Tissue and cellular spatiotemporal dynamics in colon aging.

Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects, but many of the underlying molecular cues remain unclear. Here, we built a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing ~1,500 mouse gut tissues profiled by spatial transcriptomics and ~400,000 single nucleus RNA-seq profiles. We developed a new computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region, and sex, by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identified cellular and molecular gradients along the adult colonic tract and across the main crypt axis, and multicellular programs associated with aging in the large intestine. Our multi-modal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.

A convolutional neural network for common coordinate registration of high-resolution histology images.

MOTIVATION: Registration of histology images from multiple sources is a pressing problem in large-scale studies of spatial -omics data. Researchers often perform 'common coordinate registration', akin to segmentation, in which samples are partitioned based on tissue type to allow for quantitative comparison of similar regions across samples. Accuracy in such registration requires both high image resolution and global awareness, which mark a difficult balancing act for contemporary deep learning architectures. RESULTS: We present a novel convolutional neural network (CNN) architecture that combines (i) a local classification CNN that extracts features from image patches sampled sparsely across the tissue surface and (ii) a global segmentation CNN that operates on these extracted features. This hybrid network can be trained in an end-to-end manner, and we demonstrate its relative merits over competing approaches on a reference histology dataset as well as two published spatial transcriptomics datasets. We believe that this paradigm will greatly enhance our ability to process spatial -omics data, and has general purpose applications for the processing of high-resolution histology images on commercially available GPUs. AVAILABILITY AND IMPLEMENTATION: All code is publicly available at https://github.com/flatironinstitute/st_gridnet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Assessing suitability for sacubitril-valsartan therapy in an Irish cohort: challenges and opportunities.

INTRODUCTION: Sacubitril-valsartan has been shown by the PARADIGM-HF trial to decrease hospital admissions and improve mortality in patients with heart failure with reduced ejection fraction. The PARADIGM trial had stringent exclusion criteria. It is not known how applicable these trial criteria are to real-life practice. In this study, we sought to determine the percentage of patients eligible for sacubitril-valsartan therapy in a level 3 hospital without a dedicated heart failure service. METHODS: All patients discharged from our service with a diagnosis of congestive cardiac using our hospital in-patient enquiry (HIPE) system underwent hierarchal analysis. In order to be deemed eligible for sacubitril-valsartan therapy, patients had to meet PARADIGM-HF inclusion criteria. RESULTS: Our 143 patients represented a more clinically unwell, elderly cohort than the PARADIGM trial study population. Only 24 patients (16.66%) had an ejection fraction of 40% or less. Our results indicate that only 4/143 patients in a real-world setting (2.79%) were eligible for sacubitril-valsartan therapy at the point of discharge as per the PARADIGM-HF study criteria. This is primarily due to the higher than expected percentage of patients in our cohort with an ejection fraction of over 40% (n = 120) and the low percentage of patients on therapeutic doses of ACEI/ARB (n = 15). CONCLUSIONS: Our study showed that a smaller than expected proportion of our patients in real-world practice are suitable for sacubitril-valsartan therapy at discharge. Most patients were in the HFPEF cohort which does not currently have evidence for treatment with sacubitril-valsartan. Low rates of prescribing of basic heart failure medicatons and the absence of dedicated heart failure services in a non-tertiary centre may explain the poor compliance observed. Improving guideline adherence and increasing awareness of evidence-based medication use at primary and secondary care levels would be of benefit to Irish heart failure patients.

Inference-based assessment of parameter identifiability in nonlinear biological models.

As systems approaches to the development of biological models become more mature, attention is increasingly focusing on the problem of inferring parameter values within those models from experimental data. However, particularly for nonlinear models, it is not obvious, either from inspection of the model or from the experimental data, that the inverse problem of parameter fitting will have a unique solution, or even a non-unique solution that constrains the parameters to lie within a plausible physiological range. Where parameters cannot be constrained they are termed 'unidentifiable'. We focus on gaining insight into the causes of unidentifiability using inference-based methods, and compare a recently developed measure-theoretic approach to inverse sensitivity analysis to the popular Markov chain Monte Carlo and approximate Bayesian computation techniques for Bayesian inference. All three approaches map the uncertainty in quantities of interest in the output space to the probability of sets of parameters in the input space. The geometry of these sets demonstrates how unidentifiability can be caused by parameter compensation and provides an intuitive approach to inference-based experimental design.

Reproducible model development in the cardiac electrophysiology Web Lab.

The modelling of the electrophysiology of cardiac cells is one of the most mature areas of systems biology. This extended concentration of research effort brings with it new challenges, foremost among which is that of choosing which of these models is most suitable for addressing a particular scientific question. In a previous paper, we presented our initial work in developing an online resource for the characterisation and comparison of electrophysiological cell models in a wide range of experimental scenarios. In that work, we described how we had developed a novel protocol language that allowed us to separate the details of the mathematical model (the majority of cardiac cell models take the form of ordinary differential equations) from the experimental protocol being simulated. We developed a fully-open online repository (which we termed the Cardiac Electrophysiology Web Lab) which allows users to store and compare the results of applying the same experimental protocol to competing models. In the current paper we describe the most recent and planned extensions of this work, focused on supporting the process of model building from experimental data. We outline the necessary work to develop a machine-readable language to describe the process of inferring parameters from wet lab datasets, and illustrate our approach through a detailed example of fitting a model of the hERG channel using experimental data. We conclude by discussing the future challenges in making further progress in this domain towards our goal of facilitating a fully reproducible approach to the development of cardiac cell models.

Patent foramen ovale and cryptogenic stroke: contemporary evidence and treatment.

INTRODUCTION: Patent foramen ovale (PFO) is a common anatomical variant in the adult circulation. It is a channel allowing communication between the left and right atria and is a remnant of the foetal circulation. In approximately 25% of the population, this channel persists into adulthood. PFO has been proposed as a potential pathophysiological mechanism for cryptogenic stroke. Areas covered: This review will examine the contemporary evidence for both the association between cryptogenic stroke and PFO and the management of this condition. The authors hope to provide a comprehensive overview of the current evidence and best practice in relation to PFO closure. In addition, the authors will propose some potential avenues for future research in this controversial area and try to predict how PFOs in cryptogenic stroke will be managed in the near future. Expert commentary: In carefully selected patients with cryptogenic stroke, PFO closure represents an evidence based treatment option for the prevention of further ischemic neurological events. A multidisciplinary approach is necessary to ensure appropriate patient selection for the procedure. This should include a vascular neurologist/stroke physician and an interventional cardiologist with an interest in PFO closure.

Comparing two sequential Monte Carlo samplers for exact and approximate Bayesian inference on biological models.

Bayesian methods are advantageous for biological modelling studies due to their ability to quantify and characterize posterior variability in model parameters. When Bayesian methods cannot be applied, due either to non-determinism in the model or limitations on system observability, approximate Bayesian computation (ABC) methods can be used to similar effect, despite producing inflated estimates of the true posterior variance. Owing to generally differing application domains, there are few studies comparing Bayesian and ABC methods, and thus there is little understanding of the properties and magnitude of this uncertainty inflation. To address this problem, we present two popular strategies for ABC sampling that we have adapted to perform exact Bayesian inference, and compare them on several model problems. We find that one sampler was impractical for exact inference due to its sensitivity to a key normalizing constant, and additionally highlight sensitivities of both samplers to various algorithmic parameters and model conditions. We conclude with a study of the O'Hara-Rudy cardiac action potential model to quantify the uncertainty amplification resulting from employing ABC using a set of clinically relevant biomarkers. We hope that this work serves to guide the implementation and comparative assessment of Bayesian and ABC sampling techniques in biological models.

Flip-chip integration of tilted VCSELs onto a silicon photonic integrated circuit.

In this article we describe a cost-effective approach for hybrid laser integration, in which vertical cavity surface emitting lasers (VCSELs) are passively-aligned and flip-chip bonded to a Si photonic integrated circuit (PIC), with a tilt-angle optimized for optical-insertion into standard grating-couplers. A tilt-angle of 10° is achieved by controlling the reflow of the solder ball deposition used for the electrical-contacting and mechanical-bonding of the VCSEL to the PIC. After flip-chip integration, the VCSEL-to-PIC insertion loss is -11.8 dB, indicating an excess coupling penalty of -5.9 dB, compared to Fibre-to-PIC coupling. Finite difference time domain simulations indicate that the penalty arises from the relatively poor match between the VCSEL mode and the grating-coupler.

Hodgkin-Huxley revisited: reparametrization and identifiability analysis of the classic action potential model with approximate Bayesian methods.

As cardiac cell models become increasingly complex, a correspondingly complex 'genealogy' of inherited parameter values has also emerged. The result has been the loss of a direct link between model parameters and experimental data, limiting both reproducibility and the ability to re-fit to new data. We examine the ability of approximate Bayesian computation (ABC) to infer parameter distributions in the seminal action potential model of Hodgkin and Huxley, for which an immediate and documented connection to experimental results exists. The ability of ABC to produce tight posteriors around the reported values for the gating rates of sodium and potassium ion channels validates the precision of this early work, while the highly variable posteriors around certain voltage dependency parameters suggests that voltage clamp experiments alone are insufficient to constrain the full model. Despite this, Hodgkin and Huxley's estimates are shown to be competitive with those produced by ABC, and the variable behaviour of posterior parametrized models under complex voltage protocols suggests that with additional data the model could be fully constrained. This work will provide the starting point for a full identifiability analysis of commonly used cardiac models, as well as a template for informative, data-driven parametrization of newly proposed models.

Ge/Si heterojunction photodiodes fabricated by low temperature wafer bonding.

We report on the photoresponse of an asymmetrically doped p(-)-Ge/n(+)-Si heterojunction photodiode fabricated by wafer bonding. Responsivities in excess of 1 A/W at 1.55 µm are measured with a 5.4 µm thick Ge layer under surface-normal illumination. Capacitance-voltage measurements show that the interfacial band structure is dependent on both temperature and light level, moving from depletion of holes at -50 °C to accumulation at 20 °C. Interface traps filled by photo-generated and thermally-generated carriers are shown to play a crucial role. Their filling alters the potential barrier height at the interface leading to increased flow of dark current and the above unity responsivity.

Stable locking phase limits of optically injected semiconductor lasers.

The stability of an optically injected laser is considered theoretically with an emphasis on the understanding of the locked phase whereas previous works focus primarily on the frequency detuning limits. Exemplary photon and carrier number curves for regions within and outside stable locking are presented. The dependence of the phase limits on injection ratio naturally divides into three regions with qualitatively different descriptions for the phase boundaries in each. Frequency detunings at which the locked phase is zero for different injection ratios are investigated. Using this zero phase point it is shown that the coupling rate between the injected and internal field as well as the linewidth enhancement factor can be determined in a single voltage measurement under weak injection. The modulation response parameters at these detunings are analysed and shown to be strongly interconnected.