Alejandro Granados

Distributing tasks via multiple input pathways increases cellular survival in stress

Improving in one aspect of a task can undermine performance in another, but how such opposing demands play out in single cells and impact on fitness is mostly unknown. Here we study budding yeast in dynamic environments of hyperosmotic stress and show how the corresponding signalling network increases cellular survival both by assigning the requirements of high response speed and high response accuracy to two separate input pathways and by having these pathways interact to converge on Hog1, a p38 MAP kinase. Cells with only the less accurate, reflex-like pathway are fitter in sudden stress, whereas cells with only the slow, more accurate pathway are fitter in increasing but fluctuating stress. Our results demonstrate that cellular signalling is vulnerable to trade-offs in performance, but that these trade-offs can be mitigated by assigning the opposing tasks to different signalling subnetworks. Such division of labour could function broadly within cellular signal transduction. DOI: http://dx.doi.org/10.7554/eLife.21415.001

Thimble End Effector for Palpation Skills Training

Interaction with force feedback haptic devices is often non-intuitive, obtrusive and unrealistic, particularly for the simulation of palpation skills training where a thimble is commonly found as an end-effector. A user will typically use two hands to steady the device and push one or more thimbles onto their fingers. New designs of thimbles, responsible for fastening the end effector of a haptic device onto the finger of the user have been explored, but do not solve the issue of introducing elements that are not present in the task being simulated. We introduce a number of design techniques, with early evaluation results for improving the way users engage, maintain connection and then disengage with thimble-connected haptic interfaces. The designs of the thimbles presented in this paper include rings and different opening shapes, which aim at creating a vacuum effect, as well as a mechanical grip around the finger of the user in order to hold it. Thimble effectiveness, as a function of low impedance on insertion and high impedance on removal, was assessed through a study which highlighted that the relationship between thimble opening size and finger circumference is a critical factor. We present results about the impact of the size of the rings on the insertion and extraction force, followed by a reflection on an improved experimental protocol.

Standardizing bimanual vaginal examination using cognitive task analysis

To create a standardized universal list of procedural steps for bimanual vaginal examination (BVE) for teaching, assessment, and simulator development.

Relax and Tighten—A Haptics-based Approach to Simulate Sphincter Tone Assessment

Digital Rectal Examination (DRE) is a physical examination performed by clinicians to diagnose anorectal and prostate abnormalities. Amongst these, sphincter tone assessment is a crucial task where a clinician asks the patient to relax or squeeze, whilst measuring its function by the amount of pressure felt on the examining finger. DRE is difficult to learn and current models fail to reproduce the dynamic function of anorectal abnormalities. We propose a haptics-based approach to incorporate sphincter tone into our current simulator by motor-controlled pulling and releasing of cables that are coiled around a silicone model of the sphincters. A range of healthy and abnormal sphincter tone cases can be modelled by controlling the motors symmetrically and asymmetrically.

Haptics-based modelling of pigmented skin lesions

Dermatology is under-represented in medical undergraduate education with newly graduated doctors not being able to identify common and important skin conditions. In order to become competent in diagnosing skin lesions, it is important to encounter multiple examples of a condition, as they vary between individuals. Three popular lesions have been identified due to their importance, including nodular melanoma, seborrhoeic keratosis and cherry haemangioma. In this paper we propose a haptics-enabled learning tool for pigmented skin lesions based on haptic texturing. Geometrical modelling, skin deformation and haptics modelling are described. Results of the implementation are presented along with an initial validation study comparing the haptics-based simulator with other methods, including temporary tattoos and silicon made models.

Distributed and dynamic intracellular organization of extracellular information

Significance To thrive in diverse environments, cells must represent extracellular change intracellularly despite stochastic biochemistry. Here, we introduce a quantitative framework for investigating the organization of information within a cell. Combining single-cell measurements of intracellular dynamics with a scalable methodology for estimating mutual information between time series and a discrete input, we demonstrate that extracellular information is encoded in the dynamics of the nuclear localization of transcription factors and that information is lost with alternative static statistics. Any one transcription factor is usually insufficient, but the collective dynamics of multiple transcription factors can represent complex extracellular change. We therefore show that a cell’s internal representation of its environment can be both distributed across diverse proteins and dynamically encoded. Although cells respond specifically to environments, how environmental identity is encoded intracellularly is not understood. Here, we study this organization of information in budding yeast by estimating the mutual information between environmental transitions and the dynamics of nuclear translocation for 10 transcription factors. Our method of estimation is general, scalable, and based on decoding from single cells. The dynamics of the transcription factors are necessary to encode the highest amounts of extracellular information, and we show that information is transduced through two channels: Generalists (Msn2/4, Tod6 and Dot6, Maf1, and Sfp1) can encode the nature of multiple stresses, but only if stress is high; specialists (Hog1, Yap1, and Mig1/2) encode one particular stress, but do so more quickly and for a wider range of magnitudes. In particular, Dot6 encodes almost as much information as Msn2, the master regulator of the environmental stress response. Each transcription factor reports differently, and it is only their collective behavior that distinguishes between multiple environmental states. Changes in the dynamics of the localization of transcription factors thus constitute a precise, distributed internal representation of extracellular change. We predict that such multidimensional representations are common in cellular decision-making.

Modelling of anal sphincter tone based on pneumatic and cable-driven mechanisms

Motivated by the need for improving a haptics-based simulation tool for learning and training digital rectal examinations, a sphincter tone model and its actuation is conceived and developed. Two approaches are presented: one based on pneumatics actuation and the other using cable-driven mechanical actuation using servo motors. Clinical scenarios are modelled as profiles based on studies of anorectal manometry and adapted with clinical input. Both designed mechanisms and scenarios were experimentally evaluated by six experts, Nurse Practitioners in Continence and Colorectal Surgeons. Results show that both mechanisms produce enough pressure on examining finger and profiles are able to generate a wide range of healthy and abnormal cases. Either approach could be used to provide a more realistic experience during training of sphincter tone assessment.