Biomolecular simulations under realistic macroscopic salt conditions, bioRxiv, 2017-11-30
Biomolecular simulations are typically performed in an aqueous environment where the number of ions remains fixed for the duration of the simulation, generally with either a minimally neutralizing ion environment or a number of salt pairs intended to match the macroscopic salt concentration. In contrast, real biomolecules experience local ion environments where the salt concentration is dynamic and may differ from bulk. The degree of salt concentration variability and average deviation from the macroscopic concentration remains, as yet, unknown. Here, we describe the theory and implementation of a Monte Carlo osmostat that can be added to explicit solvent molecular dynamics or Monte Carlo simulations to sample from a semigrand canonical ensemble in which the number of salt pairs fluctuates dynamically during the simulation. The osmostat reproduce the correct equilibrium statistics for a simulation volume that can exchange ions with a large reservoir at a defined macroscopic salt concentration. To achieve useful Monte Carlo acceptance rates, the method makes use of nonequilibrium candidate Monte Carlo (NCMC) moves in which monovalent ions and water molecules are alchemically transmuted using short nonequilibrium trajectories, with a modified Metropolis-Hastings criterion ensuring correct equilibrium statistics for an (Δ𝜇, 𝑁, 𝑝, 𝑇) ensemble. We demonstrate how typical protein (DHFR and the tyrosine kinase Src) and nucleic acid (Drew-Dickerson B-DNA dodecamer) systems exhibit salt concentration distributions that significantly differ from fixed-salt bulk simulations and display fluctuations that are on the same order of magnitude as the average.
biorxiv biophysics 0-100-users 2017Community-driven data analysis training for biology, bioRxiv, 2017-11-30
AbstractThe primary problem with the explosion of biomedical datasets is not the data itself, not computational resources, and not the required storage space, but the general lack of trained and skilled researchers to manipulate and analyze these data. Eliminating this problem requires development of comprehensive educational resources. Here we present a community-driven framework that enables modern, interactive teaching of data analytics in life sciences and facilitates the development of training materials. The key feature of our system is that it is not a static but a continuously improved collection of tutorials. By coupling tutorials with a web-based analysis framework, biomedical researchers can learn by performing computation themselves through a web-browser without the need to install software or search for example datasets. Our ultimate goal is to expand the breadth of training materials to include fundamental statistical and data science topics and to precipitate a complete re-engineering of undergraduate and graduate curricula in life sciences.
biorxiv bioinformatics 100-200-users 2017CRISPR-Cas12a target binding unleashes single-stranded DNase activity, bioRxiv, 2017-11-30
AbstractCRISPR-Cas12a (Cpf1) proteins are RNA-guided DNA targeting enzymes that bind and cut DNA as components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a can be used as a powerful genome editing tool based on its ability to induce genetic changes in cells at sites of double-stranded DNA (dsDNA) cuts. Here we show that RNA-guided DNA binding unleashes robust, non-specific single-stranded DNA (ssDNA) cleavage activity in Cas12a sufficient to completely degrade both linear and circular ssDNA molecules within minutes. This activity, catalyzed by the same active site responsible for site-specific dsDNA cutting, indiscriminately shreds ssDNA with rapid multiple-turnover cleavage kinetics. Activation of ssDNA cutting requires faithful recognition of a DNA target sequence matching the 20-nucleotide guide RNA sequence with specificity sufficient to distinguish between closely related viral serotypes. We find that target-dependent ssDNA degradation, not observed for CRISPR-Cas9 enzymes, is a fundamental property of type V CRISPR-Cas12 proteins, revealing a fascinating parallel with the RNA-triggered general RNase activity of the type VI CRISPR-Cas13 enzymes.One Sentence SummaryCas12a (Cpf1) and related type V CRISPR interference proteins possess non-specific, single-stranded DNase activity upon activation by guide RNA-dependent DNA binding.
biorxiv biochemistry 0-100-users 2017Laminar-specific cortical dynamics in human visual and sensorimotor cortices, bioRxiv, 2017-11-29
AbstractLower frequency, feedback, activity in the alpha and beta range is thought to predominantly originate from infragranular cortical layers, whereas feedforward signals in the gamma range stem largely from supragranular layers. Distinct anatomical and spectral channels may therefore play specialized roles in communication within hierarchical cortical networks; however, empirical evidence for this organization in humans is limited. We leverage high precision MEG to test this proposal, directly and non-invasively, in human participants during visually guided actions. Visual alpha activity mapped onto deep cortical laminae, whereas visual gamma activity predominantly arose from superficial laminae. This laminar-specificity was echoed in sensorimotor beta and gamma activity. Visual gamma activity scaled with task demands in a way compatible with feedforward signaling. For sensorimotor activity, we observed a more complex relationship with feedback and feedforward processes. Distinct frequency channels thus operate in a laminar-specific manner, but with dissociable functional roles across sensory and motor cortices.
biorxiv neuroscience 100-200-users 2017A design framework and exemplar metrics for FAIRness, bioRxiv, 2017-11-28
Abstract“FAIRness” - the degree to which a digital resource is Findable, Accessible, Interoperable, and Reusable - is aspirational, yet the means of reaching it may be defined by increased adherence to measurable indicators. We report on the production of a core set of semi-quantitative metrics having universal applicability for the evaluation of FAIRness, and a rubric within which additional metrics can be generated by the community. This effort is the output from a stakeholder-representative group, founded by a core of FAIR principles’ co-authors and drivers. We now seek input from the community to more broadly discuss their merit.
biorxiv scientific-communication-and-education 100-200-users 2017Estimating the number of missing experiments in a neuroimaging meta-analysis, bioRxiv, 2017-11-28
AbstractCoordinate-based meta-analyses (CBMA) allow researchers to combine the results from multiple fMRI studies with the goal of obtaining results that are more likely to generalise. However, the interpretation of CBMA findings can be impaired by the file drawer problem, a type of publications bias that refers to studies that are carried out but are not published due to lack of significance. Using foci per contrast count data from the BrainMap database, we propose a zero-truncated modelling approach that allows us to estimate the prevalence of non-significant contrasts. We validate our method with simulations and real coordinate data generated from the Human Connectome Project. Application of our method to the data from BrainMap provides evidence for the existence of a file drawer effect, with the rate of missing contrasts estimated as at least 6 per 100 reported.
biorxiv neuroscience 0-100-users 2017