Direct Negative Feedback Research Articles

Abstract MP17: Angiotensin II Inhibits Renin Secretion Directly By Eliciting Robust Calcium Oscillations In Juxtaglomerular Cells

Background: Renin secretion from the juxtaglomerular (JG) cells controls circulating Angiotensin II (AngII), a critical blood pressure determinant. AngII is believed to suppress renin release from JG cells to prevent excessive blood pressure elevation. However, a direct negative feedback mechanism has yet to be established in JG cells. In JG cells, Ca 2+ is a crucial second messenger that governs renin secretion by suppressing cAMP, a potent renin secretion stimulator. Thus, in contrast to most secretory cells, renin secretion from JG cells is inversely related to the intracellular Ca 2+ level. However, the role of AngII in modulating JG cell Ca 2+ dynamics remains unclear. Objective: Define intracellular Ca 2+ responses to AngII and identify the critical channels to suppress renin secretion in JG cells. Methods: Kidney slices from mice expressing JG-specific GCaMP6f, a genetically encoded Ca 2+ indicator under the control of the Ren1 c promoter, were imaged ex vivo on a widefield fluorescent microscope for 30 min per experiment (n = 5). In each experiment, slices were continuously perfused with buffer containing variable Ca 2+ and AngII concentrations, ± specific Ca 2+ channel inhibitors. Images were captured at 10 Hz and analyzed using Mesmerize Ca 2+ imaging software to identify and plot fluorescent intensity over time for each JG cell. Additional kidney slices were incubated in 24-well plates with buffer containing vehicle or AngII ± Ca 2+ channel inhibitors for 30 min. ELISA determined renin concentration. Results: 1) AngII dose-dependently evoked robust and periodic Ca 2+ -oscillations (Ca 2+ spikes) in JG cells (mean spikes/min; 50 pM: 5.4, 300 pM: 7.7, 3 nM: 13.2, and 300 nM: 17.6). 2) AngII-elicited Ca 2+ activity was markedly reduced with “Ca 2+ -free” buffer. 3) L-type voltage-dependent Ca 2+ channel (VDCC) blocker nifedipine moderately decreased AngII-elicited Ca 2+ spikes, while T-type VDCC blocker TTA-P2 did not. 4) Blocking endoplasmic reticulum (ER) Ca 2+ -release drastically reduced Ca 2+ activity. 5) AngII dose-dependently decreased renin secretion in kidney slices, congruent with the AngII-elicited Ca 2+ activity in imaging studies. Conclusion: AngII dose-dependently and directly elicited large, periodic Ca 2+ -oscillations in JG cells that suppressed renin release. Both extracellular Ca 2+ influx and intracellular Ca 2+ release from ER stores are required for sustained Ca 2+ activity. L-type, but not T-type, Ca 2+ channels participate in JG cell Ca 2+ -oscillations.

IL-17 Signaling in Keratinocytes Orchestrates the Defense against Staphylococcus aureus Skin Infection

Keratinocytes (KCs) form the outer epithelial barrier of the body, protecting against invading pathogens. Mice lacking the IL-17RA or both IL-17A and IL-17F develop spontaneous Staphylococcusaureus skin infections. We found a marked expansion of T17 cells, comprised of RORγt-expressing γδ T cells and T helper 17 cells in the skin-draining lymph nodes of these mice. Contradictory to previous suggestions, this expansion was not a result of a direct negative feedback loop because we found no expansion of T17 cells in mice lacking IL-17 signaling specifically in T cells. Instead, we found that the T17 expansion depended on the microbiota and was observed only when KCs were deficient for IL-17RA signaling. Indeed, mice that lack IL-17RA only in KCs showed an increased susceptibility to experimental epicutaneous infection with S.aureus together with an accumulation of IL-17A-producing γδ T cells. We conclude that deficiency of IL-17RA on KCs leads to microbiota dysbiosis in the skin, which triggers the expansion of IL-17A-producing T cells. Our data show that KCs are the primary target cells of IL-17A and IL-17F, coordinating the defense against microbial invaders in the skin.

STABILIZATION OF TRANSISTOR ANALOGUES OF INDUCTANCE PARAMETERS

The article analyzes methods for stabilizing the parameters of transistor analogues of inductance (TAI), their advantages and disadvantages are determined. Ways of implementation are considered, thanks to which it is possible to weaken the influence of all destabilizing factors, such as temperature, instability of power supplies, production variation of parameters, changes in parameters due to aging, and others. Allocated universal means to stabilize the parameters of all transistor devices. The stabilization of the operating mode at direct current and negative feedback at alternating current are considered. An assessment of the mode of instability of the parameters of the TAI was carried out by the magnitude of the increase in the equivalent inductance and quality factor. A technique for stabilizing the parameters of the TAI, as well as microwave devices, is defined, in each specific case, the need to select the allowable instability of the operating point, to perform the expected calculation of the instability of the parameters, and then to obtain the desired stability, input negative feedback on alternating current is described. The graphs of the dependence of the equivalent quality factor on temperature and the graphs of the dependence of the equivalent inductance on temperature are presented. An expression is given for the increase in inductance in the case when the main destabilizing effect on the operating mode of the transistor is a change in the reverse collector current, current transfer coefficient, collector-base voltage, emitter-base voltage, emitter current. The coefficient of regime instability was calculated. The effectiveness of stabilizing influences from negative feedback on alternating current, which contributes to the stabilization of almost all parameters of the TAI, is considered. Inductance is considered as a parameter characterizing the properties of TAI in the presence and absence of feedback. An expression is given for the relative error of inductance in the presence of NZS on alternating current.

Mitigating Host Burden of Genetic Circuits by Engineering Autonegatively Regulated Parts and Improving Functional Prediction.

Mitigating unintended interferences between circuits and host cells is key to realize applications of synthetic regulatory systems both for bacteria and mammalian cells. Here, we demonstrated that growth burden and circuit dysregulation occurred in a concentration-dependent manner for specific transcription factors (CymR*/CymR) in E.coli, and direct negative feedback modules were able to control the concentration of CymR*/CymR, mitigate growth burden, and restore circuit functions. A quantitative design scheme was developed for circuits embedded with autorepression modules. Four key parameters were theoretically identified to determine the performance of autoregulated switches and were experimentally modified by fine-tuning promoter architectures and cooperativity. Using this strategy, we synthesized a number of switches and demonstrated its improvement of product titers and host growth controlling the complex deoxyviolacein biosynthesis pathway. Furthermore, we restored functions of a dysregulated multilayer NOR gate by integrating autorepression modules. Our work provides a blueprint for engineering host-adaptable synthetic systems.

MicroProteins: Expanding functions and novel modes of regulation

MicroProteins: Expanding functions and novel modes of regulation

Ignored or Rejected: Retail Exclusion Effects on Construal Levels and Consumer Responses to Compensation

Abstract Among the top customer complaints regarding retailers are experiences of exclusionary treatment in the form of explicit condescension or implicit disregard. However, little is known about how consumers respond to different instances of exclusion in retail or service settings. This research focuses on how customers respond cognitively and emotionally when frontline staff reject or ignore them and on how retailers can recover from such service failures. Findings from six studies using exclusion as a hypothetical scenario or a real experience demonstrate that direct negative feedback leads customers to feel rejected and to form concrete low-level mental construals, while a lack of attention leads customers to feel ignored and to form abstract high-level construals. Explicit rejection (implicit ignoring) causes consumers to form more (less) vivid mental imagery of the exclusionary experience and to activate a concrete (abstract) mindset, resulting in preferences for tangible (intangible) and visual (textual) compensation options. Retailers are advised to align their compensation with construal levels to increase post-recovery customer satisfaction, customer reviews, intended loyalty, and brand referral behavior.

Angiotensin II Short-Loop Feedback: Is There a Role of Ang II for the Regulation of the Renin System In Vivo?

The activity of the renin-angiotensin-aldosterone system is triggered by the release of the protease renin from the kidneys, which in turn is controlled in the sense of negative feedback loops. It is widely assumed that Ang II (angiotensin II) directly inhibits renin expression and secretion via a short-loop feedback by an effect on renin-producing cells (RPCs) mediated by AT1 (Ang II type 1) receptors. Because the concept of such a direct short-loop negative feedback control, which originates mostly from in vitro experiments, has not yet been systematically proven in vivo, we aimed to test the validity of this concept by studying the regulation of renin synthesis and secretion in mice lacking Ang II-AT1 receptors on RPCs. We found that RPCs of the kidney express Ang II-AT1 receptors. Mice with conditional deletion of Ang II-AT1 receptors in RPCs were normal with regard to the number of renin cells, renal renin mRNA, and plasma renin concentrations. Renin expression and secretion of these mice responded to Ang I (angiotensin I)-converting enzyme inhibition and to Ang II infusion like in wild-type (WT) controls. In summary, we did not obtain evidence that Ang II-AT1 receptors on RPCs are of major relevance for the normal regulation of renin expression and secretion in mice. Therefore, we doubt the existence of a direct negative feedback function of Ang II on RPCs.

Evidence for rapid weathering response to climatic warming during the Toarcian Oceanic Anoxic Event

Chemical weathering consumes atmospheric carbon dioxide through the breakdown of silicate minerals and is thought to stabilize Earth’s long-term climate. However, the potential influence of silicate weathering on atmospheric pCO2 levels on geologically short timescales (103–105 years) remains poorly constrained. Here we focus on the record of a transient interval of severe climatic warming across the Toarcian Oceanic Anoxic Event or T-OAE from an open ocean sedimentary succession from western North America. Paired osmium isotope data and numerical modelling results suggest that weathering rates may have increased by 215% and potentially up to 530% compared to the pre-event baseline, which would have resulted in the sequestration of significant amounts of atmospheric CO2. This process would have also led to increased delivery of nutrients to the oceans and lakes stimulating bioproductivity and leading to the subsequent development of shallow-water anoxia, the hallmark of the T-OAE. This enhanced bioproductivity and anoxia would have resulted in elevated rates of organic matter burial that would have acted as an additional negative feedback on atmospheric pCO2 levels. Therefore, the enhanced weathering modulated by initially increased pCO2 levels would have operated as both a direct and indirect negative feedback to end the T-OAE.

Linear stability of delayed reaction–diffusion systems

A common feature of pattern formation in both space and time is the destabilization of a stable equilibrium solution of an ordinary differential equation by adding diffusion or delay, or both. Here we study linear stability of general reaction–diffusion systems with off-diagonal time delays. We show that a delay-stable system cannot be destabilized by diffusion, and that a diffusion stable system is also stable with respect to delay, if the diffusion is sufficiently fast. A system with direct negative feedback which is strongly stable with respect to diffusion can be destabilized by off-diagonal delay.

Inconsistencies across repeated eyewitness interviews: supportive negative feedback can make witnesses change their memory reports

ABSTRACTPast work shows that direct negative feedback and suggestive questioning can lead eyewitnesses to change their memory reports. Applying Gudjonsson’s [2003. The psychology of interrogations and confessions: A handbook. West Sussex: Wiley] model of interrogative suggestibility to interviews with witnesses, the present two experiments examined how indirect negative feedback delivered in a supportive manner from an interviewer can make witnesses change what they report they remember experiencing. After viewing a video of a crime, participants were interviewed twice, with either supportive negative feedback (i.e. with the interviewer sympathetically suggesting why many people’s memory may be inaccurate) or neutral feedback between the two rounds of questions. Results showed that people given supportive negative feedback changed significantly more of their responses than those given neutral feedback. Lower confidence ratings were associated with greater response change, but overall, despite having changed more responses, people given supportive negative feedback did not have reduced confidence or perceived accuracy. Type of feedback did not impact accuracy, and accuracy was not systematically related to confidence or perceived accuracy. Given the role that eyewitness reports play in the criminal justice system, better understanding factors that impact consistency and reliability is vital.

Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer.

MDM2 and MDM4 are heterodimeric, non-redundant oncoproteins that potently inhibit the p53 tumor suppressor protein. MDM2 and MDM4 also enhance the tumorigenicity of breast cancer cells in in vitro and in vivo models and are overexpressed in primary human breast cancers. Prior studies have characterized Estrogen Receptor Alpha (ERα/ESR1) as a regulator of MDM2 expression and an MDM2- and p53-interacting protein. However, similar crosstalk between ERα and MDM4 has not been investigated. Moreover, signaling pathways that mediate the overexpression of MDM4 in human breast cancer remain to be elucidated. Using the Cancer Genome Atlas (TCGA) breast invasive carcinoma patient cohort, we have analyzed correlations between ERα status and MDM4 and MDM2 expression in primary, treatment-naïve, invasive breast carcinoma samples. We report that the expression of MDM4 and MDM2 is elevated in primary human breast cancers of luminal A/B subtypes and associates with ERα-positive disease, independently of p53 mutation status. Furthermore, in cell culture models, ERα positively regulates MDM4 and MDM2 expression via p53-independent mechanisms, and these effects can be blocked by the clinically-relevant endocrine therapies fulvestrant and tamoxifen. Additionally, ERα also positively regulates p53 expression. Lastly, we report that endogenous MDM4 negatively regulates ERα expression and forms a protein complex with ERα in breast cancer cell lines and primary human breast tumor tissue. This suggests direct signaling crosstalk and negative feedback loops between ERα and MDM4 expression in breast cancer cells. Collectively, these novel findings implicate ERα as a central component of the p53-MDM2-MDM4 signaling axis in human breast cancer.

Siblings’ Understanding of Teaching in Early and Middle Childhood:‘Watch Me and You’ll Know How to Do It’

This study examined siblings’ knowledge about the teaching concept during naturalistic teaching contexts, wherein children’s communicative interactions were used as a gateway to their social understanding (Turnbull, Carpendale, & Racine, 2009). Participants included 39 sibling dyads (older age group, Mage = 6;4; younger age group, Mage = 4;5) observed for six 90-min sessions at home. Teaching episodes were identified and coded for: a) initiation of teaching (i.e., assumes role or learner requests teaching), b) knowledge states (i.e., knowledge, lack of knowledge, questioning knowledge), c) transfer of knowledge (i.e., learning), and d) teaching strategies (e.g., direct instruction). Children who assumed the teaching role referenced knowledge and questioning knowledge, whereas learners requested teaching by referencing a lack of knowledge. Firstborn learners were more likely to reference knowledge versus second-born learners who referenced a lack of knowledge. Transfer of knowledge occurred when teachers referenced knowledge. When learners referenced knowledge states, teachers were more likely to use direct instruction, demonstration, and negative feedback. Results underscore the developmental significance of sibling teaching and demonstrate a novel approach to studying children’s social understanding in the teaching context (Turnbull et al., 2009).

Evaluation and diagnostic potential of serum ghrelin in feline hypersomatotropism and diabetes mellitus.

BackgroundGhrelin is a growth hormone secretagogue. It is a potent regulator of energy homeostasis. Ghrelin concentration is down‐regulated in humans with hypersomatotropism (HS) and increases after successful treatment. Additionally, ghrelin secretion seems impaired in human diabetes mellitus (DM).HypothesisSerum ghrelin concentration is down‐regulated in cats with HS‐induced DM (HSDM) compared to healthy control cats or cats with DM unrelated to HS and increases after radiotherapy.AnimalsCats with DM (n = 20) and with HSDM (n = 32), 13 of which underwent radiotherapy (RT‐group); age‐matched controls (n = 20).MethodsRetrospective cross‐sectional study. Analytical performance of a serum total ghrelin ELISA was assessed and validated for use in cats. Differences in serum ghrelin, fructosamine, IGF‐1 and insulin were evaluated.ResultsGhrelin was significantly higher (P < .001) in control cats (mean ± SD: 12.9 ± 6.8 ng/mL) compared to HSDM‐ (7.9 ± 3.3 ng/mL) and DM‐cats (6.7 ± 2.3 ng/mL), although not different between the HSDM‐ and DM‐cats. After RT ghrelin increased significantly (P = .003) in HSDM‐cats undergoing RT (from 6.6 ± 1.9 ng/mL to 9.0 ± 2.2 ng/mL) and the after RT ghrelin concentrations of HSDM cats were no longer significantly different from the serum ghrelin concentration of control cats. Serum IGF‐1 did not significantly change in HSDM‐cats after RT, despite significant decreases in fructosamine and insulin dose.Conclusion and Clinical ImportanceGhrelin appears suppressed in cats with DM and HSDM, although increases after RT in HSDM, suggesting possible presence of a direct or indirect negative feedback system between growth hormone and ghrelin. Serum ghrelin might therefore represent a marker of treatment effect.

Ca(2+) current facilitation is CaMKII-dependent and has arrhythmogenic consequences.

The cardiac voltage gated Ca2+ current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca2+-dependent inactivation (CDI), Ca2+-dependent facilitation (CDF) and how calmodulin (CaM) and Ca2+-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca2+ current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca2+ channel, such that Ca2+ influx and Ca2+ released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in ICa via CDI provides direct negative feedback on the overall Ca2+ influx during a single beat, when myocyte Ca2+ loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca2+ channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca2+ channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.

Managing face threats and instructions in online tutoring.

Although tutoring is very effective, tutors often neglect certain strategies such as direct negative feedback. This might be because they want to avoid threatening their tutee's face. The concept of face derives from politeness theory and refers to the aspects of autonomy and social appreciation people claim for themselves and strive to negotiate cooperatively in discourse. We argue that tutors' politeness considerations can hinder effective tutoring. We compared 2 interventions in naturalistic tutoring interactions designed to influence tutors' communication acts: In a politeness condition, tutors were advised not to restrict autonomy when explaining concepts or correcting them in order to save their tutee's face. In a no-politeness condition, in contrast, they were encouraged to communicate clearly and explicitly. Results showed that tutors in the no-politeness condition used not only more direct strategies such as requests and hints, but, unexpectedly, also more politeness strategies to mitigate their directness. We conclude that there is a clear connection between politeness and instructional moves, but it remains unclear whether tutors avoid instructional face threats because they construe them as face-threatening. We suggest how further research could cast light on the conditions under which politeness is detrimental or beneficial for tutoring.

Nutritional Factors in Central Metabolic Regulation

Abstract The control of metabolism by direct negative feedback of macronutrients detected centrally has been until recently an attractive, though unconfirmed, hypothesis in the homeostatic model of energy regulation. Research advances in the last decade have greatly expanded our knowledge of how circulating carbohydrates, lipids, and proteins, reflecting amounts of recently ingested macronutrients, are detected in hypothalamic areas to not only regulate food intake, but also direct metabolic processes responsible for energy balance and anabolic pathways. For example, plasma glucose sensed centrally is a major regulator of hepatic glucose production, a process most likely mediated by ATP-sensitive potassium channels. More surprising, circulating lipids detected by hypothalamic structures also act as potent negative feedback regulators of glucose mobilization in the liver, independent of their peripheral detection in the intestines. Finally, central detection of circulating postprandial leucine levels has been shown to decrease abdominal fat mass mobilization and thermogenesis. These findings are consistent with the hypothesis that recognition of macronutrients directly by hypothalamic receptors plays a pivotal role in central regulation of metabolic processes. Moreover, the elucidated mechanisms suggest promising potential sites for pharmacological intervention in the treatment of obesity, already at epidemic proportions, although our modern environment is clearly the major cause.

Seagrass–Sediment Feedback: An Exploration Using a Non-recursive Structural Equation Model

The reciprocal effects between sediment texture and seagrass density are assumed to play an important role in the dynamics and stability of intertidal–coastal ecosystems. However, this feedback relationship has been difficult to study empirically on an ecosystem scale, so that knowledge is mainly based on theoretical models and small-scale (experimental) studies. In this paper we apply a non-recursive structural equation model (SEM) to empirically investigate, at large spatial scale, the mutual dependence between seagrass (Zostera noltii) density and sediment texture, on the pristine, seagrass-dominated, intertidal mudflats of the Banc d’Arguin, Mauritania. The non-recursive SEM allows consistent estimation and testing of a direct feedback between sediment and seagrass whilst statistically controlling for the effects of nutrients and abiotic stress. The resulting model is consistent with the hypothesized negative feedback: grain size decreases with seagrass density, whereas fine grain size has a negative impact on seagrass density because it decreases pore water exchange which leads to hypoxic sediment conditions. Another finding is that seagrass density increases with sediment organic material content up to a threshold level beyond which it levels off. In combination with decreasing grain size, accumulation of organic matter creates hypoxic sediment conditions which lead to the production of toxic hydrogen sulfide which slows down seagrass growth. The negative feedback loop implies that intertidal Z. noltii modifies its own environment, thus controlling its growing conditions. To the best of our knowledge, this study is the first to demonstrate a direct negative feedback relationship in ecosystems by means of a non-recursive SEM.

The Role of Negative Evidence in the Acquisition of Sociocultural Aspects of First Language

Children learn their native language in a relatively rapid time and are able to communicate from very early using language. But is the acquisition of their native culture and native language dependent on each other (LeVine & Norman, 2001; Riesman, 1993)? The present study aims to investigate the extent to which parents provide their children with direct and indirect negative feedback while they are acquiring sociocultural aspects of their language. A group of parents (N=75) from three social backgrounds were interviewed. The results showed that parents used direct negative feedback more than indirect negative evidence while correcting a culturally inappropriate utterance (calling parents by their first names). Also it was found that parents from middle class socioeconomic status used more direct negative evidence than parents from a working class background who showed no significant difference regarding the use of different types of negative feedback. These results show the importance of negative feedback in the acquisition of sociocultural and pragmatic aspects of the native language.

The role of the stomach in the control of appetite and the secretion of satiation peptides

It is widely accepted that gastric parameters such as gastric distention provide a direct negative feedback signal to inhibit eating; moreover, gastric and intestinal signals have been reported to synergize to promote satiation. However, there are few human data exploring the potential interaction effects of gastric and intestinal signals in the short-term control of appetite and the secretion of satiation peptides. We performed experiments in healthy subjects receiving either a rapid intragastric load or a continuous intraduodenal infusion of glucose or a mixed liquid meal. Intraduodenal infusions (3 kcal/min) were at rates comparable with the duodenal delivery of these nutrients under physiological conditions. Intraduodenal infusions of glucose elicited only weak effects on appetite and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). In contrast, identical amounts of glucose delivered intragastrically markedly suppressed appetite (P < 0.05) paralleled by greatly increased plasma levels of GLP-1 and PYY (≤3-fold, P < 0.05). Administration of the mixed liquid meal showed a comparable phenomenon. In contrast to GLP-1 and PYY, plasma ghrelin was suppressed to a similar degree with both intragastric and intraduodenal nutrients. Our data confirm that the stomach is an important element in the short-term control of appetite and suggest that gastric and intestinal signals interact to mediate early fullness and satiation potentially by increased GLP-1 and PYY secretions.

Delay-induced anomalous fluctuations in intracellular regulation

Direct negative feedback decreases fluctuations and is a ubiquitous mechanism for homoeostatic control. However, intracellular regulation frequently operates indirectly, resulting in delayed responses. Here we derive an analytical expression that quantifies the consequences from delayed negative feedback resulting from typical multistep synthesis pathways, for example, transcription or translation. We find that indirect feedback leads to more fluctuations than without feedback for intermediate delays, but surprisingly not for long delays. The anomalous fluctuations at intermediate delays emerge from positive correlations between the delayed regulatory events, and are shown to be equivalent to an increased stoichiometry in the synthesis of new molecules. The results primarily give us insight about the design principles of delayed stochastic control systems and why a fixed feedback delay gives more fluctuations than a broadly distributed feedback delay. It is also shown that the feedback delay of auto-repressed regulators can result in more sensitive regulation of downstream processes through stochastic focusing.