Autocatalytic-protection for an unknown locus CRISPR-Cas countermeasure for undesired mutagenic chain reactions.

The mutagenic chain reaction (MCR) is a genetic tool to use a CRISPR-Cas construct to introduce a homing endonuclease, allowing gene drive to influence whole populations in a minimal number of generations (Esvelt et al., 2014; Gantz and Bier, 2015; Gantz and Bier, 2016). The question arises: if an active genetic terror event is released into a population, could we prevent the total spread of the undesired allele (Gantz, et al., 2015; Webber et al., 2015)? Thus far, effective protection methods require knowledge of the terror locus (Grunwald et al., 2019). Here we introduce a novel approach, an autocatalytic-Protection for an Unknown Locus (a-PUL), whose aim is to spread through a population and arrest and decrease an active terror event's spread without any prior knowledge of the terror-modified locus, thus allowing later natural selection and ERACR drives to restore the normal locus (Hammond et al., 2017). a-PUL, using a mutagenic chain reaction, includes (i) a segment encoding a non-Cas9 endonuclease capable of homology-directed repair suggested as Type II endonuclease Cpf1 (Cas12a), (ii) a ubiquitously-expressed gene encoding a gRNA (gRNA1) with a U4AU4 3'-overhang specific to Cpf1 and with crRNA specific to some desired genomic sequence of non-coding DNA, (iii) a ubiquitously-expressed gene encoding two gRNAs (gRNA2/gRNA3) both with tracrRNA specific to Cas9 and crRNA specific to two distinct sites of the Cas9 locus, and (iv) homology arms flanking the Cpf1/gRNA1/gRNA2/gRNA3 cassette that are identical to the region surrounding the target cut directed by gRNA1 (Khan, 2016; Zetsche et al., 2015). We demonstrate the proof-of-concept and efficacy of our protection construct through a Graphical Markov model and computer simulation.

Connectome Signatures of Hyperexcitation in Cognitively Intact Middle-Aged Female APOE-ε4 Carriers.

Synaptic dysfunction is hypothesized to be one of the earliest brain changes in Alzheimer's disease, leading to "hyperexcitability" in neuronal circuits. In this study, we evaluated a novel hyperexcitation indicator (HI) for each brain region using a hybrid resting-state structural connectome to probe connectome-level excitation-inhibition balance in cognitively intact middle-aged apolipoprotein E (APOE) ε4 carriers with noncarriers (16 male/22 female in each group). Regression with three-way interactions (sex, age, and APOE-ε4 carrier status) to assess the effect of APOE-ε4 on excitation-inhibition balance within each sex and across an age range of 40-60 years yielded a significant shift toward higher HI in female carriers compared with noncarriers (beginning at 50 years). Hyperexcitation was insignificant in the male group. Further, in female carriers the degree of hyperexcitation exhibited significant positive correlation with working memory performance (evaluated via a virtual Morris Water task) in three regions: the left pars triangularis, left hippocampus, and left isthmus of cingulate gyrus. Increased excitation of memory-related circuits may be evidence of compensatory recruitment of neuronal resources for memory-focused activities. In sum, our results are consistent with known Alzheimer's disease sex differences; in that female APOE-ε4 carriers have globally disrupted excitation-inhibition balance that may confer greater vulnerability to disease neuropathology.

Investigating brain community structure abnormalities in bipolar disorder using path length associated community estimation.

In this article, we present path length associated community estimation (PLACE), a comprehensive framework for studying node-level community structure. Instead of the well-known Q modularity metric, PLACE utilizes a novel metric, Ψ(PL), which measures the difference between intercommunity versus intracommunity path lengths. We compared community structures in human healthy brain networks generated using these two metrics and argued that Ψ(PL) may have theoretical advantages. PLACE consists of the following: (1) extracting community structure using top-down hierarchical binary trees, where a branch at each bifurcation denotes a collection of nodes that form a community at that level, (2) constructing and assessing mean group community structure, and (3) detecting node-level changes in community between groups. We applied PLACE and investigated the structural brain networks obtained from a sample of 25 euthymic bipolar I subjects versus 25 gender- and age-matched healthy controls. Results showed community structural differences in posterior default mode network regions, with the bipolar group exhibiting left-right decoupling.

Optimal Perturbation Control of General Topology Molecular Networks.

In this paper, we develop a comprehensive framework for optimal perturbation control of dynamic networks. The aim of the perturbation is to drive the network away from an undesirable steady-state distribution and to force it to converge towards a desired steady-state distribution. The proposed framework does not make any assumptions about the topology of the initial network, and is thus applicable to general-topology networks. We define the optimal perturbation control as the minimum-energy perturbation measured in terms of the Frobenius-norm between the initial and perturbed probability transition matrices of the dynamic network. We subsequently demonstrate that there exists at most one optimal perturbation that forces the network into the desirable steady-state distribution. In the event where the optimal perturbation does not exist, we construct a family of suboptimal perturbations, and show that the suboptimal perturbation can be used to approximate the optimal limiting distribution arbitrarily closely. Moreover, we investigate the robustness of the optimal perturbation control to errors in the probability transition matrix, and demonstrate that the proposed optimal perturbation control is robust to data and inference errors in the probability transition matrix of the initial network. Finally, we apply the proposed optimal perturbation control method to the Human melanoma gene regulatory network in order to force the network from an initial steady-state distribution associated with melanoma and into a desirable steady-state distribution corresponding to a benign cell.

Inverse perturbation for optimal intervention in gene regulatory networks.

MOTIVATION: Analysis and intervention in the dynamics of gene regulatory networks is at the heart of emerging efforts in the development of modern treatment of numerous ailments including cancer. The ultimate goal is to develop methods to intervene in the function of living organisms in order to drive cells away from a malignant state into a benign form. A serious limitation of much of the previous work in cancer network analysis is the use of external control, which requires intervention at each time step, for an indefinite time interval. This is in sharp contrast to the proposed approach, which relies on the solution of an inverse perturbation problem to introduce a one-time intervention in the structure of regulatory networks. This isolated intervention transforms the steady-state distribution of the dynamic system to the desired steady-state distribution. RESULTS: We formulate the optimal intervention problem in gene regulatory networks as a minimal perturbation of the network in order to force it to converge to a desired steady-state distribution of gene regulation. We cast optimal intervention in gene regulation as a convex optimization problem, thus providing a globally optimal solution which can be efficiently computed using standard toolboxes for convex optimization. The criteria adopted for optimality is chosen to minimize potential adverse effects as a consequence of the intervention strategy. We consider a perturbation that minimizes (i) the overall energy of change between the original and controlled networks and (ii) the time needed to reach the desired steady-state distribution of gene regulation. Furthermore, we show that there is an inherent trade-off between minimizing the energy of the perturbation and the convergence rate to the desired distribution. We apply the proposed control to the human melanoma gene regulatory network. AVAILABILITY: The MATLAB code for optimal intervention in gene regulatory networks can be found online: http://syen.ualr.edu/nxbouaynaya/Bioinformatics2010.html.

Deep Learning Analyses of Brain MRI to Identify Sustained Attention Deficit in Treated Obstructive Sleep Apnea: A Pilot Study.

Purpose: Persistent sustained attention deficit (SAD) after continuous positive airway pressure (CPAP) treatment is a source of quality of life and occupational impairment in obstructive sleep apnea (OSA). However, persistent SAD is difficult to predict in patients initiated on CPAP treatment. We performed secondary analyses of brain magnetic resonance (MR) images in treated OSA participants, using deep learning, to predict SAD. Methods: 26 middle-aged men with CPAP use of more than 6 hours daily and MR imaging were included. SAD was defined by psychomotor vigilance task lapses of more than 2. 17 participants had SAD and 9 were without SAD. A Convolutional Neural Network (CNN) model was used for classifying the MR images into +SAD and -SAD categories. Results: The CNN model achieved an accuracy of 97.02±0.80% in classifying MR images into +SAD and -SAD categories. Assuming a threshold of 90% probability for the MR image being correctly classified, the model provided a participant-level accuracy of 99.11±0.55% and a stable image level accuracy of 97.45±0.63%. Conclusion: Deep learning methods, such as the proposed CNN model, can accurately predict persistent SAD based on MR images. Further replication of these findings will allow early initiation of adjunctive pharmacologic treatment in high-risk patients, along with CPAP, to improve quality of life and occupational fitness. Future augmentation of this approach with explainable artificial intelligence methods may elucidate the neuroanatomical areas underlying persistent SAD to provide mechanistic insights and novel therapeutic targets.

Inferring excitation-inhibition dynamics using a maximum entropy model unifying brain structure and function.

Neural activity coordinated across different scales from neuronal circuits to large-scale brain networks gives rise to complex cognitive functions. Bridging the gap between micro- and macroscale processes, we present a novel framework based on the maximum entropy model to infer a hybrid resting-state structural connectome, representing functional interactions constrained by structural connectivity. We demonstrate that the structurally informed network outperforms the unconstrained model in simulating brain dynamics, wherein by constraining the inference model with the network structure we may improve the estimation of pairwise BOLD signal interactions. Further, we simulate brain network dynamics using Monte Carlo simulations with the new hybrid connectome to probe connectome-level differences in excitation-inhibition balance between apolipoprotein E (APOE)-ε4 carriers and noncarriers. Our results reveal sex differences among APOE-ε4 carriers in functional dynamics at criticality; specifically, female carriers appear to exhibit a lower tolerance to network disruptions resulting from increased excitatory interactions. In sum, the new multimodal network explored here enables analysis of brain dynamics through the integration of structure and function, providing insight into the complex interactions underlying neural activity such as the balance of excitation and inhibition.

Deep learning applied to polysomnography to predict blood pressure in obstructive sleep apnea and obesity hypoventilation: a proof-of-concept study.

STUDY OBJECTIVES: Nocturnal blood pressure (BP) profile shows characteristic abnormalities in OSA, namely acute postapnea BP surges and nondipping BP. These abnormal BP profiles provide prognostic clues indicating increased cardiovascular disease risk. We developed a deep neural network model to perform computerized analysis of polysomnography data and predict nocturnal BP profile. METHODS: We analyzed concurrently performed polysomnography and noninvasive beat-to-beat BP measurement with a deep neural network model to predict nocturnal BP profiles from polysomnography data in 13 patients with severe OSA. RESULTS: A good correlation was noted between measured and predicted postapnea systolic and diastolic BP (Pearson r ≥ .75). Moreover, Bland-Altman analyses showed good agreement between the 2 values. Continuous systolic and diastolic BP prediction by the deep neural network model was also well correlated with measured BP values (Pearson r ≥ .83). CONCLUSIONS: We developed a deep neural network model to predict nocturnal BP profile from clinical polysomnography signals and provide a potential prognostic tool in OSA. Validation of the model in larger samples and examination of its utility in predicting CVD risk in future studies is warranted.

Attraction-repulsion expectation-maximization algorithm for image reconstruction and sensor field estimation.

In this paper, we propose an attraction-repulsion expectation-maximization (AREM) algorithm for image reconstruction and sensor field estimation. We rely on a new method for density estimation to address the problems of image reconstruction from limited samples and sensor field estimation from randomly scattered sensors. Density estimation methods often suffer from undesirable phenomena such as over-fitting and over-smoothing. Specifically, various density estimation techniques based on a Gaussian mixture model (GMM) tend to cluster the Gaussian functions together, thus resulting in over-fitting. On the other hand, other approaches repel the Gaussian functions and yield over-smooth density estimates. We propose a method that seeks an equilibrium between over-fitting and over-smoothing in density estimation by incorporating attraction and repulsion forces among the Gaussian functions and determining the optimal balance between the competing forces experimentally. We model the attractive and repulsive forces by introducing the Gibbs and inverse Gibbs distributions, respectively. The maximization of the likelihood function augmented by the Gibbs density mixture is solved under the expectation-maximization (EM) method. Computer simulation results are provided to demonstrate the effectiveness of the proposed AREM algorithm in image reconstruction and sensor field estimation.

Video event classification and image segmentation based on noncausal multidimensional hidden Markov models.

In this paper, we propose a novel solution to an arbitrary noncausal, multidimensional hidden Markov model (HMM) for image and video classification. First, we show that the noncausal model can be solved by splitting it into multiple causal HMMs and simultaneously solving each causal HMM using a fully synchronous distributed computing framework, therefore referred to as distributed HMMs. Next we present an approximate solution to the multiple causal HMMs that is based on an alternating updating scheme and assumes a realistic sequential computing framework. The parameters of the distributed causal HMMs are estimated by extending the classical 1-D training and classification algorithms to multiple dimensions. The proposed extension to arbitrary causal, multidimensional HMMs allows state transitions that are dependent on all causal neighbors. We, thus, extend three fundamental algorithms to multidimensional causal systems, i.e., 1) expectation-maximization (EM), 2) general forward-backward (GFB), and 3) Viterbi algorithms. In the simulations, we choose to limit ourselves to a noncausal 2-D model whose noncausality is along a single dimension, in order to significantly reduce the computational complexity. Simulation results demonstrate the superior performance, higher accuracy rate, and applicability of the proposed noncausal HMM framework to image and video classification.

Time-dependent ARMA modeling of genomic sequences.

BACKGROUND: Over the past decade, many investigators have used sophisticated time series tools for the analysis of genomic sequences. Specifically, the correlation of the nucleotide chain has been studied by examining the properties of the power spectrum. The main limitation of the power spectrum is that it is restricted to stationary time series. However, it has been observed over the past decade that genomic sequences exhibit non-stationary statistical behavior. Standard statistical tests have been used to verify that the genomic sequences are indeed not stationary. More recent analysis of genomic data has relied on time-varying power spectral methods to capture the statistical characteristics of genomic sequences. Techniques such as the evolutionary spectrum and evolutionary periodogram have been successful in extracting the time-varying correlation structure. The main difficulty in using time-varying spectral methods is that they are extremely unstable. Large deviations in the correlation structure results from very minor perturbations in the genomic data and experimental procedure. A fundamental new approach is needed in order to provide a stable platform for the non-stationary statistical analysis of genomic sequences. RESULTS: In this paper, we propose to model non-stationary genomic sequences by a time-dependent autoregressive moving average (TD-ARMA) process. The model is based on a classical ARMA process whose coefficients are allowed to vary with time. A series expansion of the time-varying coefficients is used to form a generalized Yule-Walker-type system of equations. A recursive least-squares algorithm is subsequently used to estimate the time-dependent coefficients of the model. The non-stationary parameters estimated are used as a basis for statistical inference and biophysical interpretation of genomic data. In particular, we rely on the TD-ARMA model of genomic sequences to investigate the statistical properties and differentiate between coding and non-coding regions in the nucleotide chain. Specifically, we define a quantitative measure of randomness to assess how far a process deviates from white noise. Our simulation results on various gene sequences show that both the coding and non-coding regions are non-random. However, coding sequences are "whiter" than non-coding sequences as attested by a higher index of randomness. CONCLUSION: We demonstrate that the proposed TD-ARMA model can be used to provide a stable time series tool for the analysis of non-stationary genomic sequences. The estimated time-varying coefficients are used to define an index of randomness, in order to assess the statistical correlations in coding and non-coding DNA sequences. It turns out that the statistical differences between coding and non-coding sequences are more subtle than previously thought using stationary analysis tools: Both coding and non-coding sequences exhibit statistical correlations, with the coding regions being "whiter" than the non-coding regions. These results corroborate the evolutionary periodogram analysis of genomic sequences and revoke the stationary analysis' conclusion that coding DNA behaves like random sequences.

Theoretical foundations of spatially-variant mathematical morphology part ii: gray-level images.

In this paper, we develop a spatially-variant (SV) mathematical morphology theory for gray-level signals and images in the Euclidean space. The proposed theory preserves the geometrical concept of the structuring function, which provides the foundation of classical morphology and is essential in signal and image processing applications. We define the basic SV gray-level morphological operators (i.e., SV gray-level erosion, dilation, opening, and closing) and investigate their properties. We demonstrate the ubiquity of SV gray-level morphological systems by deriving a kernel representation for a large class of systems, called V-systems, in terms of the basic SV graylevel morphological operators. A V-system is defined to be a gray-level operator, which is invariant under gray-level (vertical) translations. Particular attention is focused on the class of SV flat gray-level operators. The kernel representation for increasing V-systems is a generalization of Maragos' kernel representation for increasing and translation-invariant function-processing systems. A representation of V-systems in terms of their kernel elements is established for increasing and upper-semi-continuous V-systems. This representation unifies a large class of spatially-variant linear and non-linear systems under the same mathematical framework. Finally, simulation results show the potential power of the general theory of gray-level spatially-variant mathematical morphology in several image analysis and computer vision applications.

Theoretical foundations of spatially-variant mathematical morphology part I: binary images.

We develop a general theory of spatially-variant (SV) mathematical morphology for binary images in the Euclidean space. The basic SV morphological operators (i.e., SV erosion, SV dilation, SV opening and SV closing) are defined. We demonstrate the ubiquity of SV morphological operators by providing a SV kernel representation of increasing operators. The latter representation is a generalization of Matheron's representation theorem of increasing and translation-invariant operators. The SV kernel representation is redundant, in the sense that a smaller subset of the SV kernel is sufficient for the representation of increasing operators. We provide sufficient conditions for the existence of the minimal basis representation in terms of upper-semi-continuity in the hit-or-miss topology. The latter minimal basis representation is a generalization of Maragos' minimal basis representation for increasing and translation-invariant operators. Moreover, we investigate the upper-semi-continuity property of the basic SV morphological operators. Several examples are used to demonstrate that the theory of spatially-variant mathematical morphology provides a general framework for the unification of various morphological schemes based on spatiallyvariant geometrical structuring elements (e.g., circular, affine and motion morphology). Simulation results illustrate the theory of the proposed spatially-variant morphological framework and show its potential power in various image processing applications.

Image reconstruction and multidimensional field estimation from randomly scattered sensors.

Many important problems in statistical signal processing can be formulated as function estimation from randomly scattered sensors in a multidimensional space, e.g., image reconstruction from photon-limited images and field estimation from scattered sensors. We present a novel approach to the study of signal reconstruction from random samples in a multidimensional space. In particular, we study a classical iterative reconstruction method and demonstrate that it forms a sequence of unbiased estimates for band-limited signals, which converge to the true function in the mean-square sense. We subsequently rely on the iterative estimation method for multidimensional image reconstruction and field estimation from sensors scattered according to a multidimensional Poisson and uniform distribution. Computer simulation experiments are used to demonstrate the efficiency of the iterative estimation method in image reconstruction and field estimation from randomly scattered sensors.

Robust control-based object tracking.

This correspondence presents a video tracking framework using control-based observer design. It unifies several kernel-based approaches into a consistent theoretical framework by modeling tracking as a recursive inverse problem. The framework relies on observability theory to handle the "singularity" problem and provides explicit criteria for kernel design and dynamics evaluation.

Maximum-entropy expectation-maximization algorithm for image reconstruction and sensor field estimation.

In this paper, we propose a maximum-entropy expectation-maximization (MEEM) algorithm. We use the proposed algorithm for density estimation. The maximum-entropy constraint is imposed for smoothness of the estimated density function. The derivation of the MEEM algorithm requires determination of the covariance matrix in the framework of the maximum-entropy likelihood function, which is difficult to solve analytically. We, therefore, derive the MEEM algorithm by optimizing a lower-bound of the maximum-entropy likelihood function. We note that the classical expectation-maximization (EM) algorithm has been employed previously for 2-D density estimation. We propose to extend the use of the classical EM algorithm for image recovery from randomly sampled data and sensor field estimation from randomly scattered sensor networks. We further propose to use our approach in density estimation, image recovery and sensor field estimation. Computer simulation experiments are used to demonstrate the superior performance of the proposed MEEM algorithm in comparison to existing methods.

Real-time decentralized articulated motion analysis and object tracking from videos.

In this paper, we present two new articulated motion analysis and object tracking approaches: the decentralized articulated object tracking method and the hierarchical articulated object tracking method. The first approach avoids the common practice of using a high-dimensional joint state representation for articulated object tracking. Instead, we introduce a decentralized scheme and model the interpart interaction within an innovative Bayesian framework. Specifically, we estimate the interaction density by an efficient decomposed interpart interaction model. To handle severe self-occlusions, we further extend the first approach by modeling high-level interunit interaction and develop the second algorithm within a consistent hierarchical framework. Preliminary experimental results have demonstrated the superior performance of the proposed approaches on real-world videos in both robustness and speed compared with other articulated object tracking methods.

Object trajectory-based activity classification and recognition using hidden Markov models.

Motion trajectories provide rich spatiotemporal information about an object's activity. This paper presents novel classification algorithms for recognizing object activity using object motion trajectory. In the proposed classification system, trajectories are segmented at points of change in curvature, and the subtrajectories are represented by their principal component analysis (PCA) coefficients. We first present a framework to robustly estimate the multivariate probability density function based on PCA coefficients of the subtrajectories using Gaussian mixture models (GMMs). We show that GMM-based modeling alone cannot capture the temporal relations and ordering between underlying entities. To address this issue, we use hidden Markov models (HMMs) with a data-driven design in terms of number of states and topology (e.g., left-right versus ergodic). Experiments using a database of over 5700 complex trajectories (obtained from UCI-KDD data archives and Columbia University Multimedia Group) subdivided into 85 different classes demonstrate the superiority of our proposed HMM-based scheme using PCA coefficients of subtrajectories in comparison with other techniques in the literature.

Spatially variant morphological restoration and skeleton representation.

The theory of spatially variant (SV) mathematical morphology is used to extend and analyze two important image processing applications: morphological image restoration and skeleton representation of binary images. For morphological image restoration, we propose the SV alternating sequential filters and SV median filters. We establish the relation of SV median filters to the basic SV morphological operators (i.e., SV erosions and SV dilations). For skeleton representation, we present a general framework for the SV morphological skeleton representation of binary images. We study the properties of the SV morphological skeleton representation and derive conditions for its invertibility. We also develop an algorithm for the implementation of the SV morphological skeleton representation of binary images. The latter algorithm is based on the optimal construction of the SV structuring element mapping designed to minimize the cardinality of the SV morphological skeleton representation. Experimental results show the dramatic improvement in the performance of the SV morphological restoration and SV morphological skeleton representation algorithms in comparison to their translation-invariant counterparts.