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Motivated by the benefits that recent finite-time continuous control approaches have proven to give rise, this work aims to design a proportional–integral–derivative (PID) type control scheme for the global regulation of constrained-input mechanical systems that incorporates design features characteristic of such finite-time continuous algorithms. This is proven to be achieved through a more general PID type control structure that incorporates exponential weights on the P and D type terms, through which such control actions are permitted to loose Lipschitz-continuity at the desired equilibrium values. This entails an important challenge consisting on the introduction of an appropriate analytical framework and the development of a suitable closed-loop analysis through which the resulting design is properly supported. The study is complemented by experimental tests which show that appropriate (less-than-unity) values on the incorporated exponential weights indeed give rise to closed-loop improvements characteristic of finite-time continuous control approaches, such as reduction of overshoot on the position error responses and of the control effort, alleviating such a performance adjustment task. • PID control with non-Lipschitz control actions improve the closed-loop performance. • Exponential weights on the control actions potentiate performance adjustment. • PID control innovated by involving continuous finite-time control design techniques. [ABSTRACT FROM AUTHOR]

Aggregatibacter actinomycetemcomitans ApiA is a trimeric autotransporter outer membrane protein (Omp) that participates in multiple functions, enabling A. actinomycetemcomitans to adapt to a variety of environments. The goal of this study is to identify regions in the apiA gene responsible for three of these functions: auto-aggregation, buccal epithelial cell binding, and complement resistance. Initially, apiA was expressed in Escherichia coli. Finally, wild-type A. actinomycetemcomitans and an apiA-deleted version were tested for their expression in the presence and absence of serum and genes related to stress adaptation, such as oxygen regulation, catalase activity, and Omp proteins. Sequential deletions in specific regions in the apiA gene as expressed in E. coli were examined for membrane proteins, which were confirmed by microscopy. The functional activity of epithelial cell binding, auto-aggregation, and complement resistance were then assessed, and regions in the apiA gene responsible for these functions were identified. A region spanning amino acids 186–217, when deleted, abrogated complement resistance and Factor H (FH) binding, while a region spanning amino acids 28–33 was related to epithelial cell binding. A 13-amino-acid peptide responsible for FH binding was shown to promote serum resistance. An apiA deletion in a clinical isolate (IDH781) was created and tested in the presence and/or absence of active and inactive serum and genes deemed responsible for prominent functional activity related to A. actinomycetemcomitans survival using qRT-PCR. These experiments suggested that apiA expression in IDH781 is involved in global regulatory mechanisms that are serum-dependent and show complement resistance. This is the first study to identify specific apiA regions in A. actinomycetemcomitans responsible for FH binding, complement resistance, and other stress-related functions. Moreover, the role of apiA in overall gene regulation was observed. [ABSTRACT FROM AUTHOR]

Fungi are rich sources of secondary metabolites of agrochemical, pharmaceutical, and food importance, such as mycotoxins, antibiotics, and antitumor agents. Secondary metabolites play vital roles in fungal pathogenesis, growth and development, oxidative status modulation, and adaptation/resistance to various environmental stresses. LaeA contains an S-adenosylmethionine binding site and displays methyltransferase activity. The members of velvet proteins include VeA, VelB, VelC, VelD and VosA for each member with a velvet domain. LaeA and velvet proteins can form multimeric complexes such as VosA-VelB and VelB-VeA-LaeA. They belong to global regulators and are mainly impacted by light. One of their most important functions is to regulate gene expressions that are responsible for secondary metabolite biosynthesis. The aim of this mini-review is to represent the newest cognition of the biosynthetic regulation of mycotoxins and other fungal secondary metabolites by LaeA and velvet proteins. In most cases, LaeA and velvet proteins positively regulate production of fungal secondary metabolites. The regulated fungal species mainly belong to the toxigenic fungi from the genera of Alternaria, Aspergillus, Botrytis, Fusarium, Magnaporthe, Monascus, and Penicillium for the production of mycotoxins. We can control secondary metabolite production to inhibit the production of harmful mycotoxins while promoting the production of useful metabolites by global regulation of LaeA and velvet proteins in fungi. Furthermore, the regulation by LaeA and velvet proteins should be a practical strategy in activating silent biosynthetic gene clusters (BGCs) in fungi to obtain previously undiscovered metabolites. [ABSTRACT FROM AUTHOR]

We consider a global regulation problem for almost feedforward nonlinear systems with uncertain time‐varying parameters using an adaptive event‐triggered controller. The systems we consider are called "almost" feedforward systems because, in addition to the feedforward nonlinearity with the unknown linear growth rate, there is a non‐zero input‐matching term. Notably, this input‐matching term is a non‐feedforward term and it cannot be directly canceled due to the presence of input uncertainty and the use of event‐triggered control. To solve our considered problem, we propose an adaptive event‐triggered controller with multi‐triggering conditions and dynamic gain. We show that the closed‐loop system is globally regulated and the times between executions are positively lower bounded. Moreover, we show that the positive lower bounds of interexecution times can be enlarged by a control parameter. For a clear illustration, a practical example is given. [ABSTRACT FROM AUTHOR]

Aggregatibacter actinomycetemcomitans ApiA is a trimeric autotransporter outer membrane protein (Omp) that participates in multiple functions, enabling A. actinomycetemcomitans to adapt to a variety of environments. The goal of this study is to identify regions in the apiA gene responsible for three of these functions: auto-aggregation, buccal epithelial cell binding, and complement resistance. Initially, apiA was expressed in Escherichia coli. Finally, wild-type A. actinomycetemcomitans and an apiA-deleted version were tested for their expression in the presence and absence of serum and genes related to stress adaptation, such as oxygen regulation, catalase activity, and Omp proteins. Sequential deletions in specific regions in the apiA gene as expressed in E. coli were examined for membrane proteins, which were confirmed by microscopy. The functional activity of epithelial cell binding, auto-aggregation, and complement resistance were then assessed, and regions in the apiA gene responsible for these functions were identified. A region spanning amino acids 186–217, when deleted, abrogated complement resistance and Factor H (FH) binding, while a region spanning amino acids 28–33 was related to epithelial cell binding. A 13-amino-acid peptide responsible for FH binding was shown to promote serum resistance. An apiA deletion in a clinical isolate (IDH781) was created and tested in the presence and/or absence of active and inactive serum and genes deemed responsible for prominent functional activity related to A. actinomycetemcomitans survival using qRT-PCR. These experiments suggested that apiA expression in IDH781 is involved in global regulatory mechanisms that are serum-dependent and show complement resistance. This is the first study to identify specific apiA regions in A. actinomycetemcomitans responsible for FH binding, complement resistance, and other stress-related functions. Moreover, the role of apiA in overall gene regulation was observed.

Summary: We consider a global regulation problem for a chain of integrators with an unknown time‐varying input delay by event‐triggered output feedback control. We show that the considered system is globally regulated by the proposed event‐triggered output feedback controller with a dynamic gain‐scaling factor. Moreover, we show that interexecution times are lower bounded and these lower bounds can be increased with our control method. An example is given for clear illustration. [ABSTRACT FROM AUTHOR]

Legionella pneumophila is a gram‐negative bacteria found in natural and anthropogenic aquatic environments such as evaporative cooling towers, where it reproduces as an intracellular parasite of cohabiting protozoa. If L. pneumophila is aerosolized and inhaled by a susceptible person, bacteria may colonize their alveolar macrophages causing the opportunistic pneumonia Legionnaires' disease. L. pneumophila utilizes an elaborate regulatory network to control virulence processes such as the Dot/Icm Type IV secretion system and effector repertoire, responding to changing nutritional cues as their host becomes depleted. The bacteria subsequently differentiate to a transmissive state that can survive in the environment until a replacement host is encountered and colonized. In this review, we discuss the lifecycle of L. pneumophila and the molecular regulatory network that senses nutritional depletion via the stringent response, a link to stationary phase‐like metabolic changes via alternative sigma factors, and two‐component systems that are homologous to stress sensors in other pathogens, to regulate differentiation between the intracellular replicative phase and more transmissible states. Together, we highlight how this prototypic intracellular pathogen offers enormous potential in understanding how molecular mechanisms enable intracellular parasitism and pathogenicity. [ABSTRACT FROM AUTHOR]

7-Dehydrocholesterol (7-DHC), a key pharmaceutical intermediate in the production of vitamin D3, has a wide range of applications. To explore fermentative synthesis of 7-DHC, a 7-DHC-producing Saccharomyces cerevisiae strain was constructed by blocking the competitive pathway, eliminating rate-limiting steps, altering global regulation, and pathway compartmentalization. After blocking the competitive pathway by disrupting ERG5 and ERG6 and introducing DHCR24 from Gallus gallus, S. cerevisiae produced 139.72 mg/L (17.04 mg/g dry cell weight, hereafter abbreviated as DCW) 7-DHC. Subsequent alteration of global regulation by deleting ROX1 and overexpressing UPC2-1 increased 7-DHC production to 217.68 mg/L (37.56 mg/g DCW). To remove the accumulated squalene, the post-squalene pathway was strengthened by co-overexpression of PGAL1-driven ERG11 and PGAL10-driven ERG1, which improved 7-DHC titer and yield to 281.73 mg/L and 46.78 mg/g DCW, respectively, and reduced squalene content by 90.12%. We surmised that the sterol precursors in the plasma membrane and peroxisomes may not be accessible to the pathway enzymes, thus we re-localized DHCR24p and Erg2p-GGGGS-Erg3p to the plasma membrane and peroxisomes, boosting 7-DHC production to 357.53 mg/L (63.12 mg/g DCW). Iron supplementation further increased 7-DHC production to 370.68 mg/L in shake flasks and 1.56 g/L in fed-batch fermentation. This study demonstrates the power of global regulation and subcellular relocalization of key enzymes to improve 7-DHC synthesis in yeast.

LysR-type transcriptional regulators (LTTRs) form one of the largest families of bacterial regulators. They are widely distributed and contribute to all aspects of metabolism and physiology. Most are homotetramers, with each subunit composed of an N-terminal DNA-binding domain followed by a long helix connecting to an effector-binding domain. LTTRs typically bind DNA in the presence or absence of a small-molecule ligand (effector). In response to cellular signals, conformational changes alter DNA interactions, contact with RNA polymerase, and sometimes contact with other proteins. Many are dual-function repressor–activators, although different modes of regulation may occur at multiple promoters. This review presents an update on the molecular basis of regulation, the complexity of regulatory schemes, and applications in biotechnology and medicine. The abundance of LTTRs reflects their versatility and importance. While a single regulatory model cannot describe all family members, a comparison of similarities and differences provides a framework for future study. [ABSTRACT FROM AUTHOR]

This article concentrates on the global regulation problem for a class of large‐scale nonlinear systems with unknown growth rate and unknown external disturbances. In contrast to closely related works, the highlight of this article is that a novel decentralized output‐feedback switching control method is proposed for the first time to offset the serious uncertainties. By integrating logic‐based switching technique and gain scaling technique, this method can instantly adjust the controller parameters (that is, the scaling gain can be tuned online in a piecewise constant manner), and thus has strong adaptive capability as well as disturbance tolerance. Moreover, the decentralized output‐feedback switching controller designed by such the method has a concise linear‐like form and low complexity. It is shown that the objective of global regulation is finally achieved after a finite number of switching moments. Finally, two examples, including an engineering feedback control system design example, are given to verify the effectiveness of the proposed control method. [ABSTRACT FROM AUTHOR]

Surfactin has many biological activities, such as inhibiting plant diseases, resisting bacteria, fungi, viruses, tumors, mycoplasma, anti-adhesion, etc. It has great application potential in agricultural biological control, clinical medical treatment, environmental treatment and other fields. However, the low yield has been the bottleneck of its popularization and application. It is very important to understand the synthesis route and control strategy of surfactin to improve its yield and purity. In this paper, based on the biosynthetic pathway and regulatory factors of surfactin, its biosynthesis regulation strategy was comprehensively summarized, involving enhancement of endogenous and exogenous precursor supply, modification of the synthesis pathway of lipid chain and peptide chain, improvement of secretion and efflux, and manipulation some global regulatory factors, such as Spo0A, AbrB, ComQXP, phrCSF, etc. to directly or indirectly stimulate surfactin synthesis. And the current production and separation and purification process of surfactin are briefly described. This review also provides a scientific reference for promoting surfactin production and its applications in various fields. [ABSTRACT FROM AUTHOR]

Filamentous fungi are one of the most important producers of secondary metabolites. Some of them can have a toxic effect on the human body, leading to diseases. On the other hand, they are widely used as pharmaceutically significant drugs, such as antibiotics, statins, and immunosuppressants. A single fungus species in response to various signals can produce 100 or more secondary metabolites. Such signaling is possible due to the coordinated regulation of several dozen biosynthetic gene clusters (BGCs), which are mosaically localized in different regions of fungal chromosomes. Their regulation includes several levels, from pathway-specific regulators, whose genes are localized inside BGCs, to global regulators of the cell (taking into account changes in pH, carbon consumption, etc.) and global regulators of secondary metabolism (affecting epigenetic changes driven by velvet family proteins, LaeA, etc.). In addition, various low-molecular-weight substances can have a mediating effect on such regulatory processes. This review is devoted to a critical analysis of the available data on the "turning on" and "off" of the biosynthesis of secondary metabolites in response to signals in filamentous fungi. To describe the ongoing processes, the model of "piano regulation" is proposed, whereby pressing a certain key (signal) leads to the extraction of a certain sound from the "musical instrument of the fungus cell", which is expressed in the production of a specific secondary metabolite. [ABSTRACT FROM AUTHOR]

The development of artificial intelligence (AI) is bringing transformative changes to the political landscape of the world by having profound effects on numerous spheres. In addition, it poses challenges to global governance by intensifying international competition, fostering aggressive diplomacy, and subverting existing international norms. This study seeks to investigate the challenges of AI development to global economic and political governance, as well as the challenges of global AI regulation, in order to provide recommendations for the development of international AI regulatory frameworks. [ABSTRACT FROM AUTHOR]

Copyright of Anales de Derecho is the property of Servicio de Publicaciones de la Universidad de Murcia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ABSTRACT The rapid development of methicillin-resistant Staphylococcus aureus (MRSA) drug resistance and the formation of biofilms seriously challenge the clinical application of classic antibiotics. Extracts of the traditional herb Chenopodium ambrosioides L. were found to have strong antibiofilm activity against MRSA, but their mechanism of action remains poorly understood. This study was designed to investigate the antibacterial and antibiofilm activities against MRSA of flavonoids identified from C. ambrosioides L. in combination with classic antibiotics, including ceftazidime, erythromycin, levofloxacin, penicillin G, and vancomycin. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the nonvolatile chemical compositions. Reverse transcription (RT)-PCR was used to investigate potential multitargets of flavonoids based on global transcriptional responses of virulence and antibiotic resistance. A synergistic antibacterial and biofilm-inhibiting activity of the alcoholic extract of the ear of C. ambrosioides L. in combination with penicillin G was observed against MRSA, which proved to be closely related to the interaction of the main components of kaempferol rhamnosides with quercetin. In regard to the mechanism, the increased sensitivity of MRSA to penicillin G was shown to be related to the downregulation of penicillinase with SarA as a potential drug target, while the antibiofilm activity was mainly related to downregulation of various virulence factors involved in the initial and mature stages of biofilm development, with SarA and/or σB as drug targets. This study provides a theoretical basis for further exploration of the medicinal activity of kaempferol rhamnosides and quercetin and their application in combination with penicillin G against MRSA biofilm infection. IMPORTANCE In this study, the synergistic antibacterial and antibiofilm effects of the traditional herb C. ambrosioides L. and the classic antibiotic penicillin G on MRSA provide a potential strategy to deal with the rapid development of MRSA antibiotic resistance. This study also provides a theoretical basis for further optimizing the combined effect of kaempferol rhamnosides, quercetin, and penicillin G and exploring anti-MRSA biofilm infection research with SarA and σB as drug targets.

ABSTRACT Phylogenetic and sequence similarity network analyses of the CRP (cyclic AMP receptor protein)/FNR (fumarate and nitrate reductase regulatory protein) family of transcription factors indicate the presence of numerous subgroups, many of which have not been analyzed. Five homologs of the CRP/FNR family are present in the Rhodobacter capsulatus genome. One is a member of a broadly disseminated, previously uncharacterized CRP/FNR family subgroup encoded by the gene rcc01561. In this study, we utilize mutational disruption, transcriptome sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the role of RCC01561 in regulating R. capsulatus physiology. This analysis shows that a mutant strain disrupted for rcc01561 exhibits altered expression of 451 genes anaerobically. A detailed analysis of the affected loci shows that RCC01561 represses photosynthesis and favors catabolism over anabolism and the use of the Entner-Doudoroff shunt and glycolysis over that of the tricarboxylic acid (TCA) cycle to limit NADH and ATP formation. This newly characterized CRP/FNR family member with a predominant role in reducing the production of reducing potential and ATP is given the nomenclature RedB as it functions as an energy and redox brake. Beyond limiting energy production, RedB also represses the expression of numerous genes involved in protein synthesis, including those involved in translation initiation, tRNA synthesis and charging, and amino acid biosynthesis. IMPORTANCE CRP and FNR are well-characterized members of the CRP/FNR family of regulatory proteins that function to maximize cellular energy production. In this study, we identify several new subgroups of the CRP/FNR family, many of which have not yet been characterized. Using Rhodobacter capsulatus as a model, we have mutationally disrupted the gene rcc01561, which codes for a transcription factor that is a member of a unique subgroup of the CRP/FNR family. Transcriptomic analysis shows that the disruption of rcc01561 leads to the altered expression of 451 genes anaerobically. Analysis of these regulated genes indicates that RCC01561 has a novel role in limiting cellular energy production. To our knowledge, this is first example of a member of the CRP/FNR family that functions as a brake on cellular energy production.

An ideal microbial cell factory (MCF) should deliver maximal resources to production, which conflicts with the microbe's native growth-oriented resource allocation strategy and can therefore lead to early termination of the high-yield period. Reallocating resources from growth to production has become a critical factor in constructing robust MCFs. Instead of strengthening specific biosynthetic pathways, emerging endeavors are focused on rearranging the gene regulatory network to fundamentally reprogram the resource allocation pattern. Combining this idea with transcriptional regulation within the hierarchical regulatory network, this review discusses recent engineering strategies targeting the transcription machinery, module networks, regulatory edges, and bottom network layer. This global view will help to construct a production-oriented phenotype that fully harnesses the potential of MCFs. Resources are allocated to different functional regimes in a top-down manner via the hierarchical transcriptional regulatory network. The RNA polymerase core enzyme is a multiway valve that governs global resource allocation to growth, maintenance, and production, through interacting with different σ factors. Global resource reallocation is achieved through manipulating σ distribution in the RNA polymerase holoenzyme population by remolding major core–σ binding regions. Resource allocation within functional modules could be coordinated via engineering vertical or parallel interactions between master regulators and different layers of the gene regulatory network. Rewiring node edges enables trade-offs between stringent and loose regulation in biosynthetic pathways. [ABSTRACT FROM AUTHOR]

The development of the Internet affects human society in two ways: it enables society to progress and endangers security.Online access platforms facilitate business, education and contacts.On the other hand, individuals who access virtual platforms expose their privacy and their assets to the risk of cyber attacks.Unfortunately, one gets the impression that legislation cannot keep pace with technological advances so that many crimes committed on the internet remain unsanctioned. This paper points out the characteristics of cybercrime, gives an overview of international documents aimed at establishing cyber security.A list of domestic legislative regulations by which the Republic of Serbia seeks to solve the problems caused by cybercrime is also given.It also points out the characteristics of this type of crime that directly affect the impossibility of global regulation and protection of Internet users.

At the present stage of the development of international trade, online platforms have a defining impact on its development, as new business models appear, on the basis of which it becomes possible to significantly reduce marginal costs and increase productivity. The relevance of the problems investigated in the article increases as the format of international trade changes, when in a recession, new tools are needed to raise the efficiency of export-import operations between countries. The theoretical and methodological framework of the considered aspects includes foreign and domestic studies in the field of digitalization and the digital transformation of the world economy.An attempt of the conceptual justification and typology of online platforms and their significance in the international exchange system has been made in the paper. The main advantages of cross-border transaction platforms have been shown, it has been concluded that the attributes of online platforms may not be unique or specific, but it is their competent combination that often determines the intensive growth of platforms. According to authors, in the current conditions of the pandemic COVID-19, the role of online platforms in international trade is increasing, and this happens both at the national (through, for example, the growing use of delivery services) and at the international level (ensuring the operation of international payment systems, or individual components global value chains). Approaches to the global regulation of online platforms also have been considered. It has been established that the adaptation of trade policy rules developed internationally regarding the activities of online platforms plays a very important role, and one of the key aspects in this regard is the prohibition of tariffs on electronic commerce transactions. At least, this approach is followed by developed countries. However, developing countries often challenge it, pointing to the distortion of fair international competition rules as an argument.

Copyright of Revista Iberoamericana de Ciencia, Tecnologia y Sociedad is the property of Centro de Estudios sobre Ciencia, Desarrollo y Educacion Superior and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Gac-rsm pathway is a global regulatory network that governs mayor lifestyle and metabolic changes in gamma-proteobacteria. In a previous study, we uncovered the role of CsrA proteins promoting growth and repressing motility, alginate production and virulence in the model phytopathogen Pseudomonas syringae pv. tomato (Pto) DC3000. Here, we focus on the expression and regulation of the rsm regulatory sRNAs, since Pto DC3000 exceptionally has seven variants (rsmX1-5, rsmY and rsmZ). The presented results offer further insights into the functioning of the complex Gac-rsm pathway and the interplay among its components. Overall, rsm expressions reach maximum levels at high cell densities, are unaffected by surface detection, and require GacA for full expression. The rsm levels of expression and GacA-dependence are determined by the sequences found in their −35/-10 promoter regions and GacA binding boxes, respectively. rsmX5 stands out for being the only rsm in Pto DC3000 whose high expression does not require GacA, constituting the main component of the total rsm pool in a gacA mutant. The deletion of rsmY and rsmZ had minor effects on Pto DC3000 motility and virulence phenotypes, indicating that rsmX1-5 can functionally replace them. On the other hand, rsmY or rsmZ overexpression in a gacA mutant did not revert its phenotype. Additionally, a negative feedback regulatory loop in which the CsrA3 protein promotes its own titration by increasing the levels of several rsm RNAs in a GacA-dependent manner has been disclosed as part of this work. [ABSTRACT FROM AUTHOR]

Early research on the cyanobacterial clock focused on characterizing the genes needed to keep, entrain, and convey time within the cell. As the scope of assays used in molecular genetics has expanded to capture systems-level properties (e.g., RNA-seq, ChIP-seq, metabolomics, high-throughput screening of genetic variants), so has our understanding of how the clock fits within and influences a broader cellular context. Here we review the work that has established a global perspective of the clock, with a focus on (a) an emerging network-centric view of clock architecture, (b) mechanistic insights into how temporal and environmental cues are transmitted and integrated within this network,

The 76th session of the Marine Environment Committee (MEPC 76) of the International Maritime Organization adopted several mandatory measures in June 2021 to reduce carbon emissions from ships. One of the measures is the carbon intensity indicator (CII), which is the carbon emissions per unit transport work for each ship. Several options of CIIs are available and none of them is chosen to be applied yet. We prove that, at least in theory, requiring the attained annual CII of a ship to be less than a reference value, no matter which CII option is applied, may increase its carbon emissions. Therefore, more elaborate models, combined with real data, should be developed to analyze the effectiveness of each CII option and possibly to design a new CII.

Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and their cellular sources are and how they are regulated remain unclear. In this study, we analyzed bone and extraskeletal tissues, osteoblast (OB) conditioned media, bone marrow supernatant (BMS), and serum, for basal osteokines and those responsive to aging and mechanical loading/unloading. We identified 375 candidate osteokines and their changes in response to aging and mechanical dynamics by integrating data from RNA-seq, scRNA-seq, and proteomic approaches. Furthermore, we analyzed their cellular sources in the bone and inter-organ communication facilitated by them (bone-brain, liver, and aorta). Notably, we discovered that senescent OBs secrete fatty-acid-binding protein 3 to propagate senescence toward vascular smooth muscle cells (VSMCs). Taken together, we identified previously unknown candidate osteokines and established a dynamic regulatory network among them, thus providing valuable resources to further investigate their systemic roles. [Display omitted] • Multi-omic analysis reveals previously unknown osteokines and their cellular sources • Osteokines change in response to aging and mechanical dynamics • Osteokines establish intercellular crosstalk between bone and extraskeletal organs • FABP3, an aging-related osteokine, promotes VSMC senescence related to atherogenesis Liang et al. use an integrated multi-omics approach to identify osteokines under physiological, aging, and mechanical loading/unloading conditions. They identified 375 candidate osteokines and analyzed their cellular sources and inter-organ communication regulated by them (bone-brain, liver, and aorta). [ABSTRACT FROM AUTHOR]

Plants respond to abiotic stressors through a suite of strategies including differential regulation of stress-responsive genes. Hence, characterizing the influences of the relevant global regulators or on stress-related transcription factors is critical to understand plant stress response. Rice seed development is highly sensitive to elevated temperatures. To elucidate the extent and directional hierarchy of gene regulation in rice seeds under heat stress, we developed and implemented a robust multi-level optimization-based algorithm called Minimal Regulatory Network identifier (MiReN). MiReN could predict the minimal regulatory relationship between a gene and its potential regulators from our temporal transcriptomic dataset. MiReN predictions for global regulators including stress-responsive gene Slender Rice 1 (SLR1) and disease resistance gene XA21 were validated with published literature. It also predicted novel regulatory influences of other major regulators such as Kinesin-like proteins KIN12C and STD1, and WD repeat-containing protein WD40. Out of the 228 stress-responsive transcription factors identified, we predicted de novo regulatory influences on three major groups (MADS-box M-type, MYB, and bZIP) and investigated their physiological impacts during stress. Overall, MiReN results can facilitate new experimental studies to enhance our understanding of global regulatory mechanisms triggered during heat stress, which can potentially accelerate the development of stress-tolerant cultivars.

In this paper, the global regulation problem is considered for a class of high-order nonlinear systems with unknown time-varying delays. More specifically, the considered systems consist of a chain of power integrators with high-order nonlinearity and there are unknown input and state delays. From the system structural point of view, the high-order feedforward nonlinearity is further extended to include non-feedforward terms. In our controller design, our controller is a memoryless one which does not use any past input values such that any a priori information on time-varying delays is not needed. The global regulation of the controlled system is analyzed by using the Razumikhin theorem and adding a power integrator method. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulation is an important step in the control of bacterial gene expression in response to environmental and cellular signals. Pseudomonas putida KT2440 harbors three known members of the CsrA/RsmA family of post-transcriptional regulators: RsmA, RsmE and RsmI. We have carried out a global analysis to identify RNA sequences bound in vivo by each of these proteins. Affinity purification and sequencing of RNA molecules associated with Rsm proteins were used to discover direct binding targets, corresponding to 437 unique RNA molecules, 75 of them being common to the three proteins. Relevant targets include genes encoding proteins involved in signal transduction and regulation, metabolism, transport and secretion, stress responses, and the turnover of the intracellular second messenger c-di-GMP. To our knowledge, this is the first combined global analysis in a bacterium harboring three Rsm homologs. It offers a broad overview of the network of processes subjected to this type of regulation and opens the way to define what are the sequence and structure determinants that define common or differential recognition of specific RNA molecules by these proteins.

ABSTRACT Small noncoding RNAs (sRNAs) are key regulators of bacterial gene expression. Through complementary base pairing, sRNAs affect mRNA stability and translation efficiency. Here, we describe a network inference approach designed to identify sRNA-mediated regulation of transcript levels. We use existing transcriptional data sets and prior knowledge to infer sRNA regulons using our network inference tool, the Inferelator. This approach produces genome-wide gene regulatory networks that include contributions by both transcription factors and sRNAs. We show the benefits of estimating and incorporating sRNA activities into network inference pipelines using available experimental data. We also demonstrate how these estimated sRNA regulatory activities can be mined to identify the experimental conditions where sRNAs are most active. We uncover 45 novel experimentally supported sRNA-mRNA interactions in Escherichia coli, outperforming previous network-based efforts. Additionally, our pipeline complements sequence-based sRNA-mRNA interaction prediction methods by adding a data-driven filtering step. Finally, we show the general applicability of our approach by identifying 24 novel, experimentally supported, sRNA-mRNA interactions in Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis. Overall, our strategy generates novel insights into the functional context of sRNA regulation in multiple bacterial species. IMPORTANCE Individual bacterial genomes can have dozens of small noncoding RNAs with largely unexplored regulatory functions. Although bacterial sRNAs influence a wide range of biological processes, including antibiotic resistance and pathogenicity, our current understanding of sRNA-mediated regulation is far from complete. Most of the available information is restricted to a few well-studied bacterial species; and even in those species, only partial sets of sRNA targets have been characterized in detail. To close this information gap, we developed a computational strategy that takes advantage of available transcriptional data and knowledge about validated and putative sRNA-mRNA interactions for inferring expanded sRNA regulons. Our approach facilitates the identification of experimentally supported novel interactions while filtering out false-positive results. Due to its data-driven nature, our method prioritizes biologically relevant interactions among lists of candidate sRNA-target pairs predicted in silico from sequence analysis or derived from sRNA-mRNA binding experiments.

Poly-(3-hydroxyalkanoates) (PHAs) are bacterial carbon and energy storage compounds. These polymers are synthesized under conditions of nutritional imbalance, where a nutrient is growth-limiting while there is still enough carbon source in the medium. On the other side, the accumulated polymer is mobilized under conditions of nutrient accessibility or by limitation of the carbon source. Thus, it is well known that the accumulation of PHAs is affected by the availability of nutritional resources and this knowledge has been used to establish culture conditions favoring high productivities. In addition to this effect of the metabolic status on PHAs accumulation, several genetic regulatory networks have been shown to drive PHAs metabolism, so the expression of the PHAs genes is under the influence of global or specific regulators. These regulators are thought to coordinate PHAs synthesis and mobilization with the rest of bacterial physiology. While the metabolic and biochemical knowledge related to the biosynthesis of these polymers has led to the development of processes in bioreactors for high-level production and also to the establishment of strategies for metabolic engineering for the synthesis of modified biopolymers, the use of knowledge related to the regulatory circuits controlling PHAs metabolism for strain improvement is scarce. A better understanding of the genetic control systems involved could serve as the foundation for new strategies for strain modification in order to increase PHAs production or to adjust the chemical structure of these biopolymers. In this review, the regulatory systems involved in the control of PHAs metabolism are examined, with emphasis on those acting at the level of expression of the enzymes involved and their potential modification for strain improvement, both for higher titers, or manipulation of polymer properties. The case of the PHAs producer Azotobacter vinelandii is taken as an example of the complexity and variety of systems controlling the accumulation of these interesting polymers in response to diverse situations, many of which could be engineered to improve PHAs production.

Transcription can be regulated by controlling the provision of transcriptional factors (TFs), because TFs determine the transcription process by specifying the binding of RNA polymerase holoenzyme on promoters. Manipulations, such as replacing endogenous TFs with mutants obtained through directed evolution (or rational design), and introducing compatible heterogeneous TFs, are effective ways to regulate transcription. Designing artificial TFs with desired properties by following the principles of protein design and reconstructing ancestral TFs with the information gained from a perspective of evolution by multiple sequence alignments of the related TFs, are feasible alternative options. The engineered TFs can be used to create inducible protein expression systems that respond to a specific stimulus. Moreover, the engineered TFs could lead to a transcriptional profile different from that of the wild‐type strains. Accordingly, these engineered TFs could be utilized to construct strains resistant to adverse conditions, since the emergence of resistance generally requires global transcriptional changes at the transcriptomic scale. Meanwhile, these engineered TFs can also be employed in the construction of sophisticatedly designed genetic circuits for diverse purposes. In this paper, we reviewed the advances in the above‐mentioned aspects. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Summary: In this paper, we consider a global regulation problem for a class of feedforward nonlinear systems. The key features of our considered system are identified by the presence of uncertain time‐varying parameters associated with main diagonal states and input and an unknown time‐varying delay in the input. Moreover, the growth rates of nonlinearity and the input‐delay are only known to be finite. To solve our considered problem, we give a process to obtain a compact set that contains the allowed time‐varying parameters. Then, we propose an adaptive controller which handles both unknown growth rate of nonlinearity and input‐delay for system regulation. We carry out the rigorous system analysis and show the effectiveness of our proposed control scheme via an application example. [ABSTRACT FROM AUTHOR]

This article critiques New Interdependence Approach (NIA) explanations of global regulation, positing instead a State Transformation Approach (STA). Rightly critical of state-centric frameworks on the politics of globalisation, the NIA seeks to explain the emergence and distributional outcomes of global regulatory regimes, arguing that they stem from struggles sparked by overlapping rules that cut across national boundaries and which reshape domestic and international institutions. While the NIA presents a useful description of this process, and its efforts to overcome methodological nationalism are welcome, its explanatory power is limited by its roots in historical institutionalism, which fails to specify adequately the context that shapes political struggles, producing unsystematic, ad hoc accounts. Conversely, the STA explicitly locates struggles over global regulatory regimes within the wider context of evolving global capitalism and associated shifts in the nature of statehood, providing a more grounded and determinate explanation of outcomes. The argument is illustrated empirically throughout with reference to the global anti-money laundering regime. This study's findings raise question marks regarding historical institutionalism's potential to advance International Political Economy. [ABSTRACT FROM AUTHOR]

This paper is concerned with the global regulation via output feedback for the time-delay nonlinear systems with unknown continuous output function and unknown growth rate. Different from the existing literature, the output is perturbed by an unknown continuous function, and nonlinearities are upper bounded by unmeasured states multiplying an unknown constant and a polynomial of the output. A unified methodology is proposed to construct a new type of full-order observer with a dynamic gain by filtering unknown nonlinearities and time-varying delay. In light of a delicate scaling transformation, a combined system is derived to perform the one-step assignment of the controller instead of traditional backstepping recursive design. The stability analysis is completed by reductio and another scaling transformation with the upper bound of the dynamic gain. The efficiency of the proposed control scheme is demonstrated by two simulation examples including a practical one. [ABSTRACT FROM AUTHOR]

The article analyzes the influence of the WTO regulation function on energy markets in general. The WTO system does not include any specific agreement on energy trading for historical reasons. However, with new WTO members, who export hydrocarbons, including Russia, the regulation of energy sales is becoming more important. The analysis of theoretical papers and the WTO legislation identifies WTO rules that indirectly influence the global energy market. Hence, the analysis in the article is focused on consequences of Russia’s WTO accession in different aspects of the energy dialogue with the EU. As a result, the author demonstrates problematic issues in the Russia-EU energy cooperation and the way the WTO solves or complicates them for Russia. Moreover, there is a comprehensive analysis of current and potential disputes between Russia and the EU, and prospects of their settlement by means of a special WTO Dispute Settlement Body.

Abstract Pseudomonas putida KT2440 is a model bacteria used commonly for medium-chain-length polyhydroxyalkanoates (mcl-PHAs) production using various substrates. However, despite many studies conducted on P. putida KT2440 strain, the molecular mechanisms of leading to mcl-PHAs synthesis in reaction to environmental stimuli are still not clear. The rearrangement of the metabolism in response to environmental stress could be controlled by stringent response that modulates the transcription of many genes in order to promote survival under nutritional deprivation conditions. Therefore, in this work we investigated the relation between mcl-PHAs synthesis and stringent response. For this study, a relA/spoT mutant of P. putida KT2440, unable to induce the stringent response, was used. Additionally, the transcriptome of this mutant was analyzed using RNA-seq in order to examine rearrangements of the metabolism during cultivation. The results show that the relA/spoT mutant of P. putida KT2440 is able to accumulate mcl-PHAs in both optimal and nitrogen limiting conditions. Nitrogen starvation did not change the efficiency of mcl-PHAs synthesis in this mutant. The transition from exponential growth to stationary phase caused significant upregulation of genes involved in transport system and nitrogen metabolism. Transcriptional regulators, including rpoS, rpoN and rpoD, did not show changes in transcript abundance when entering the stationary phase, suggesting their limited role in mcl-PHAs accumulation during stationary phase.

ABSTRACT Toxin-antitoxin (TA) systems are broadly distributed modules whose biological roles remain mostly unknown. The mqsRA system is a noncanonical TA system in which the toxin and antitoxins genes are organized in operon but with the particularity that the toxin gene precedes that of the antitoxin. This system was shown to regulate global processes such as resistance to bile salts, motility, and biofilm formation. In addition, the MqsA antitoxin was shown to be a master regulator that represses the transcription of the csgD, cspD, and rpoS global regulator genes, thereby displaying a pleiotropic regulatory role. Here, we identified two promoters located in the toxin sequence driving the constitutive expression of mqsA, allowing thereby excess production of the MqsA antitoxin compared to the MqsR toxin. Our results show that both antitoxin-specific and operon promoters are not regulated by stresses such as amino acid starvation, oxidative shock, or bile salts. Moreover, we show that the MqsA antitoxin is not a global regulator as suggested, since the expression of csgD, cspD and rpoS is similar in wild-type and ΔmqsRA mutant strains. Moreover, these two strains behave similarly in terms of biofilm formation and sensitivity to oxidative stress or bile salts. IMPORTANCE There is growing controversy regarding the role of chromosomal toxin-antitoxin systems in bacterial physiology. mqsRA is a peculiar toxin-antitoxin system, as the gene encoding the toxin precedes that of the antitoxin. This system was previously shown to play a role in stress response and biofilm formation. In this work, we identified two promoters specifically driving the constitutive expression of the antitoxin, thereby decoupling the expression of antitoxin from the toxin. We also showed that mqsRA contributes neither to the regulation of biofilm formation nor to the sensitivity to oxidative stress and bile salts. Finally, we were unable to confirm that the MqsA antitoxin is a global regulator. Altogether, our data are ruling out the involvement of the mqsRA system in Escherichia coli regulatory networks.

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This paper investigates the problem of global regulation via output feedback for a class of triangular structural nonlinear systems with unknown measurement sensitivity. Two kinds of triangular structure nonlinear systems, namely upper triangular systems and lower triangular systems, are considered here, and the key features of our considered systems are that there are uncertain linear growth condition in the nonlinear terms. Firstly, for a class of upper triangular nonlinear systems with unknown measurement sensitivity, an output feedback controller is designed such that global regulation of the system is achieved. Then, for a class of lower triangular nonlinear systems with unknown measurement sensitivity, global regulation is realised in a unifying framework. Finally, two simulation examples are respectively given to demonstrate the effectiveness of the theoretical results. [ABSTRACT FROM AUTHOR]

Abstract Complex regulatory programs control cell adaptation to environmental changes by setting condition‐specific proteomes. In balanced growth, bacterial protein abundances depend on the dilution rate, transcript abundances and transcript‐specific translation efficiencies. We revisited the current theory claiming the invariance of bacterial translation efficiency. By integrating genome‐wide transcriptome datasets and datasets from a library of synthetic gfp‐reporter fusions, we demonstrated that translation efficiencies in Bacillus subtilis decreased up to fourfold from slow to fast growth. The translation initiation regions elicited a growth rate‐dependent, differential production of proteins without regulators, hence revealing a unique, hard‐coded, growth rate‐dependent mode of regulation. We combined model‐based data analyses of transcript and protein abundances genome‐wide and revealed that this global regulation is extensively used in B. subtilis. We eventually developed a knowledge‐based, three‐step translation initiation model, experimentally challenged the model predictions and proposed that a growth rate‐dependent drop in free ribosome abundance accounted for the differential protein production.

This paper concerns the global regulation for a class of stochastic high-order nonlinear systems which admit more general system form than the existing works. For details, except for the serious system nonlinearities which show that the considered systems are the generalisations of the strict-feedback systems, the most distinct feature of the systems is exhibited by the multiple unknown control directions, that is, all control coefficients of the virtual and actual control have unknown signs. By skillfully employing the Nussbaum function, and applying themethod of adding a power integrator, an effective regulation control scheme is successfully provided for the considered systems. In particular, the presented controller can guarantee that all the closed-loop systemstates are bounded, and especially the original system states converge to the origin, both in the sense of probability one. [ABSTRACT FROM AUTHOR]

What are the origins of global regulation? This article proposes that the developmental state — the state investing in economic development — can be a source of global environmental regulation. Through industrial policy, the developmental state can promote structural economic change in polluting sectors that supports global regulatory policy in two ways: first, providing state support to green industries creates economic interests in support of global regulation; and, second, driving down the cost of technology through government subsidies alters the pay-offs of global cooperation for other states. This article examines the two mechanisms in the case of climate change: the global leadership of the European Union; and international cooperation on the Paris Agreement. The argument advances our theory of the state in global regulatory politics as both a developmental and a regulatory force. This article identifies significant scope for the developmental strategies of major economies to change the interest and cost structures of polluting sectors to support global environmental regulation. [ABSTRACT FROM AUTHOR]

Shikimate, a precursor to the antiviral drug oseltamivir (Tamiflu®), can influence aromatic metabolites and finds extensive use in antimicrobial, antitumor, and cardiovascular applications. Consequently, various strategies have been developed for chemical synthesis and plant extraction to enhance shikimate biosynthesis, potentially impacting environmental conditions, economic sustainability, and separation and purification processes. Microbial engineering has been developed as an environmentally friendly approach for shikimate biosynthesis. In this review, we provide a comprehensive summary of microbial strategies for shikimate biosynthesis. These strategies primarily include chassis construction, biochemical optimization, pathway remodelling, and global regulation. Furthermore, we discuss future perspectives on shikimate biosynthesis and emphasize the importance of utilizing advanced metabolic engineering tools to regulate microbial networks for constructing robust microbial cell factories. • Summary of advances in shikimate biosynthesis. • Highlights of strategies with chassis construction, biochemical strategy, pathway remold, and global regulation. [ABSTRACT FROM AUTHOR]