Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis.

Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response.

Uncovering the Signatures of Cellular Senescence in the Human Dorsolateral Prefrontal Cortex.

Identifying senescent cells poses challenges due to their rarity, heterogeneity, and lack of a definitive marker. We performed Visium spatial transcriptomics (ST) and single nucleus RNA sequencing (snRNA-seq) on non-pathological human tissue to build a transcriptomic atlas of aging and senescence in the dorsolateral prefrontal cortex (dlPFC). We identified markers characteristic of aging dlPFC cortical layers and cell types.

Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS.

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.

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.

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.

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'.

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.

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

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.

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.

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.

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.

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.

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.