Cellular-level versus receptor-level response threshold hierarchies in T-Cell activation

Peptide-MHC (pMHC) ligand engagement by T-cell receptors (TCRs) elicits a variety of cellular responses, some of which require substantially more TCR-mediated stimulation than others. This threshold hierarchy could reside at the receptor level, where different response pathways branch off at different stages of the TCR/CD3 triggering cascade, or at the cellular level, where the cumulative TCR signal registered by the T-cell is compared to different threshold values. Alternatively, dual-level thresholds could exist. In this study, we show that the cellular hypothesis provides the most parsimonious explanation consistent with data obtained from an in-depth analysis of distinct functional responses elicited in a clonal T-cell system by a spectrum of biophysically defined altered peptide ligands across a range of concentrations. Further, we derive a mathematical model that describes how ligand density, affinity, and off-rate all affect signaling in distinct ways. However, under the kinetic regime prevailing in the experiments reported here, the TCR/pMHC class I (pMHCI) dissociation rate was found to be the main governing factor. The CD8 coreceptor modulated the TCR/pMHCI interaction and altered peptide ligand potency. Collectively, these findings elucidate the relationship between TCR/pMHCI kinetics and cellular function, thereby providing an integrated mechanistic understanding of T-cell response profiles

Dynamic deployment of context-aware access control policies for constrained security devices

Securing the access to a server, guaranteeing a certain level of protection over an encrypted communication channel, executing particular counter measures when attacks are detected are examples of security requirements. Such requirements are identi ed based on organizational purposes and expectations in terms of resource access and availability and also on system vulnerabilities and threats. All these requirements belong to the so-called security policy. Deploying the policy means enforcing, i.e., con guring, those security components and mechanisms so that the system behavior be nally the one speci ed by the policy. The deployment issue becomes more di cult as the growing organizational requirements and expectations generally leave behind the integration of new security functionalities in the information system: the information system will not always embed the necessary security functionalities for the proper deployment of contextual security requirements. To overcome this issue, our solution is based on a central entity approach which takes in charge unmanaged contextual requirements and dynamically redeploys the policy when context changes are detected by this central entity. We also present an improvement over the OrBAC (Organization-Based Access Control) model. Up to now, a controller based on a contextual OrBAC policy is passive, in the sense that it assumes policy evaluation triggered by access requests. Therefore, it does not allow reasoning about policy state evolution when actions occur. The modi cations introduced by our work overcome this limitation and provide a proactive version of the model by integrating concepts from action speci cation languages

Hierarchical coexistence of universality and diversity controls robustness and multi-functionality in intermediate filament protein networks

Proteins constitute the elementary building blocks of a vast variety of biological materials such as cellular protein networks, spider silk or bone, where they create extremely robust, multi-functional materials by self-organization of structures over many length- and time scales, from nano to macro. Some of the structural features are commonly found in a many different tissues, that is, they are highly conserved. Examples of such universal building blocks include alpha-helices, beta-sheets or tropocollagen molecules. In contrast, other features are highly specific to tissue types, such as particular filament assemblies, beta-sheet nanocrystals in spider silk or tendon fascicles. These examples illustrate that the coexistence of universality and diversity – in the following referred to as the universality-diversity paradigm (UDP) – is an overarching feature in protein materials. This paradigm is a paradox: How can a structure be universal and diverse at the same time? In protein materials, the coexistence of universality and diversity is enabled by utilizing hierarchies, which serve as an additional dimension beyond the 3D or 4D physical space. This may be crucial to understand how their structure and properties are linked, and how these materials are capable of combining seemingly disparate properties such as strength and robustness. Here we illustrate how the UDP enables to unify universal building blocks and highly diversified patterns through formation of hierarchical structures that lead to multi-functional, robust yet highly adapted structures. We illustrate these concepts in an analysis of three types of intermediate filament proteins, including vimentin, lamin and keratin

Semantic memory redux: an experimental test of hierarchical category representation

Four experiments investigated the classic issue in semantic memory of whether people organize categorical information in hierarchies and use inference to retrieve information from them, as proposed by Collins & Quillian (1969). Past evidence has focused on RT to confirm sentences such as “All birds are animals” or “Canaries breathe.” However, confounding variables such as familiarity and associations between the terms have led to contradictory results. Our experiments avoided such problems by teaching subjects novel materials. Experiment 1 tested an implicit hierarchical structure in the features of a set of studied objects (e.g., all brown objects were large). Experiment 2 taught subjects nested categories of artificial bugs. In Experiment 3, subjects learned a tree structure of novel category hierarchies. In all three, the results differed from the predictions of the hierarchical inference model. In Experiment 4, subjects learned a hierarchy by means of paired associates of novel category names. Here we finally found the RT signature of hierarchical inference. We conclude that it is possible to store information in a hierarchy and retrieve it via inference, but it is difficult and avoided whenever possible. The results are more consistent with feature comparison models than hierarchical models of semantic memory

The Role of Social Context in Modulating Gene Expression, Neural Activity, and Neuroendocrine Response in Individuals of Varying Social Status

Social context, which includes both the direct social experience of individuals as well as the characteristics of their social network as a whole, has been shown to be an important modulator of behavior across species. However, relatively little is known about the role of social context in regulating the complex relationships between neurobiology, neuroendocrine response, and behavior in mammals. Historically, the neurobiology of social behavior has been studied at the dyadic level, looking at brief social interactions between pairs of individuals. Given that all social species live in groups, rather than pairs, it is essential that we begin to understand the role social context at the group level plays in regulating physiology. Throughout this thesis, I use a novel behavioral housing system to study how the characteristics of stable social groups and how instances of social opportunity, when individuals are ascending up a social hierarchy, are associated with differential brain gene expression, neuroendocrine output, and behavior. I first extensively analyze the social dynamics of male dominance hierarchies, showing that they are both consistent, in that males reliably form significantly linear dominance hierarchies, and unique, in that the characteristics of these hierarchies vary from group to group. I further prove that mice living in these social hierarchies are extremely socially competent, displaying the ability to respond appropriately to individuals of varying social status. I demonstrate that females are capable of forming dominance hierarchies as well, but that their hierarchies differ from those of males. I then use this foundational knowledge to investigate how these different hierarchy characteristics can lead to differences in physiology, how one’s social status is associated with brain gene expression and neuroendocrine response, and how disruption of a hierarchy through removal of the alpha male leads to robust behavioral as well as physiological consequences. Finally, I use the insights gained from this immediate early gene work to demonstrate the crucial role of the infralimbic/prelimbic region of the medial prefrontal cortex in regulating socially competent response to changing social contexts. Taken together, this work establishes the broad role social context plays in regulating the complex relationships between behavior, brain gene expression, neural activation, and neuroendocrine output

A physiologically based approach to consciousness

The nature of a scientific theory of consciousness is defined by comparison with scientific theories in the physical sciences. The differences between physical, algorithmic and functional complexity are highlighted, and the architecture of a functionally complex electronic system created to relate system operations to device operations is compared with a scientific theory. It is argued that there are two qualitatively different types of functional architecture, and that electronic systems have the instruction architecture based on exchange of unambiguous information between functional components, and biological brains have been constrained by natural selection pressures into the recommendation architecture based on exchange of ambiguous information. The mechanisms by which a recommendation architecture could heuristically define its own functionality are described, and compared with memory in biological brains. Dream sleep is interpreted as the mechanism for minimizing information exchange between functional components in a heuristically defined functional system. The functional role of consciousness of self is discussed, and the route by which the experience of that function described at the psychological level can be related to physiology through a functional architecture is outlined

The Role of Consciousness in Memory

Conscious events interact with memory systems in learning, rehearsal and retrieval (Ebbinghaus 1885/1964; Tulving 1985). Here we present hypotheses that arise from the IDA computional model (Franklin, Kelemen and McCauley 1998; Franklin 2001b) of global workspace theory (Baars 1988, 2002). Our primary tool for this exploration is a flexible cognitive cycle employed by the IDA computational model and hypothesized to be a basic element of human cognitive processing. Since cognitive cycles are hypothesized to occur five to ten times a second and include interaction between conscious contents and several of the memory systems, they provide the means for an exceptionally fine-grained analysis of various cognitive tasks. We apply this tool to the small effect size of subliminal learning compared to supraliminal learning, to process dissociation, to implicit learning, to recognition vs. recall, and to the availability heuristic in recall. The IDA model elucidates the role of consciousness in the updating of perceptual memory, transient episodic memory, and procedural memory. In most cases, memory is hypothesized to interact with conscious events for its normal functioning. The methodology of the paper is unusual in that the hypotheses and explanations presented are derived from an empirically based, but broad and qualitative computational model of human cognition