Multiple Levels Of Control Research Articles

Power management via STL specifications of a DC microgrid integrating renewables and storage devices: a smart railway station case study

This paper presents a method for defining and managing complex power management behaviors in microgrids that incorporate renewable energy sources, storage devices with different characteristics, and a connection to the main grid. In particular, we focus on a smart railway station that integrates regenerative braking energy from trains. The challenge lies in coordinating diverse microgrid components while adhering to constraints across multiple control levels. We use signal temporal logic (STL) to precisely define these complex objectives and integrate them into a model predictive control (MPC) framework. We present numerical simulations using a mixed-integer strategy to demonstrate the approach’s effectiveness.

Protein Kinases and Cross-talk between Post-translational Modifications in the Regulation of Drug Transporters.

Drug transporters are modulators for drug absorption, distribution, and excretion. Key drug transporters including P-glycoprotein and breast cancer resistance protein of the ABC superfamily; organic anion transporting polypeptide 1B1 and 1B3, organic anion transporter 1 and 3, and organic cation transporter 2, as well as multidrug and toxin extrusion 1 and 2 of the SLC superfamily have been recommended by regulatory agencies to be investigated and evaluated in drug-drug interaction (DDI) studies due to their important roles in determining the efficacy, toxicity and DDI of various drugs. Drug transporters are subjected to multiple levels of control and post-translational modifications (PTMs) provide rapid and versatile ways of regulation. Under pathologic and/or pharmacological conditions, PTMs may be altered in the cellular system, leading to functional changes of transporter proteins. Phosphorylation is by far the most actively investigated form of PTMs in the regulation of transporters. Further, studies in recent years also found that protein kinases coordinate with other PTMs for the dynamic control of these membrane proteins. Here we summarized the regulation of major drug transporters by protein kinases and their cross-talking with other PTMs that may generate a complex regulatory network for fine-tuning the function of these important drug processing modulators. SIGNIFICANCE STATEMENT: Kinases regulate drug transporters in versatile manners; Kinase regulation cross-talks with other PTMs, forming a complex network for transporter regulation; Pathological and/or pharmacological conditions may alter PTMs and affect transporter function with different molecular mechanisms.

Controlling strokes in fast neural style transfer using content transforms

Fast style transfer methods have recently gained popularity in art-related applications as they make a generalized real-time stylization of images practicable. However, they are mostly limited to one-shot stylizations concerning the interactive adjustment of style elements. In particular, the expressive control over stroke sizes or stroke orientations remains an open challenge. To this end, we propose a novel stroke-adjustable fast style transfer network that enables simultaneous control over the stroke size and intensity, and allows a wider range of expressive editing than current approaches by utilizing the scale-variance of convolutional neural networks. Furthermore, we introduce a network-agnostic approach for style-element editing by applying reversible input transformations that can adjust strokes in the stylized output. At this, stroke orientations can be adjusted, and warping-based effects can be applied to stylistic elements, such as swirls or waves. To demonstrate the real-world applicability of our approach, we present StyleTune, a mobile app for interactive editing of neural style transfers at multiple levels of control. Our app allows stroke adjustments on a global and local level. It furthermore implements an on-device patch-based upsampling step that enables users to achieve results with high output fidelity and resolutions of more than 20 megapixels. Our approach allows users to art-direct their creations and achieve results that are not possible with current style transfer applications.

The miR-27a/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells.

Simple SummaryCellular and mitochondrial metabolism can be dysregulated during tumorigenesis. miR-27a plays a central role in redirecting cell metabolism in colorectal cancer. In this study, we searched for new miR-27a targets that could influence mitochondria and identified FOXJ3 a master regulator of mitochondrial biogenesis. We validated FOXJ3 as an miR-27a target in an in vitro cell model system that was genetically modified for miR-27a expression and showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and regulates other members of the pathway. The miR-27a/FOXJ3 axis also influences mitochondrial dynamics, superoxide production, respiration capacity, and membrane potential. A mouse xenograft model confirmed that miR-27a downregulates FOXJ3 in vivo and a survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and the impact on mitochondrial biogenesis. The miR-27a/FOXJ3 axis is a major actor in regulating mitochondrial homeostasis, and its discovery may contribute to therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities.miR-27a plays a driver role in rewiring tumor cell metabolism. We searched for new miR-27a targets that could affect mitochondria and identified FOXJ3, an apical factor of mitochondrial biogenesis. We analyzed FOXJ3 levels in an in vitro cell model system that was genetically modified for miR-27a expression and validated it as an miR-27a target. We showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and other key members of the pathway, implying multiple levels of control. As assessed by specific markers, the miR-27a/FOXJ3 axis also dysregulates mitochondrial dynamics, resulting in fewer, short, and punctate organelles. Consistently, in high miR-27a-/low FOXJ3-expressing cells, mitochondria are functionally characterized by lower superoxide production, respiration capacity, and membrane potential, as evaluated by OCR assays and confocal microscopy. The analysis of a mouse xenograft model confirmed FOXJ3 as a target and suggested that the miR-27a/FOXJ3 axis affects mitochondrial abundance in vivo. A survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and reinforced cellular component organization or biogenesis as the most affected pathway. The miR-27a/FOXJ3 axis acts as a central hub in regulating mitochondrial homeostasis. Its discovery paves the way for new therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities.

Synthesizing Geologically Coherent Cave Networks

AbstractWe present a geologically‐based method to generate complex karstic networks. Karsts are a type of landscape formed by the dissolution of highly soluble rocks (generally limestones). In particular, they are characterized by complex underground networks made of varieties of tunnels and breakout chambers with stalagmites and stalactites. Our method computes skeletons of karstic networks by using a gridless anisotropic shortest path algorithm according to field data of the underground system (such as inlets and outlets), geomorphological features and parameters such as faults, inception horizons, fractures, and permeability contrasts. From this skeleton, we define the geometry of the conduits as a signed distance function construction tree combining primitives with blending and warping operators. Our framework provides multiple levels of control, allowing us to author both the structure of the karstic network and the geometric cross‐section shapes and details of the generated conduits.

Everything in Modulation: Neuromodulators as Keys to Understanding Communication Dynamics.

Across the animal kingdom, the ability to produce communication signals appropriate to social encounters is essential, but how these behaviors are selected and adjusted in a context-dependent manner are poorly understood. This question can be addressed on many levels, including sensory processing by peripheral organs and the central nervous system, sensorimotor integration in decision-making brain regions, and motor circuit activation and modulation. Because neuromodulator systems act at each of these levels, they are a useful lens through which to explore the mechanisms underlying complex patterns of communication. It has been clear for decades that understanding the logic of input-output decision making by the nervous system requires far more than simply identifying the connections linking sensory organs to motor circuits; this is due in part to the fact that neuromodulators can promote distinct and temporally dynamic responses to similar signals. We focus on the vocal circuit dynamics of Xenopus frogs, and describe complementary examples from diverse vertebrate communication systems. While much remains to be discovered about how neuromodulators direct flexibility in communication behaviors, these examples illustrate that several neuromodulators can act upon the same circuit at multiple levels of control, and that the functional consequence of neuromodulation can depend on species-specific factors as well as dynamic organismal characteristics like internal state.

Modeling rocky scenery using implicit blocks

We present a novel geologically based method to generate vertical walls of rocky cliffs, crags or promontories. Our method procedurally generates a distribution of fractures in the bedrock to create a set of tiling blocks defined as implicit volumetric primitives. Blocks are in turn implicitly replicated over the vertical parts of the terrain and combined together to obtain a consistent volumetric representation of the fractured bedrock patterns using generalized union and blending operators. Our framework provides multiple levels of control: In addition to automatically generated blocks, the geometry of specific ones can be prescribed by the user using implicit primitives or construction trees, the shape of the blocks can be controlled by several parameters, and the placement rules may adapt according to the underlying geological strata and geometry of the terrain.

List-level control in the flanker task.

Current theories posit multiple levels of cognitive control for resolving conflict, including list-level control: the global or proactive biasing of attention across a list of trials. However, to date, evidence for pure list-level control has largely been confined to the Stroop task. Our goals were twofold: (a) test the generality of theoretical accounts by seeking evidence for list-level control in the letter flanker task, using an established method involving diagnostic items, and investigating the conditions under which list-level control may and may not be observed and (b) develop and test a potential solution to the challenge of isolating list-level control in tasks with a relatively limited set of stimuli and responses such as arrow flanker. Our key findings were that list-level control was observed for the first time in a letter flanker task on diagnostic items (Experiment 1), and it was not observed when the design was altered to encourage learning and use of simple stimulus-response associations (Experiment 2). These findings support the generalisability of current theoretical accounts positing dual-mechanisms or multiple levels of control, and the associations as antagonists to control account positing that list-level control may be a last resort, to conflict tasks besides Stroop. List-level control was also observed in the arrow flanker task using a modified design (Experiment 3), which could be extended to other conflict tasks with limited sets of stimuli (four or fewer), although this solution is not entirely free of confounds.

A mitochondrial journey through acetaminophen hepatotoxicity

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the United States and APAP-induced hepatotoxicity is initiated by formation of a reactive metabolite which depletes hepatic glutathione and forms protein adducts. Studies over the years have established the critical role of c-Jun N terminal kinase (JNK) and its mitochondrial translocation, as well as mitochondrial oxidant stress and subsequent induction of the mitochondrial permeability transition in APAP pathophysiology. However, it is now evident that mitochondrial responses to APAP overdose are more nuanced than appreciated earlier, with multiple levels of control, for example, to dose of APAP. In addition, mitochondrial dynamics, as well as the organelle's importance in recovery and regeneration after APAP-induced liver injury is also being recognized, which are exciting new areas with significant therapeutic potential. Thus, this review examines the temporal course of hepatocyte mitochondrial responses to an APAP overdose with an emphasis on mechanistic response to various trigger checkpoints such as NAPQI-mitochondrial protein adduct formation and activated JNK translocation. Mitochondrial dynamics, the organelle's role in recovery after APAP and emerging areas of research which promise to provide further insight into modulation of APAP pathophysiology by these fascinating organelles will also be discussed.

Plant microRNAs: Biogenesis, Homeostasis, and Degradation.

MicroRNAs (miRNAs), a class of endogenous, tiny, non-coding RNAs, are master regulators of gene expression among most eukaryotes. Intracellular miRNA abundance is regulated under multiple levels of control including transcription, processing, RNA modification, RNA-induced silencing complex (RISC) assembly, miRNA-target interaction, and turnover. In this review, we summarize our current understanding of the molecular components and mechanisms that influence miRNA biogenesis, homeostasis, and degradation in plants. We also make comparisons with findings from other organisms where necessary.

BLNCR is a long non-coding RNA adjacent to integrin beta-1 that is rapidly lost during epidermal progenitor cell differentiation

As our understanding of transcriptional regulation improves so does our appreciation of its complexity. Both coding and (long) non-coding RNAs provide cells with multiple levels of control and thereby flexibility to adapt gene expression to the environment. However, few long non-coding RNAs (lncRNAs) have been studied in human epidermal stem cells. Here, we characterized the expression of 26 lncRNAs in human epidermal keratinocytes, 7 of which we found to be dynamically expressed during differentiation. We performed in depth analysis of a lncRNA located proximal to the epidermal stem cell marker integrin beta-1 (ITGB1) and transcribed in the opposite direction. We dubbed this gene Beta1-adjacent long non-coding RNA, or BLNCR, and found that its expression is regulated by p63 and AP1 transcription factors. Furthermore, BLNCR expression is regulated downstream the integrin and EGF signaling pathways that are key to epidermal stem cell maintenance. Finally, we found that BLNCR expression is rapidly reduced upon induction of differentiation, preceding the down regulation of integrin beta-1 expression. These dynamics closely mirror the loss of proliferative and adhesion capacity of epidermal stem cells in colony formation assays. Together, these results suggest that loss of BLNCR expression marks the switch from a proliferative state towards terminal differentiation in human epidermal stem cells.

Post-transcriptional control of miRNA biogenesis.

MicroRNAs (miRNAs) are important regulators of gene expression that bind complementary target mRNAs and repress their expression. Precursor miRNA molecules undergo nuclear and cytoplasmic processing events, carried out by the endoribonucleases DROSHA and DICER, respectively, to produce mature miRNAs that are loaded onto the RISC (RNA-induced silencing complex) to exert their biological function. Regulation of mature miRNA levels is critical in development, differentiation, and disease, as demonstrated by multiple levels of control during their biogenesis cascade. Here, we will focus on post-transcriptional mechanisms and will discuss the impact of cis-acting sequences in precursor miRNAs, as well as trans-acting factors that bind to these precursors and influence their processing. In particular, we will highlight the role of general RNA-binding proteins (RBPs) as factors that control the processing of specific miRNAs, revealing a complex layer of regulation in miRNA production and function.

An sRNA and Cold Shock Protein Homolog-Based Feedforward Loop Post-transcriptionally Controls Cell Cycle Master Regulator CtrA.

Adjustment of cell cycle progression is crucial for bacterial survival and adaptation under adverse conditions. However, the understanding of modulation of cell cycle control in response to environmental changes is rather incomplete. In α-proteobacteria, the broadly conserved cell cycle master regulator CtrA underlies multiple levels of control, including coupling of cell cycle and cell differentiation. CtrA levels are known to be tightly controlled through diverse transcriptional and post-translational mechanisms. Here, small RNA (sRNA)-mediated post-transcriptional regulation is uncovered as an additional level of CtrA fine-tuning. Computational predictions as well as transcriptome and proteome studies consistently suggested targeting of ctrA and the putative cold shock chaperone cspA5 mRNAs by the trans-encoded sRNA (trans-sRNA) GspR (formerly SmelC775) in several Sinorhizobium species. GspR strongly accumulated in the stationary growth phase, especially in minimal medium (MM) cultures. Lack of the gspR locus confers a fitness disadvantage in competition with the wild type, while its overproduction hampers cell growth, suggesting that this riboregulator interferes with cell cycle progression. An eGFP-based reporter in vivo assay, involving wild-type and mutant sRNA and mRNA pairs, experimentally confirmed GspR-dependent post-transcriptional down-regulation of ctrA and cspA5 expression, which most likely occurs through base-pairing to the respective mRNA. The energetically favored secondary structure of GspR is predicted to comprise three stem-loop domains, with stem-loop 1 and stem-loop 3 targeting ctrA and cspA5 mRNA, respectively. Moreover, this work reports evidence for post-transcriptional control of ctrA by CspA5. Thus, this regulation and GspR-mediated post-transcriptional repression of ctrA and cspA5 expression constitute a coherent feed-forward loop, which may enhance the negative effect of GspR on CtrA levels. This novel regulatory circuit involving the riboregulator GspR, CtrA, and a cold shock chaperone may contribute to fine-tuning of ctrA expression.

Transcriptome-wide analysis of the Trypanosoma cruzi proliferative cycle identifies the periodically expressed mRNAs and their multiple levels of control.

Trypanosoma cruzi is the protozoan parasite causing American trypanosomiasis or Chagas disease, a neglected parasitosis with important human health impact in Latin America. The efficacy of current therapy is limited, and its toxicity is high. Since parasite proliferation is a fundamental target for rational drug design, we sought to progress into its understanding by applying a genome-wide approach. Treating a TcI linage strain with hydroxyurea, we isolated epimastigotes in late G1, S and G2/M cell cycle stages at 70% purity. The sequencing of each phase identified 305 stage-specific transcripts (1.5-fold change, p≤0.01), coding for conserved cell cycle regulated proteins and numerous proteins whose cell cycle dependence has not been recognized before. Comparisons with the parasite T. brucei and the human host reveal important differences. The meta-analysis of T. cruzi transcriptomic and ribonomic data indicates that cell cycle regulated mRNAs are subject to sub-cellular compartmentalization. Compositional and structural biases of these genes- including CAI, GC content, UTR length, and polycistron position- may contribute to their regulation. To discover nucleotide motifs responsible for the co-regulation of cell cycle regulated genes, we looked for overrepresented motifs at their UTRs and found a variant of the cell cycle sequence motif at the 3' UTR of most of the S and G2 stage genes. We additionally identified hairpin structures at the 5' UTRs of a high proportion of the transcripts, suggesting that periodic gene expression might also rely on translation initiation in T. cruzi. In summary, we report a comprehensive list of T. cruzi cell cycle regulated genes, including many previously unstudied proteins, we show evidence favoring a multi-step control of their expression, and we identify mRNA motifs that may mediate their regulation. Our results provide novel information of the T. cruzi proliferative proteins and the integrated levels of their gene expression control.

Hand Grasping Synergies As Biometrics.

Recently, the need for more secure identity verification systems has driven researchers to explore other sources of biometrics. This includes iris patterns, palm print, hand geometry, facial recognition, and movement patterns (hand motion, gait, and eye movements). Identity verification systems may benefit from the complexity of human movement that integrates multiple levels of control (neural, muscular, and kinematic). Using principal component analysis, we extracted spatiotemporal hand synergies (movement synergies) from an object grasping dataset to explore their use as a potential biometric. These movement synergies are in the form of joint angular velocity profiles of 10 joints. We explored the effect of joint type, digit, number of objects, and grasp type. In its best configuration, movement synergies achieved an equal error rate of 8.19%. While movement synergies can be integrated into an identity verification system with motion capture ability, we also explored a camera-ready version of hand synergies—postural synergies. In this proof of concept system, postural synergies performed well, but only when specific postures were chosen. Based on these results, hand synergies show promise as a potential biometric that can be combined with other hand-based biometrics for improved security.

The mazy case of Notch and immunoregulatory cells.

The Notch pathway represents a conserved signal transduction machinery that is straightforward and based on a few elements (ligands, receptors, transducers). However, the existence of multiple control levels of the Notch signaling final outcome makes it strictly context dependent and dose dependent. The function of Notch as a regulator of cell development and differentiation, as well as the aberrant consequences of its modulation, either positive or negative, is well established. In this review, we will discuss our current knowledge about Notch-dependent regulation of generation and function of 2 subsets of the immunoregulatory system, namely regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Then, we will focus on an unforeseen mechanism that may unveil an additional way of Notch to govern the surrounding environment in cancer.

Mesenchymal Stem Cells from Adipose Tissue in Clinical Applications for Dermatological Indications and Skin Aging.

Operating at multiple levels of control, mesenchymal stem cells from adipose tissue (ADSCs) communicate with organ systems to adjust immune response, provide signals for differentiation, migration, enzymatic reactions, and to equilibrate the regenerative demands of balanced tissue homeostasis. The identification of the mechanisms by which ADSCs accomplish these functions for dermatological rejuvenation and wound healing has great potential to identify novel targets for the treatment of disorders and combat aging. Herein, we review new insights into the role of adipose-derived stem cells in the maintenance of dermal and epidermal homeostasis, and recent advances in clinical applications of ADSCs related to dermatology.

Monitoring Autophagic Responses in Caenorhabditis elegans.

Autophagy, from the Greek auto (self) and phagy (eating), is a self-degradative process critical for eukaryotic cell homeostasis. Its rapidly responsive, highly dynamic nature renders this process essential for adapting to and offsetting acute/harsh conditions such as starvation, organelle dysfunction, and deoxyribonucleic acid (DNA) damage. Autophagy involves an intricate network of interacting factors with multiple levels of control. Importantly, dysregulation of autophagy has been linked to numerous debilitating pathologies, including cancer and neurodegenerative conditions in humans. Methods to monitor and quantify autophagic activity reliably are essential both for studying the basic mechanisms of autophagy and for dissecting its involvement in disease. The nematode Caenorhabditis elegans is a particularly suitable model organism to effectively visualize and study autophagy, in vivo, in a physiological and pathological context due to its optical transparency, experimental malleability, and precise developmental and anatomical characterization. Here, we outline the main tools and approaches to monitor and measure autophagic responses in C. elegans.

Creative choices and fan practices in the transformation of theme park space

This article describes and interprets fan activities within the theme park space related to a particular fan object. It examines an evolving paradigm wherein the role of theme park visitors is changed. Rather than being perceived as observers of spectacles, they can participate and interact with the environment in new ways. An example of this is Sorcerers of the Magic Kingdom (2012), an interactive role-playing quest and collector card game at Disney's Magic Kingdom Park in Florida. Fans participate in a variety of practices that have dynamically redefined theme park activities. Together, management, designers, and fans have cocreated and reconstructed the theme park experience as one of exploration and participation. Despite multiple levels of control, fans will likewise persist in engagement with activities (in park and online) that help shape and interrogate the theme park space.

Mechanism of Ribonuclease III Catalytic Regulation by Serine Phosphorylation

Ribonuclease III (RNase III) is a conserved, gene-regulatory bacterial endonuclease that cleaves double-helical structures in diverse coding and noncoding RNAs. RNase III is subject to multiple levels of control, reflective of its global regulatory functions. Escherichia coli (Ec) RNase III catalytic activity is known to increase during bacteriophage T7 infection, reflecting the expression of the phage-encoded protein kinase, T7PK. However, the mechanism of catalytic enhancement is unknown. This study shows that Ec-RNase III is phosphorylated on serine in vitro by purified T7PK, and identifies the targets as Ser33 and Ser34 in the N-terminal catalytic domain. Kinetic experiments reveal a 5-fold increase in kcat and a 1.4-fold decrease in Km following phosphorylation, providing a 7.4–fold increase in catalytic efficiency. Phosphorylation does not change the rate of substrate cleavage under single-turnover conditions, indicating that phosphorylation enhances product release, which also is the rate-limiting step in the steady-state. Molecular dynamics simulations provide a mechanism for facilitated product release, in which the Ser33 phosphomonoester forms a salt bridge with the Arg95 guanidinium group, thereby weakening RNase III engagement of product. The simulations also show why glutamic acid substitution at either serine does not confer enhancement, thus underscoring the specific requirement for a phosphomonoester.