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The acid-base relevant molecules carbon dioxide (CO2 ), protons (H+ ), and bicarbonate (HCO3 - ) are substrates and end products of some of the most essential physiological functions including aerobic and anaerobic respiration, ATP hydrolysis, photosynthesis, and calcification. The structure and function of many enzymes and other macromolecules are highly sensitive to changes in pH, and thus maintaining acid-base homeostasis in the face of metabolic and environmental disturbances is essential for proper cellular function. On the other hand, CO2 , H+ , and HCO3 - have regulatory effects on various proteins and processes, both directly through allosteric modulation and indirectly through signal transduction pathways. Life in aquatic environments presents organisms with distinct acid-base challenges that are not found in terrestrial environments. These include a relatively high CO2 relative to O2 solubility that prevents internal CO2 /HCO3 - accumulation to buffer pH, a lower O2 content that may favor anaerobic metabolism, and variable environmental CO2 , pH and O2 levels that require dynamic adjustments in acid-base homeostatic mechanisms. Additionally, some aquatic animals purposely create acidic or alkaline microenvironments that drive specialized physiological functions. For example, acidifying mechanisms can enhance O2 delivery by red blood cells, lead to ammonia trapping for excretion or buoyancy purposes, or lead to CO2 accumulation to promote photosynthesis by endosymbiotic algae. On the other hand, alkalinizing mechanisms can serve to promote calcium carbonate skeletal formation. This nonexhaustive review summarizes some of the distinct acid-base homeostatic mechanisms that have evolved in aquatic organisms to meet the particular challenges of this environment.

Music is a non-verbal human language, built on logical structures and articulated in balanced hierarchies between sounds, offering excellent opportunities to explore how the brain creates meaning for complex spatiotemporal auditory patterns. Using the high temporal resolution of magnetoencephalography in 70 participants, we investigated their unfolding brain dynamics during the recognition of previously memorized J.S. Bach’s musical patterns from prelude in C minor BWV 847 compared to novel patterns matched in terms of entropy and information content. Remarkably, the recognition of the memorized music ignited a widespread brain network comprising primary auditory cortex, superior temporal gyrus, insula, frontal operculum, cingulate gyrus, orbitofrontal cortex, basal ganglia, thalamus and hippocampus. Furthermore, measures of both brain activity and functional connectivity presented an overall increase over time, following the evolution and unfolding of the memorized musical patterns. Specifically, while the auditory cortex responded mainly to the first tones of the patterns, the activity and synchronization of higher-order brain areas such as cingulate, frontal operculum, hippocampus and orbitofrontal cortex largely increased over time, arguably representing the key whole-brain mechanisms for conscious recognition of auditory patterns as predicted by the global neuronal workspace hypothesis. In conclusion, our study described the fine-grained whole-brain activity and functional connectivity dynamics responsible for processing and recognition of previously memorized music. Further, the study highlights how the use of musical patterns in combination with a wide array of analytical tools and neuroscientific measures spanning from decoding to fast neural phase synchronization can shed new light on meaningful, complex cognitive processes.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders. Electronic supplementary material The online version of this article (10.1007/s00401-020-02179-x) contains supplementary material, which is available to authorized users.

In the field of robotic hands, tendon actuation is one of the most common ways to control self-adaptive underactuated fingers thanks to its compact size. Either differential or direct drive mechanisms are usually used in these systems to perform synchronised grasping using a single actuator. However, synchronisation problems arise in underactuated grippers whose position of proximal joints varies with time to perform manipulation operations, as this results in a tendon-driven system with dynamic anchor pulleys. This paper introduces a novel passively compliant idler mechanism to avoid unsynchronisation in grippers with a dynamic multi-tendon routing system, such that adequate grasping contact forces are kept under changes in the proximal joints’ positions. A re-configurable palm underactuated dexterous gripper is used as a case study, with the performance of the proposed compliant idler system being evaluated and compared through a contact force analysis during rotation and translation in-hand manipulation tasks. Experiment results clearly demonstrate the ability of the mechanism to synchronise a dynamic tendon routing gripper. A video summarising experiments and findings can be found at https://imperialcollegelondon.box.com/s/hk58688q2hjnu8dhw7uskr7vi9tqr9r5.

Coral calcification is intricately linked to the chemical composition of the fluid in the extracellular calcifying medium (ECM), which is situated between the calcifying cells and the skeleton. Here we demonstrate that the acid-base sensing enzyme soluble adenylyl cyclase (sAC) is expressed in calcifying cells of the coral Stylophora pistillata. Furthermore, pharmacological inhibition of sAC in coral microcolonies resulted in acidification of the ECM as estimated by the pH-sensitive ratiometric indicator SNARF, and decreased calcification rates, as estimated by calcein labeling of crystal growth. These results indicate that sAC activity modulates some of the molecular machinery involved in producing the coral skeleton, which could include ion-transporting proteins and vesicular transport. To our knowledge this is the first study to directly demonstrate biological regulation of the alkaline pH of the coral ECM and its correlation with calcification.

While the grasping capability of robotic grippers has shown significant development, the ability to manipulate objects within the hand is still limited. One explanation for this limitation is the lack of controlled contact variation between the grasped object and the gripper. For instance, human hands have the ability to firmly grip object surfaces, as well as slide over object faces, an aspect that aids the enhanced manipulation of objects within the hand without losing contact. In this letter, we present a parametric, origami-inspired thin surface capable of transitioning between a high friction and a low friction state, suitable for implementation as an epidermis in robotic fingers. A numerical analysis of the proposed surface based on its design parameters, force analysis, and performance in in-hand manipulation tasks is presented. Through the development of a simple two-fingered two-degree-of-freedom gripper utilizing the proposed variable-friction surfaces with different parameters, we experimentally demonstrate the improved manipulation capabilities of the hand when compared to the same gripper without changeable friction. Results show that the pattern density and valley gap are the main parameters that effect the in-hand manipulation performance. The origami-inspired thin surface with a higher pattern density generated a smaller valley gap and smaller height change, producing a more stable improvement of the manipulation capabilities of the hand.

For the majority of tasks performed by traditional serial robot arms, such as bin picking or pick and place, only two or three degrees of freedom (DOF) are required for motion; however, by augmenting the number of degrees of freedom, further dexterity of robot arms for multiple tasks can be achieved. Instead of increasing the number of joints of a robot to improve flexibility and adaptation, which increases control complexity, weight, and cost of the overall system, malleable robots utilise a variable stiffness link between joints allowing the relative positioning of the revolute pairs at each end of the link to vary, thus enabling a low DOF serial robot to adapt across tasks by varying its workspace. In this paper, we present the design and prototyping of a 2-DOF malleable robot, calculate the general equation of its workspace using a parameterisation based on distance geometry---suitable for robot arms of variable topology, and characterise the workspace categories that the end effector of the robot can trace via reconfiguration. Through the design and construction of the malleable robot we explore design considerations, and demonstrate the viability of the overall concept. By using motion tracking on the physical robot, we show examples of the infinite number of workspaces that the introduced 2-DOF malleable robot can achieve., Comment: 7 Pages, 7 figures, conference

Background The potential for HIV transmission between a pregnant woman and her unborn child was first recognized in 1982. Since then a complex package of measures to reduce risk has been developed. This project aims to review UK management of HIV in pregnancy as part of the British HIV Association (BHIVA) audit programme. Methods The National Study of HIV in Pregnancy and Childhood (NSHPC), a population-based surveillance study, provided data for pregnancies with an expected delivery date from 1/1/13 - 30/6/14. Services also completed a survey on local management policies. Data were audited against the 2012 BHIVA pregnancy guidelines. Results During the audit period 1483 pregnancies were reported and 112 services completed the survey. Use of dedicated multidisciplinary teams was reported by 99% although 26% included neither a specialist midwife nor nurse. 17% of services reported delays >1 week for HIV specialist review of women diagnosed antenatally. Problematic urgent HIV testing had been experienced by 9% of services although in a further 49% the need for urgent testing had not arisen. Delays of >2 h in obtaining urgent results were common. Antiretroviral therapy (ART) was started during pregnancy in 37% women with >94% regimens in accordance with guidelines. Late ART initiation was common, particularly in those with a low CD4 count or high viral load. Eleven percent of services reported local policy contrary to guidelines regarding delivery mode for women with a VL

Prosthetic hands, while having shown significant progress in affordability, typically suffer from limited repairability, specifically by the user themselves. Several modular hands have been proposed to address this, but these solutions require handling of intricate components or are unsuitable for prosthetic use due to the large volume and weight resulting from added mechanical complexity to achieve this modularity. In this letter, we propose a fully modular design for a prosthetic hand with finger and wrist level modularity, allowing the removal and attachment of tendon-driven fingers without the need for tools, retendoning, and rewiring. Our innovative design enables placement of the motors behind the hand for remote actuation of the tendons, which are contained solely within the fingers. Details of the novel coupling-transmission mechanisms enabling this are presented, and the capabilities of a prototype using a control-independent grasping benchmark are discussed. The modular detachment torque of the fingers is also computed to analyse the trade-off between intentional removal and the ability to withstand external loads. Experiment results demonstrate that the prosthetic hand is able to grasp a wide range of household and food items, of different shape, size, and weight, without resulting in the ejection of fingers, while allowing a user to remove them easily using a single hand.

The Inverse Base Rate Effect (IBRE; Medin and Edelson (1988)) is a non-rational behavioural phenomenon in predictive learning. In the IBRE, participants learn that a stimulus compound AB leads to one outcome and that another compound AC leads to a different outcome. Importantly, AB and its outcome are presented three times as often as AC (and its outcome). On test, when asked which outcome to expect on presentation of the novel compound BC, participants preferentially select the rarer outcome, previously associated with AC. This is irrational because, objectively, the common outcome is more likely. Usually, the IBRE is attributed to greater attention paid to cue C than to cue B, and so is an excellent test for attentional learning models. The current experiment tested a simple model of attentional learning proposed by Le Pelley, Mitchell, Beesley, George, and Wills (2016) where attention paid to a stimulus is determined by its associative strength. This model struggles to capture the IBRE, but a potential solution suggested by the authors appeals to the role of experimental context. In the present paper, we derive three predictions from their account concerning the effect of changing to a novel experimental context at test, and examine these predictions empirically. Only one of the predictions was supported, concerning the effect of a context shift on responding to a novel cue, was supported. In contrast, Kruschke (2001b)’s EXIT model, in which attention and associative strength can vary independently, captured the data with a high degree of quantitative accuracy.

Background: Mapping of health-related quality-of-life measures to health utility values can facilitate cost-utility evaluation. Regression-based methods tend to lead to shrinkage of variance. This study aims to map the Medical Outcomes Study HIV Health Survey (MOS-HIV) to EuroQoL 5 Dimensions (EQ-5D-3 L) utility index, and to characterize the performance of three mapping methods, including ordinary least squares (OLS), equi-percentile method (EPM), and a recently proposed method called Mean Rank Method (MRM). Methods: This is a secondary analysis of data from a randomized HIV treatment trial. Baseline data from 421 participants were used to develop mapping functions. Follow-up data from 236 participants was used to validate the mapping functions. Results: In the training dataset, MRM and OLS, but not EPM, reproduced the observed mean utility (0.731). MRM, OLS and EPM under-estimated the standard deviation by 0.3, 26.6 and 1.7%, respectively. MRM had the lowest mean absolute error (0.143) and highest intraclass correlation coefficient (0.723) with the observed utility values, whereas OLS had the lowest mean squared error (0.038) and highest R-squared (0.542). Regressing the MRM- and OLS-mapped utility values upon body mass index and log-viral load gave covariate associations comparable to those estimated from the observed utility data (all P > 0.10). EPM did not achieve this property. Findings from the validation data were similar. Conclusions: Functions are available for mapping the MOS-HIV to the EQ-5D-3 L utility values. MRM and OLS were comparable in terms of agreement with the observed utility values at the individual level. MRM had better performance at the group level in terms of describing the utility distribution. Trial registration: NCT00988039. Registered 30 September 2009., The EARNEST trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP, Grant Code: IP.2007.33011.003) with contributions from the Medical Research Council, UK; Institito de Salud Carlos III, Spain (Grant A107/90015); Irish Aid, Ireland; Swedish International Development Cooperation Agency (SIDA), Sweden; Instituto Superiore di Sanita (ISS), Italy; The World Health Organisation; and Merck, USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK [MC_UU_12023/23], CINECA, Bologna, Italy, Janssen Diagnostics, Beerse, Belgium; GSK/ViiV Healthcare Ltd., UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi

Summary The safe establishment of a protocol for a human challenge model for Salmonella Paratyphi A can be used to expedite the evaluation of novel vaccine candidates and provides insight into the clinical and immune response to paratyphoid infection., Background. To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods. Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1–5 × 103 colony-forming units [CFU] and group 2: 0.5–1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results. The primary study objective was achieved following challenge with 1–5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24–85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions. Challenge with S. Paratyphi A at a dose of 1–5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration. NCT02100397.

The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep., Spanish Research Project PSI2016-75688-P (AEI/FEDER) and by the European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 720270 (HBP SGA1). M.L.K. was supported by the ERC Consolidator Grant CAREGIVING (615539) and the Center for Music in the Brain, funded by the Danish National Research Foundation Grant DNRF117. J.C. was supported under the project NORTE-01-0145-FEDER-000023

Robotic arms built from stiffness-adjustable, continuously bending segments serially connected with revolute joints have the ability to change their mechanical architecture and workspace, thus allowing high flexibility and adaptation to different tasks with less than six degrees of freedom, a concept that we call malleable robots. Known stiffening mechanisms may be used to implement suitable links for these novel robotic manipulators; however, these solutions usually show a reduced performance when bending due to structural deformation. By including an inner support structure this deformation can be minimised, resulting in an increased stiffening performance. This paper presents a new multi-material spine-inspired flexible structure for providing support in stiffness-controllable layer-jamming-based robotic links of large diameter. The proposed spine mechanism is highly movable with type and range of motions that match those of a robotic link using solely layer jamming, whilst maintaining a hollow and light structure. The mechanics and design of the flexible spine are explored, and a prototype of a link utilising it is developed and compared with limb segments based on granular jamming and layer jamming without support structure. Results of experiments verify the advantages of the proposed design, demonstrating that it maintains a constant central diameter across bending angles and presents an improvement of more than 203% of resisting force at 180°.

Insomnia Disorder is the most prevalent sleep disorder and it involves both sleep difficulties and daytime complaints. The neural underpinnings of Insomnia Disorder are poorly understood. Existing neuroimaging studies are limited by their focus on local measures and specific regions of interests. To address this shortcoming, we applied a data-driven approach to assess differences in whole-brain structural connectivity between adults with Insomnia Disorder and matched controls without sleep complaints. We used diffusion tensor imaging and probabilistic tractography to assess whole-brain structural connectivity and examined group differences using Network-Based Statistics. The results revealed a significant difference in the structural connectivity of the two groups. Participants with Insomnia Disorder showed reduced connectivity in a subnetwork that was largely left lateralized, including mainly fronto-subcortical connections with the insula as a key region. By taking a whole-brain network perspective, our study succeeds at integrating previous inconsistent findings, and our results reveal that reduced structural connectivity of the left insula and the connections between frontal and subcortical regions are central neurobiological features of Insomnia Disorder. The importance of these areas for interoception, emotional processing, stress responses and the generation of slow wave sleep may help guide the development of neurobiology-based models of the highly prevalent condition of Insomnia Disorder.