A senescence restriction point acting on chromatin integrates oncogenic signals.

We identify a senescence restriction point (SeRP) as a critical event for cells to commit to senescence. The SeRP integrates the intensity and duration of oncogenic stress, keeps a memory of previous stresses, and combines oncogenic signals acting on different pathways by modulating chromatin accessibility. Chromatin regions opened upon commitment to senescence are enriched in nucleolar-associated domains, which are gene-poor regions enriched in repeated sequences. Once committed to senescence, cells no longer depend on the initial stress signal and exhibit a characteristic transcriptome regulated by a transcription factor network that includes ETV4, RUNX1, OCT1, and MAFB. Consistent with a tumor suppressor role for this network, the levels of ETV4 and RUNX1 are very high in benign lesions of the pancreas but decrease dramatically in pancreatic ductal adenocarcinomas. The discovery of senescence commitment and its chromatin-linked regulation suggests potential strategies for reinstating tumor suppression in human cancers.

The effectiveness of simple heuristic features in sensor orientation and placement problems in human activity recognition using a single smartphone accelerometer.

BACKGROUND: Human activity Recognition (HAR) using smartphone sensors suffers from two major problems: sensor orientation and placement. Sensor orientation and sensor placement problems refer to the variation in sensor signal for a particular activity due to sensors' altering orientation and placement. Extracting orientation and position invariant features from raw sensor signals is a simple solution for tackling these problems. Using few heuristic features rather than numerous time-domain and frequency-domain features offers more simplicity in this approach. The heuristic features are features which have very minimal effects of sensor orientation and placement. In this study, we evaluated the effectiveness of four simple heuristic features in solving the sensor orientation and placement problems using a 1D-CNN-LSTM model for a data set consisting of over 12 million samples. METHODS: We accumulated data from 42 participants for six common daily activities: Lying, Sitting, Walking, and Running at 3-Metabolic Equivalent of Tasks (METs), 5-METs and 7-METs from a single accelerometer sensor of a smartphone. We conducted our study for three smartphone positions: Pocket, Backpack and Hand. We extracted simple heuristic features from the accelerometer data and used them to train and test a 1D-CNN-LSTM model to evaluate their effectiveness in solving sensor orientation and placement problems. RESULTS: We performed intra-position and inter-position evaluations. In intra-position evaluation, we trained and tested the model using data from the same smartphone position, whereas, in inter-position evaluation, the training and test data was from different smartphone positions. For intra-position evaluation, we acquired 70-73% accuracy; for inter-position cases, the accuracies ranged between 59 and 69%. Moreover, we performed participant-specific and activity-specific analyses. CONCLUSIONS: We found that the simple heuristic features are considerably effective in solving orientation problems. With further development, such as fusing the heuristic features with other methods that eliminate placement issues, we can also achieve a better result than the outcome we achieved using the heuristic features for the sensor placement problem. In addition, we found the heuristic features to be more effective in recognizing high-intensity activities.

Neurophysiological mental fatigue assessment for developing user-centered Artificial Intelligence as a solution for autonomous driving.

The human factor plays a key role in the automotive field since most accidents are due to drivers' unsafe and risky behaviors. The industry is now pursuing two main solutions to deal with this concern: in the short term, there is the development of systems monitoring drivers' psychophysical states, such as inattention and fatigue, and in the medium-long term, there is the development of fully autonomous driving. This second solution is promoted by recent technological progress in terms of Artificial Intelligence and sensing systems aimed at making vehicles more and more accurately aware of their "surroundings." However, even with an autonomous vehicle, the driver should be able to take control of the vehicle when needed, especially during the current transition from the lower (SAE < 3) to the highest level (SAE = 5) of autonomous driving. In this scenario, the vehicle has to be aware not only of its "surroundings" but also of the driver's psychophysical state, i.e., a user-centered Artificial Intelligence. The neurophysiological approach is one the most effective in detecting improper mental states. This is particularly true if considering that the more automatic the driving will be, the less available the vehicular data related to the driver's driving style. The present study aimed at employing a holistic approach, considering simultaneously several neurophysiological parameters, in particular, electroencephalographic, electrooculographic, photopletismographic, and electrodermal activity data to assess the driver's mental fatigue in real time and to detect the onset of fatigue increasing. This would ideally work as an information/trigger channel for the vehicle AI. In all, 26 professional drivers were engaged in a 45-min-lasting realistic driving task in simulated conditions, during which the previously listed biosignals were recorded. Behavioral (reaction times) and subjective measures were also collected to validate the experimental design and to support the neurophysiological results discussion. Results showed that the most sensitive and timely parameters were those related to brain activity. To a lesser extent, those related to ocular parameters were also sensitive to the onset of mental fatigue, but with a delayed effect. The other investigated parameters did not significantly change during the experimental session.

Cell Decision Making through the Lens of Bayesian Learning.

Cell decision making refers to the process by which cells gather information from their local microenvironment and regulate their internal states to create appropriate responses. Microenvironmental cell sensing plays a key role in this process. Our hypothesis is that cell decision-making regulation is dictated by Bayesian learning. In this article, we explore the implications of this hypothesis for internal state temporal evolution. By using a timescale separation between internal and external variables on the mesoscopic scale, we derive a hierarchical Fokker-Planck equation for cell-microenvironment dynamics. By combining this with the Bayesian learning hypothesis, we find that changes in microenvironmental entropy dominate the cell state probability distribution. Finally, we use these ideas to understand how cell sensing impacts cell decision making. Notably, our formalism allows us to understand cell state dynamics even without exact biochemical information about cell sensing processes by considering a few key parameters.

Exploring Orientation Invariant Heuristic Features with Variant Window Length of 1D-CNN-LSTM in Human Activity Recognition.

Many studies have explored divergent deep neural networks in human activity recognition (HAR) using a single accelerometer sensor. Multiple types of deep neural networks, such as convolutional neural networks (CNN), long short-term memory (LSTM), or their hybridization (CNN-LSTM), have been implemented. However, the sensor orientation problem poses challenges in HAR, and the length of windows as inputs for the deep neural networks has mostly been adopted arbitrarily. This paper explores the effect of window lengths with orientation invariant heuristic features on the performance of 1D-CNN-LSTM in recognizing six human activities; sitting, lying, walking and running at three different speeds using data from an accelerometer sensor encapsulated into a smartphone. Forty-two participants performed the six mentioned activities by keeping smartphones in their pants pockets with arbitrary orientation. We conducted an inter-participant evaluation using 1D-CNN-LSTM architecture. We found that the average accuracy of the classifier was saturated to 80 ± 8.07% for window lengths greater than 65 using only four selected simple orientation invariant heuristic features. In addition, precision, recall and F1-measure in recognizing stationary activities such as sitting and lying decreased with increment of window length, whereas we encountered an increment in recognizing the non-stationary activities.

Building Effective Machine Learning Models for Ankle Joint Power Estimation During Walking Using FMG Sensors.

Ankle joint power is usually determined by a complex process that involves heavy equipment and complex biomechanical models. Instead of using heavy equipment, we proposed effective machine learning (ML) and deep learning (DL) models to estimate the ankle joint power using force myography (FMG) sensors. In this study, FMG signals were collected from nine young, healthy participants. The task was to walk on a special treadmill for five different velocities with a respective duration of 1 min. FMG signals were collected from an FMG strap that consists of 8 force resisting sensor (FSR) sensors. The strap was positioned around the lower leg. The ground truth value for ankle joint power was determined with the help of a complex biomechanical model. At first, the predictors' value was preprocessed using a rolling mean filter. Following, three sets of features were formed where the first set includes raw FMG signals, and the other two sets contained time-domain and frequency-domain features extracted using the first set. Cat Boost Regressor (CBR), Long-Short Term Memory (LSTM), and Convolutional Neural Network (CNN) were trained and tested using these three features sets. The results presented in this study showed a correlation coefficient of R = 0.91 ± 0.07 for intrasubject testing and were found acceptable when compared to other similar studies. The CNN on raw features and the LSTM on time-domain features outperformed the other variations. Aside from that, a performance gap between the slowest and fastest walking distance was observed. The results from this study showed that it was possible to achieve an acceptable correlation coefficient in the prediction of ankle joint power using FMG sensors with an appropriate combination of feature set and ML model.

Close to Optimal Cell Sensing Ensures the Robustness of Tissue Differentiation Process: The Avian Photoreceptor Mosaic Case.

The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility), but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.

A least microenvironmental uncertainty principle (LEUP) as a generative model of collective cell migration mechanisms.

Collective migration is commonly observed in groups of migrating cells, in the form of swarms or aggregates. Mechanistic models have proven very useful in understanding collective cell migration. Such models, either explicitly consider the forces involved in the interaction and movement of individuals or phenomenologically define rules which mimic the observed behavior of cells. However, mechanisms leading to collective migration are varied and specific to the type of cells involved. Additionally, the precise and complete dynamics of many important chemomechanical factors influencing cell movement, from signalling pathways to substrate sensing, are typically either too complex or largely unknown. The question is how to make quantitative/qualitative predictions of collective behavior without exact mechanistic knowledge. Here we propose the least microenvironmental uncertainty principle (LEUP) that may serve as a generative model of collective migration without precise incorporation of full mechanistic details. Using statistical physics tools, we show that the famous Vicsek model is a special case of LEUP. Finally, to test the biological applicability of our theory, we apply LEUP to construct a model of the collective behavior of spherical Serratia marcescens bacteria, where the underlying migration mechanisms remain elusive.

Postprandial Metabolic Effects of Fiber Mixes Revealed by in vivo Stable Isotope Labeling in Humans.

Food supplementation with a fiber mix of guar gum and chickpea flour represents a promising approach to reduce the risk of type 2 diabetes mellitus (T2DM) by attenuating postprandial glycemia. To investigate the effects on postprandial metabolic fluxes of glucose-derived metabolites in response to this fiber mix, a randomized, cross-over study was designed. Twelve healthy, male subjects consumed three different flatbreads either supplemented with 2% guar gum or 4% guar gum and 15% chickpea flour or without supplementation (control). The flatbreads were enriched with ~2% of 13C-labeled wheat flour. Blood was collected at 16 intervals over a period of 360 min after bread intake and plasma samples were analyzed by GC-MS based metabolite profiling combined with stable isotope-assisted metabolomics. Although metabolite levels of the downstream metabolites of glucose, specifically lactate and alanine, were not altered in response to the fiber mix, supplementation of 4% guar gum was shown to significantly delay and reduce the exogenous formation of these metabolites. Metabolic modeling and computation of appearance rates revealed that the effects induced by the fiber mix were strongest for glucose and attenuated downstream of glucose. Further investigations to explore the potential of fiber mix supplementation to counteract the development of metabolic diseases are warranted.