The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance.
Ontology highlight
ABSTRACT:
SUBMITTER: Arias CF
PROVIDER: S-EPMC4632576 | biostudies-other | 2015 Jul
REPOSITORIES: biostudies-other
Publications
The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance.
Arias Clemente F CF Herrero Miguel A MA Cuesta José A JA Acosta Francisco J FJ Fernández-Arias Cristina C
Royal Society open science 20150708 7
Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract ...[more]
Similar Datasets
Project description:Sleep is one of the most noticeable and widespread phenomena occurring in multicellular animals. Nevertheless, no consensus for a theory of its origins has emerged. In particular, no explicit, quantitative theory exists that elucidates or distinguishes between the myriad hypotheses proposed for sleep. Here, we develop a general, quantitative theory for mammalian sleep that relates many of its fundamental parameters to metabolic rate and body size. Several mechanisms suggested for the function of sleep can be placed in this framework, e.g., cellular repair of damage caused by metabolic processes as well as cortical reorganization to process sensory input. Our theory leads to predictions for sleep time, sleep cycle time, and rapid eye movement time as functions of body and brain mass, and it explains, for example, why mice sleep approximately 14 hours per day relative to the 3.5 hours per day that elephants sleep. Data for 96 species of mammals, spanning six orders of magnitude in body size, are consistent with these predictions and provide strong evidence that time scales for sleep are set by the brain's, not the whole-body, metabolic rate.
| S-EPMC1783362 | biostudies-literature
Project description:BackgroundCD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Therefore, conceptual understanding of induced heterogeneous differentiation will shed light on the mechanisms controlling the response of populations of CD4+ T cells under physiological conditions.ResultsWe present a simple theoretical framework to show how heterogeneous differentiation in a two-master-regulator paradigm can be governed by a signaling network motif common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. We provide three prototype models illustrating how to use this framework to explain experimental observations and make specific testable predictions.ConclusionsThe process in which several types of T helper cells are generated simultaneously to mount complex immune responses upon pathogenic challenges can be highly regulated, and a simple signaling network motif can be responsible for generating all possible types of heterogeneous populations with respect to a pair of master regulators controlling CD4+ T cell differentiation. The framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cells, and it can be helpful for interpreting experimental results. Mathematical models based on the framework make specific testable predictions that may improve our understanding of this differentiation system.
| S-EPMC3436737 | biostudies-literature
Project description:One of the last uncharted territories in evolutionary biology concerns the link with cell biology. Because all phenotypes ultimately derive from events at the cellular level, this connection is essential to building a mechanism-based theory of evolution. Given the impressive developments in cell biological methodologies at the structural and functional levels, the potential for rapid progress is great. The primary challenge for theory development is the establishment of a quantitative framework that transcends species boundaries. Two approaches to the problem are presented here: establishing the long-term steady-state distribution of mean phenotypes under specific regimes of mutation, selection, and drift and evaluating the energetic costs of cellular structures and functions. Although not meant to be the final word, these theoretical platforms harbor potential for generating insight into a diversity of unsolved problems, ranging from genome structure to cellular architecture to aspects of motility in organisms across the Tree of Life.
| S-EPMC8025685 | biostudies-literature
Project description:T cell tolerance depends on the T cell receptor's affinity for peptide/major histocompatibility complex (MHC) ligand; this critical parameter determines whether a thymocyte will be included (positive selection) or excluded (negative selection) from the T cell repertoire. A quantitative analysis of ligand binding was performed using an experimental system permitting receptor-coreceptor interactions on live cells under physiological conditions. Using three transgenic mouse strains expressing distinct class I MHC-restricted T cell receptors, we determined the affinity that defines the threshold for negative selection. The affinity threshold for self-tolerance appears to be a constant for cytotoxic T lymphocytes.
| S-EPMC2118488 | biostudies-other
Project description:Different cellular signal transduction pathways are often interconnected, so that the potential for undesirable crosstalk between pathways exists. Nevertheless, signaling networks have evolved that maintain specificity from signal to cellular response. Here, we develop a framework for the analysis of networks containing two or more interconnected signaling pathways. We define two properties, specificity and fidelity, that all pathways in a network must possess in order to avoid paradoxical situations where one pathway activates another pathway's output, or responds to another pathway's input, more than its own. In unembellished networks that share components, it is impossible for all pathways to have both mutual specificity and mutual fidelity. However, inclusion of either of two related insulating mechanisms--compartmentalization or the action of a scaffold protein--allows both properties to be achieved, provided deactivation rates are fast compared to exchange rates.
| S-EPMC1681467 | biostudies-literature
Project description:Metabolic rate reduction has been considered the mechanism by which sleep conserves energy, similar to torpor or hibernation. This mechanism of energy savings is in conflict with the known upregulation (compared to wake) of diverse functions during sleep and neglects a potential role in energy conservation for partitioning of biological operations by behavioral state. Indeed, energy savings as derived from state-dependent resource allocations have yet to be examined. A mathematical model is presented based on relative rates of energy deployment for biological processes upregulated during either wake or sleep. Using this model, energy savings from sleep-wake cycling over constant wakefulness is computed by comparing stable limit cycles for systems of differential equations. A primary objective is to compare potential energy savings derived from state-dependent metabolic partitioning versus metabolic rate reduction. Additionally, energy conservation from sleep quota and the circadian system are also quantified in relation to a continuous wake condition. As a function of metabolic partitioning, our calculations show that coupling of metabolic operations with behavioral state may provide comparatively greater energy savings than the measured decrease in metabolic rate, suggesting that actual energy savings derived from sleep may be more than 4-fold greater than previous estimates. A combination of state-dependent metabolic partitioning and modest metabolic rate reduction during sleep may enhance energy savings beyond what is achievable through metabolic partitioning alone; however, the relative contribution from metabolic partitioning diminishes as metabolic rate is decreased during the rest phase. Sleep quota and the circadian system further augment energy savings in the model. Finally, we propose that state-dependent resource allocation underpins both sleep homeostasis and the optimization of daily energy conservation across species. This new paradigm identifies an evolutionary selective advantage for the upregulation of central and peripheral biological processes during sleep, presenting a unifying construct to understand sleep function.
| S-EPMC5634544 | biostudies-literature
Project description:BackgroundBreast cancer survivorship guidelines with specific recommendations on managing long-term effects are available, but uptake in clinical practice remains low. Using the lens of the Theoretical Domains Framework, we aimed to understand key factors in guideline-concordant management of long-term effects to inform future implementation efforts in clinical practice contexts.MethodsAs part of a broader survey of oncologists, a theory-guided questionnaire was developed. Oncologists were asked to report level of agreement with Theoretical Domains Framework-based statements, current usage and perceived value of survivorship resources, and frequency of managing long-term effects in routine care. Data analyses included psychometric assessment of the questionnaire, descriptive summaries of theoretical domains and survivorship resources, and multivariable logistic regression models.ResultsIn total, 217 oncologists completed the Theoretical Domains Framework-based questionnaire; 54% of oncologists reported "always or almost always" evaluating physical effects at routine survivorship appointments, while 34% did so for psychosocial effects. In regression models, Environmental Context and Resources was the only theoretical domain found to be statistically significantly associated with "always or almost always" evaluating both physical (odds ratio = 0.29, 95% confidence interval = 0.09 to 0.80) and psychosocial (odds ratio = 0.09, 95% confidence interval = 0.02 to 0.35) effects.ConclusionsFindings support application of the Theoretical Domains Framework in understanding oncologists' behaviors and perceived barriers in managing long-term effects in breast cancer survivors. In future implementation efforts, this theory-informed approach can be used to target relevant domains and strategies focused on embedding guideline recommendations in the clinical context through structured resources and environmental supports.
| S-EPMC10868380 | biostudies-literature
Project description:BackgroundThe Canadian CT Head Rule was prospectively derived and validated to assist clinicians with diagnostic decision-making regarding the use of computed tomography (CT) in adult patients with minor head injury. A recent intervention trial failed to demonstrate a decrease in the rate of head CTs following implementation of the rule in Canadian emergency departments. Yet, the same intervention, which included a one-hour educational session and reminders at the point of requisition, was successful in reducing cervical spine imaging rates in the same emergency departments. The reason for the varied effect of the intervention across these two behaviours is unclear. There is an increasing appreciation for the use of theory to conduct process evaluations to better understand how strategies are linked with outcomes in implementation trials. The Theoretical Domains Framework (TDF) has been used to explore health professional behaviour and to design behaviour change interventions but, to date, has not been used to guide a theory-based process evaluation. In this proof of concept study, we explored whether the TDF could be used to guide a retrospective process evaluation to better understand emergency physicians' responses to the interventions employed in the Canadian CT Head Rule trial.MethodsA semi-structured interview guide, based on the 12 domains from the TDF, was used to conduct telephone interviews with project leads and physician participants from the intervention sites in the Canadian CT Head Rule trial. Two reviewers independently coded the anonymised interview transcripts using the TDF as a coding framework. Relevant domains were identified by: the presence of conflicting beliefs within a domain; the frequency of beliefs; and the likely strength of the impact of a belief on the behaviour.ResultsEight physicians from four of the intervention sites in the Canadian CT Head Rule trial participated in the interviews. Barriers likely to assist with understanding physicians' responses to the intervention in the trial were identified in six of the theoretical domains: beliefs about consequences; beliefs about capabilities; behavioural regulation; memory, attention and decision processes; environmental context and resources; and social influences. Despite knowledge that the Canadian CT Head Rule was highly sensitive and reliable for identifying clinically important brain injuries and strong beliefs about the benefits for using the rule, a number of barriers were identified that may have prevented physicians from consistently applying the rule.ConclusionThis proof of concept study demonstrates the use of the TDF as a guiding framework to design a retrospective theory-based process evaluation. There is a need for further development and testing of methods for using the TDF to guide theory-based process evaluations running alongside behaviour change intervention trials.
| S-EPMC3585785 | biostudies-literature
Project description:Throughout the life sciences, biological populations undergo multiple phases of growth, often referred to as biphasic growth for the commonly encountered situation involving two phases. Biphasic population growth occurs over a massive range of spatial and temporal scales, ranging from microscopic growth of tumours over several days, to decades-long regrowth of corals in coral reefs that can extend for hundreds of kilometres. Different mathematical models and statistical methods are used to diagnose, understand and predict biphasic growth. Common approaches can lead to inaccurate predictions of future growth that may result in inappropriate management and intervention strategies being implemented. Here, we develop a very general computationally efficient framework, based on profile likelihood analysis, for diagnosing, understanding and predicting biphasic population growth. The two key components of the framework are as follows: (i) an efficient method to form approximate confidence intervals for the change point of the growth dynamics and model parameters and (ii) parameter-wise profile predictions that systematically reveal the influence of individual model parameters on predictions. To illustrate our framework we explore real-world case studies across the life sciences.
| S-EPMC9727659 | biostudies-literature
Project description:BackgroundClinical practice guidelines recommend further testing for people with tetraplegia and signs and symptoms of obstructive sleep apnoea (OSA), followed by treatment with positive airway pressure therapy. Little is known about how clinicians manage OSA in tetraplegia. The theoretical domains framework (TDF) is commonly used to identify determinants of clinical behaviours. This study aimed to describe OSA management practices in tetraplegia, and to explore factors influencing clinical practice.MethodsSemi-structured interviews were conducted with 20 specialist doctors managing people with tetraplegia from spinal units in Europe, UK, Canada, USA, Australia and New Zealand. Interviews were audiotaped for verbatim transcription. OSA management was divided into screening, diagnosis and treatment components for inpatient and outpatient services, allowing common practices to be categorised. Data were thematically coded to the 12 constructs of the TDF. Common beliefs were identified and comparisons were made between participants reporting different practices.ResultsRoutine screening for OSA signs and symptoms was reported by 10 (50%) doctors in inpatient settings and eight (40%) in outpatient clinics. Doctors commonly referred to sleep specialists for OSA diagnosis (9/20 in inpatients; 16/20 in outpatients), and treatment (12/20, 17/20). Three doctors reported their three spinal units were managing non-complicated OSA internally, without referral to sleep specialists. Ten belief statements representing six domains of the TDF were generated about screening. Lack of time and support staff (Environmental context and resources) and no prompts to screen for OSA (Memory, attention and decision processes) were commonly identified barriers to routine screening. Ten belief statements representing six TDF domains were generated for diagnosis and treatment behaviours. Common barriers to independent management practices were lack of skills (Skills), low confidence (Beliefs about capabilities), and the belief that OSA management was outside their scope of practice (Social/Professional role and identity). The three units independently managing OSA were well resourced with multidisciplinary involvement (Environmental context and resources), had 'clinical champions' to lead the program (Social influences).ConclusionClinical management of OSA in tetraplegia is highly varied. Several influences on OSA management within spinal units have been identified, facilitating the development of future interventions aiming to improve clinical practice.
| S-EPMC6588842 | biostudies-literature