Single-Cell Patch-Clamp/Proteomics of Human Alzheimer's Disease iPSC-Derived Excitatory Neurons Versus Isogenic Wild-Type Controls Suggests Novel Causation and Therapeutic Targets.

Standard single-cell (sc) proteomics of disease states inferred from multicellular organs or organoids cannot currently be related to single-cell physiology. Here, a scPatch-Clamp/Proteomics platform is developed on single neurons generated from hiPSCs bearing an Alzheimer's disease (AD) genetic mutation and compares them to isogenic wild-type controls. This approach provides both current and voltage electrophysiological data plus detailed proteomics information on single-cells. With this new method, the authors are able to observe hyperelectrical activity in the AD hiPSC-neurons, similar to that observed in the human AD brain, and correlate it to ≈1400 proteins detected at the single neuron level. Using linear regression and mediation analyses to explore the relationship between the abundance of individual proteins and the neuron's mutational and electrophysiological status, this approach yields new information on therapeutic targets in excitatory neurons not attainable by traditional methods. This combined patch-proteomics technique creates a new proteogenetic-therapeutic strategy to correlate genotypic alterations to physiology with protein expression in single-cells.

Multiclass classification of environmental chemical stimuli from unbalanced plant electrophysiological data.

Plant electrophysiological response contains useful signature of its environment and health which can be utilized using suitable statistical analysis for developing an inverse model to classify the stimulus applied to the plant. In this paper, we have presented a statistical analysis pipeline to tackle a multiclass environmental stimuli classification problem with unbalanced plant electrophysiological data. The objective here is to classify three different environmental chemical stimuli, using fifteen statistical features, extracted from the plant electrical signals and compare the performance of eight different classification algorithms. A comparison using reduced dimensional projection of the high dimensional features via principal component analysis (PCA) has also been presented. Since the experimental data is highly unbalanced due to varying length of the experiments, we employ a random under-sampling approach for the two majority classes to create an ensemble of confusion matrices to compare the classification performances. Along with this, three other multi-classification performance metrics commonly used for unbalanced data viz. balanced accuracy, F1-score and Matthews correlation coefficient have also been analyzed. From the stacked confusion matrices and the derived performance metrics, we choose the best feature-classifier setting in terms of the classification performances carried out in the original high dimensional vs. the reduced feature space, for this highly unbalanced multiclass problem of plant signal classification due to different chemical stress. Difference in the classification performances in the high vs. reduced dimensions are also quantified using the multivariate analysis of variance (MANOVA) hypothesis testing. Our findings have potential real-world applications in precision agriculture for exploring multiclass classification problems with highly unbalanced datasets, employing a combination of existing machine learning algorithms. This work also advances existing studies on environmental pollution level monitoring using plant electrophysiological data.

A time-series analysis of blood-based biomarkers within a 25-year longitudinal dolphin cohort.

Causal interactions and correlations between clinically-relevant biomarkers are important to understand, both for informing potential medical interventions as well as predicting the likely health trajectory of any individual as they age. These interactions and correlations can be hard to establish in humans, due to the difficulties of routine sampling and controlling for individual differences (e.g., diet, socio-economic status, medication). Because bottlenose dolphins are long-lived mammals that exhibit several age-related phenomena similar to humans, we analyzed data from a well controlled 25-year longitudinal cohort of 144 dolphins. The data from this study has been reported on earlier, and consists of 44 clinically relevant biomarkers. This time-series data exhibits three starkly different influences: (A) directed interactions between biomarkers, (B) sources of biological variation that can either correlate or decorrelate different biomarkers, and (C) random observation-noise which combines measurement error and very rapid fluctuations in the dolphin's biomarkers. Importantly, the sources of biological variation (type-B) are large in magnitude, often comparable to the observation errors (type-C) and larger than the effect of the directed interactions (type-A). Attempting to recover the type-A interactions without accounting for the type-B and type-C variation can result in an abundance of false-positives and false-negatives. Using a generalized regression which fits the longitudinal data with a linear model accounting for all three influences, we demonstrate that the dolphins exhibit many significant directed interactions (type-A), as well as strong correlated variation (type-B), between several pairs of biomarkers. Moreover, many of these interactions are associated with advanced age, suggesting that these interactions can be monitored and/or targeted to predict and potentially affect aging.