On the origins of the compressive cochlear nonlinearity

Various simple mathematical models of the dynamics of the organ of Corti in the mammalian cochlea are analysed. The models are assessed against their ability to explain the compressive nonlinear response of the basilar membrane. The speci fic models considered are: phenomenological Hopf and cusp normal forms, a recently-proposed description combining active hair-bundle motility and somatic motility, a reduction thereof, and finally a new model highlighting the importance of the coupling between the nonlinear transduction current and somatic motility. The overall conclusion is that neither a Hopf bifurcation nor cusp bifurcation are necessary for realistic compressive nonlinearity. Moreover, two physiological models are discussed showing compressive nonlinearities similar to experimental observations without the need for tuning near any bifurcation

Resource use data by patient report or hospital records: Do they agree?

Background: Economic evaluations alongside clinical trials are becoming increasingly common. Cost data are often collected through the use of postal questionnaires; however, the accuracy of this method is uncertain. We compared postal questionnaires with hospital records for collecting data on physiotherapy service use. Methods: As part of a randomised trial of orthopaedic medicine compared with orthopaedic surgery we collected physiotherapy use data on a group of patients from retrospective postal questionnaires and from hospital records. Results: 315 patients were referred for physiotherapy. Hospital data on attendances was available for 30% (n = 96), compared with 48% (n = 150) of patients completing questionnaire data (95% Cl for difference = 10% to 24%); 19% (n = 59) had data available from both sources. The two methods produced an intraclass correlation coefficient of 0.54 (95% Cl 0.31 to 0.70). However, the two methods produced significantly different estimates of resource use with patient self report recalling a mean of 1.3 extra visits (95% Cl 0.4 to 2.2) compared with hospital records. Conclusions: Using questionnaires in this study produced data on a greater number of patients compared with examination of hospital records. However, the two data sources did differ in the quantity of physiotherapy used and this should be taken into account in any analysi

Color comparisons and interpersonal variation

An important challenge to color objectivists, who hold that statements concerning color are made true or false by objective (non-subject-involving) facts, is the argument from interpersonal variation in where normal observers locate the unique hues. Recently, an attractive objectivist response to the argument has been proposed that draws on the semantics of gradable adjectives and which does not require defending the idea that there is a single correct location for each of the unique hues (Gómez-Torrente, 2016). In Hansen (2015), I argued that the recent objectivist response doesn’t apply to comparative occurrences of color adjectives, so a revised, comparative, version of the argument from interpersonal variation remains a powerful objection to certain types of objectivism. In this paper, I address several unsatisfactory objectivist replies to the comparative version of the argument from interpersonal variation, and offer what I think is a more plausible objectivist reply to the comparative argument from interpersonal variation

Stable Isotopic Evidence for Methane Seeps in Neoproterozoic Postglacial Cap Carbonates

The Earth's most severe glaciations are thought to have occurred about 600 million years ago, in the late Neoproterozoic era. A puzzling feature of glacial deposits from this interval is that they are overlain by 1–5-m-thick 'cap carbonates' (particulate deep-water marine carbonate rocks) associated with a prominent negative carbon isotope excursion. Cap carbonates have been controversially ascribed to the aftermath of almost complete shutdown of the ocean ecosystems for millions of years during such ice ages—the 'snowball Earth' hypothesis. Conversely, it has also been suggested that these carbonate rocks were the result of destabilization of methane hydrates during deglaciation and concomitant flooding of continental shelves and interior basins. The most compelling criticism of the latter 'methane hydrate' hypothesis has been the apparent lack of extreme isotopic variation in cap carbonates inferred locally to be associated with methane seeps. Here we report carbon isotopic and petrographic data from a Neoproterozoic postglacial cap carbonate in south China that provide direct evidence for methane-influenced processes during deglaciation. This evidence lends strong support to the hypothesis that methane hydrate destabilization contributed to the enigmatic cap carbonate deposition and strongly negative carbon isotopic anomalies following Neoproterozoic ice ages. This explanation requires less extreme environmental disturbance than that implied by the snowball Earth hypothesis

Escitalopram—translating molecular properties into clinical benefit: reviewing the evidence in major depression

The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents

Building collaboration in multi-agent systems using reinforcement learning

© Springer Nature Switzerland AG 2018. This paper presents a proof-of concept study for demonstrating the viability of building collaboration among multiple agents through standard Q learning algorithm embedded in particle swarm optimisation. Collaboration is formulated to be achieved among the agents via competition, where the agents are expected to balance their action in such a way that none of them drifts away of the team and none intervene any fellow neighbours territory, either. Particles are devised with Q learning for self training to learn how to act as members of a swarm and how to produce collaborative/collective behaviours. The produced experimental results are supportive to the proposed idea suggesting that a substantive collaboration can be build via proposed learning algorithm

Nonlinear models of development, amplification and compression in the mammalian cochlea

This paper reviews current understanding and presents new results on some of the nonlinear processes that underlie the function of the mammalian cochlea. These processes occur within mechano-sensory hair cells that form part of the organ of Corti. After a general overview of cochlear physiology, mathematical modelling results are presented in three parts. First, the dynamic interplay between ion channels within the sensory inner hair cells is used to explain some new electrophysiological recordings from early development. Next, the state of the art is reviewed in modelling the electro-motility present within the outer hair cells (OHCs), including the current debate concerning the role of cell body motility versus active hair bundle dynamics. A simplified model is introduced that combines both effects in order to explain observed amplification and compression in experiments. Finally, new modelling evidence is presented that structural longitudinal coupling between OHCs may be necessary in order to capture all features of the observed mechanical responses.</jats:p

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b+Ly-6G/C+ myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control

Testing special relativity with geodetic VLBI

Geodetic Very Long Baseline Interferometry (VLBI) measures the group delay in the barycentric reference frame. As the Earth is orbiting around the Solar system barycentre with the velocity $V$ of 30 km/s, VLBI proves to be a handy tool to detect the subtle effects of the special and general relativity theory with a magnitude of $(V/\textrm{c})^2$. The theoretical correction for the second order terms reaches up to 300~ps, and it is implemented in the geodetic VLBI group delay model. The total contribution of the second order terms splits into two effects - the variation of the Earth scale, and the deflection of the apparent position of the radio source. The Robertson-Mansouri-Sexl (RMS) generalization of the Lorenz transformation is used for many modern tests of the special relativity theory. We develop an alteration of the RMS formalism to probe the Lorenz invariance with the geodetic VLBI data. The kinematic approach implies three parameters (as a function of the moving reference frame velocity) and the standard Einstein synchronisation. A generalised relativistic model of geodetic VLBI data includes all three parameters that could be estimated. Though, since the modern laboratory Michelson-Morley and Kennedy-Thorndike experiments are more accurate than VLBI technique, the presented equations may be used to test the VLBI group delay model itself.Comment: Proceedings of the IAG 2017 Scientific Meeting, Kobe, Japa