,092 single B cells from lymph nodes and peripheral blood. Reactivity to the protein tyrosine phosphatase domain of the IA-2 autoantigen was detected in two cloned antibodies: one derived from a pancreatic lymph node and one from peripheral blood. Epitopes for these two antibodies were similar to each other and to those for circulat- ing antibodies in type 1 diabetes. The remaining 861 antibod- ies were negative for reactivity to IA-2, GAD65 or ZnT8 by both assays tested. Reactivity to a Coxsackie viral protein 2 was detected in one antibody derived from a peripheral blood B cell, but not from lymph nodes. Conclusions/interpretation We show evidence for the infre- quent presence of autoantigen-specific IgG+ B lymphocytes in the pancreatic-draining lymph nodes of islet autoantibody- positive individuals

Change escalation processes and complex adaptive systems: from incremental reconfigurations to discontinuous restructuring

This study examines when “incremental” change is likely to trigger “discontinuous” change, using the lens of complex adaptive systems theory. Going beyond the simulations and case studies through which complex adaptive systems have been approached so far, we study the relationship between incremental organizational reconfigurations and discontinuous organizational restructurings using a large-scale database of U.S. Fortune 50 industrial corporations. We develop two types of escalation process in organizations: accumulation and perturbation. Under ordinary conditions, it is perturbation rather than the accumulation that is more likely to trigger subsequent discontinuous change. Consistent with complex adaptive systems theory, organizations are more sensitive to both accumulation and perturbation in conditions of heightened disequilibrium. Contrary to expectations, highly interconnected organizations are not more liable to discontinuous change. We conclude with implications for further research, especially the need to attend to the potential role of managerial design and coping when transferring complex adaptive systems theory from natural systems to organizational systems

Jay Forrester

Jay Wright Forrester was an American engineer and management thinker. He founded System Dynamics, an approach based on computer modelling which arguably has done more than any other method to provide a practical and realistic analysis of change processes in systems. System Dynamics (SD) has been taken up across the world, initially by Forrester’s students and colleagues, but increasingly by a much wider community. It has had profound and influential applications in a range of fields, most prominently organisational management, urban planning and environmental policy. Forrester summed up his concerns and his understanding of SD in an ‘elevator pitch’ (a statement short enough to be spoken in an elevator ride) on an email list: System dynamics deals with how things change through time, which includes most of what most people find important. It uses computer simulation to take the knowledge we already have about details in the world around us and to show why our social and physical systems behave the way they do. System dynamics demonstrates how most of our own decision-making policies are the cause of the problems that we usually blame on others, and how to identify policies we can follow to improve our situation. (Forrester JW. System dynamics in the elevator. System-dynamics email list. https://www.ventanasystems.co.uk/forum/viewtopic.php?t=1787#p1964. Accessed 25 Sept 2019, 1997