Smartphone-based gaze estimation for in-home autism research.

Atypical gaze patterns are a promising biomarker of autism spectrum disorder. To measure gaze accurately, however, it typically requires highly controlled studies in the laboratory using specialized equipment that is often expensive, thereby limiting the scalability of these approaches. Here we test whether a recently developed smartphone-based gaze estimation method could overcome such limitations and take advantage of the ubiquity of smartphones. As a proof-of-principle, we measured gaze while a small sample of well-assessed autistic participants and controls watched videos on a smartphone, both in the laboratory (with lab personnel) and in remote home settings (alone). We demonstrate that gaze data can be efficiently collected, in-home and longitudinally by participants themselves, with sufficiently high accuracy (gaze estimation error below 1° visual angle on average) for quantitative, feature-based analysis. Using this approach, we show that autistic individuals have reduced gaze time on human faces and longer gaze time on non-social features in the background, thereby reproducing established findings in autism using just smartphones and no additional hardware. Our approach provides a foundation for scaling future research with larger and more representative participant groups at vastly reduced cost, also enabling better inclusion of underserved communities.

A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aß Peptide.

The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aß42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aß42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.

A kinetic ensemble of the Alzheimer's Aß peptide.

The conformational and thermodynamic properties of disordered proteins are commonly described in terms of structural ensembles and free energy landscapes. To provide information on the transition rates between the different states populated by these proteins, it would be desirable to generalize this description to kinetic ensembles. Approaches based on the theory of stochastic processes can be particularly suitable for this purpose. Here, we develop a Markov state model and apply it to determine a kinetic ensemble of Aß42, a disordered peptide associated with Alzheimer's disease. Through the Google Compute Engine, we generated 315-µs all-atom molecular dynamics trajectories. Using a probabilistic-based definition of conformational states in a neural network approach, we found that Aß42 is characterized by inter-state transitions on the microsecond timescale, exhibiting only fully unfolded or short-lived, partially folded states. Our results illustrate how kinetic ensembles provide effective information about the structure, thermodynamics and kinetics of disordered proteins.

Accelerating eye movement research via accurate and affordable smartphone eye tracking.

Eye tracking has been widely used for decades in vision research, language and usability. However, most prior research has focused on large desktop displays using specialized eye trackers that are expensive and cannot scale. Little is known about eye movement behavior on phones, despite their pervasiveness and large amount of time spent. We leverage machine learning to demonstrate accurate smartphone-based eye tracking without any additional hardware. We show that the accuracy of our method is comparable to state-of-the-art mobile eye trackers that are 100x more expensive. Using data from over 100 opted-in users, we replicate key findings from previous eye movement research on oculomotor tasks and saliency analyses during natural image viewing. In addition, we demonstrate the utility of smartphone-based gaze for detecting reading comprehension difficulty. Our results show the potential for scaling eye movement research by orders-of-magnitude to thousands of participants (with explicit consent), enabling advances in vision research, accessibility and healthcare.

Google-Accelerated Biomolecular Simulations.

Biomolecular simulations rely heavily on the availability of suitable compute infrastructure for data-driven tasks like modeling, sampling, and analysis. These resources are typically available on a per-lab and per-facility basis, or through dedicated national supercomputing centers. In recent years, cloud computing has emerged as an alternative by offering an abundance of on-demand, specialist-maintained resources that enable efficiency and increased turnaround through rapid scaling.Scientific computations that take the shape of parallel workloads using large datasets are commonplace, making them ideal candidates for distributed computing in the cloud. Recent developments have greatly simplified the task for the experimenter to configure the cloud for use and job submission. This chapter will show how to use Google's Cloud Platform for biomolecular simulations by example of the molecular dynamics package GROningen MAchine for Chemical Simulations (GROMACS). The instructions readily transfer to a large variety of other tasks, allowing the reader to use the cloud for their specific purposes.Importantly, by using Docker containers, a popular light-weight virtualization solution, and cloud storage, key issues in scientific research are addressed: reproducibility of results, record keeping, and the possibility for other researchers to obtain copies and directly build upon previous work for further experimentation and hypothesis testing.

Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways.

Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle cloud-computing platform to simulate two milliseconds of dynamics of a major drug target, the G-protein-coupled receptor ß2AR. Markov state models aggregate independent simulations into a single statistical model that is validated by previous computational and experimental results. Moreover, our models provide an atomistic description of the activation of a G-protein-coupled receptor and reveal multiple activation pathways. Agonists and inverse agonists interact differentially with these pathways, with profound implications for drug design.

The iFly tracking system for an automated locomotor and behavioural analysis of Drosophila melanogaster.

The use of animal models in medical research provides insights into molecular and cellular mechanisms of human disease, and helps identify and test novel therapeutic strategies. Drosophila melanogaster--the common fruit fly--is one of the most well-established model organisms, as its study can be performed more readily and with far less expense than for other model animal systems, such as mice, fish, or primates. In the case of fruit flies, standard assays are based on the analysis of longevity and basic locomotor functions. Here we present the iFly tracking system, which enables to increase the amount of quantitative information that can be extracted from these studies, and to reduce significantly the duration and costs associated with them. The iFly system uses a single camera to simultaneously track the trajectories of up to 20 individual flies with about 100 µm spatial and 33 ms temporal resolution. The statistical analysis of fly movements recorded with such accuracy makes it possible to perform a rapid and fully automated quantitative analysis of locomotor changes in response to a range of different stimuli. We anticipate that the iFly method will reduce very considerably the costs and the duration of the testing of genetic and pharmacological interventions in Drosophila models, including an earlier detection of behavioural changes and a large increase in throughput compared to current longevity and locomotor assays.

CAMPAIGN: an open-source library of GPU-accelerated data clustering algorithms.

MOTIVATION: Data clustering techniques are an essential component of a good data analysis toolbox. Many current bioinformatics applications are inherently compute-intense and work with very large datasets. Sequential algorithms are inadequate for providing the necessary performance. For this reason, we have created Clustering Algorithms for Massively Parallel Architectures, Including GPU Nodes (CAMPAIGN), a central resource for data clustering algorithms and tools that are implemented specifically for execution on massively parallel processing architectures. RESULTS: CAMPAIGN is a library of data clustering algorithms and tools, written in 'C for CUDA' for Nvidia GPUs. The library provides up to two orders of magnitude speed-up over respective CPU-based clustering algorithms and is intended as an open-source resource. New modules from the community will be accepted into the library and the layout of it is such that it can easily be extended to promising future platforms such as OpenCL. AVAILABILITY: Releases of the CAMPAIGN library are freely available for download under the LGPL from https://simtk.org/home/campaign. Source code can also be obtained through anonymous subversion access as described on https://simtk.org/scm/?group_id=453. CONTACT: kjk33@cantab.net.

Detection of early locomotor abnormalities in a Drosophila model of Alzheimer's disease.

Behavioural assays represent sensitive methods for detecting neuronal dysfunction in model organisms. A number of manual methods have been established for Drosophila, however these are time-consuming and generate parameter-poor phenotype descriptors. Here, we have developed an automated computer vision system to monitor accurately the three-dimensional locomotor trajectories of flies. This approach allows the quantitative description of fly trajectories, using small fly cohorts and short acquisition times. The application of this approach to a Drosophila model of Alzheimer's disease enables the early detection of progressive locomotor deficits and the quantitative assessment of phenotype severity. The approach can be widely applied to different disease models in a number of model organisms.

Using NMR chemical shifts as structural restraints in molecular dynamics simulations of proteins.

We introduce a procedure to determine the structures of proteins by incorporating NMR chemical shifts as structural restraints in molecular dynamics simulations. In this approach, the chemical shifts are expressed as differentiable functions of the atomic coordinates and used to compute forces to generate trajectories that lead to the reduction of the differences between experimental and calculated chemical shifts. We show that this strategy enables the folding of a set of proteins with representative topologies starting from partially denatured initial conformations without the use of additional experimental information. This method also enables the straightforward combination of chemical shifts with other standard NMR restraints, including those derived from NOE, J-coupling, and residual dipolar coupling measurements. We illustrate this aspect by calculating the structure of a transiently populated excited state conformation from chemical shift and residual dipolar coupling data measured by relaxation dispersion NMR experiments.

Fast and accurate predictions of protein NMR chemical shifts from interatomic distances.

We present a method, CamShift, for the rapid and accurate prediction of NMR chemical shifts from protein structures. The calculations performed by CamShift are based on an approximate expression of the chemical shifts in terms of polynomial functions of interatomic distances. Since these functions are very fast to compute and readily differentiable, the CamShift approach can be utilized in standard protein structure calculation protocols.

B-DNA under stress: over- and untwisting of DNA during molecular dynamics simulations.

The twist flexibility of DNA is central to its many biological functions. Explicit solvent molecular dynamics simulations in combination with an umbrella sampling restraining potential have been employed to study induced twist deformations in DNA. Simulations allowed us to extract free energy profiles for twist deformations and were performed on six DNA dodecamer duplexes to cover all 10 possible DNA basepair steps. The shape of the free energy curves was similar for all duplexes. The calculated twist deformability was in good agreement with experiment and showed only modest variation for the complete duplexes. However, the response of the various basepair steps on twist stress was highly nonuniform. In particular, pyrimidine/purine steps were much more flexible than purine/purine steps followed by purine/pyrimidine steps. It was also possible to extract correlations of twist changes and other helical as well as global parameters of the DNA molecules. Twist deformations were found to significantly alter the local as well as global shape of the DNA modulating the accessibility for proteins and other ligands. Severe untwisting of DNA below an average of 25 degrees per basepair step resulted in the onset of a global structural transition with a significantly smaller twist at one end of the DNA compared to the other.