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Photopsia is a phenomenon that sometimes disturbs patients after cataract surgery. To evaluate the impact of the edge design of intraocular lenses (IOL) on the location, shape and relative intensity of photic effects at the retina caused by photopsia in pseudophakic eyes, photopsia was simulated using ZEMAX software. The structural parameters of the pseudophakic eye model are based on the Liou-Brennan eye model parameters with a pupil diameter of 4.5 mm. The IOLs implanted in the eye model have a power of 21 diopter (D) with optical diameter of 6 mm and 7 mm. From the ray-tracing analysis, covering variations of incident ray angle of 50° to 90° from temporally, a photic image is detected at the fovea at specific ray angles of 77.5° (6 mm IOL) and 78.2° (7 mm IOL). This photic image disappears when a thin IOL with an edge thickness of 0 mm or a thick IOL with absorbing edges is replaced in the eye model. With an anti-reflective edge, this photic image remains, but with a fully reflecting edge it disappears at the critical angles and appears with different shapes at other angles. The intensity of this photic image can be reduced by changing the edge design to a frosted surface. Most of the photic patterns in IOLs are not observed with absorbing and thin edge designs. IOLs with anti-reflecting and fully reflecting edges generate disturbing photic effects at different angles on the fovea. IOLs with frosted edges reduce the contrast of the photic effects and make them less disturbing for patients.

Hearing one’s own voice is critical for fluent speech production as it allows for the detection and correction of vocalization errors in real time. This behavior known as the auditory feedback control of speech is impaired in various neurological disorders ranging from stuttering to aphasia; however, the underlying neural mechanisms are still poorly understood. Computational models of speech motor control suggest that, during speech production, the brain uses an efference copy of the motor command to generate an internal estimate of the speech output. When actual feedback differs from this internal estimate, an error signal is generated to correct the internal estimate and update necessary motor commands to produce intended speech. We were able to localize the auditory error signal using electrocorticographic recordings from neurosurgical participants during a delayed auditory feedback (DAF) paradigm. In this task, participants hear their voice with a time delay as they produced words and sentences (similar to an echo on a conference call), which is well known to disrupt fluency by causing slow and stutter-like speech in humans. We observed a significant response enhancement in auditory cortex that scaled with the duration of feedback delay, indicating an auditory speech error signal. Immediately following auditory cortex, dorsal precentral gyrus (dPreCG), a region that has not been implicated in auditory feedback processing before, exhibited a markedly similar response enhancement, suggesting a tight coupling between the 2 regions. Critically, response enhancement in dPreCG occurred only during articulation of long utterances due to a continuous mismatch between produced speech and reafferent feedback. These results suggest that dPreCG plays an essential role in processing auditory error signals during speech production to maintain fluency., Hearing one’s own voice is critical for fluent speech production, allowing detection and correction of vocalization errors in real-time. This study shows that the dorsal precentral gyrus is a critical component of a cortical network that monitors auditory feedback to produce fluent speech; this region is engaged specifically when speech production is effortful during articulation of long utterances.

Current methods for identification of oxygenator clotting during prolonged extracorporeal life support include visual inspection, evaluation of oxygenator resistance and oxygen exchange performance, and assessment of clotting-related laboratory parameters. However, these observations do not provide a quantitative assessment of oxygenator clot formation. By measuring changes in the dynamic oxygenator blood volume this study aimed to evaluate the relation to oxygenator resistance and oxygen transfer performance. Sixty-seven oxygenators were studied during adult extracorporeal life support. Oxygenator blood volume, oxygenator resistance, and oxygen transfer efficiency were monitored. Oxygenator blood volume decreased with increasing runtime (r = -0.462; p 2 transfer was found. Oxygenator blood volume declined over time and was clearly associated with an increasing oxygenator resistance during prolonged extracorporeal life support, though O2 transfer was less affected.

Suids (Sus sp.) played a crucial role in the transition to farming in northern Europe and, like in many regions, in the Netherlands pig husbandry became an important subsistence activity at Neolithic sites. Yet little is known about wild boar palaeoecology and hunting in the Late Mesolithic Netherlands with which to contextualize this transition. This paper presents the first multi-proxy analysis of archaeological suid remains in the Netherlands. It explores human-suid interactions at the Swifterbant culture sites of Hardinxveld-Giessendam Polderweg and De Bruin (5450–4250 BC) through biometric analysis, estimation of age-at-death, and stable carbon and nitrogen isotope analysis. The results reveal targeted hunting of adult wild boar in the Late Mesolithic (5450–4850 BC), with a possible shift over time towards more juveniles. The wild boar in this period are demonstrated to be of comparably large size to contemporary northern European populations and exhibiting a wide range of dietary regimes. In the final occupational period (4450–4250 BC), small suids are present, possibly domestic pigs, but there is no evidence of pig management. This study demonstrates that the nature of human-suid interactions varied over time, which may have been connected to changing environmental conditions, human mobility, and wild boar behaviour. This study also contributes the first biometric and dietary baseline for mid-Holocene wild boar in the Netherlands.

Dysregulation of calcium homeostasis has been hypothesized to play a role in Alzheimer’s disease (AD) pathogenesis. Increased calcium levels can impair axonal transport, disrupt synaptic transmission, and ultimately lead to cell death. Given the potential role of calcium dyshomeostasis in AD, there is interest in testing the ability of already approved drugs targeting various calcium channels to affect amyloid pathology and other aspects of disease. The objective of this study was to test the effects of FDA-approved L-type calcium channel antagonist nimodipine on amyloid accumulation and dystrophic neurite formation in 5XFAD mice, a mouse model of amyloid pathology. 5XFAD transgenic mice and non-transgenic littermates were treated with vehicle or nimodipine-containing chow from two to eight months of age, then brains were harvested and amyloid pathology assessed by immunoblot and immunofluorescence microscopy analyses. Nimodipine was well tolerated and crossed the blood brain barrier, as expected, but there was no effect on Aβ accumulation or on the relative amount of neuritic dystrophy, as assessed by either immunoblot, dot blot or immunofluorescence imaging of Aβ42 and dystrophic neurite marker LAMP1. While we conclude that nimodipine treatment is not likely to improve amyloid pathology or decrease neuritic dystrophy in AD, it is worth noting that nimodipine did not worsen the phenotype suggesting its use is safe in AD patients.

This paper explores the potential of combining different isotope systems from different tissues to improve resolution when reconstructing breastfeeding and weaning practices (BWP) in archaeology. Additionally, we tested whether changes in diet can be detected in deciduous teeth. Rib collagen samples from 22 infants/children from the archaeological site of Bacuranao I (Mayabeque, Cuba) were processed for nitrogen (δ15N) and carbon (δ13Cco) stable isotopes and assessed using a Bayesian model (WARN). In addition, enamel of 48 teeth from 30 infants/children were analyzed for oxygen (δ18Oen) and carbon (δ13Cen) stable isotopes. Data revealed that the timing of weaning cannot be characterized precisely by analyzing either δ18O or δ15N. While a depletion in both δ15N and δ13Cco is only evident after one year, the WARN model suggested that the weaning process started at around 3 months and ended around 1.7 years. Most teeth were enriched in δ18Oen compared to deciduous incisors, suggesting a breastfeeding signal. However, a high variability in δ18O was found between similar teeth from the same individuals. Higher enrichment in δ18Oen, and variability, was observed in tissues formed during the first six months of life. A δ13C enrichment of 1.0‰ was observed among deciduous teeth and ribs. While most individuals enriched in δ15N showed enrichment in δ13C, the δ18O values were more variable. Our data suggests that stable isotopes of deciduous teeth, especially δ13Cen, can be used to detect changes in diet during the weaning process. It is also possible that the δ18O enrichment observed in M1 is influenced by the effects of cooking techniques on weaning foods. The combination of multiple isotope systems and tissues overcome some of the limitations posed by single tissue approaches.

Within the human respiratory tract (HRT), virus diffuses through the periciliary fluid (PCF) bathing the epithelium. But virus also undergoes advection: as the mucus layer sitting atop the PCF is pushed along by the ciliated cell’s beating cilia, the PCF and its virus content are also pushed along, upwards towards the nose and mouth. While many mathematical models (MMs) have described the course of influenza A virus (IAV) infections in vivo, none have considered the impact of both diffusion and advection on the kinetics and localization of the infection. The MM herein represents the HRT as a one-dimensional track extending from the nose down towards the lower HRT, wherein stationary cells interact with IAV which moves within (diffusion) and along with (advection) the PCF. Diffusion was found to be negligible in the presence of advection which effectively sweeps away IAV, preventing infection from disseminating below the depth at which virus first deposits. Higher virus production rates (10-fold) are required at higher advection speeds (40 μm/s) to maintain equivalent infection severity and timing. Because virus is entrained upwards, upper parts of the HRT see more virus than lower parts. As such, infection peaks and resolves faster in the upper than in the lower HRT, making it appear as though infection progresses from the upper towards the lower HRT, as reported in mice. When the spatial MM is expanded to include cellular regeneration and an immune response, it reproduces tissue damage levels reported in patients. It also captures the kinetics of seasonal and avian IAV infections, via parameter changes consistent with reported differences between these strains, enabling comparison of their treatment with antivirals. This new MM offers a convenient and unique platform from which to study the localization and spread of respiratory viral infections within the HRT., Author summary This work proposes a new way to think about and model the dissemination of an influenza A virus (IAV) infection within the human respiratory tract (HRT). The computational model takes into account the physiological environment in which the infection takes place by representing the HRT spatially in one dimension (depth), and by incorporating the effect of virion diffusion within the periciliary fluid that bathes infectable cells, and the remarkable physiological barrier that is the mucus escalator, sweeping virus upwards. Cell regeneration, the immune response, and infection with human vs avian IAV strains are explored in this spatial context. The numerical efficiency of this model, compared to agent-based models, makes it an attractive alternative to model respiratory virus infections in vivo.

Background The subjective experience of fatigue impairs an individual’s ability to sustain physical endurance performance. However, precise understanding of the specific role perceived fatigue plays in the central regulation of performance remains unclear. Here, we examined whether the subjective intensity of a perceived state of fatigue, pre-induced through prior upper body activity, differentially impacted performance and altered perceived effort and affect experienced during a sustained, isometric contraction in lower body. We also explored whether (cardiac) interoception predicted the intensity of experienced perceptual and affective responses and moderated the relationships between constructs during physical activity. Methods Using a repeated-measures study design, thirty male participants completed three experimental conditions, with the intensity of a pre-induced state of fatigue manipulated to evoke moderate (MOD), severe (SEV) and minimal (control; CON) intensity of perceptions prior to performance of the sustained contraction. Results Performance of the sustained contraction was significantly impaired under a perceived state of fatigue, with reductions of 10% and 14% observed in the MOD and SEV conditions, respectively. Performance impairment was accompanied by greater perceived effort and more negative affective valence reported during the contraction. However, effects were limited to comparisons to CON, with no difference evident between the two experimental trials (i.e. MOD vs. SEV). Individuals’ awareness of their accuracy in judging resting heartbeats was shown to predict the subjective intensity of fatigue experienced during the endurance task. However, interoception did not moderate the relationships evident between fatigue and both perceived effort and affective valence. Conclusions A perceived state of fatigue limits endurance performance, influencing both how effortful activity is perceived to be and the affective experience of activity. Though awareness of interoceptive representations of bodily states may be important to the subjective experience of fatigue, interoception does not modulate the relationships between perceived fatigue and other perceptual (i.e. effort) and affective constructs.

Background Robotic assisted gait training (RAGT) uses a powered exoskeleton to support an individual’s body and move their limbs, with the aim of activating latent, pre-existing movement patterns stored in the lower spinal cord called central pattern generators (CPGs) to facilitate stepping. The parameters that directly stimulate the stepping CPGs (hip extension and ipsilateral foot unloading) should be targeted to maximise the rehabilitation benefits of these devices. Aim To compare the biomechanical profiles of individuals with a spinal cord injury (SCI) and able-bodied individuals inside the ReWalkTM powered exoskeleton and to contrast the users’ profiles with the exoskeleton. Methods Eight able-bodied and four SCI individuals donned a ReWalkTM and walked along a 12-meter walkway, using elbow crutches. Whole-body kinematics of the users and the ReWalkTM were captured, along with GRF and temporal-spatial characteristics. Discreet kinematic values were analysed using a Kruskall-Wallis H and Dunn’s post-hoc analysis. Upper-body differences, GRF and temporal-spatial characteristics were analysed using a Mann-Whitney U test (P Results Walking speed ranged from 0.32–0.39m/s. Hip abduction, peak knee flexion and ankle dorsiflexion for both the SCI and able-bodied groups presented with significant differences to the ReWalkTM. The able-bodied group presented significant differences to the ReWalkTM for all kinematic variables except frontal plane hip ROM (P = 0.093,δ = -0.56). Sagittal plane pelvic and trunk ROM were significantly greater in the SCI vs. able-bodied (P = 0.004,δ = -1; P = 0.008,δ = -0.94, respectively). Posterior braking force was significantly greater in the SCI group (P = 0.004, δ = -1). Discussion The different trunk movements used by the SCI group and the capacity for the users’ joint angles to exceed those of the device suggest that biomechanical profiles varied according to the user group. However, upright stepping with the ReWalkTM device delivered the appropriate afferent stimulus to activate CPGs as there were no differences in key biomechanical parameters between the two user groups.

The experience often described as feeling moved, understood chiefly as a social-relational emotion with social bonding functions, has gained significant research interest in recent years. Although listening to music often evokes what people describe as feeling moved, very little is known about the appraisals or musical features contributing to the experience. In the present study, we investigated experiences of feeling moved in response to music using a continuous rating paradigm. A total of 415 US participants completed an online experiment where they listened to seven moving musical excerpts and rated their experience while listening. Each excerpt was randomly coupled with one of seven rating scales (perceived sadness, perceived joy, feeling moved or touched, sense of connection, perceived beauty, warmth [in the chest], or chills) for each participant. The results revealed that musically evoked experiences of feeling moved are associated with a similar pattern of appraisals, physiological sensations, and trait correlations as feeling moved by videos depicting social scenarios (found in previous studies). Feeling moved or touched by both sadly and joyfully moving music was associated with experiencing a sense of connection and perceiving joy in the music, while perceived sadness was associated with feeling moved or touched only in the case of sadly moving music. Acoustic features related to arousal contributed to feeling moved only in the case of joyfully moving music. Finally, trait empathic concern was positively associated with feeling moved or touched by music. These findings support the role of social cognitive and empathic processes in music listening, and highlight the social-relational aspects of feeling moved or touched by music.

Conductive olfactory dysfunction (COD) is caused by an obstruction in the nasal cavity and is characterized by changeable olfaction. COD can occur even when the olfactory cleft is anatomically normal, and therefore, the cause in these cases remains unclear. Herein, we used computational fluid dynamics to examine olfactory cleft airflow with a retrospective cohort study utilizing the cone beam computed tomography scan data of COD patients. By measuring nasal–nasopharynx pressure at maximum flow, we established a cut-off value at which nasal breathing can be differentiated from combined mouth breathing in COD patients. We found that increased nasal resistance led to mouth breathing and that the velocity and flow rate in the olfactory cleft at maximum flow were significantly reduced in COD patients with nasal breathing only compared to healthy olfactory subjects. In addition, we performed a detailed analysis of common morphological abnormalities associated with concha bullosa. Our study provides novel insights into the causes of COD, and therefore, it has important implications for surgical planning of COD, sleep apnea research, assessment of adenoid hyperplasia in children, and sports respiratory physiology.

Non-visual photoreceptors (ipRGCs) and rods both exert a strong influence on the human pupil, yet pupil models regularly use cone-derived sensitivity as their basis. This inconsistency is further exacerbated by the fact that circadian effects can modulate the wavelength sensitivity. We assessed the pupillary reaction to narrowband light stimuli in the mesopic range. Pupil size for eighty-three healthy participants with normal color vision was measured in nine experimental protocols with varying series of continuous or discontinuous light stimuli under Ganzfeld conditions, presented after 90 seconds of dark adaptation. One hundred and fifty series of stimulation were conducted across three experiments, and were analyzed for wavelength-dependency on the normalized pupillary constriction (nPC), conditional on experimental settings and individual traits. Traits were surveyed by questionnaire; color vision was tested by Ishihara plates or the Lanthony D15 test. Data were analyzed with generalized additive mixed models (GAMM). The normalized pupillary constriction response is consistent with L+M-cone derived sensitivity when the series of light stimuli is continuous, i.e., is not interrupted by periods of darkness, but not otherwise. The results also show that a mesopic illuminance weighing led to an overall best prediction of pupillary constriction compared to other types of illuminance measures. IpRGC influence on nPC is not readily apparent from the results. When we explored the interaction of chronotype and time of day on the wavelength dependency, differences consistent with ipRGC influence became apparent. The models indicate that subjects of differing chronotype show a heightened or lowered sensitivity to short wavelengths, depending on their time of preference. IpRGC influence is also seen in the post-illumination pupil reflex if the prior light-stimulus duration is one second. However, shorter wavelengths than expected become more important if the light-stimulus duration is fifteen or thirty seconds. The influence of sex on nPC was present, but showed no interaction with wavelength. Our results help to define the conditions, under which the different wavelength sensitivities in the literature hold up for narrowband light settings. The chronotype effect might signify a mechanism for strengthening the individual´s chronotype. It could also be the result of the participant’s prior exposure to light (light history). Our explorative findings for this effect demand replication in a controlled study.

Optically pumped magnetometers (OPMs) have recently become so sensitive that they are suitable for use in magnetoencephalography (MEG). These sensors solve operational problems of the current standard MEG, where superconducting quantum interference device (SQUID) gradiometers and magnetometers are being used. The main advantage of OPMs is that they do not require cryogenics for cooling. Therefore, they can be placed closer to the scalp and are much easier to use. Here, we measured auditory evoked fields (AEFs) with both SQUID- and OPM-based MEG systems for a group of subjects to better understand the usage of a limited sensor count OPM-MEG. We present a theoretical framework that transforms the within subject data and equivalent simulation data from one MEG system to the other. This approach works on the principle of solving the inverse problem with one system, and then using the forward model to calculate the magnetic fields expected for the other system. For the source reconstruction, we used a minimum norm estimate (MNE) of the current distribution. Two different volume conductor models were compared: the homogeneous conducting sphere and the three-shell model of the head. The transformation results are characterized by a relative error and cross-correlation between the measured and the estimated magnetic field maps of the AEFs. The results for both models are encouraging. Since some commercial OPMs measure multiple components of the magnetic field simultaneously, we additionally analyzed the effect of tangential field components. Overall, our dual-axis OPM-MEG with 15 sensors yields similar information to a 62-channel SQUID-MEG with its field of view restricted to the right hemisphere.

Physics-based predictive simulations have been shown to capture many salient features of human walking. Yet they often fail to produce realistic stance knee and ankle mechanics. While the influence of the performance criterion on the predicted walking pattern has been previously studied, the influence of musculoskeletal mechanics has been less explored. Here, we investigated the influence of two mechanical assumptions on the predicted walking pattern: the complexity of the foot model and the stiffness of the Achilles tendon. We found, through three-dimensional muscle-driven predictive simulations of walking, that modeling the toes, and thus using two-segment instead of single-segment foot models, contributed to robustly eliciting physiological stance knee flexion angles, knee extension torques, and knee extensor activity. Modeling toes also slightly decreased the first vertical ground reaction force peak, increasing its agreement with experimental data, and improved stance ankle kinetics. It nevertheless slightly worsened predictions of ankle kinematics. Decreasing Achilles tendon stiffness improved the realism of ankle kinematics, but there remain large discrepancies with experimental data. Overall, this simulation study shows that not only the performance criterion but also mechanical assumptions affect predictive simulations of walking. Improving the realism of predictive simulations is required for their application in clinical contexts. Here, we suggest that using more complex foot models might contribute to such realism. ispartof: PLOS ONE vol:17 issue:1 ispartof: location:United States status: published

The mouse has dichromatic color vision based on two different types of opsins: short (S)- and middle (M)-wavelength-sensitive opsins with peak sensitivity to ultraviolet (UV; 360 nm) and green light (508 nm), respectively. In the mouse retina, cone photoreceptors that predominantly express the S-opsin are more sensitive to contrasts and denser towards the ventral retina, preferentially sampling the upper part of the visual field. In contrast, the expression of the M-opsin gradually increases towards the dorsal retina that encodes the lower visual field. Such a distinctive retinal organization is assumed to arise from a selective pressure in evolution to efficiently encode the natural scenes. However, natural image statistics of UV light remain largely unexplored. Here we developed a multi-spectral camera to acquire high-quality UV and green images of the same natural scenes, and examined the optimality of the mouse retina to the image statistics. We found that the local contrast and the spatial correlation were both higher in UV than in green for images above the horizon, but lower in UV than in green for those below the horizon. This suggests that the dorsoventral functional division of the mouse retina is not optimal for maximizing the bandwidth of information transmission. Factors besides the coding efficiency, such as visual behavioral requirements, will thus need to be considered to fully explain the characteristic organization of the mouse retina.

Background The ligaments in the knee are prone to injury especially during dynamic activities. The resulting instability can have a profound impact on a patient’s daily activities and functional capacity. Musculoskeletal knee modelling provides a non-invasive tool for investigating ligament force-strain behaviour in various dynamic scenarios, as well as potentially complementing existing pre-planning tools to optimise surgical reconstructions. However, despite the development and validation of many musculoskeletal knee models, the effect of modelling parameters on ligament mechanics has not yet been systematically reviewed. Objectives This systematic review aimed to investigate the results of the most recent studies using musculoskeletal modelling techniques to create models of the native knee joint, focusing on ligament mechanics and modelling parameters in various simulated movements. Data sources PubMed, ScienceDirect, Google Scholar, and IEEE Xplore. Eligibility criteria for selecting studies Databases were searched for articles containing any numerical ligament strain or force data on the intact, ACL-deficient, PCL-deficient, or lateral extra-articular reconstructed (LER) knee joints. The studies had to derive these results from musculoskeletal modelling methods. The dates of the publications were between 1 January 1995 and 30 November 2021. Method A customised data extraction form was created to extract each selected study’s critical musculoskeletal model development parameters. Specific parameters of the musculoskeletal knee model development used in each eligible study were independently extracted, including the (1) musculoskeletal model definition (i.e., software used for modelling, knee type, source of geometry, the inclusion of cartilage and menisci, and articulating joints and joint boundary conditions (i.e., number of degrees of freedom (DoF), subjects, type of activity, collected data and type of simulation)), (2) specifically ligaments modelling techniques (i.e., ligament bundles, attachment points, pathway, wrapping surfaces and ligament material properties such as stiffness and reference length), (3) sensitivity analysis, (4) validation approaches, (5) predicted ligament mechanics (i.e., force, length or strain) and (6) clinical applications if available. The eligible papers were then discussed quantitatively and qualitatively with respect to the above parameters. Results and discussion From the 1004 articles retrieved by the initial electronic search, only 25 met all inclusion criteria. The results obtained by aggregating data reported in the eligible studies indicate that considerable variability in the predicted ligament mechanics is caused by differences in geometry, boundary conditions and ligament modelling parameters. Conclusion This systematic review revealed that there is currently a lack of consensus on knee ligament mechanics. Despite this lack of consensus, some papers highlight the potential of developing translational tools using musculoskeletal modelling. Greater consistency in model design, incorporation of sensitivity assessment of the model outcomes and more rigorous validation methods should lead to better agreement in predictions for ligament mechanics between studies. The resulting confidence in the musculoskeletal model outputs may lead to the development of clinical tools that could be used for patient-specific treatments.

Cell segmentation is crucial to the field of cell biology, as the accurate extraction of single-cell morphology, migration, and ultimately behavior from time-lapse live cell imagery are of paramount importance to elucidate and understand basic cellular processes. In an effort to increase available segmentation tools that can perform across research groups and platforms, we introduce a novel segmentation approach centered around optical flow and show that it achieves robust segmentation of single cells by validating it on multiple cell types, phenotypes, optical modalities, and in-vitro environments with or without labels. By leveraging cell movement in time-lapse imagery as a means to distinguish cells from their background and augmenting the output with machine vision operations, our algorithm reduces the number of adjustable parameters needed for manual optimization to two. We show that this approach offers the advantage of quicker processing times compared to contemporary machine learning based methods that require manual labeling for training, and in most cases achieves higher quality segmentation as well. This algorithm is packaged within MATLAB, offering an accessible means for general cell segmentation in a time-efficient manner.

Minimum toe clearance (MTC) is an important indicator of the risk of tripping. Aging and neuromuscular diseases often decrease MTC height and increase its variability, leading to a higher risk of tripping. Previous studies have developed visual feedback-based gait training systems to modify MTC. However, these systems are bulky and expensive, and the effects of the training continue only for a short time. We paid attention to the efficacy of vibration in decreasing the variability of gait parameters, and hypothesized that proper vibration applied to soles can reduce the MTC variability. Using shoes embedded with active vibrating insoles, we assessed the efficacy of both sub- and supra-threshold vibration in affecting MTC distribution. Experiment results with 17 young and healthy adults showed that vibration applied throughout the walking task with constant intensity of 130% of sensory threshold significantly decreased MTC variability, whereas sub-threshold vibration yielded no significant effect. These results demonstrate that a properly designed tactile sensory input which is controlled and delivered by a simple wearable device, the active insole, can reduce the MTC variability during walking.

This study sought to determine whether lower extremity muscle size, power and strength could be a determinant of whole-body maximal aerobic performance in athletes. 20 male and 19 female young athletes (18 ± 4 years) from various sporting disciplines participated in this study. All athletes performed a continuous ramp-incremental cycling to exhaustion for the determination of peak oxygen uptake (V˙O2peak: the highest V˙O2 over a 15-s period) and maximal power output (MPO: power output corresponding to V˙O2peak). Axial scanning of the right leg was performed with magnetic resonance imaging, and anatomical cross-sectional areas (CSAs) of quadriceps femoris (QF) and hamstring muscles at 50% of thigh length were measured. Moreover, bilateral leg extension power and unilateral isometric knee extension and flexion torque were determined. All variables were normalised to body mass, and six independent variables (V˙O2peak, CSAs of thigh muscles, leg extension power and knee extension and flexion torque) were entered into a forward stepwise multiple regression model with MPO being dependent variable for males and females separately. In the males, V˙O2peak was chosen as the single predictor of MPO explaining 78% of the variance. In the females, MPO was attributed to, in the order of importance, V˙O2peak (p < 0.001) and the CSA of QF (p = 0.011) accounting for 84% of the variance. This study suggests that while oxygen transport capacity is the main determinant of MPO regardless of sex, thigh muscle size also has a role in whole-body maximal aerobic performance in female athletes.

Knee osteoarthritis (KOA) is a leading cause of knee pain and disability due to irreversible cartilage degeneration. Previous studies have not identified modifiable risk factors for KOA. In this preliminary cross-sectional study, we aimed to test the following hypotheses: individuals with severe KOA would have a significantly lower quadriceps rate of force development (RFD) than individuals with early KOA, and the decrease in quadriceps RFD would be greater than the decrease in maximum quadriceps strength in individuals with severe KOA. The maximum isometric strength of the quadriceps was assessed in individuals with mild (Kellgren and Lawrence [K&L] grade 1–2) and severe KOA (K&L grade 3–4) using a handheld dynamometer. The RFD was analyzed at 200 ms from torque onset and normalized to the body mass and maximum voluntary isometric contraction torque. To test whether the quadriceps RFD was lowered and whether the lower in the quadriceps RFD was greater than the lower in maximum quadriceps strength in individuals with severe knee OA, the Mann–Whitney U-test and analysis of covariance were performed, respectively. The effect size (ES) based on Hedges’ g with a 95% confidence interval (CI) was calculated for the quadriceps RFD and maximum quadriceps strength. Sixty-six participants were analyzed. Individuals with severe KOA displayed significantly lower quadriceps RFD (p = 0.009), the lower being greater than the lower in maximum quadriceps strength (between-group difference, ES: 0.88, -1.07 vs. 0.06, -0.22). Our results suggest that a decreased quadriceps RFD is a modifiable risk factor for progressive KOA. Our finding could help in the early detection and prevention of severe KOA.

The loaded mechanical function of transtibial prostheses that result from the clinical assembly, tuning, and alignment of modular prosthetic components can directly influence an end user’s biomechanics and overall mobility. Footwear is known to affect prosthesis mechanical properties, and while the options of footwear are limited for most commercial feet due to their fixed geometry, there exists a selection of commercial prosthetic feet that can accommodate a moderate rise in heel height. These feet are particularly relevant to women prosthesis users who often desire to don footwear spanning a range of heel heights. The aim of this study was to assess the effects of adding women’s footwear (flat, trainer, 5.08 cm heel) on the mechanical properties (deformation and energy efficiency) of four models of heel-height accommodating prosthetic feet. Properties were measured through loading-unloading at simulated initial contact, midstance and terminal stance orientations with a universal materials test system, and statistically compared to a barefoot condition. Results suggest that the addition of footwear can alter the level of foot deformation under load, which may be a function of the shoe and alignment. Moreover, while each foot displayed different amounts of energy storage and return, the addition of footwear yielded similar levels of energy efficiency across foot models. Overall, prosthesis users who don shoes of varying heel heights onto adjustable prosthetic feet and their treating clinicians should be aware of the potential changes in mechanical function that could affect the user experience.

Objective Human gait requires complex somatosensory processing of various inputs such as proprioception. Proprioception can be altered in the presence of pain. This has been shown mostly during controlled tasks, thereby limiting the influence of external perturbations. While controlling the environment is sometimes warranted, it limits the ecological validity of the data. Using robotic orthoses to apply perturbations during movements seems a promising tool to functionally assess proprioception, where the complex somatosensory processing required in real-life situations is at play. The main objective of this study was to compare the proprioceptive threshold of healthy participants during gait in the presence and absence of an acute experimental pain. Methods 36 healthy participants walked on a treadmill while wearing a robotized ankle–foot orthosis (rAFO) around their right ankle. The rAFO applied torque perturbations of graded magnitudes during the swing phase of gait. Participants had to report the presence/absence of such perturbations, as a measure of proprioceptive threshold. Following initial assessment, they were randomly assigned to one of three experimental groups: Control (no stimulation), Painless (non-nociceptive stimulation) and Painful (nociceptive stimulation). Electrodes placed on the right lateral malleolus delivered an electrical stimulation during the second assessment for Painless and Painful groups. A Kruskal-Wallis was used to compare the percentage of change of the three groups between the two assessments. Results A 31.80±32.94% increase in proprioceptive threshold, representing an increase of 1.3±1.2 Nm in the detection threshold, was observed for the Painful group only (p Conclusion Findings show that the presence of pain at the ankle can alter participants’ proprioceptive threshold during gait. Clinical assessment of proprioception should therefore carefully consider the presence of pain when evaluating a patient’s performance using clinical proprioceptive test and consider the negative effect of pain on proprioceptive threshold for test interpretation.

Glycation process refers to reactions between reduction sugars and amino acids that can lead to formation of advanced glycation end products (AGEs) which are related to changes in chemical and functional properties of biological structures that accumulate during aging and diseases. The aim of this study was to perform and analyze in vitro glycation by fructose and methylglyoxal (MGO) using salivary fluid, albumin, lysozyme, and salivary α-amylase (sAA). Glycation effect was analyzed by biochemical and spectroscopic methods. The results were obtained by fluorescence analysis, infrared spectroscopy (total attenuated reflection—Fourier transform, ATR-FTIR) followed by multivariate analysis of principal components (PCA), protein profile, immunodetection, enzymatic activity and oxidative damage to proteins. Fluorescence increased in all glycated samples, except in saliva with fructose. The ATR-FTIR spectra and PCA analysis showed structural changes related to the vibrational mode of glycation of albumin, lysozyme, and salivary proteins. Glycation increased the relative molecular mass (Mr) in protein profile of albumin and lysozyme. Saliva showed a decrease in band intensity when glycated. The analysis of sAA immunoblotting indicated a relative reduction in intensity of its correspondent Mr after sAA glycation; and a decrease in its enzymatic activity was observed. Carbonylation levels increased in all glycated samples, except for saliva with fructose. Thiol content decreased only for glycated lysozyme and saliva with MGO. Therefore, glycation of salivary fluid and sAA may have the potential to identify products derived by glycation process. This opens perspectives for further studies on the use of saliva, an easy and non-invasive collection fluid, to monitor glycated proteins in the aging process and evolution of diseases.

Assistive exoskeletons can reduce the metabolic cost of walking, and recent advances in exoskeleton device design and control have resulted in large metabolic savings. Most exoskeleton devices provide assistance at either the ankle or hip. Exoskeletons that assist multiple joints have the potential to provide greater metabolic savings, but can require many actuators and complicated controllers, making it difficult to design effective assistance. Coupled assistance, when two or more joints are assisted using one actuator or control signal, could reduce control dimensionality while retaining metabolic benefits. However, it is unknown which combinations of assisted joints are most promising and if there are negative consequences associated with coupled assistance. Since designing assistance with human experiments is expensive and time-consuming, we used musculoskeletal simulation to evaluate metabolic savings from multi-joint assistance and identify promising joint combinations. We generated 2D muscle-driven simulations of walking while simultaneously optimizing control strategies for simulated lower-limb exoskeleton assistive devices to minimize metabolic cost. Each device provided assistance either at a single joint or at multiple joints using massless, ideal actuators. To assess if control could be simplified for multi-joint exoskeletons, we simulated different control strategies in which the torque provided at each joint was either controlled independently or coupled between joints. We compared the predicted optimal torque profiles and changes in muscle and whole-body metabolic power consumption across the single joint and multi-joint assistance strategies. We found multi-joint devices–whether independent or coupled–provided 50% greater metabolic savings than single joint devices. The coupled multi-joint devices were able to achieve most of the metabolic savings produced by independently-controlled multi-joint devices. Our results indicate that device designers could simplify multi-joint exoskeleton designs by reducing the number of torque control parameters through coupling, while still maintaining large reductions in metabolic cost.

The capability to establish accurate predictions is an integral part of learning. Whether predictions about different dimensions of a stimulus interact with each other, and whether such an interaction affects learning, has remained elusive. We conducted a statistical learning study with EEG (electroencephalography), where a stream of consecutive sound triplets was presented with deviants that were either: (a) statistical, depending on the triplet ending probability, (b) physical, due to a change in sound location or (c) double deviants, i.e. a combination of the two. We manipulated the predictability of stimulus-onset by using random stimulus-onset asynchronies. Temporal unpredictability due to random onsets reduced the neurophysiological responses to statistical and location deviants, as indexed by the statistical mismatch negativity (sMMN) and the location MMN. Our results demonstrate that the predictability of one stimulus attribute influences the processing of prediction error signals of other stimulus attributes, and thus also learning of those attributes.

Deep brain stimulation (DBS) is an established clinical therapy, and directional DBS electrode designs are now commonly used in clinical practice. Directional DBS leads have the ability to increase the therapeutic window of stimulation, but they also increase the complexity of clinical programming. Therefore, computational models of DBS have become available in clinical software tools that are designed to assist in the identification of therapeutic settings. However, the details of how the DBS model is implemented can influence the predictions of the software. The goal of this study was to compare different methods for representing directional DBS electrodes within finite element volume conductor (VC) models. We evaluated 15 different DBS VC model variants and quantified how their differences influenced estimates on the spatial extent of axonal activation from DBS. Each DBS VC model included the same representation of the brain and head, but the details of the current source and electrode contact were different for each model variant. The more complex VC models explicitly represented the DBS electrode contacts, while the more simple VC models used boundary condition approximations. The more complex VC models required 2–3 times longer to mesh, build, and solve for the DBS voltage distribution than the more simple VC models. Differences in individual axonal activation thresholds across the VC model variants were substantial (-24% to +47%). However, when comparing total activation of an axon population, or estimates of an activation volume, the differences between model variants decreased (-7% to +8%). Nonetheless, the technical details of how the electrode contact and current source are represented in the DBS VC model can directly affect estimates of the voltage distribution and electric field in the brain tissue.

International audience; Numerous empirical and modeling studies have been done to find a relationship between postural stability and the susceptibility to motion sickness (MS). However, while the demonstration of a causal relationship between postural stability and the susceptibility to MS is still lacking, recent studies suggest that motion sick individuals have genuine deficits in selecting and reweighting multimodal sensory information. Here we investigate how the adaptation to changing postural situations develops and how the dynamics in multisensory integration is modulated on an individual basis along with MS susceptibility. We used a postural task in which participants stood on a posturographic platform with either eyes open (EO) or eyes closed (EC) during three minutes. The platform was static during the first minute (baseline phase), oscillated harmonically during the second minute (perturbation phase) and returned to its steady state for the third minute (return phase). Principal component (PC) analysis was applied to the sequence of short-term power density spectra of the antero-posterior position of the center of pressure. Results showed that the less motion-sick a participant is, the more similar is his balance between high and low frequencies for EO and EC conditions (as calculated from the eigenvector of the first PC). By fitting exponential decay models to the first PC score in the return phase, we estimated, for each participant in each condition, the sluggishness to return to the baseline spectrum. We showed that the de-adaptation following platform oscillation depends on the susceptibility to MS. These results suggest that non motion-sick participants finely adjust their spectrum in the perturbation phase (i.e. reweighting) and therefore take longer to return to their initial postural control particularly with eyes closed. Thus, people have idiosyncratic ways of doing sensory reweighting for postural control, these processes being tied to MS susceptibility.

Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects almost 2% of the population above the age of 65. To better quantify the effects of new medications, fast and objective methods are needed. Touchscreen-based tapping tasks are simple yet effective tools for quantifying drug effects on PD-related motor symptoms, especially bradykinesia. However, there is no consensus on the optimal task set-up. The present study compares four tapping tasks in 14 healthy participants. In alternate finger tapping (AFT), tapping occurred with the index and middle finger with 2.5 cm between targets, whereas in alternate side tapping (AST) the index finger with 20 cm between targets was used. Both configurations were tested with or without the presence of a visual cue. Moreover, for each tapping task, within- and between-day repeatability and (potential) sensitivity of the calculated parameters were assessed. Visual cueing reduced tapping speed and rhythm, and improved accuracy. This effect was most pronounced for AST. On average, AST had a lower tapping speed with impaired accuracy and improved rhythm compared to AFT. Of all parameters, the total number of taps and mean spatial error had the highest repeatability and sensitivity. The findings suggest against the use of visual cueing because it is crucial that parameters can vary freely to accurately capture medication effects. The choice for AFT or AST depends on the research question, as these tasks assess different aspects of movement. These results encourage further validation of non-cued AFT and AST in PD patients.

Background and purpose Clinical comparisons do not usually take laterality into account and thus may report erroneous or misleading data. The concept of laterality, well evaluated in brain and motor systems, may also apply at the level of peripheral nerves. Therefore, we sought to evaluate the extent to which we could observe an effect of laterality in MRI-collected white matter indices of the sciatic nerve and its two branches (tibial and fibular). Materials and methods We enrolled 17 healthy persons and performed peripheral nerve diffusion weighted imaging (DWI) and magnetization transfer imaging (MTI) of the sciatic, tibial and fibular nerve. Participants were scanned bilaterally, and findings were divided into ipsilateral and contralateral nerve fibers relative to self-reporting of hand dominance. Generalized estimating equation modeling was used to evaluate nerve fiber differences between ipsilateral and contralateral legs while controlling for confounding variables. All findings controlled for age, sex and number of scans performed. Results A main effect of laterality was found in radial, axial, and mean diffusivity for the tibial nerve. Axial diffusivity was found to be lateralized in the sciatic nerve. When evaluating mean MTR, a main effect of laterality was found for each nerve division. A main effect of sex was found in the tibial and fibular nerve fiber bundles. Conclusion For the evaluation of nerve measures using DWI and MTI, in either healthy or disease states, consideration of underlying biological metrics of laterality in peripheral nerve fiber characteristics need to considered for data analysis. Integrating knowledge regarding biological laterality of peripheral nerve microstructure may be applied to improve how we diagnosis pain disorders, how we track patients’ recovery and how we forecast pain chronification.

Most sensory systems are remarkable in their temporal precision, reflected in such phrases as “a flash of light” or “a twig snap”. Yet taste is complicated by the transport processes of stimuli through the papilla matrix to reach taste receptors, processes that are poorly understood. We computationally modeled the surface of the human tongue as a microfiber porous medium and found that time-concentration profiles within the papilla zone rise with significant delay that well match experimental ratings of perceived taste intensity to a range of sweet and salty stimuli for both rapid pulses and longer sip-and-hold exposures. Diffusivity of these taste stimuli, determined mostly by molecular size, correlates greatly with time and slope to reach peak intensity: smaller molecular size may lead to quicker taste perception. Our study demonstrates the novelty of modeling the human tongue as a porous material to drastically simplify computational approaches and that peripheral transport processes may significantly affect the temporal profile of taste perception, at least to sweet and salty compounds., Author summary Taste perception is an important gateway for food selection, food intake, energy and nutrition balance–as world is facing epidemic of obesity and diabetes. Information conveyed via the taste system provide crucial behavior choices, e.g. in identifying edible and nutritious food source, driving hedonic evaluation and craving, as well as avoiding poisonous substances. Thus, the interest to understand early taste responses is important, not only for basic science, but also for clinical and public health applications.

The human gut symbiont Ruminococcus gnavus displays strain-specific repertoires of glycoside hydrolases (GHs) contributing to its spatial location in the gut. Sequence similarity network analysis identified strain-specific differences in blood-group endo-β-1,4-galactosidase belonging to the GH98 family. We determined the substrate and linkage specificities of GH98 from R. gnavus ATCC 29149, RgGH98, against a range of defined oligosaccharides and glycoconjugates including mucin. We showed by HPAEC-PAD and LC-FD-MS/MS that RgGH98 is specific for blood group A tetrasaccharide type II (BgA II). Isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR confirmed RgGH98 affinity for blood group A over blood group B and H antigens. The molecular basis of RgGH98 strict specificity was further investigated using a combination of glycan microarrays, site-directed mutagenesis, and X-ray crystallography. The crystal structures of RgGH98 in complex with BgA trisaccharide (BgAtri) and of RgGH98 E411A with BgA II revealed a dedicated hydrogen network of residues, which were shown by site-directed mutagenesis to be critical to the recognition of the BgA epitope. We demonstrated experimentally that RgGH98 is part of an operon of 10 genes that is overexpresssed in vitro when R. gnavus ATCC 29149 is grown on mucin as sole carbon source as shown by RNAseq analysis and RT-qPCR confirmed RgGH98 expression on BgA II growth. Using MALDI-ToF MS, we showed that RgGH98 releases BgAtri from mucin and that pretreatment of mucin with RgGH98 confered R. gnavus E1 the ability to grow, by enabling the E1 strain to metabolise BgAtri and access the underlying mucin glycan chain. These data further support that the GH repertoire of R. gnavus strains enable them to colonise different nutritional niches in the human gut and has potential applications in diagnostic and therapeutics against infection., Ruminococcus gnavus is a human gut symbiont that displays strain-specific repertoires of glycoside hydrolases (GH). This study finds that the R. gnavus enzyme GH98 is specific for blood group A (BgA) tetrasaccharide type II, and that it can release BgA trisaccharide from mucins, showing that the GH repertoire of R. gnavus strains enables them to colonise different nutritional niches in the human gut.

Significance Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a conventional anomaloscope, the “red/white dissociation ratio” (RWR) allows to describe protanopia numerically. For the majority of subjects with protanopia a restriction for faint red stimuli was found. Purpose Comparing the horizontal visual field extensions for red and white stimuli in subjects with protanopia and those with normal trichromacy and assessing the related intra-subject intra-session repeatability. Methods The subjects were divided into groups with protanopia and with normal trichromacy, based on color vision testing (HMC anomaloscope, Oculus, Wetzlar/FRG). Two stimulus characteristics, III4e and III1e, according to the Goldmann-classification, were presented with semi-automated kinetic perimetry (Octopus 900 perimeter, Haag-Streit, Köniz/CH). They moved along the horizontal meridian, with an angular velocity of 3°/s towards the visual field center, starting from either the temporal or nasal periphery. If necessary, a 20° nasal fixation point offset was chosen to capture the temporal periphery of the visual field. For each condition the red/white dissociation ratio (RWR); Pat Appl. DPMA DRN 43200082D) between the extent of the isopter for red (RG610, Schott, Mainz/ FRG) and white stimuli along the horizontal meridian was determined. Results All data are listed as median/interquartile range: Five males with protanopia (age 22.1/4.5 years) and six males with normal trichromacy (control group, age 30.5/15.2 years) were enrolled. The RWR is listed for the right eye, as no clinically relevant difference between right and left eye occurred. Protanopes’ RWR for mark III4e (in brackets: control group) was 0.941/0.013 (0.977/0.019) and for mark III1e 0.496/0.062 (0.805/0.051), respectively. Conclusions In this exploratory “proof-of-concept study” red/white dissociation ratio perimetry is introduced as a novel technique aiming at assessing and quantifying the severity of protanopia. Further effort is needed to understand the magnitude of the observed red-/white dissociation and to extend this methodology to a wider age range of the sample and to anomalous trichromacies (protanomalia) with varying magnitude.

Horseshoes influence how horses’ hooves interact with different ground surfaces, during the impact, loading and push-off phases of a stride cycle. Consequently, they impact on the biomechanics of horses’ proximal limb segments and upper body. By implication, different shoe and surface combinations could drive changes in the magnitude and stability of movement patterns in horse-jockey dyads. This study aimed to quantify centre of mass (COM) displacements in horse-jockey dyads galloping on turf and artificial tracks in four shoeing conditions: 1) aluminium; 2) barefoot; 3) GluShu; and 4) steel. Thirteen retired racehorses and two jockeys at the British Racing School were recruited for this intervention study. Triaxial acceleration data were collected close to the COM for the horse (girth) and jockey (kidney-belt), using iPhones (Apple Inc.) equipped with an iOS app (SensorLog, sample rate =50 Hz). Shoe-surface combinations were tested in a randomized order and horse-jockey pairings remained constant. Tri-axial acceleration data from gallop runs were filtered using bandpass Butterworth filters with cut-off frequencies of 15 Hz and 1 Hz, then integrated for displacement using Matlab. Peak displacement was assessed in both directions (positive ‘maxima’, negative ‘minima’) along the cranio-caudal (CC, positive = forwards), medio-lateral (ML, positive = right) and dorso-ventral (DV, positive = up) axes for all strides with frequency �2 Hz (mean = 2.06 Hz). Linear mixed-models determined whether surfaces, shoes or shoe-surface interactions (fixed factors) significantly affected the displacement patterns observed, with day, run and horse-jockey pairs included as random factors; significance was set at pparameters except ML-axis minima for the horse (psignificantly affect horse and jockey upper-body displacements. Greater sink of hooves on impact, combined with increased push-off during the propulsive phase, could explain the higher vertical displacements on the artificial track. Variations in distal limb mass associated with shoe-type may drive compensatory COM displacements to minimize the energetic cost of movement. The artificial surface and steel shoes provoked the least CC-axis movementof the jockey, so may promote greatest stability. However, differences between horse and jockey mean displacements indicated DV-axis and CC-axis offsets with compensatory increases and decreases, suggesting the dyad might operate within displacement limits to maintain stability. Further work is needed to relate COM displacements to hoof kinematics and to determine whether there is an optimum configuration of COM displacement to optimise performance and minimise injury.

Background Changes in brain structure and cognitive decline occur in Chronic Obstructive Pulmonary Disease (COPD). They also occur with smoking and coronary artery disease (CAD), but it is unclear whether a common mechanism is responsible. Methods Brain MRI markers of brain structure were tested for association with disease markers in other organs. Where possible, principal component analysis (PCA) was used to group markers within organ systems into composite markers. Univariate relationships between brain structure and the disease markers were explored using hierarchical regression and then entered into multivariable regression models. Results 100 participants were studied (53 COPD, 47 CAD). PCA identified two brain components: brain tissue volumes and white matter microstructure, and six components from other organ systems: respiratory function, plasma lipids, blood pressure, glucose dysregulation, retinal vessel calibre and retinal vessel tortuosity. Several markers could not be grouped into components and were analysed as single variables, these included brain white matter hyperintense lesion (WMH) volume. Multivariable regression models showed that less well organised white matter microstructure was associated with lower respiratory function (p = 0.028); WMH volume was associated with higher blood pressure (p = 0.036) and higher C-Reactive Protein (p = 0.011) and lower brain tissue volume was associated with lower cerebral blood flow (pp = 0.001). Smoking history was not an independent correlate of any brain marker. Conclusions Measures of brain structure were associated with a range of markers of disease, some of which appeared to be common to both COPD and CAD. No single common pathway was identified, but the findings suggest that brain changes associated with smoking-related diseases may be due to vascular, respiratory, and inflammatory changes.

Purpose To evaluate the age-related change in color visual acuity (CVA) in normal eyes. Methods In total, 162 normal eyes (162 subjects, women: 52, men: 110, age range: 15–68 years) with best-corrected visual acuity (BCVA) ≥20/13 were enrolled. Fifteen colors from the New Color Test (chroma 6) were applied to Landolt “C” rings, white point D65 was applied as background, and a luminance of 30 cd/m2 was set for both the rings and the background. These rings were used to measure the chromatic spatial discrimination acuity as the CVA value, while changing the stimulus size. Correlations of the CVA value of each color and age were evaluated. Mean CVA values of all 15 colors (logarithm of the minimum angle of resolution) were compared between age groups in 10-year increments. Results Nine CVA values (red, yellow-red, red-yellow, green, blue-green, green-blue, purple, red-purple, and purple-red) were negatively correlated with age (all pp Conclusions The CVA values related to the medium/long-wavelength-sensitive cones were more susceptible to aging than those related to the short-wavelength-sensitive cones. This differed from previous reports, and may be related to the difference in the range of foveal cone function evaluated with each examination.

αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye lenses and muscles. Therefore, mutations in the gene of this protein (CRYAB) might have many pathological consequences. A new mutation has recently been discovered in the α-crystallin domain of this chaperone protein which replaces aspartate 109 with alanine (D109A). This mutation can cause myofibrillar myopathy (MFM), cataracts, and cardiomyopathy. In the current study, several spectroscopic and microscopic analyses, as well as gel electrophoresis assessment were applied to elucidate the pathogenic contribution of human αB-crystallin bearing D109A mutation in development of eye lens cataract and myopathies. The protein oligomerization, chaperone-like activity and chemical/thermal stabilities of the mutant and wild-type protein were also investigated in the comparative assessments. Our results suggested that the D109A mutation has a significant impact on the important features of human αB-crystallin, including its structure, size of the protein oligomers, tendency to form amyloid fibrils, stability, and chaperone-like activity. Given the importance of aspartate 109 in maintaining the proper structure of the α-crystallin domain, its role in the dimerization and chaperone-like activity, as well as preserving protein stability through the formation of salt bridges; mutation at this important site might have critical consequences and can explain the genesis of myopathy and cataract disorders. Also, the formation of large light-scattering aggregates and disruption of the chaperone-like activity by D109A mutation might be considered as important contributing factors in development of the eye lens opacity.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Meniscus tears of the knee are among the most common orthopedic knee injury. Specifically, tears of the posterior root can result in abnormal meniscal extrusion leading to decreased function and progressive osteoarthritis. Despite contemporary surgical treatments of posterior meniscus root tears, there is a low rate of healing and an incidence of residual meniscus extrusion approaching 30%, illustrating an inability to recapitulate native meniscus function. Here, we characterized the differential functional behavior of the medial and lateral meniscus during axial compression load and dynamic knee motion using a cadaveric model. We hypothesized essential differences in extrusion between the medial and lateral meniscus in response to axial compression and knee range of motion. We found no differences in the amount of meniscus extrusion between the medial and lateral meniscus with a competent posterior root (0.338mm vs. 0.235mm; p-value = 0.181). However, posterior root detachment resulted in a consistently increased meniscus extrusion for the medial meniscus compared to the lateral meniscus (2.233mm vs. 0.4705mm; p-value < 0.0001). Moreover, detachment of the posterior root of the medial meniscus resulted in an increase in extrusion at all angles of knee flexion and was most pronounced (4.00mm ± 1.26mm) at 30-degrees of knee flexion. In contrast, the maximum mean extrusion of the lateral meniscus was 1.65mm ± 0.97mm, occurring in full extension. Furthermore, only the medial meniscus extruded during dynamic knee flexion after posterior root detachment. Given the differential functional behaviors between the medial and lateral meniscus, these findings suggest that posterior root repair requires reducing overall meniscus extrusion and recapitulating the native functional responses specific to each meniscus.

A common feature of morphogenesis is the formation of three-dimensional structures from the folding of two-dimensional epithelial sheets, aided by cell shape changes at the cellular-level. Changes in cell shape must be studied in the context of cell-polarised biomechanical processes within the epithelial sheet. In epithelia with highly curved surfaces, finding single-cell alignment along a biological axis can be difficult to automate in silico. We present ‘Origami’, a MATLAB-based image analysis pipeline to compute direction-variant cell shape features along the epithelial apico-basal axis. Our automated method accurately computed direction vectors denoting the apico-basal axis in regions with opposing curvature in synthetic epithelia and fluorescence images of zebrafish embryos. As proof of concept, we identified different cell shape signatures in the developing zebrafish inner ear, where the epithelium deforms in opposite orientations to form different structures. Origami is designed to be user-friendly and is generally applicable to fluorescence images of curved epithelia., Author summary During embryonic development, two-dimensional epithelial sheets bend and fold into complex three-dimensional structures–like paper in the origami art form. The genetic and biomechanical processes driving epithelial folding can be polarised in the epithelium, leading to asymmetric shape changes at the single cell level. Defects in such epithelial shaping have been linked to many developmental anomalies and diseases. It is, therefore, important not only to quantify shape change at the single cell level, but also to orientate these asymmetrical changes along an epithelial axis of polarity when studying morphogenetic processes. Origami is a MATLAB-based software that has been developed to automatically extract such single-cell asymmetrical shape features along the epithelial apico-basal axis from fluorescence microscopy images of folding epithelia. Origami provides a solution to computing directional vectors along the epithelial apico-basal axis followed by extracting direction-variant shape features of each segmented cell. It is generally applicable to epithelial structures regardless of complexity or direction of folding and is robust to imaging conditions. As proof of concept, Origami successfully differentiated between different cell shape signatures in highly curved structures at different developmental timepoints in the zebrafish inner ear.

Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. Our study presents a grey-box linear model that was developed from a physiologically detailed multi-compartmental neurovascular unit model consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. Then, model linearization was performed on the physiologically detailed nonlinear model to find appropriate complexity (Akaike information criterion) to fit functional near-infrared spectroscopy (fNIRS) based measure of blood volume changes, called cerebrovascular reactivity (CVR), to high-definition (HD) tDCS. The grey-box linear model was applied on the fNIRS-based CVR during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. The grey-box linear models for each of the four nested pathways starting from tDCS scalp current density that perturbed synaptic potassium released from active neurons for Pathway 1, astrocytic transmembrane current for Pathway 2, perivascular potassium concentration for Pathway 3, and voltage-gated ion channel current on the smooth muscle cell for Pathway 4 were fitted to the total hemoglobin concentration (tHb) changes from optodes in the vicinity of 4x1 HD-tDCS electrodes as well as on the contralateral sensorimotor cortex. We found that the tDCS perturbation Pathway 3 presented the least mean square error (MSE, median, Author summary Non-invasive brain stimulation techniques, including transcranial direct current stimulation (tDCS), is increasingly being used for the neuromodulation of human brain; however, the vascular mechanisms of action have not been investigated systematically. We applied a rational computational modeling approach to human portable neuroimaging data and found that the tDCS effects in the tissues surrounding a blood vessel explained the blood volume changes, called cerebrovascular reactivity to tDCS, during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. In this study, we limited our investigation to initial hemodynamics response to non-invasive brain stimulation. Future studies need to investigate the non-invasive brain stimulation effects on steady-state oscillations where transcranial alternating current stimulation may be effective in entraining beneficial oscillations. Such a mechanistic understanding from system identification of the hemodynamic responses based on portable neuroimaging can facilitate adequate delivery of the current density to the neurovascular tissue where hypoperfusion has been associated with cerebrovascular diseases, including cognitive impairment. Furthermore, low-cost wearable portable neuroimaging approach in conjunction with non-invasive brain stimulation is amenable to point of care settings including home-based therapy.

Modern histopathology is built on the cornerstone principle of tissue fixation, however there are currently no analytical methods of detecting fixation and as a result, in clinical practice fixation is highly variable and a persistent source of error. We have previously shown that immersion in cold formalin followed by heated formalin is beneficial for preservation of histomorphology and have combined two-temperature fixation with ultra-sensitive acoustic monitoring technology that can actively detect formalin diffusing into a tissue. Here we expand on our previous work by developing a predictive statistical model to determine when a tissue is properly diffused based on the real-time acoustic signal. We trained the model based on the morphology and characteristic diffusion curves of 30 tonsil cores. To test our model, a set of 87 different tonsil samples were fixed with four different protocols: dynamic fixation according to our predictive algorithm (C/H:Dynamic, N = 18), gold-standard 24 hour room temperature (RT:24hr, N = 24), 6 hours in cold formalin followed by 1 hour in heated formalin (C/H:6+1, N = 21), and 2 hours in cold formalin followed by 1 hour in heated formalin (C/H:2+1, N = 24). Digital pathology analysis revealed that the C/H:Dynamic samples had FOXP3 staining that was spatially uniform and statistically equivalent to RT:24hr and C/H:6+1 fixation protocols. For comparison, the intentionally underfixed C/H:2+1 samples had significantly suppressed FOXP3 staining (p.002). Furthermore, our dynamic fixation protocol produced bcl-2 staining concordant with standard fixation techniques. The dynamically fixed samples were on average only submerged in cold formalin for 4.2 hours, representing a significant workflow improvement. We have successfully demonstrated a first-of-its-kind analytical method to assess the quality of fixation in real-time and have confirmed its performance with quantitative analysis of downstream staining. This innovative technology could be used to ensure high-quality and standardized staining as part of an expedited and fully documented preanalytical workflow.

Background We previously reported that there were no differences between the lung-protective actions of pressure-controlled inverse ratio ventilation and volume control ventilation based on the changes in serum cytokine levels. Dead space represents a ventilation-perfusion mismatch, and can enable us to understand the heterogeneity and elapsed time changes in ventilation-perfusion mismatch. Methods This study was a secondary analysis of a randomized controlled trial of patients who underwent robot-assisted laparoscopic radical prostatectomy. The inspiratory to expiratory ratio was adjusted individually by observing the expiratory flow-time wave in the pressure-controlled inverse ratio ventilation group (n = 14) and was set to 1:2 in the volume-control ventilation group (n = 13). Using volumetric capnography, the physiological dead space was divided into three dead space components: airway, alveolar, and shunt dead space. The influence of pressure-controlled inverse ratio ventilation and time factor on the changes in each dead space component rate was analyzed using the Mann-Whitney U test and Wilcoxon’s signed rank test. Results The physiological dead space and shunt dead space rate were decreased in the pressure-controlled inverse ratio ventilation group compared with those in the volume control ventilation group (p < 0.001 and p = 0.003, respectively), and both dead space rates increased with time in both groups. The airway dead space rate increased with time, but the difference between the groups was not significant. There were no significant changes in the alveolar dead space rate. Conclusions Pressure-controlled inverse ratio ventilation reduced the physiological dead space rate, suggesting an improvement in the total ventilation/perfusion mismatch due to improved inflation of the alveoli affected by heterogeneous expansion disorder without hyperinflation of the normal alveoli. However, the shunt dead space rate increased with time, suggesting that atelectasis developed with time in both groups.

Interruptions in nonlinear wave propagation, commonly referred to as wave breaks, are typical of many complex excitable systems. In the heart they lead to lethal rhythm disorders, the so-called arrhythmias, which are one of the main causes of sudden death in the industrialized world. Progress in the treatment and therapy of cardiac arrhythmias requires a detailed understanding of the triggers and dynamics of these wave breaks. In particular, two very important questions are: 1) What determines the potential of a wave break to initiate re-entry? and 2) How do these breaks evolve such that the system is able to maintain spatiotemporally chaotic electrical activity? Here we approach these questions numerically using optogenetics in an in silico model of human atrial tissue that has undergone chronic atrial fibrillation (cAF) remodelling. In the lesser studied sub-threshold illumination régime, we discover a new mechanism of wave break initiation in cardiac tissue that occurs for gentle slopes of the restitution characteristics. This mechanism involves the creation of conduction blocks through a combination of wavefront-waveback interaction, reshaping of the wave profile and heterogeneous recovery from the excitation of the spatially extended medium, leading to the creation of re-excitable windows for sustained re-entry. This finding is an important contribution to cardiac arrhythmia research as it identifies scenarios in which low-energy perturbations to cardiac rhythm can be potentially life-threatening., Author summary Electric turbulence in the heart is associated with complex spatiotemporal dynamics of nonlinear excitation waves. This life-threatening state is initiated by wavebreaks and maintained by self-organized vortices of abnormal excitation. Control over this state is achieved via defibrillation, a method whose efficacy relies on understanding the role of electric vortices in the onset and perpetuation of the turbulent state. However, in biological tissue, these vortices remain largely elusive in experiments due to limitations of visualisation. In order to study the spatiotemporal evolution of vortices in the heart precisely, reversibly and in real-time, we apply computational cardiac optogenetics on a mathematical model for human atrial tissue. Our study demonstrates a heretofore unidentified mechanism of wavebreak initiation, in the absence of standard markers of excitable medium vulnerability. This finding is an important contribution to cardiac arrhythmia research as it identifies how low-energy perturbations to cardiac rhythm can be potentially life-threatening, and render a defibrillation strategy to backfire.

Background Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). On the other hand, in some patients, the efficacy of IFX therapy is not adequate, or gradually diminishes with the lapse of the treatment. Although previous studies have reported a positive relationship between serum IFX levels and therapeutic efficacy, the potential application of IFX therapeutic drug monitoring (TDM) in clinical practice remains unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Methods Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance, KURAMA,cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. Results Out of the 311 RA patients who received IFX therapy, 41 were eligible for analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.4 µg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the High-IFX group (n = 31) than in the Low-IFX group (n = 10). Conversely, at the maximum effect point, when DAS28-ESR (the 28 joint disease activity score incorporating erythrocyte sedimentation rate) was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the Low- and High-IFX groups. Conclusions In clinical practice, IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement. However, IFX TDM could facilitate the identification of secondary non-responders, and in turn, proper IFX use.

When people interact, they fall into synchrony. This synchrony has been demonstrated in a range of contexts, from walking or playing music together to holding a conversation, and has been linked to prosocial outcomes such as development of rapport and efficiency of cooperation. While the basis of synchrony remains unclear, several studies have found synchrony to increase when an interaction is made challenging, potentially providing a means of facilitating interaction. Here we focus on head movement during free conversation. As verbal information is obscured when conversing over background noise, we investigate whether synchrony is greater in high vs low levels of noise, as well as addressing the effect of background noise complexity. Participants held a series of conversations with unfamiliar interlocutors while seated in a lab, and the background noise level changed every 15-30s between 54, 60, 66, 72, and 78 dB. We report measures of head movement synchrony recorded via high-resolution motion tracking at the extreme noise levels (i.e., 54 vs 78 dB) in dyads (n = 15) and triads (n = 11). In both the dyads and the triads, we report increased movement coherence in high compared to low level speech-shaped noise. Furthermore, in triads we compare behaviour in speech-shaped noise vs multi-talker babble, and find greater movement coherence in the more complex babble condition. Key synchrony differences fall in the 0.2–0.5 Hz frequency bands, and are discussed in terms of their correspondence to talkers’ average utterance durations. Additional synchrony differences occur at higher frequencies in the triads only (i.e., >5 Hz), which may relate to synchrony of backchannel cues (as multiple individuals were listening and responding to the same talker). Not only do these studies replicate prior work indicating interlocutors’ increased reliance on behavioural synchrony as task difficulty increases, but they demonstrate these effects using multiple difficulty manipulations and across different sized interaction groups.

Rhodopsins are light-detecting proteins coupled with retinal chromophores essential for visual function. Coincidentally, dysfunctional Rhodopsin homeostasis underlies retinal degeneration in humans and model organisms. Drosophila ninaEG69D mutant is one such example, where the encoded Rh1 protein imposes endoplasmic reticulum (ER) stress and causes light-dependent retinal degeneration. The underlying reason for such light-dependency remains unknown. Here, we report that Drosophila fatty acid binding protein (fabp) is a gene induced in ninaEG69D/+ photoreceptors, and regulates light-dependent Rhodopsin-1 (Rh1) protein clearance and photoreceptor survival. Specifically, our photoreceptor-specific gene expression profiling study in ninaEG69D/+ flies revealed increased expression of fabp together with other genes that control light-dependent Rh1 protein degradation. fabp induction in ninaEG69D photoreceptors required vitamin A and its transporter genes. In flies reared under light, loss of fabp caused an accumulation of Rh1 proteins in cytoplasmic vesicles. The increase in Rh1 levels under these conditions was dependent on Arrestin2 that mediates feedback inhibition of light-activated Rh1. fabp mutants exhibited light-dependent retinal degeneration, a phenotype also found in other mutants that block light-induced Rh1 degradation. These observations reveal a previously unrecognized link between light-dependent Rh1 proteostasis and the ER-stress imposing ninaEG69D mutant that cause retinal degeneration., Author summary Rhodopsins are light-detecting proteins that use retinoids as chromophore co-factors. Rhodopsins are tighly regulated in photoreceptors, as dysfunctional Rhodopsins cause photoreceptor degeneration. The precise mechanisms by which photoreceptors regulate Rhodopsin homeostasis remains unclear. Here, we report that Drosophila fatty acid binding protein (fabp) is a gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we found that fabp is among the genes induced by an endoplasmic reticulum (ER) stress-imposing Rhodopsin-1 (Rh1) mutant, ninaEG69D, which serves as a Drosophila model for Retinitis Pigmentosa. We further found that fabp induction in ninaEG69D photoreceptors required vitamin A and its transporter genes. fabp was required in photoreceptors to help degrade light-activated Rh1. In the absence of fabp, Rh1 accumulated in cytoplasmic vesicles in a light-dependent manner, and exhibited light-dependent retinal degeneration. These observations indicate that fabp is required for light-induced Rh1 degradation and photoreceptor survival.

Ectopic beats (EBs) are cellular arrhythmias that can trigger lethal arrhythmias. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses can pose a huge computational burden. Here, we develop a simplified approach in which logistic regression models (LRMs) are used to define a mapping between the parameters of complex cell models and the probability of EBs (P(EB)). As an example, in this study, we build an LRM for P(EB) as a function of the initial value of diastolic cytosolic Ca2+ concentration ([Ca2+]iini), the initial state of sarcoplasmic reticulum (SR) Ca2+ load ([Ca2+]SRini), and kinetic parameters of the inward rectifier K+ current (IK1) and ryanodine receptor (RyR). This approach, which we refer to as arrhythmia sensitivity analysis, allows for evaluation of the relationship between these arrhythmic event probabilities and their associated parameters. This LRM is also used to demonstrate how uncertainties in experimentally measured values determine the uncertainty in P(EB). In a study of the role of [Ca2+]SRini uncertainty, we show a special property of the uncertainty in P(EB), where with increasing [Ca2+]SRini uncertainty, P(EB) uncertainty first increases and then decreases. Lastly, we demonstrate that IK1 suppression, at the level that occurs in heart failure myocytes, increases P(EB)., Author summary An ectopic beat is an abnormal cellular electrical event which can trigger dangerous arrhythmias in the heart. Complex biophysical models of the cardiac myocyte can be used to reveal how cell properties affect the probability of ectopic beats. However, such analyses can pose a huge computational burden. We develop a simplified approach that enables a highly complex biophysical model to be reduced to a rather simple statistical model from which the functional relationship between myocyte model parameters and the probability of an ectopic beat is determined. We refer to this approach as arrhythmia sensitivity analysis. Given the efficiency of our approach, we also use it to demonstrate how uncertainties in experimentally measured myocyte model parameters determine the uncertainty in ectopic beat probability. We find that, with increasing model parameter uncertainty, the uncertainty in probability of ectopic beat first increases and then decreases. In general, our approach can efficiently analyze the relationship between cardiac myocyte parameters and the probability of ectopic beats and can be used to study how uncertainty of these cardiac myocyte parameters influences the ectopic beat probability.