Predictive model of transcriptional elongation control identifies trans regulatory factors from chromatin signatures.

Promoter-proximal Polymerase II (Pol II) pausing is a key rate-limiting step for gene expression. DNA and RNA-binding trans-acting factors regulating the extent of pausing have been identified. However, we lack a quantitative model of how interactions of these factors determine pausing, therefore the relative importance of implicated factors is unknown. Moreover, previously unknown regulators might exist. Here we address this gap with a machine learning model that accurately predicts the extent of promoter-proximal Pol II pausing from large-scale genome and transcriptome binding maps and gene annotation and sequence composition features. We demonstrate high accuracy and generalizability of the model by validation on an independent cell line which reveals the model's cell line agnostic character. Model interpretation in light of prior knowledge about molecular functions of regulatory factors confirms the interconnection of pausing with other RNA processing steps. Harnessing underlying feature contributions, we assess the relative importance of each factor, quantify their predictive effects and systematically identify previously unknown regulators of pausing. We additionally identify 16 previously unknown 7SK ncRNA interacting RNA-binding proteins predictive of pausing. Our work provides a framework to further our understanding of the regulation of the critical early steps in transcriptional elongation.

DeepSom: a CNN-based approach to somatic variant calling in WGS samples without a matched normal.

MOTIVATION: Somatic mutations are usually called by analyzing the DNA sequence of a tumor sample in conjunction with a matched normal. However, a matched normal is not always available, for instance, in retrospective analysis or diagnostic settings. For such cases, tumor-only somatic variant calling tools need to be designed. Previously proposed approaches demonstrate inferior performance on whole-genome sequencing (WGS) samples. RESULTS: We present the convolutional neural network-based approach called DeepSom for detecting somatic single nucleotide polymorphism and short insertion and deletion variants in tumor WGS samples without a matched normal. We validate DeepSom by reporting its performance on five different cancer datasets. We also demonstrate that on WGS samples DeepSom outperforms previously proposed methods for tumor-only somatic variant calling. AVAILABILITY AND IMPLEMENTATION: DeepSom is available as a GitHub repository at https://github.com/heiniglab/DeepSom. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Super-resolution photoacoustic and ultrasound imaging with sparse arrays.

It has previously been demonstrated that model-based reconstruction methods relying on a priori knowledge of the imaging point spread function (PSF) coupled to sparsity priors on the object to image can provide super-resolution in photoacoustic (PA) or in ultrasound (US) imaging. Here, we experimentally show that such reconstruction also leads to super-resolution in both PA and US imaging with arrays having much less elements than used conventionally (sparse arrays). As a proof of concept, we obtained super-resolution PA and US cross-sectional images of microfluidic channels with only 8 elements of a 128-elements linear array using a reconstruction approach based on a linear propagation forward model and assuming sparsity of the imaged structure. Although the microchannels appear indistinguishable in the conventional delay-and-sum images obtained with all the 128 transducer elements, the applied sparsity-constrained model-based reconstruction provides super-resolution with down to only 8 elements. We also report simulation results showing that the minimal number of transducer elements required to obtain a correct reconstruction is fundamentally limited by the signal-to-noise ratio. The proposed method can be straigthforwardly applied to any transducer geometry, including 2D sparse arrays for 3D super-resolution PA and US imaging.

Overcoming the acoustic diffraction limit in photoacoustic imaging by the localization of flowing absorbers.

The resolution of photoacoustic imaging deep inside scattering media is limited by the acoustic diffraction limit. In this Letter, taking inspiration from super-resolution imaging techniques developed to beat the optical diffraction limit, we demonstrate that the localization of individual optical absorbers can provide super-resolution photoacoustic imaging well beyond the acoustic diffraction limit. As a proof-of-principle experiment, photoacoustic cross-sectional images of microfluidic channels were obtained with a 15 MHz linear capacitive micromachined ultrasonic transducer array, while absorbing beads were flown through the channels. The localization of individual absorbers allowed us to obtain a super-resolved cross-sectional image of the channels by reconstructing both the channel width and position with an accuracy better than λ/10. Given the discrete nature of endogenous absorbers such as red blood cells, or that of exogenous particular contrast agents, localization is a promising approach to push the current resolution limits of photoacoustic imaging.

Molecular electrometer and binding of cations to phospholipid bilayers.

Despite the vast amount of experimental and theoretical studies on the binding affinity of cations - especially the biologically relevant Na+ and Ca2+ - for phospholipid bilayers, there is no consensus in the literature. Here we show that by interpreting changes in the choline headgroup order parameters according to the 'molecular electrometer' concept [Seelig et al., Biochemistry, 1987, 26, 7535], one can directly compare the ion binding affinities between simulations and experiments. Our findings strongly support the view that in contrast to Ca2+ and other multivalent ions, Na+ and other monovalent ions (except Li+) do not specifically bind to phosphatidylcholine lipid bilayers at sub-molar concentrations. However, the Na+ binding affinity was overestimated by several molecular dynamics simulation models, resulting in artificially positively charged bilayers and exaggerated structural effects in the lipid headgroups. While qualitatively correct headgroup order parameter response was observed with Ca2+ binding in all the tested models, no model had sufficient quantitative accuracy to interpret the Ca2+:lipid stoichiometry or the induced atomistic resolution structural changes. All scientific contributions to this open collaboration work were made publicly, using nmrlipids.blogspot.fi as the main communication platform.