Localization and phosphorylation in the Snf1 network is controlled by two independent pathways

AMPK/SNF1 is the master regulator of energy homeostasis in eukaryotic cells and has a key role in glucose de-repression. If glucose becomes depleted, Snf1 is phosphorylated and activated. Activation of Snf1 is required but is not sufficient for mediating glucose de-repression indicating a second glucose-regulated step that adjusts the Snf1 pathway. To elucidate this regulation, we further explore the spatial dynamics of Snf1 and Mig1 and how they are controlled by concentrations of hexose sugars. We utilize fluorescence recovery after photobleaching (FRAP) to study the movement of Snf1 and how it responds to external glucose concentrations. We show that the Snf1 pathway reacts both to the presence and to the absolute concentration of glucose. Furthermore, we identify a negative feedback loop regulating Snf1 activity. We also show that Mig1 localization correlates with the Snf1 phosphorylation pattern and not with the Mig1 phosphorylation pattern, suggesting that inactivation of Snf1 has a more pronounced effect on the localization of Mig1 than on the phosphorylation of Mig1. Our data offer insight into the true complexity of regulation of this central signaling pathway by one signal (glucose depletion) interpreted by the cell in different ways.

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3D micro-environment regulates NF–κβ dependent adhesion to induce monocyte differentiation

10.1101/279943 ◽

2018 ◽

Author(s):

Anindita Bhattacharya ◽

Mahesh Agarwal ◽

Rachita Mukherjee ◽

Prosenjit Sen ◽

Deepak Kumar Sinha

Keyword(s):

Positive Feedback ◽

Feedback Loop ◽

The Novel ◽

Monocyte Adhesion ◽

Cellular Functions ◽

Monocyte Differentiation ◽

Summary Statement ◽

Necessary And Sufficient ◽

Multiple Signaling ◽

Insight Into

AbstractDifferentiation of monocytes entails their relocation from blood to the tissue, hence accompanied by an altered physicochemical micro-environment. While the mechanism by which the biochemical make-up of the micro-environment induces differentiation is known, the fluid-like to gel-like transition in the physical micro-environment is not well understood. Monocytes maintain non-adherent state to prevent differentiation. We establish that irrespective of the chemical makeup, a 3D gel-like micro-environment induces a positive-feedback loop of adhesion-MAPK-NF-κβ activation to facilitate differentiation. In 2D fluid-like micro-environment, adhesion alone is capable of inducing differentiation via the same positive-feedback signalling. Chemical inducer treatment in fluid-like micro-environment, increases the propensity of monocyte adhesion via a brief pulse of p-MAPK. The adhesion subsequently elicit differentiation, establishing that adhesion is both necessary and sufficient to induce differentiation in 2D/3D micro-environment. Our findings challenge the notion that adhesion is a result of monocyte differentiation. Rather it’s the adhesion which triggers the differentiation of monocytes. MAPK, and NF-κβ being key molecules of multiple signaling pathways, we hypothesize that biochemically inert 3D gel-like micro-environment would also influence other cellular functions.Summary statementThis article brings out a new insight into the novel mechanisms of monocyte differentiation solely driven by physical micro-environment and adhesion.

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Steam Atmospheres and Magma Oceans on Planets

Oxford Research Encyclopedia of Planetary Science ◽

10.1093/acrefore/9780190647926.013.203 ◽

2020 ◽

Author(s):

Keiko Hamano

Keyword(s):

Feedback Loop ◽

Radiative Energy ◽

Terrestrial Planets ◽

Magma Ocean ◽

Planetary Body ◽

Oxidation Of H2 ◽

Giant Impacts ◽

Magma Oceans ◽

Greenhouse Effects ◽

Insight Into

A magma ocean is a global layer of partially or fully molten rocks. Significant melting of terrestrial planets likely occurs due to heat release during planetary accretion, such as decay heat of short-lived radionuclides, impact energy released by continuous planetesimal accretion, and energetic impacts among planetary-sized bodies (giant impacts). Over a magma ocean, all water, which is released upon impact or degassed from the interior, exists as superheated vapor, forming a water-dominated, steam atmosphere. A magma ocean extending to the surface is expected to interact with the overlying steam atmosphere through material and heat exchange. Impact degassing of water starts when the size of a planetary body becomes larger than Earth’s moon or Mars. The degassed water could build up and form a steam atmosphere on protoplanets growing by planetesimal accretion. The atmosphere has a role in preventing accretion energy supplied by planetesimals from escaping, leading to the formation of a magma ocean. Once a magma ocean forms, part of the steam atmosphere would start to dissolve into the surface magma due to the high solubility of water into silicate melt. Theoretical studies indicated that as long as the magma ocean is present, a negative feedback loop can operate to regulate the amount of the steam atmosphere and to stabilize the surface temperature so that a radiative energy balance is achieved. Protoplanets can also accrete the surrounding H2-rich disk gas. Water could be produced by oxidation of H2 by ferrous iron in the magma. The atmosphere and water on protoplanets could be a mixture of outgassed and disk-gas components. Planets formed by giant impact would experience a global melting on a short timescale. A steam atmosphere could grow by later outgassing from the interior. Its thermal blanketing and greenhouse effects are of great importance in controlling the cooling rate of the magma ocean. Due to the presence of a runaway greenhouse threshold, the crystallization timescale and water budget of terrestrial planets can depend on the orbital distance from the host star. The terrestrial planets in our solar system essentially have no direct record of their earliest history, whereas observations of young terrestrial exoplanets may provide us some insight into what early terrestrial planets and their atmosphere are like. Evolution of protoplanets in the framework of pebble accretion remains unexplored.

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Circadian regulation of c-MYC in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011225117 ◽

2020 ◽

Vol 117 (35) ◽

pp. 21609-21617

Author(s):

Zhenxing Liu ◽

Christopher P. Selby ◽

Yanyan Yang ◽

Laura A. Lindsey-Boltz ◽

Xuemei Cao ◽

...

Keyword(s):

Cell Cycle ◽

Circadian Clock ◽

Tumor Suppressors ◽

Feedback Loop ◽

Cell Cycle Progression ◽

Regulatory Mechanism ◽

Clock Genes ◽

Circadian Regulation ◽

Cycle Progression ◽

Insight Into

The circadian clock is a global regulatory mechanism that controls the expression of 50 to 80% of transcripts in mammals. Some of the genes controlled by the circadian clock are oncogenes or tumor suppressors. Among theseMychas been the focus of several studies which have investigated the effect of clock genes and proteins onMyctranscription and MYC protein stability. Other studies have focused on effects ofMycmutation or overproduction on the circadian clock in comparison to their effects on cell cycle progression and tumorigenesis. Here we have used mice with mutations in the essential clock genesBmal1,Cry1,andCry2to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of bothCry1andCry2, which abolishes the negative arm of the clock transcription–translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation ofBmal1,which abolishes the positive arm of TTFL, causes up-regulation of the c-MYC protein level in mouse spleen. These findings must be taken into account in models of the clock disruption–cancer connection.

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An insight into testis and gubernaculum dynamics of INSL3 - RXFP2 signalling during testicular descent in the dog

Reproduction Fertility and Development ◽

10.1071/rd09260 ◽

2010 ◽

Vol 22 (5) ◽

pp. 751 ◽

Cited By ~ 11

Author(s):

S. Arrighi ◽

G. Bosi ◽

D. Groppetti ◽

M. Aralla ◽

F. Cremonesi

Keyword(s):

Sertoli Cells ◽

Leydig Cells ◽

Feedback Loop ◽

Testicular Descent ◽

Fetal Period ◽

Male Development ◽

Dog Testis ◽

Gubernaculum Testis ◽

Insight Into ◽

Different Tissues

Insulin-like 3 (INSL3) plays a prominent role in male development and is supposed to induce the growth of the gubernaculum testis (g.t.), thus being directly involved in testicular descent in humans and rodents. This happens through activation of the RXFP2 receptor (GREAT or LGR8). The INSL3–RXFP2 complex is reputed to play an additional paracrine role in the testis, possibly acting as part of an autocrine feedback loop. The present work provides evidence of the immunolocalisation of INSL3 in the Leydig cells of canine fetuses and of the expression of RXFP2 receptor in different tissues of the g.t. of the same specimens. RXFP2 was localised at the cell membrane of g.t. muscle and connective cells, as well as in the epithelial cells of the developing excurrent ducts. Notably, RXFP2 immunoreactivity of the g.t. was limited to fetuses at ~35–45 days of gestation, which is also the fetal period when the endocrine compartment of the dog testis is active endocrinologically, as confirmed by the anti-P450c17 and anti-INSL3 immunoreactivities of the fetal Leydig cells, and by anti-Müllerian hormone immunoreactivity of the Sertoli cells. The same immunoreactivities were also evaluated in the testes of cryptorchid dogs of different ages. RXFP2 immunoreactivity was absent from genital tracts of cryptorchid testes and g.t. remnants.

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Case Study in Using Integrated Rubrics in Assessment

Journal of Education and Culture Studies ◽

10.22158/jecs.v4n3p81 ◽

2020 ◽

Vol 4 (3) ◽

pp. p81

Author(s):

Tabetha Hazels ◽

Kelli Schutte ◽

Shelly McVay

Keyword(s):

Learning Outcomes ◽

Feedback Loop ◽

Integrated Approach ◽

Work Processes ◽

College Mission ◽

Departmental Climate ◽

Insight Into ◽

Multiple Stages

This case study takes a look at an integrated approach to assessment. The paper walks through the process of alignment of college mission and learning outcomes with departmental and course level outcomes. The department developed integrated assignments that are implemented across a four-year program to ensure learning outcomes. In order to assess those outcomes, the department developed an integrated rubric that is applied at multiple stages of the program levels as well as in various courses. This allows for feedback that is both summative and formative for future changes. The feedback loop has helped provide insight into course level and department level changes, but it has also enhanced departmental climate and work processes.

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Conceptual Framework for Modeling Business Capabilities

10.28945/3148 ◽

2007 ◽

Cited By ~ 5

Author(s):

Jean-Pierre Brits ◽

Gerrit Botha ◽

Marlien Herselman

Keyword(s):

Conceptual Framework ◽

Feedback Loop ◽

Enterprise Architecture ◽

Research Study ◽

Feedback Loops ◽

Organizational Analysis ◽

Conceptual Approach ◽

Business Environments ◽

Agile Organization ◽

Insight Into

Staying competitive in today’s fast changing markets and business environments has become a big issue in organizations these days. To be able to foresee the future of the industry and have insight into customer’s articulated and unarticulated needs are critical capabilities that organizations need to acquire in order to stay competitive. The objective of this research project is to provide a conceptual approach to analyze an organization and to provide a foundation that would support the architecture of an agile organization. Enterprise architecture, business capabilities, organizational analysis and innovation are the main practices that contribute towards the construction of capabilities and the development of the conceptual business capability framework. The most significant findings from this research study were the development of a conceptual framework that is later utilized to construct business capabilities. A business capability model has also been produced to visually depict a business capability. This study also provided two feedback loops, namely the organizational feedback loop and the innovative feedback loop.

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The Homeostatic Logic of Reward

10.1101/242974 ◽

2018 ◽

Cited By ~ 3

Author(s):

Tobias Morville ◽

Karl Friston ◽

Denis Burdakov ◽

Hartwig R. Siebner ◽

Oliver J. Hulme

Keyword(s):

Reinforcement Learning ◽

Energy Homeostasis ◽

Active Inference ◽

Neural Basis ◽

Homeostatic Control ◽

Dopaminergic Cells ◽

Time Horizons ◽

Metabolic States ◽

Circular Definitions ◽

Insight Into

AbstractEnergy homeostasis depends on behavior to predictively regulate metabolic states within narrow bounds. Here we review three theories of homeostatic control and ask how they provide insight into the circuitry underlying energy homeostasis. We offer two contributions. First, we detail how control theory and reinforcement learning are applied to homeostatic control. We show how these schemes rest on implausible assumptions; either via circular definitions, unprincipled drive functions, or by ignoring environmental volatility. We argue active inference can elude these shortcomings while retaining important features of each model. Second, we review the neural basis of energetic control. We focus on a subset of arcuate subpopulations that project directly to, and are thus in a privileged position to opponently modulate, dopaminergic cells as a function of energetic predictions over a spectrum of time horizons. We discuss how this can be interpreted under these theories, and how this can resolve paradoxes that have arisen. We propose this circuit constitutes a homeostatic-reward interface that underwrites the conjoint optimisation of physiological and behavioural homeostasis.

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Teaching the role of secretin in the regulation of gastric acid secretion using a classic paper by Johnson and Grossman

AJP Advances in Physiology Education ◽

10.1152/advan.00023.2009 ◽

2009 ◽

Vol 33 (3) ◽

pp. 165-168 ◽

Cited By ~ 5

Author(s):

Kristen L. W. Walton

Keyword(s):

Gastrointestinal Tract ◽

Acid Secretion ◽

Gastric Acid Secretion ◽

Gastric Acid ◽

Feedback Loop ◽

Gastrointestinal Hormones ◽

The Subject ◽

Classic Paper ◽

Insight Into

The regulation of gastric acid secretion has been the subject of investigation for over a century. Inhibition of gastrin-induced acid secretion by the intestine-derived hormone secretin provides a classic physiological example of negative feedback in the gastrointestinal tract. A classic paper by Leonard R. Johnson and Morton I. Grossman clearly shows the ability of secretin to negatively regulate gastric acid secretion, providing students with an example of this feedback loop. In addition, this article demonstrates the step forward in gastrointestinal endocrinology that occurred when pure preparations of secretin and other gastrointestinal hormones first became available. The comparison of the effects of exogenous, purified secretin to the physiological stimulus of acid in the duodenum is an important example of how newly available reagents allow scientists such as Johnson and Grossman to clarify the mechanisms behind previously established processes. One or more figures from this classic paper can be used to give students insight into the role of secretin in the regulation of the function of the gastrointestinal tract and will also give students a clear example of how the careful experimentation and clear interest in gastrointestinal physiology led Johnson and Grossman to advance the field.

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Carbohydrate and PepO control bimodality in competence development byStreptococcus mutans

10.1101/670752 ◽

2019 ◽

Author(s):

Simon A.M. Underhill ◽

Robert C. Shields ◽

Robert A. Burne ◽

Stephen J. Hagen

Keyword(s):

Growth Medium ◽

Feedback Loop ◽

Feedback System ◽

Alternative Sigma Factor ◽

Small Peptides ◽

Carbohydrate Source ◽

Genetic Competence ◽

Mechanistic Insight ◽

Defined Media ◽

Insight Into

AbstractInStreptococcus mutans, the alternative sigma factor ComX controls entry into genetic competence. Competence signaling peptide (CSP) induces bimodal expression ofcomX, with only a fraction of cells in the population becoming transformable. Curiously, bimodalcomXactivation in response to CSP is affected by peptides in the growth medium and by carbohydrate source. CSP elicits bimodal expression ofcomXin media rich in small peptides, but in defined media lacking small peptides CSP induces no response incomX. In addition, growth on certain sugars other than glucose increases the proportion of the population that activatescomXin response to CSP, relative to growth on glucose. By investigating the connection between media and bimodalcomXexpression, we find evidence for two mechanisms that modulate transcriptional positive feedback in the ComRS system, which is the origin ofcomXbimodality. We find that the endopeptidase PepO suppresses the ComRS feedback loop, most likely by degrading the intracellular XIP/ComS signal. Deletion ofpepOeliminates bimodality incomX, leading to a unimodalcomXresponse to CSP in defined and complex media. We also find that CSP upregulatescomRin a carbohydrate source-dependent fashion, providing an additional stimulus to the ComRS feedback system. Our data provide mechanistic insight into how CSP regulates the bistable competence circuit and explain the puzzle of growth medium-dependence inS. mutanscompetence regulation.

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A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

10.1101/2020.09.02.279356 ◽

2020 ◽

Author(s):

Joanna L. Gillis ◽

Josephine A. Hinneh ◽

Natalie Ryan ◽

Swati Irani ◽

Max Moldovan ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Feedback Loop ◽

Pentose Phosphate ◽

Cancer Growth ◽

Prostate Cancer Cells ◽

Clinical Patient ◽

Castration Resistant ◽

Insight Into ◽

Specific Inhibitors

ABSTRACTAlterations to androgen receptor (AR) signalling and cellular metabolism are hallmarks of prostate cancer. This study uncovers a novel link between AR and the pentose phosphate pathway (PPP) through 6-phosphogluoconate dehydrogenase (6PGD), an androgen-regulated gene that is upregulated in prostate cancer. Knockdown of 6PGD impairs growth and elicits death of prostate cancer cells, at least in part due to oxidative stress. Targeting 6PGD using 2 specific inhibitors, physcion and S3, was efficacious in multiple models of prostate cancer, including aggressive castration-resistant models. Importantly, S3 also suppressed proliferation of clinical patient-derived explants (PDEs). Mechanistically, 6PGD decreased expression and activity of AR in cell lines and PDEs, revealing a novel positive feedback loop between these factors. The enhanced efficacy of co-targeting AR and 6PGD further supported the biological relevance of this feedback. This work provides insight into the dysregulated metabolism of prostate cancer and supports investigation of co-targeting AR and the PPP.

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