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Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems.

It is becoming increasingly clear that bistability (or, more generally, multistability) is an important recurring theme in cell signaling. Bistability may be of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex. Here, we show that for a class of feedback systems of arbitrary order the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this open-loop, feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable mitogen-activated protein kinase cascade.

CDC2 Protein Kinase↗

Interlocked feedback loops contribute to the robustness of the Neurospora circadian clock.

Interlocked feedback loops may represent a common feature among the regulatory systems controlling circadian rhythms. The Neurospora circadian feedback loops involve white collar-1 (wc-1), wc-2, and frequency (frq) genes. We show that WC-1 and WC-2 proteins activate the transcription of frq gene, whereas FRQ protein plays dual roles: repressing its own transcription, probably by interacting with the WC-1/WC-2 complex, and activating the expression of both WC proteins. Thus, they form two interlocked feedback loops: one negative and one positive. We establish the physiological significance of the interlocked positive feedback loops by showing that the levels of WC-1 and WC-2 determine the robustness and stability of the clock. Our data demonstrate that with WC-1 being the limiting factor in the WC-1/WC-2 complex, the greater the levels of WC-1 and WC-2, the higher the level of the FRQ oscillation and the more robust the overt rhythms. Our data also show that, despite considerable changes in the levels of WC-1, WC-2, and FRQ, the period of the clock has been limited to a small range, suggesting that the interlocked circadian feedback loops are also important for determining the circadian period length of the clock.

Circadian Rhythm↗

A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis.

Although the existence of a regulatory paracrine feedback system between oocytes and follicular somatic cells has been postulated for some time, there has not yet been any definitive evidence that such a communication system exists. Herein we present a previously undescribed oocyte-granulosa cell (GC) feedback communication system involving an oocyte-derived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both of which have been shown to be crucial regulators of female reproduction. We used a coculture system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative feedback loop. Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presence of oocytes. Because c-kit (KL receptor) is expressed in oocytes but not GCs, the oocytes must be involved in mediating the KL-induced GC mitosis. Furthermore, the blockage of c-kit signaling in oocytes by using a c-kit neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte must play a role in the GC responses to BMP-15. In contrast, the c-kit antibody had no effect on the mitotic activities of two other known GC mitogens, activin-A and BMP-7. Altogether, this study presents direct evidence of a negative feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte-GC communication system. We hypothesize that the negative feedback system most likely plays a pivotal role in early folliculogenesis.

Animals↗

Isoform-dependent differences in feedback regulation and subcellular localization of serine acetyltransferase involved in cysteine biosynthesis from Arabidopsis thaliana.

Serine acetyltransferase (SATase; EC 2.3.1.30), which catalyzes the formation of O-acetyl-L-serine (OAS) from acetyl-CoA and L-serine, plays a regulatory role in the biosynthesis of cysteine by its property of feedback inhibition by cysteine in bacteria and certain plants. Three cDNA clones encoding SATase isoforms (SAT-c, SAT-p, and SAT-m) have been isolated from Arabidopsis thaliana. However, the significance of the feedback regulation has not yet been clear in these different isoforms of SATase from A. thaliana. We constructed the overexpression vectors for cDNAs encoding three SATase isoforms of A. thaliana and analyzed the inhibition of SATase activity by cysteine using the recombinant SATase proteins. In the case of SAT-c, the activity was feedback-inhibited by a low concentration of cysteine (the concentration that inhibits 50% activity; IC50 = 1.8 microM). By contrast, SAT-p and SAT-m were feedback inhibition-insensitive isozymes. We also determined the subcellular localization of three SATase isozymes by the transient expression of fusion proteins of each SATase N-terminal region with jellyfish green fluorescent protein (GFP) in 4-week-old Arabidopsis leaves. The SAT-c-GFP fusion protein was stayed in cytosol, whereas SAT-p-GFP and SAT-m-GFP fusion proteins were localized in chloroplasts and in mitochondria, respectively. These results suggest that these three SATase isoforms, which are localized in the different organelles, are subjected to different feedback regulation, presumably so as to play the particular roles for the production of OAS and cysteine in Arabidopsis cells. Regulatory circuit of cysteine biosynthesis in the plant cells is discussed.

Acetyltransferases↗

Feedback inhibition of amidophosphoribosyltransferase regulates the rate of cell growth via purine nucleotide, DNA, and protein syntheses.

To clarify the contributions of amidophosphoribosyltransferase (ATase) and its feedback regulation to the rates of purine de novo synthesis, DNA synthesis, protein synthesis, and cell growth, mutated human ATase (mhATase) resistant to feedback inhibition by purine ribonucleotides was engineered by site-directed mutagenesis and expressed in CHO ade (-)A cells (an ATase-deficient cell line of Chinese hamster ovary fibroblasts) and in transgenic mice (mhATase-Tg mice). In Chinese hamster ovary transfectants with mhATase, the following parameters were examined: ATase activity and its subunit structure, the metabolic rates of de novo and salvage pathways, DNA and protein synthesis rates, and the rate of cell growth. In mhATase-Tg mice, ATase activity in the liver and spleen, the metabolic rate of the de novo pathway in the liver, serum uric acid concentration, urinary excretion of purine derivatives, and T lymphocyte proliferation by phytohemagglutinin were examined. We concluded the following. 1) ATase and its feedback inhibition regulate not only the rate of purine de novo synthesis but also DNA and protein synthesis rates and the rate of cell growth in cultured fibroblasts. 2) Suppression of the de novo pathway by the salvage pathway is mainly due to the feedback inhibition of ATase by purine ribonucleotides produced via the salvage pathway, whereas the suppression of the salvage pathway by the de novo pathway is due to consumption of 5-phosphoribosyl 1-pyrophosphate by the de novo pathway. 3) The feedback inhibition of ATase is more important for the regulation of the de novo pathway than that of 5-phosphoribosyl 1-pyrophosphate synthetase. 4) ATase superactivity leads to hyperuricemia and an increased bromodeoxyuridine incorporation in T lymphocytes stimulated by phytohemagglutinin.

Adenosine Monophosphate↗

Realizing the potential of empowerment: the impact of a feedback intervention on the performance of complex technology.

An empowerment initiative involving enhanced fault-management responsibility for operators of complex technology had not led to expected increases in performance, and investigations suggested that this was due to a lack of appropriate feedback. Thus, a feedback intervention was designed to provide specific, timely feedback on operator-correctable faults. It was hypothesized that the intervention would increase operator self-reliance in operating complex technology and promote system performance. Moreover, given the feedback was continuous from the point of intervention, it was predicted that gains would increase over time. Time series analysis of data on engineer call-outs (self-reliance) and machine utilization (performance) showed clear positive effects of the feedback intervention, with call-outs also showing progressive improvement. Self-report data showed no change over time in motivation, but an increase in knowledge dissemination and a reduction in the likelihood of making expensive mistakes. There were no detrimental effects on operator well being. Implications for theory and practice in the management of complex technology are discussed.

Data Collection↗

A comparison of tactile, auditory, and visual feedback in a pointing task using a mouse-type device.

A mouse was modified to add tactile feedback via a solenoid-driven pin projecting through a hole in the left mouse button. An experiment is described using a target selection task under five different sensory feedback conditions ('normal', auditory, colour, tactile, and combined). No differences were found in overall response times, error rates, or bandwidths; however, significant differences were found in the final positioning times (from the cursor entering the target to selecting the target). For the latter, tactile feedback was the quickest, normal feedback was the slowest. An examination of the spatial distributions in responses showed a peaked, narrow distribution for the normal condition, and a flat, wide distribution for the tactile (and combined) conditions. It is argued that tactile feedback allows subjects to use a wider area of the target and to select targets more quickly once the cursor is inside the target. Design considerations for human-computer interfaces are discussed.

Attention↗

The effect of mood and pleasant versus unpleasant information feedback on performing a motor skill.

The effect of negative, positive, or neutral feedback on a rotary pursuit task as a function of the subject's depressed or elated mood was ascertained. Specifically, the self-schema hypothesis was examined. Ninety female volunteers, ranging in age from 18 to 25 years, participated. They were randomly assigned to one of eight conditions based on depressed or elated mood states, elicited by Velten's (1968) mood induction procedure, and feedback. A control group received no feedback and was not subjected to a mood inducing treatment. Baseline measures and changes in mood were determined by the Multiple Adjective Affective Checklist (MAACL). Bogus feedback was offered after all but one of the trials. The subjects' mood changed significantly during the mood-inducing treatment. For motor performance, partial support was lent to self-schema. Elated and depressed subjects performed best under positive and negative feedback, respectively. The effects, however, were temporary.

Adolescent↗

Supporting the implementation of breast pathology recommendations: feasibility of a feedback mechanism to pathologists.

AIMS: The aims of the study were to explore the feasibility, acceptability, impact and cost of a feedback program to pathologists reporting on breast specimens through a BreastScreen Service. METHODS: The study was conducted at a single BreastScreen NSW Screening and Assessment Service. Pathology reports were audited against the ACN recommendations about pathology reporting [Australian Cancer Network Pathology Working Party. The Pathology Reporting of Breast Cancer: a guide for pathologists, surgeons and radiologists. Sydney: Australian Cancer Network, 1997] during two consecutive periods. Feedback was provided to pathologists at the completion of each audit. A comparison of completeness of pathology reports between audits was undertaken. The Screening and Assessment Service staff and participating pathologists were interviewed to assess acceptability and information about resource allocation. RESULTS: The study demonstrated that the feedback mechanism was acceptable to pathologists and staff at the BreastScreen Screening and Assessment Service, and that participation in the study resulted in some improvements in pathology reporting. CONCLUSIONS: The study demonstrated the feasibility of providing feedback to pathologists about their reporting of breast specimens. However, there were costs to the Service of participating. A way of managing these costs would need to be explored if the feedback mechanism was made a routine BreastScreen procedure.

Breast Diseases↗

External quality assessment of general practice laboratories: organizational issues and interpretation of feedback reports.

OBJECTIVE: To describe and evaluate organizational issues and handling of feedback reports in the Norwegian external quality assessment scheme (EQAS) for general practice laboratories. METHODS: Postal questionnaire survey including three EQAS feedback reports (one with acceptable analytical quality, one indicating a problem with precision and one indicating bias of the measurement method) to 535 randomly selected general practices. RESULTS: The response rate was 80%. Two-thirds of practices were group practices, and 16% of practices employed a medical technologist. Nearly all practices found the manual for analysing quality control material easy to understand, and samples seemed to be handled as part of routine laboratory work. Feedback reports were primarily studied by those responsible for laboratory work in the practice, and only in 60% of practices by doctors. Practice routines for follow-up of deviant results in the EQAS seemed to have been established. Internal quality control was performed in 90% of group practices and in 71% of solo practices. Concerning responses to feedback reports, there seemed to be a substantial need for assistance even for less deviant results, although most actions suggested by the practices were adequate. On the other hand, assistance was not always sought for "critical" problems. CONCLUSIONS: EQAS is feasible in primary care, but instructions must be clear and conclusions in the feedback reports made very explicit. Easy-to-reach assistance from medical technologists with expertise in general practice laboratory instruments and routines seems paramount.

Family Practice↗

Auditory concurrent feedback benefits on the circle performed in gymnastics.

In this study, we examined the effectiveness of auditory concurrent feedback on body segmental alignment during the circle movement performed on a pommel horse. Eighteen gymnasts were assigned to one of two groups: a concurrent auditory feedback group (experimental) or a control group that received no concurrent feedback. After 2 weeks of training (300 circles), the body segmental alignment (BSA) of the experimental group had improved by 2.3% between the pre test (85.7 +/- 4.8% BSA(max)) and the post test (87.7 +/- 4.0% BSA(max)). Furthermore, the results of a retention test administered 2 weeks after the post test revealed no decline in performance for the experimental group. No gains in body segmental alignment were found for the control group. It was concluded that augmented auditory feedback made available in real time can be used to correct complex movements, such as the circle movement on a pommel horse, and does not appear to lead to information-dependence despite the frequent administration of feedback. The auditory signal available in real time could help gymnasts to become more objective about their own intrinsic information necessary for the refinement of the circle movement.

Adolescent↗

Effects of a verbal and visual feedback system on running technique, perceived exertion and running economy in female novice runners.

The purpose of this study was to determine the effects of a verbal and visual feedback system on running technique, ratings of perceived exertion (RPE), and running economy. Twenty-two female novice runners were randomly assigned to experimental (n = 11) and control (n = 11) groups. The experimental subjects received verbal and visual feedback concerning their running technique prior to and during each training run. Training involved 15 20-min treadmill running sessions over a 5-week period. The control group adhered to the same training routine but did not receive feedback concerning their running technique. High-speed (100 Hz) photography was used to collect biomechanical data. A submaximal oxygen consumption test and Borg's RPE scale were used to collect data concerning running economy and perceived exertion, respectively. Statistical analysis using ANCOVA revealed that the proposed feedback system had a significant (P less than 0.01) effect on the experimental group's running technique by affecting the following desired changes relative to the control group: greater relative stride lengths, shorter support time, greater ankle dorsiflexion during support and greater knee flexion during support and non-support. There were no significant differences between the groups in submaximal VO2 or RPE. The results of this study suggest that verbal and visual feedback are effective means of eliciting modifications in running style in female novice runners. The link between modifications in running style and improvements in running economy and perceived exertion remains unclear.

Adolescent↗

Effects of a learning model and augmented feedback on tennis skill acquisition.

This experiment investigated the effects of observing a learning model and receiving augmented verbal feedback on the acquisition and retention of the tennis volley. Female undergraduate students were randomly assigned to four groups: (a) AFB--received augmented verbal feedback from an instructor, (b) LMFB--monitored a learning model's trials and feedback, (c) LMFB+AFB--monitored a learning model's trials and feedback and received verbal feedback from an instructor, and (d) Control--received neither treatment. Subjects were pretested, given 50 acquisition trials, and then a retention test. Outcome and movement pattern dependent variables were employed. Repeated measures analyses indicated that all three experimental groups were significantly better than the Control group on movement pattern and outcome, with the greatest success experienced by the LMFB+AFB group. Findings are discussed relative to previous research findings and implications for practitioners.

Adult↗

Feedforward and feedback consistency effects for high- and low-frequency words in lexical decision and naming.

In three experiments, we examined feedforward and feedback consistency effects in word recognition. Feedforward consistency is the degree to which a word's pronunciation is consistent with that of similarly spelled words, and feedback consistency refers to whether there is more than one way to spell a pronunciation. Previously, Stone, Vanhoy, and Van Orden (1997) reported feedforward and feedback consistency effects for low-frequency words in a lexical decision task. We investigated the effect of feedforward and feedback consistency for both high- and low-frequency words in lexical decision and naming. In both tasks, we found that feedforward and feedback inconsistent words were processed more slowly than consistent words, regardless of word frequency. These findings indicate that both types of consistency are involved in visual word recognition.

Comprehension↗

Information feedback, reaction time and error rates in young and old subjects.

Reaction times and error rates in a letter classification task were examined in two groups of subjects, one with a mean age of 20.7 years, the other with a mean age of 63.6 years, under conditions where specific feedback regarding the speed and accuracy of performance on each trial either was or was not provided. Feedback produced a speed-accuracy trade-off for younger subjects. This finding offers no support for the position that feedback results in a general improvement in performance. Older subjects did not show a speed-accuracy trade-off. Rather, feedback resulted in trends toward both longer reaction times and higher error rates. These results are interpreted as showing that feedback has a phasic alerting effect in the younger subjects, but not in the older subjects.

Achievement↗

On being a supervisor: the importance of feedback and how to give it.

OBJECTIVE: We outline some of the dominant opinions regarding the provision of formative feedback, as expressed by both trainees and their supervisors. METHODS: Trainee psychiatrists and their supervisors were interviewed and asked to identify 'good' as opposed to 'poor' supervision. RESULTS: A recurrent theme in interview data was that of formative feedback. Trainees expressed a desire to receive it, but some supervisors discussed misgivings and a lack of skill in providing such feedback. CONCLUSIONS: Formative feedback is an essential part of the supervisor's role. We describe the principles of how to best deliver feedback, in order to increase supervisors' confidence and ability in utilizing this learning and teaching skill.

Clinical Competence↗

IkappaBepsilon provides negative feedback to control NF-kappaB oscillations, signaling dynamics, and inflammatory gene expression.

NF-kappaB signaling is known to be critically regulated by the NF-kappaB-inducible inhibitor protein IkappaBalpha. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-kappaB activity. We report integrated experimental and computational studies that demonstrate that another IkappaB isoform, IkappaBepsilon, also provides negative feedback on NF-kappaB activity, but with distinct functional consequences. Upon stimulation, NF-kappaB-induced transcription of IkappaBepsilon is delayed, relative to that of IkappaBalpha, rendering the two negative feedback loops to be in antiphase. As a result, IkappaBepsilon has a role in dampening IkappaBalpha-mediated oscillations during long-lasting NF-kappaB activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-kappaB activity and NF-kappaB-mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of IkappaB-NF-kappaB signaling and reveal a novel regulatory module of two antiphase negative feedback loops that allows for the fine-tuning of the dynamics of a mammalian signaling pathway.

Animals↗

Intrinsic cone adaptation modulates feedback efficiency from horizontal cells to cones.

Processing of visual stimuli by the retina changes strongly during light/dark adaptation. These changes are due to both local photoreceptor-based processes and to changes in the retinal network. The feedback pathway from horizontal cells to cones is known to be one of the pathways that is modulated strongly during adaptation. Although this phenomenon is well described, the mechanism for this change is poorly characterized. The aim of this paper is to describe the mechanism for the increase in efficiency of the feedback synapse from horizontal cells to cones. We show that a train of flashes can increase the feedback response from the horizontal cells, as measured in the cones, up to threefold. This process has a time constant of approximately 3 s and can be attributed to processes intrinsic to the cones. It does not require dopamine, is not the result of changes in the kinetics of the cone light response and is not due to changes in horizontal cells themselves. During a flash train, cones adapt to the mean light intensity, resulting in a slight (4 mV) depolarization of the cones. The time constant of this depolarization is approximately 3 s. We will show that at this depolarized membrane potential, a light-induced change of the cone membrane potential induces a larger change in the calcium current than in the unadapted condition. Furthermore, we will show that negative feedback from horizontal cells to cones can modulate the calcium current more efficiently at this depolarized cone membrane potential. The change in horizontal cell response properties during the train of flashes can be fully attributed to these changes in the synaptic efficiency. Since feedback has major consequences for the dynamic, spatial, and spectral processing, the described mechanism might be very important to optimize the retina for ambient light conditions.

Adaptation, Ocular↗