Reciprocal regulation of PKA and rac signaling

Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac–bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTP-Rac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA–boosted activation of Raf-Mek-Erk. Consequently GTP-Rac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac–mediated activation of nuclear Erk1/2 signaling

Distributed Spacecraft Path Planning and Collision Avoidance via Reciprocal Velocity Obstacle Approach

This paper presents the development of a combined linear quadratic regulation and reciprocal velocity obstacle (LQR/RVO) control algorithm for multiple satellites during close proximity operations. The linear quadratic regulator (LQR) control effort drives the spacecraft towards their target position while the reciprocal velocity obstacle (RVO) provides collision avoidance capabilities. Each spacecraft maneuvers independently, without explicit communication or knowledge in term of collision avoidance decision making of the other spacecraft in the formation. To assess the performance of this novel controller different test cases are implemented. Numerical results show that this method guarantees safe and collision-free maneuvers for all the satellites in the formation and the control performance is presented in term of Δv and fuel consumption

Trade Regulation: District Court Clarifies Test for Conglomerate Merger Violation of Clayton Act

In a divestiture suit under the Clayton Act, the Southern District of New York limited the investigation necessary to ascertain a section 7 violation on the basis of reciprocity and brought reciprocal dealing standing apart from an acquisition within the purview of section 1 of the Sherman Act by analogy to tying arrangements. The reasoning and conclusions of the court may give significant impetus to the reciprocity concept as a basis for antitrust regulation with important implications for business expansion by diversification acquisition

Fixed to VoIP Interconnection: Regulation with Asymmetric Termination Costs

Typically, incumbent providers enjoy a demand-side advantage over any entrant. However, market entrants may enjoy a supply-side advantage in costs over the incumbent, since they are more efficient or operate on innovative technologies, such as the voice of internet protocol (VoIP) telephony. Regulation with a supply-side asymmetry has rarely been addressed. Considering both a supply-side and a demand- side asymmetry, the present model analyzes the effects different regulation regimes. Regulation may have adverse effects on subscribers, market shares, and profits. If providers can discriminate between on-net and off-net prices, asymmetric regulation has no local effect on market shares, independent of any demand- and supply-side asymmetry. Otherwise, with reciprocal termination charges, price discrimination leads to qualitatively same effects than nondiscriminatory pricing. --Termination charges,Interconnection,Regulation,Price Discrimination,Voice over Internet Protocol (VoIP)

Reciprocal regulation of A-to-I RNA editing and the vertebrate nervous system

The fine control of molecules mediating communication in the nervous system is key to adjusting neuronal signaling during development and in maintaining the stability of established networks in the face of altered sensory input. To prevent the culmination of pathological recurrent network excitation or debilitating periods of quiescence, adaptive alterations occur in the signaling molecules and ion channels that control membrane excitability and synaptic transmission. However, rather than encoding (and thus "hardwiring") modified gene copies, the nervous systems of metazoa have opted for expanding on post-transcriptional pre-mRNA splicing by altering key encoded amino acids using a conserved mechanism of A-to-I RNA editing: the enzymatic deamination of adenosine to inosine. Inosine exhibits similar base-pairing properties to guanosine with respect to tRNA codon recognition, replication by polymerases, and RNA secondary structure (i.e.,: forming-capacity). In addition to recoding within the open reading frame, adenosine deamination also occurs with high frequency throughout the non-coding transcriptome, where it affects multiple aspects of RNA metabolism and gene expression. Here, we describe the recoding function of key RNA editing targets in the mammalian central nervous system and their potential to be regulated. We will then discuss how interactions of A-to-I editing with gene expression and alternative splicing could play a wider role in regulating the neuronal transcriptome. Finally, we will highlight the increasing complexity of this multifaceted control hub by summarizing new findings from high-throughput studies. © 2013 Penn, Balik and Greger

Glycemia Regulation: From Feedback Loops to Organizational Closure.

Endocrinologists apply the idea of feedback loops to explain how hormones regulate certain bodily functions such as glucose metabolism. In particular, feedback loops focus on the maintenance of the plasma concentrations of glucose within a narrow range. Here, we put forward a different, organicist perspective on the endocrine regulation of glycaemia, by relying on the pivotal concept of closure of constraints. From this perspective, biological systems are understood as organized ones, which means that they are constituted of a set of mutually dependent functional structures acting as constraints, whose maintenance depends on their reciprocal interactions. Closure refers specifically to the mutual dependence among functional constraints in an organism. We show that, when compared to feedback loops, organizational closure can generate much richer descriptions of the processes and constraints at play in the metabolism and regulation of glycaemia, by making explicit the different hierarchical orders involved. We expect that the proposed theoretical framework will open the way to the construction of original mathematical models, which would provide a better understanding of endocrine regulation from an organicist perspective

Metabolic signaling directs the reciprocal lineage decisions of αβ and γδ T cells

Wiring metabolic signaling circuits in thymocytes Cell differentiation is often accompanied by metabolic changes. Yang et al. report that generation of double-positive (DP) thymocytes from double-negative (DN) cells coincides with dynamic regulation of glycolytic and oxidative metabolism. Given the central role of mechanistic target of rapamycin complex 1 (mTORC1) signaling in regulating metabolic changes, they examined the role of mTORC1 pathway in thymocyte development by conditionally deleting RAPTOR, the key component of the mTORC1 complex, in thymocytes. Loss of RAPTOR impaired the DN-to-DP transition, but unexpectedly also perturbed the balance between αβ and γδ T cells and promoted the generation of γδ T cells. Their studies highlight an unappreciated role for mTORC1-dependent metabolic changes in controlling thymocyte fates. The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the αβ and γδ T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of αβ T cells but promotes γδ T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating αβ and γδ T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal αβ and γδ T cell development and provide insight into metabolic control of cell signaling and fate decisions. Development of αβ and γδ T cells requires coupling of environmental signals with metabolic and redox regulation by mTORC1. Development of αβ and γδ T cells requires coupling of environmental signals with metabolic and redox regulation by mTORC1

Penerapan Pembelajaran Reciprocal Teaching Dipadu Think Pair Share untuk Meningkatkan Keterampilan Berpikir Kritis dan Hasil Belajar Siswa Kelas V

This research aims to describe implementation of combined reciprocal teaching and think pair share to increase critical thinking skills and student learning outcomes in science. The study design was a classroom action research. The subject was 5th graders (B) Al Hikmah Surabaya Elementary School. The results showed that the learning process reach very well criteria. Critical thinking skills of students has increased. Indicators of critical thinking skills include interpretation, analysis, evaluation, inference, explanation, and self regulation. Student learning outcomes increased in the attitudes aspect, knowledge, and skills. This reaearch concluded that the combined reciprocal teaching and think pair share can increased critical thinking skills and student learning outcomes.Tujuan penelitian adalah mendeskripsikan keterlaksanaan pembelajaran reciprocal teaching dipadu think pair share untuk meningkatkan keterampilan berpikir kritis dan hasil belajar pelajaran IPA. Rancangan penelitian adalah penelitian tindakan kelas. Kancah penelitian pada kelas VB SD Al Hikmah Surabaya. Hasil penelitian menunjukkan pembelajaran terlaksana dengan kriteria sangat baik. Keterampilan berpikir kritis siswa mengalami peningkatan. Indikator keterampilan bepikir kritis mencakup interpretation, analysis, evaluation, inference, explanation, dan self regulation. Hasil belajar siswa mengalami peingkatan pada aspek sikap, pengetahuan, dan keterampilan. Dari hasil penelitian dapat disimpulkan bahwa pembelajaran Reciprocal Teaching dipadu Think Pair Share dapat meningkatkan keterampilan berpikir kritis dan hasil belajar siswa

Real-time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake human subjects

In order to understand the central neural processes involved in blood pressure regulation we recorded muscle sympathetic nerve activity (MSNA) via a tungsten microelectrode in the common peroneal nerve while performing functional Magnetic Resonance Imaging (fMRI) of the brainstem at 3T. Blood Oxygen Level Dependent (BOLD) changes in signal intensity were measured over 4 s every 8 s (200) volumes. Using the MSNA as the input model, we found that increases in sympathetic outflow were associated with robust increases in signal intensity in the region of the rostal ventrolateral medulla (RVLM). Reciprocal decreases in signal intensity occurred in the regions of the nucleus tractus solitarius (NTS) and caudal ventrolateral medulla (CVLM). We show for the first time that this combined approach of recording sympathetic neural activity and fMRI can provide "real-time" imaging of the neural processes responsible for the generation of sympathetic nerve activity in awake human subjects

The accounting regulation in the French context: The case of corporate groups (1921-1943)

The aim of this paper is to shed light on the role of legislators and lawyers in establishing accounting regulations concerning corporate groups in France during the 1930s and the Occupation (1940 - 1944). A review of bills proposing accounting regulation shows that no significant progress was to be achieved. Furthermore, while some lawyers called for a comprehensive regulation of corporate groups, no such progress was made during the inter-war period. Ultimately it's the Vichy government which introduced the first regulations on accounting subsidiaries in the French Plan Comptable and limited the reciprocal shareholdings in the Act of March 4, 1943.Accounting history, corporate groups, accounting regulation, inter war period, Occupation period, France