Feedback Loop Mechanism Research Articles

Interplay between cellular redox oscillations and circadian clocks.

The circadian clock is a cellular timekeeping mechanism that helps organisms from bacteria to humans to organize their behaviour and physiology around the solar cycle. Current models for circadian timekeeping incorporate transcriptional/translational feedback loop mechanisms in the predominant model systems. However, recent evidence suggests that non-transcriptional oscillations such as metabolic and redox cycles may play a fundamental role in circadian timekeeping. Peroxiredoxins, an antioxidant protein family, undergo rhythmic oxidation on the circadian time scale in a variety of species, including bacteria, insects and mammals, but also in red blood cells, a naturally occurring, non-transcriptional system. The profound interconnectivity between circadian and redox pathways strongly suggests that a conserved timekeeping mechanism based on redox cycles could be integral to generating circadian rhythms.

Stock Market Bubbles and Unemployment

This paper introduces endogenous credit constraints in a search model of unemployment. These constraints generate multiple equilibria supported by self-fulfilling beliefs. A stock market bubble exists through a positive feedback loop mechanism. The collapse of the bubble tightens the credit constraints, causing firms to reduce investment and hirings. Unemployed workers are hard to find jobs generating high and persistent unemployment.

Maximum velocity of self-propulsion for an active segment

The motor part of a crawling eukaryotic cell can be represented schematically as an active continuum layer. The main active processes in this layer are protrusion, originating from non-equilibrium polymerization of actin fibers, contraction, induced by myosin molecular motors, and attachment due to active bonding of trans-membrane proteins to a substrate. All three active mechanisms are regulated by complex signaling pathways involving chemical and mechanical feedback loops whose microscopic functioning is still poorly understood. In this situation, it is instructive to consider the problem of finding the spatial organization of standard active elements inside a crawling layer ensuring an optimal cost-performance trade-off. If we assume that (in the range of interest) the energetic cost of self-propulsion is velocity independent, we obtain, as an optimality criterion, the maximization of the overall velocity. We choose a prototypical setting, formulate the corresponding variational problem and obtain a set of bounds suggesting that radically different spatial distributions of adhesive complexes would be optimal depending on the domineering active mechanism of self-propulsion. Thus, for contraction-dominated motility, adhesion has to cooperate with ‘pullers’ which localize at the trailing edge of the cell, while for protrusion-dominated motility it must conspire with ‘pushers’ concentrating at the leading edge of the cell. Both types of crawling mechanisms have been observed experimentally.

Glucose-Based Regulation of miR-451/AMPK Signaling Depends on the OCT1 Transcription Factor

In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose-regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment.

Banking bubbles and financial crises

This paper develops a tractable macroeconomic model with a banking sector in which banks face endogenous borrowing constraints. There is no uncertainty about economic fundamentals. Banking bubbles can emerge through a positive feedback loop mechanism. Changes in household confidence can cause the bubbles to burst, resulting in a financial crisis. Credit policy can mitigate economic downturns. The welfare gain is larger when the government interventions are more front loaded, given that the government injects the same amount of liquidity in terms of present value. Bank capital requirements can prevent the formation of banking bubbles by limiting leverage, but if too restrictive will lead to less lending and hence lower production.

Exploring analytical proteomics platforms toward the definition of human cardiac stem cells receptome.

Human cardiac stem cells (hCSC) express a portfolio of plasma membrane receptors that are involved in the regulatory auto/paracrine feedback loop mechanism of activation of these cells, and consequently contribute to myocardial regeneration. In order to attain a comprehensive description of hCSC receptome and overcoming the inability demonstrated by other technologies applied in receptor identification, mainly due to the transmembrane nature, high hydrophobic character and relative low concentration of these proteins, we have exploited and improved a proteomics workflow. This approach was based on the enrichment of hCSC plasma membrane fraction and addition of prefractionation steps prior to MS analysis. More than 100 plasma membrane receptors were identified. The data reported herein constitute a valuable source of information to further understand cardiac stem cells activation mechanisms and the subsequent cardiac repair process. All MS data have been deposited in the ProteomeXchange with identifier PXD001117 (http://proteomecentral.proteomexchange.org/dataset/PXD001117).

Experimental Investigation of Influences of Roughness Receptivity on Protuberance Noise

When a two-dimensional protuberance is set in a laminar boundary layer, tonal sound is radiated through a feedback-loop mechanism between sound radiation from the protuberance and generation of Tollmien–Schlichting (T–S) waves in the receptivity region. In this paper, influences of a small-height roughness glued upstream of the protuberance on the feedback mechanism were examined experimentally in a zero-pressure-gradient laminar boundary layer at low Mach numbers. The results showed that depending on the location and height of roughness, competition between leading-edge-generated and roughness-generated T–S waves occurred and consequently governed sound radiation. Even when the roughness height was on the order of one-tenth the displacement thickness, tonal sound due to the feedback-loop between the roughness and protuberance could be more dominant than that between the leading edge and protuberance. It was also shown that the roughness receptivity reduced the critical protuberance height for the occurre...

Sprouty2 mediated tuning of signalling is essential for somite myogenesis.

BackgroundNegative regulators of signal transduction cascades play critical roles in controlling different aspects of normal embryonic development. Sprouty2 (Spry2) negatively regulates receptor tyrosine kinases (RTK) and FGF signalling and is important in differentiation, cell migration and proliferation. In vertebrate embryos, Spry2 is expressed in paraxial mesoderm and in forming somites. Expression is maintained in the myotome until late stages of somite differentiation. However, its role and mode of action during somite myogenesis is still unclear.ResultsHere, we analysed chick Spry2 expression and showed that it overlaps with that of myogenic regulatory factors MyoD and Mgn. Targeted mis-expression of Spry2 led to inhibition of myogenesis, whilst its C-terminal domain led to an increased number of myogenic cells by stimulating cell proliferation.ConclusionsSpry2 is expressed in somite myotomes and its expression overlaps with myogenic regulatory factors. Overexpression and dominant-negative interference showed that Spry2 plays a crucial role in regulating chick myogenesis by fine tuning of FGF signaling through a negative feedback loop. We also propose that mir-23, mir-27 and mir-128 could be part of the negative feedback loop mechanism. Our analysis is the first to shed some light on in vivo Spry2 function during chick somite myogenesis.

The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NFκB. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD.

TRPM8 is an Ionotropic Testosterone Receptor

Testosterone is a key steroid hormone in the development of male reproductive tissues and in the regulation of the central nervous system. Rapid signaling mechanism induced by testosterone affects numerous behavioral traits, including sexual behavior, aggressiveness, or fear conditioning. However, currently identified testosterone receptor(s) are not believed to underlie the fast signaling. Here we report that an ion channel from the transient receptor potential family, TRPM8, commonly known as the cold and menthol receptor is the major component of testosterone-induced rapid actions.TRPM8 is highly expressed in the prostate epithelial cells. Using an immunohistochemistry approach, we detected a colocalization pattern of TRPM8 with endogenous androgens on human prostate tissues obtained from healthy individuals and patients with prostate cancer. Co-immunoprecipitation experiments performed on cultured prostate epithelial cells, prostate cancer cells, and HEK-293 cells stably expressing TRPM8, further confirmed direct binding of testosterone to TRPM8.Using cultured and primary cell lines and the purified TRPM8 protein we demonstrate that testosterone can directly activate TRPM8 channel at low picomolar range. Specifically, testosterone induced TRPM8 responses in primary human prostate cells, prostate cancer cells PC3, dorsal root ganglion (DRG) neurons, and hippocampus neurons. Picomolar concentrations of testosterone resulted in full openings of the purified TRPM8 channel in planar lipid bilayers. Furthermore, acute applications of testosterone on human skin elicited cooling sensation, implying testosterone-induced activation of TRPM8. Additionally, animal studies showed altered sniffing behavior and increased blood concentration of testosterone in the TRPM8 knockout mice, suggesting the existence of a feedback loop mechanism in the absence of the receptor. Our data demonstrate that testosterone is an endogenous and highly potent agonist of TRPM8, suggesting a role of TRPM8 channels well beyond their well-established function in somatosensory neurons. This discovery may further imply TRPM8 channel function in testosterone-dependent behavioral traits.

Effects of the global regulator CsrA on the BarA/UvrY two-component signaling system.

The hybrid sensor kinase BarA and its cognate response regulator UvrY, members of the two-component signal transduction family, activate transcription of CsrB and CsrC noncoding RNAs. These two small RNAs act by sequestering the RNA binding protein CsrA, which posttranscriptionally regulates translation and/or stability of its target mRNAs. Here, we provide evidence that CsrA positively affects, although indirectly, uvrY expression, at both the transcriptional and translational levels. We also demonstrate that CsrA is required for properly switching BarA from its phosphatase to its kinase activity. Thus, the existence of a feedback loop mechanism that involves the Csr and BarA/UvrY global regulatory systems is exposed.

A Proposed GA Based PID Controller for Three Phase Brushless DC Motor

Brushless DC motors are widely used for many industrial applications because of their high efficiency, high torque, higher speed ranges, noiseless operation and low volume. More advanced controllers are used to manage acceleration, control speed and fine-tune efficiency of BLDC motor. A proportional–integral–derivative controller is a generic control loop feedback mechanism widely used in industrial control systems because of its simple structure and easy implementation. The conventionally tuned PID controller is not providing optimum performance under nonlinear conditions and parameter variations. The aim of this research is to develop a complete model of the BLDC motor and to design an optimal controller for its control. The Genetic Algorithm is proposed as a global optimizer to find the optimized PID gains for control of BLDC motor.

Breast cancer anti-estrogen resistance 3 inhibits transforming growth factor β/Smad signaling and associates with favorable breast cancer disease outcomes.

IntroductionThis study helps to define the implications of breast cancer anti-estrogen resistance 3 (BCAR3) in breast cancer and extends the current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received tamoxifen treatment, high BCAR3 mRNA levels were associated with favorable progression-free survival outcome. These results suggest that, besides its established roles, BCAR3 may have additional mechanisms of action that regulate breast cancer aggressive phenotype. In this study, we investigated whether BCAR3 is a novel antagonist of the canonical transforming growth factor β (TGFβ) pathway, which induces potent migration and invasion responses in breast cancer cells.MethodsWe surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGFβ/Smad signaling axis using Western blot analysis, coimmunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGFβ-induced cell migration and invasion by using an automated imaging system and a confocal microscopy imaging–based matrix degradation assay, respectively.ResultsRelatively low levels of BCAR3 expression in primary breast tumors correlate with poor distant metastasis-free survival and relapse-free survival outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be downregulated by TGFβ through proteasome degradation, thus defining a novel positive feedback loop mechanism downstream of the TGFβ/Smad signaling pathway.ConclusionBCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the prometastatic TGFβ/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3’s molecular mechanism of action and highlight BCAR3 as a novel TGFβ/Smad antagonist in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0476-9) contains supplementary material, which is available to authorized users.

The nature and impact of the market forecasting errors in the Federal funds futures market

In this paper we examine the impact of the forecasting errors arising from a monetary policy shock arising in the Federal funds rate market. Our empirical results indicate that forecasting errors in the Federal funds futures market do have implications for the asset market's natural price discovery process, since expectations in this market affect long term interest rates and inflation. We also find that the price discovery process may be exacerbated if the policy transmission mechanism is more pronounced under a transparency objective because of the negative feedback loop mechanism. The results further show that the aggregate demand and inflation expectations channels appear to be much more pronounced under the Bernanke regime than Greenspan leading to a much stronger policy transmission. In fact a policy tightening through both channels would have a visibly stronger deflationary and employment impact under Bernanke relative to Greenspan.

Application of various PID Controller Tuning Techniques for a Temperature System

Control of temperature level in the process tank is vital in process industries. A proportional-integral-derivative controller (PID controller) is a control loop feedback mechanism (controller) widely used in industrial control systems.PID control is a control strategy that has been successfully used over many years. This algorithm involves three separate constant parameters. And it is otherwise called as three term controller. Where, P depends on the present error, I on the accumulation of past errors, and D is a prediction of future errors, based on current rate of change. It is highly used in chemical industries because of their success rate in practical applications, robustness and simplicity The PID temperature control algorithm is used for the control of almost all loops in the process industries, and is also the basis for many advanced control algorithms and strategies. A PID temperature controller works by measuring the current temperature to generate the error signal and altering the output to bring it closer to the target. The main alternative for temperature PID controller is ON/OFF controller which works like a thermostat. To determine the appropriate controller parameters settings, a conventional PID control tuning techniques and model based PID were characterized and their results to be obtained are simulated. With the yield of time domain and error criterion analysis, the most suitable controller for temperature controlled process is obtained. The best among the tuned controlled technique is pointed out as a good result of minimum rise time, setting time and overshoot. General Terms Process Control, Control System.

Stochasticity in plant cellular growth and patterning

Plants, along with other multicellular organisms, have evolved specialized regulatory mechanisms to achieve proper tissue growth and morphogenesis. During development, growing tissues generate specialized cell types and complex patterns necessary for establishing the function of the organ. Tissue growth is a tightly regulated process that yields highly reproducible outcomes. Nevertheless, the underlying cellular and molecular behaviors are often stochastic. Thus, how does stochasticity, together with strict genetic regulation, give rise to reproducible tissue development? This review draws examples from plants as well as other systems to explore stochasticity in plant cell division, growth, and patterning. We conclude that stochasticity is often needed to create small differences between identical cells, which are amplified and stabilized by genetic and mechanical feedback loops to begin cell differentiation. These first few differentiating cells initiate traditional patterning mechanisms to ensure regular development.

Experimental investigation of sound generation by a protuberance in a laminar boundary layer

Sound radiation from a two-dimensional protuberance glued on the wall in a laminar boundary layer was investigated experimentally at low Mach numbers. When the protuberance was as high as the boundary-layer thickness, a feedback-loop mechanism set in between protuberance-generated sound and Tollmien-Schlichting (T-S) waves generated by the leading-edge receptivity to the upstream-propagating sound. Although occurrence of a separation bubble immediately upstream of the protuberance played important roles in the evolution of instability waves into vortices interacting with the protuberance, the frequency of tonal vortex sound was determined by the selective amplification of T-S waves in the linear instability stage upstream of the separation bubble and was not affected by the instability of the separation bubble.

Expression and functional characterization of NOD2 in decidual stromal cells isolated during the first trimester of pregnancy.

NOD2, one of the cytosolic proteins that contain a nuclear oligomerization domain (NOD), is a pattern recognition receptor (PRR) involved in innate immune responses to intracellular pathogens. Little is known, however, about the effect of NOD2 expression on the maternal–fetal relationship. Our aim was to elucidate the functions of NOD2 in normal decidual stromal cells (DSCs) from the first trimester. Tissues and DSCs were isolated from 26 patients with normal pregnancies that required abortion. The expression of NOD2 in deciduas/decidual stromal cells (DSCs) was examined by real-time PCR, immunohistochemistry, and In-cell western. DSCs containing NOD2 were stimulated by its ligand, muramyl dipeptide (MDP). The secretion of various cytokines and chemokines were measured by ELISA and the apoptotic rate was determined by flow cytometry. Treatment with MDP significantly elevated the expression of both NOD2 mRNA and protein levels in DSCs. In addition, MDP activation of NOD2 significantly increased IL-1β and MCP-1 cytokine expression in a dose dependent manner but had no effect on IL-12 expression. IL-1β and TNF-α also significantly increased the expression of NOD2 in DSCs, suggesting a positive feedback loop mechanism. Moreover, MDP stimulation augmented DSC apoptosis. In summary, the results suggest that NOD2 expression in DSCs plays an important role in protecting the embryo and preventing infection in the maternal-fetal interface.

The Cochlear Amplifier: Is it Hair Bundle Motion of Outer Hair Cells?

Cochlear outer hair cells (OHCs) are involved in a mechanical feedback loop in which the fast somatic motility of OHCs is required for cochlear amplification. Alternatively, amplification is thought to arise from active hair bundle movements observed in non-mammalian hair cells. We measured the voltage-evoked hair bundle motions in the gerbil cochlea to determine if such movements are also present in mammalian OHCs. The OHCs displayed a large hair bundle movement that was not based on mechanotransducer channels but based on somatic motility. Significantly, bundle movements were able to generate radial motion of the tectorial membrane in situ. This result implies that the motility-associated hair bundle motion may be part of the cochlear amplifier.

Light and circadian regulation of clock components aids flexible responses to environmental signals.

The circadian clock measures time across a 24 h period, increasing fitness by phasing biological processes to the most appropriate time of day. The interlocking feedback loop mechanism of the clock is conserved across species; however, the number of loops varies. Mathematical and computational analyses have suggested that loop complexity affects the overall flexibility of the oscillator, including its responses to entrainment signals.We used a discriminating experimental assay, at the transition between different photoperiods, in order to test this proposal in a minimal circadian network (in Ostreococcus tauri) and a more complex network (in Arabidopsis thaliana).Transcriptional and translational reporters in O. tauri primarily tracked dawn or dusk, whereas in A. thaliana, a wider range of responses were observed, consistent with its more flexible clock. Model analysis supported the requirement for this diversity of responses among the components of the more complex network. However, these and earlier data showed that the O. tauri network retains surprising flexibility, despite its simple circuit.We found that models constructed from experimental data can show flexibility either from multiple loops and/or from multiple light inputs. Our results suggest that O. tauri has adopted the latter strategy, possibly as a consequence of genomic reduction.