Bidirectional Transitions Research Articles

MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells

Large-scale transcriptomic profiling of glioblastoma(GBM) into subtypes has provided remarkable insight into the pathobiology and heterogeneous nature of this disease. The mechanisms of speciation and inter-subtype transitions of these molecular subtypes require better characterization to facilitate the development of subtype-specific targeting strategies. The deregulation of microRNA expression among GBM subtypes and their subtype-specific targeting mechanisms are poorly understood. To reveal the underlying basis of microRNA-driven complex subpopulation dynamics within the heterogeneous intra-tumoral ecosystem, we characterized the expression of the subtype-enriched microRNA-128 (miR-128) in transcriptionally and phenotypicallydiverse subpopulations of patient-derived glioblastoma stem-like cells. Because microRNAs are capable of re-arranging the molecular landscape in a cell-type-specific manner, we argue that alterations in miR-128 levels are a potent mechanism of bidirectional transitions between GBM subpopulations, resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking.

Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.

Epithelial–mesenchymal transition (EMT) and its reverse process, mesenchymal–epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial–mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re‐undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple‐negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus‐labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E‐box‐binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT–MET dynamics that could affect the development of triple‐negative breast cancer.

P01.13 The role of non-coding RNAs in GBM stem-like cells subtype identity maintenance and transition

AbstractDecades of research on protein coding genes (2% of the genome) led to only incremental improvements of outcomes in glioblastoma multiforme (GBM) patients. Meanwhile, research on non-protein-coding genes, which constitute the vast majority of the human transcriptome, have received comparatively little attention to date. Large scale transcriptomic profiling of GBM into four subtypes has provided remarkable insight about the pathobiology and heterogeneous nature of this disease, including the mechanisms of subtype maintenance and adaptation to tumor anatomic niche and microenvironmental challenges. The co-existence of several molecular subtypes of differentiated tumor cells and GBM stem-like cells (GSCs) within individual tumors is further complicated by their complex speciation, inter-subtype transitions and hybrid stages. The role of non-coding RNAs (such as microRNAs and long, non-coding RNAs) in these processes is poorly understood. Through their unique capability of targeting multiple mRNA targets, microRNAs, whose expression is often de-regulated in cancers, play pivotal role in pathophysiology of tumor. Subtype-specific expression of microRNA-128 (miR-128) affects complex subpopulation dynamics within the heterogeneous GBM tumors. Alterations in miR-128 levels, acting through de-regulation of multiple mRNA targets that control epigenetic landscape, are a potent mechanism of bi-directional transitions between proneural and mesenchymal GSC subpopulations resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking. Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of GBM. Hypoxia Inducible Factor 1 Alpha-Anti Sense RNA 2 (HIF1A-AS2) was identified as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Knockdown of HIF1A-AS2 affected GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming, leading to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of downstream genes. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context. These examples highlight immense, yet not fully appreciated, role of non-coding RNAs in pathophysiology of GBM.

Non-isolated stacked bidirectional soft-switching DC-DC converter with PWM plus phase-shift control scheme

In this paper, a non-isolated stacked bidirectional DC-DC converter with zero-voltage-switching (ZVS) is introduced for the high step-up/step-down conversion systems. The extremely narrow turn-on and/or turn-off duty cycle existing in the conventional bidirectional buck-boost converters can be extended due to the stacked module configuration for large voltage conversion ratio applications. Furthermore, the switch voltage stress is halved because of the series connection of half bridge modules. The PWM plus phase-shift control strategy is employed, where the duty cycle is adopted to regulate the voltages between the input and output sides and the phase-shift angle is applied to achieve the power flow regulation. This decoupled control scheme can not only realize seam-less bidirectional transition operation, but also achieve adaptive voltage balance for the power switches. In addition, ZVS soft-switching operation for all active switches is realized to minimize the switching losses. Finally, a prototype of 1 kW operating at 100 kHz is built and tested to demonstrate the effectiveness of the proposed converter and the control strategy.

Coral snakes predict the evolution of mimicry across New World snakes.

Batesian mimicry, in which harmless species (mimics) deter predators by deceitfully imitating the warning signals of noxious species (models), generates striking cases of phenotypic convergence that are classic examples of evolution by natural selection. However, mimicry of venomous coral snakes has remained controversial because of unresolved conflict between the predictions of mimicry theory and empirical patterns in the distribution and abundance of snakes. Here we integrate distributional, phenotypic and phylogenetic data across all New World snake species to demonstrate that shifts to mimetic coloration in nonvenomous snakes are highly correlated with coral snakes in both space and time, providing overwhelming support for Batesian mimicry. We also find that bidirectional transitions between mimetic and cryptic coloration are unexpectedly frequent over both long- and short-time scales, challenging traditional views of mimicry as a stable evolutionary ‘end point' and suggesting that insect and snake mimicry may have different evolutionary dynamics.

Hidden Markov latent variable models with multivariate longitudinal data.

Cocaine addiction is chronic and persistent, and has become a major social and health problem in many countries. Existing studies have shown that cocaine addicts often undergo episodic periods of addiction to, moderate dependence on, or swearing off cocaine. Given its reversible feature, cocaine use can be formulated as a stochastic process that transits from one state to another, while the impacts of various factors, such as treatment received and individuals' psychological problems on cocaine use, may vary across states. This article develops a hidden Markov latent variable model to study multivariate longitudinal data concerning cocaine use from a California Civil Addict Program. The proposed model generalizes conventional latent variable models to allow bidirectional transition between cocaine-addiction states and conventional hidden Markov models to allow latent variables and their dynamic interrelationship. We develop a maximum-likelihood approach, along with a Monte Carlo expectation conditional maximization (MCECM) algorithm, to conduct parameter estimation. The asymptotic properties of the parameter estimates and statistics for testing the heterogeneity of model parameters are investigated. The finite sample performance of the proposed methodology is demonstrated by simulation studies. The application to cocaine use study provides insights into the prevention of cocaine use.

Polysubstance use patterns and trajectories in vocational students — A latent transition analysis

BackgroundThe transition from late adolescence to early adulthood (16–20years) represents a time of exploration and self-discovery for many young people. As such, it is often associated with experimentation in substance use. Vocational students in particular report high substance use. Thus, the aim of this study is to examine patterns and trajectories of their substance use behavior. MethodsOn two occasions (interval 18months), we investigated 5214 students (M=19.39years; 54% male) from 49 vocational schools in seven German federal states. We identified classes of substance use and trajectories via latent transition analysis, controlling for gender, age, and socio-economic status. Additionally, we investigated work-related (job demands/stress/satisfaction) and psychopathological (depressive symptoms) predictors of substance use via multinomial regressions. ResultsWe found three latent stages of substance use: low use (baseline: 43%/follow-up: 44%), mainly alcohol use (50%/45%), and polysubstance use (7%/11%). Over time, 10% of alcohol users at baseline transitioned to polysubstance use at follow-up, while there were smaller transition rates (2–9%) between the other stages. Compared to low use, polysubstance use at follow-up was predicted by high job stress (aOR=1.45, 1.07–1.96) at baseline. ConclusionsHigh alcohol use is associated with bidirectional transitions in young adults. Hence, future research needs to identify mechanisms of change to identify protective factors. Regarding vocational practice, early stress management seems to be a viable path to prevent polysubstance use in vocational students.

Optimized joint motion planning for redundant industrial robots

Abstract The paper presents a model and solution method for optimized robot joint motion planning of redundant industrial robots that execute a set of tasks in a complex work environment, in face of various technological and geometric constraints. The approach aims at directly exploiting redundancy to optimize a given performance measure, e.g., cycle time. Alternative configurations along the path are captured in a graph model, whereas bi-directional transition between task and configuration spaces facilitates generating relevant, collision-free configurations only. Re-parametrization of the trajectory warrants compliance with the robot's kinematic constraints. Successful application of the method is demonstrated in remote laser welding.

Community reintegration: Transition between the figured worlds of military and family life

ABSTRACTThis paper argues the benefits of characterizing occupational transitions as movement between figured worlds, which are socially constructed units that are characterized by particular people and activities, and that shape identities. Further, positive withdrawal, which is a purposeful decision to limit participation when the requirements of engaging surpass self-perceived ability, describes limited engagement with a figured world. To illustrate the utility of this lens, the community reintegration of military service members as they finish deployment and return to family and community life is explored. The figured worlds of military and family are drawn from first person accounts of deployment and reintegration experiences from the perspectives of both service members and spouses. The constructs of figured world and positive withdrawal are found to be useful ways to describe community reintegration for both service members and families and the complex shifts in identity associated with the transition process. The framework presented expands on the occupational science literature by presenting a framework for non-linear, bidirectional occupational transitions in which individuals return to familiar settings rather than enter novel ones. The constructs of figured world and positive withdrawal can contribute to future theory development and research with populations that experience similar occupational transitions.

A Testis-Specific Chaperone and the Chromatin Remodeler ISWI Mediate Repackaging of the Paternal Genome.

During spermatogenesis, the paternal genome is repackaged into a non-nucleosomal, highly compacted chromatin structure. Bioinformatic analysis revealed that Drosophila sperm chromatin proteins are characterized by a motif related to the high-mobility group (HMG) box, which we termed male-specific transcript (MST)-HMG box. MST77F is a MST-HMG-box protein that forms an essential component of sperm chromatin. The deposition of MST77F onto the paternal genome requires the chaperone function of tNAP, a testis-specific NAP protein. MST77F, in turn, enables the stable incorporation of MST35Ba and MST35Bb into sperm chromatin. Following MST-HMG-box protein deposition,the ATP-dependent chromatin remodeler ISWI mediates the appropriate organization of sperm chromatin. Conversely, at fertilization, maternal ISWI targets the paternal genome and drives its repackaging into de-condensed nucleosomal chromatin. Failure of this transition in ISWI mutant embryos is followed by mitotic defects, aneuploidy, and haploid embryonic divisions. Thus, ISWI enables bi-directional transitions between two fundamentally different forms of chromatin.

Unsupervised lineage-based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ.

ABSTRACTGeneration of the primate cortex is characterized by the diversity of cortical precursors and the complexity of their lineage relationships. Recent studies have reported miscellaneous precursor types based on observer classification of cell biology features including morphology, stemness, and proliferative behavior. Here we use an unsupervised machine learning method for Hidden Markov Trees (HMTs), which can be applied to large datasets to classify precursors on the basis of morphology, cell‐cycle length, and behavior during mitosis. The unbiased lineage analysis automatically identifies cell types by applying a lineage‐based clustering and model‐learning algorithm to a macaque corticogenesis dataset. The algorithmic results validate previously reported observer classification of precursor types and show numerous advantages: It predicts a higher diversity of progenitors and numerous potential transitions between precursor types. The HMT model can be initialized to learn a user‐defined number of distinct classes of precursors. This makes it possible to 1) reveal as yet undetected precursor types in view of exploring the significant features of precursors with respect to specific cellular processes; and 2) explore specific lineage features. For example, most precursors in the experimental dataset exhibit bidirectional transitions. Constraining the directionality in the HMT model leads to a reduction in precursor diversity following multiple divisions, thereby suggesting that one impact of bidirectionality in corticogenesis is to maintain precursor diversity. In this way we show that unsupervised lineage analysis provides a valuable methodology for investigating fundamental features of corticogenesis. J. Comp. Neurol. 524:535–563, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

On the transition between regular and irregular shock patterns of shock-wave/boundary-layer interactions

The reflection of strong oblique shock waves at turbulent boundary layers is studied numerically and analytically. A particular emphasis is put on the transition between regular shock-wave/boundary-layer interaction (SWBLI) and Mach reflection (irregular SWBLI). The classical two- and three-shock theory and a generalised form of the free interaction theory are used for the analysis of well-resolved large-eddy simulations (LES) and for the derivation of stability criteria. We found that at a critical deflection angle across the incident shock wave, the perturbations related to the turbulent boundary layer cause bi-directional transition processes between regular and irregular shock patterns for a free-stream Mach number of$\mathit{Ma}_{0}=2$. Computational results show that the mean deflection angle across the separation shock is decoupled from the incident shock wave and can be accurately modelled by the generalised free interaction theory. On the basis of these observations, and the von Neumann and detachment criteria for the asymmetric intersection of shock waves, we derive the critical incident shock deflection angles at which the shock pattern may/must become irregular. Numerical data for a free-stream Mach number of$\mathit{Ma}_{0}=3$confirm the existence of the dual-solution domain predicted by theory.

Cycle-flow–based module detection in directed recurrence networks

We present a new cycle-flow–based method for finding fuzzy partitions of weighted directed networks coming from time series data. We show that this method overcomes essential problems of most existing clustering approaches, which tend to ignore important directional information by considering only one-step, one-directional node connections. Our method introduces a novel measure of communication between nodes using multi-step, bidirectional transitions encoded by a cycle decomposition of the probability flow. Symmetric properties of this measure enable us to construct an undirected graph that captures the information flow of the original graph seen by the data and apply clustering methods designed for undirected graphs. Finally, we demonstrate our algorithm by analyzing earthquake time series data, which naturally induce (time-)directed networks.

Managing landscape heterogeneity in different socio-ecological contexts: contrasting cases from central Loess Plateau of China and southern Finland

Landscape transition drives environmental change across the globe. However, landscape and its change are complex with high spatial heterogeneity, which challenges strategic decision-making. This paper aims to derive management meaningful units based on landscape status and change analysis and the generalization of landscape spatial heterogeneity. Based on contrasting cases from Finland (Vanajavesi) and China (Baota District), this paper analyzed the landscape attributes and change since 2000. A k-means clustering approach was used to generalize the landscape types based on indicators of landscape composition and its change, spatial pattern, population, and income. Most significant change in land covers was the expansion of artificial surfaces, and the bi-directional transitions between agricultural areas and forests and semi-natural areas in Vanajavesi, while the expansion of artificial land and shrinkage of cropland were most significant in Baota District. Larger changes in landscape metrics were also observed in Baota District. Finally, three landscape clusters were generalized in both of the case areas. For each cluster, the landscapes and their change characteristics were interpreted as pertinent to the average land cover pattern and its change and socioeconomic conditions. Brief landscape management recommendations were also given for the resulting clusters. This paper contributes to enriching the understanding of the analysis and management of landscape spatial heterogeneity based on the information from both landscape status and change. The contrasting case analyses from an international perspective indicate the usefulness of clustering approach in accommodating spatial heterogeneity, which imply a regionalized need for landscape monitoring, assessment, and management.

An integral fluctuation theorem for systems with unidirectional transitions

The fluctuations of a Markovian jump process with one or more unidirectional transitions, where Rij > 0 but Rji = 0, are studied. We find that such systems satisfy an integral fluctuation theorem. The fluctuating quantity satisfying the theorem is a sum of the entropy produced in the bidirectional transitions and a dynamical contribution, which depends on the residence times in the states connected by the unidirectional transitions. The convergence of the integral fluctuation theorem is studied numerically and found to show the same qualitative features as systems exhibiting microreversibility.

A Study of Wind Power Inverter Operating in Grid-Connected and Stand-Alone Mode

Wind turbine system (WTS) is a representative distributed power generation (DG). Establishment of WTS model and control strategies is of important practical significance. One critical field is the research of inverter system. It should be operated in stand-alone (SA) or grid-connected (GC) mode. The purpose of this thesis is to establish simulation platform of WTS inverter control model in Matlab/Simulink environment, which includes two typical DG control strategies, PQ and V/f. The wind fluctuation makes inverter output power harder to follow wind turbine (WT) power. In GC mode, PQ strategy was adopted to balance inverter output power and WT generated power. In SA mode, V/f strategy was applied to keep emergency load voltage stable. The bidirectional smooth transitions between SA and GC mode were well accomplished. Simulation proves the model can survive grid failures or load shedding. The study can be used in research of DG operation control.

Repeated evolution of tricellular (and bicellular) pollen

Male gametophytes of seed plants are sexually immature at the time they are dispersed as pollen, but approximately 30% of flowering plants have tricellular pollen containing fully formed sperm at anthesis. The classic study of Brewbaker (1967: American Journal of Botany 54: 1069-1083) provided a powerful confirmation of the long-standing hypothesis that tricellular pollen had many parallel and irreversible origins within angiosperms. We readdressed the main questions of that study with modern comparative phylogenetic methods. We used our own and more recent reports to greatly expand the Brewbaker data set. We modeled trait evolution for 2511 species on a time-calibrated angiosperm phylogeny using (1) Binary State Speciation and Extinction (BiSSE), which accounts for the effect of species diversification rates on character transition rates and, (2) the hidden rates model (HRM), which incorporates variation in transition rates across a phylogeny. Seventy percent of species had bicellular pollen. BiSSE found a 1.9-fold higher bicellular to tricellular transition rate than in the reverse direction, and bicellular lineages had a 1.8-fold higher diversification rate than tricellular lineages. HRM found heterogeneity in evolutionary rates, with bidirectional transition rates in three of four rate classes. The tricellular condition is not irreversible. Pollen cell numbers are maintained at intermediate frequencies because lower net diversification rates of tricellular lineages are counterbalanced by slower state shifts to the bicellular condition. That tricellular lineages diversify slowly and give rise to bicellular lineages slowly reflects a linkage between the evolution of sporophyte lifestyles and the developmental lability of male gametophytes.

On Bidirectional Transitions between Localist and Distributed Representations: The Case of Common Substrings Search Using Vector Symbolic Architecture

The contribution of this article is twofold. First, it presents an encoding approach for seamless bidirectional transitions between localist and distributed representation domains. Second, the approach is demonstrated on the example of using Vector Symbolic Architecture for solving a problem of finding common substrings. The proposed algorithm uses elementary operations on long binary vectors. For the case of two patterns with respective lengths L1 and L2 it requires Θ(L1 + L2 – 1) operations on binary vectors, which is equal to the suffix trees approach – the fastest algorithm for this problem. The simulation results show that in order to be robustly detected by the proposed approach the length of a common substring should be more than 4% of the longest pattern.

Evolving views of breast cancer stem cells and their differentiation States.

Cellular heterogeneity is a prominent characteristic of breast cancers, and accumulating evidence indicates that variability in the differentiation state of tumor cells contributes to this phenomenon. Breast cancers are among the tumor types in which the existence of cancer stem cells has been widely supported, and specific markers, including CD44/CD24 and ALDH1, have been consistently used to identify such cells. Recent studies have revealed the potential for dynamic bidirectional transitions of breast cancer cells between differentiated and stem-like phenotypes. In addition, the potential importance of intermediate states along differentiation axes, including the epithelial-to-mesenchymal transition and the basal-luminal differentiation axis, has emerged. These findings provide a view of breast cancer stem cells that departs from the traditional unidirectional hierarchical model, as well as new insights into the mechanisms by which differentiation events contribute to breast cancer biology. Herein we discuss these advances.

CFD ANALYSIS OF FLOW THROUGH HORIZONTAL CEILING OPENING DUE TO BUOYANCY AND PRESSURE DIFFERENCE

The buoyancy driven exchange flow through the large openings in horizontal partitions occurs in many practical situations such as in enclosed regions with a ceiling opening and a heat source such as fire. The density difference between two compartments arises partly due to difference in composition and partly from the difference in temperature. A heavier fluid located on the top of a lighter fluid and separated by a horizontal vent constitutes a gravitationally unstable system. Horizontal vents produce flow, which are unstable with irregular oscillatory behavior. However, when lower compartment is slightly pressurized the flow becomes stable and unidirectional. A numerical study has been performed to characterize the bi-directional flow and transition to unidirectional flow through a horizontal vent in an enclosure, due to differences in pressure and density across the vent. Fresh and salt water has been considered as working fluids to create density difference across the vent with a pressure field imposed in the lower compartment. The pressure in the lower region was increased to find the critical pressure corresponding to transition to unidirectional from bi-directional flow. Unsteady, 2D axisymmetric, incompressible Navier–Stokes equation along with species, turbulence and continuity equation have been solved with finite volume method using the in-house computational fluid dynamics (CFD) code. Several cases were examined to compute the critical pressure for various density differences for low opening aspect ratio. The code has been validated with reported experiments and used to simulate various other practical cases occurred during fire induced flow through such openings.