Cheating the Hunger Games; Mechanisms Controlling Clonal Diversity of CD8 Effector and Memory Populations

Effector and memory CD8 T cells have an intrinsic difference in the way they must approach antigen; effector cells need to address the pathogen at hand and therefore favor outgrowth of only high-affinity clones. In contrast, the memory pool benefits from greater clonal diversity to recognize and eliminate pathogens with mutations in their immunogenic epitopes. Effector and memory fates are ultimately the result of the same three signals that control T cell activation; T cell receptor (TCR) engagement together with co-stimulation and cytokines. Great progress has been made in our understanding of the transcriptional programs that drive effector or memory differentiation. However, how these two different programs result from the same initial cues is still a matter of debate. An emerging image is that not only the classical three signals determine T cell differentiation, but also the ability of cells to access these signals relative to that of other activated clones. Inter-clonal competition is therefore not only a selective force, but also a mediator of CD8 T cell fate. How this is regulated on a transcriptional level, especially in the context of a selective “hunger game” based on antigen-affinity in which only cells of high-affinity are supposed to survive, is still poorly defined. In this review, we discuss recent literature that illustrates how antigen-affinity dependent inter-clonal competition shapes effector and memory populations in an environment of antigen affinity-driven selection. We argue that fine-tuning of TCR signal intensity presents an attractive target for regulating the scope of CD8 T cell vaccines

Interactive prototypes in the participatory development of product-service systems

Stakeholders who are part of the development process of a new Product-Service System (PSS) could use interactive prototypes during meetings to exchange different point of views. Based on the findings of a conversation analyst and the reflections of a design researcher we compared three explication techniques of how a prototype was involved during such a meeting (for pointing and manipulating, for demonstrating its function and for imitating and/or demonstration through body movement and gesture) with the phases of a co-reflection session (exploration, ideation and confrontation). We found that the prototype was especially useful during the exploration and confrontation phases. Pointing and manipulating helped to make reflections concrete, made it easier to propose small design changes and helped the participants to reach common goals. Interactive prototypes do have their limits, during the ideation phase the prototype did not play an important role

The “Big Bang” in obese fat: Events initiatingobesity-induced adipose tissue inflammation

Obesity is associated with the accumulation of pro-inflammatory cells in visceral adiposetissue (VAT), which is an important underlying cause of insulin resistance and progres-sion to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokinesin disease development is established, the initiating events leading to immune cell acti-vation remain elusive. Lean adipose tissue is predominantly populated with regulatorycells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissuehomeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13,which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state.Diet-induced obesity is associated with the loss of tissue homeostasis and developmentof type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shiftof ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocytehypertrophy results in upregulated surface expression of stress markers. Adipose stressis detected by local sentinels, such as NK cells and CD8+T cells, which produce IFN-γ,driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VATfollows, leading to inflammation. In this review, we provide an overview of events lead-ing to adipose tissue inflammation, with a special focus on adipose homeostasis and theobesity-induced loss of homeostasis which marks the initiation of VAT inflammation

Cheating the Hunger Games; Mechanisms Controlling Clonal Diversity of CD8 Effector and Memory Populations

Effector and memory CD8 T cells have an intrinsic difference in the way they must approach antigen; effector cells need to address the pathogen at hand and therefore favor outgrowth of only high-affinity clones. In contrast, the memory pool benefits from greater clonal diversity to recognize and eliminate pathogens with mutations in their immunogenic epitopes. Effector and memory fates are ultimately the result of the same three signals that control T cell activation; T cell receptor (TCR) engagement together with co-stimulation and cytokines. Great progress has been made in our understanding of the transcriptional programs that drive effector or memory differentiation. However, how these two different programs result from the same initial cues is still a matter of debate. An emerging image is that not only the classical three signals determine T cell differentiation, but also the ability of cells to access these signals relative to that of other activated clones. Inter-clonal competition is therefore not only a selective force, but also a mediator of CD8 T cell fate. How this is regulated on a transcriptional level, especially in the context of a selective "hunger game" based on antigen-affinity in which only cells of high-affinity are supposed to survive, is still poorly defined. In this review, we discuss recent literature that illustrates how antigen-affinity dependent inter-clonal competition shapes effector and memory populations in an environment of antigen affinity-driven selection. We argue that fine-tuning of TCR signal intensity presents an attractive target for regulating the scope of CD8 T cell vaccines

Binocular deficits associated with early alternating monocular defocus. II. Neurophysiological observations

Experiencing binocularly conflicting signals early in life dramatically alters the binocular responses of cortical neurons. Because visual cortex is highly plastic during a critical period of development, cortical deficits resulting from early abnormal visual experience often mirror the nature of interocular decorrelation of neural signals from the two eyes. In the preceding paper, we demonstrated that monkeys that experienced early alternating monocular defocus (-1.5, -3.0, or -6.0 D) show deficits in stereopsis that generally reflected the magnitude of imposed monocular defocus. Because these results indicated that alternating monocular defocus affected the higher spatial frequency components of visual scenes more severely, we employed microelectrode recording methods to investigate whether V1 neurons in these lens-reared monkeys exhibited spatial-frequency-dependent alterations in their binocular response properties. We found that a neuron\u27s sensitivity to interocular spatial phase disparity was reduced in the treated monkeys and that this reduction was generally more severe for units tuned to higher spatial frequencies. In the majority of the affected units, the disparity-sensitivity loss was associated with interocular differences in monocular receptive field properties. The present results suggest that the behavioral deficits in stereopsis produced by abnormal visual experience reflect at least in part the constraints imposed by alterations at the earliest stages of binocular cortical processing and support the hypothesis that the local disparity processing mechanisms in primates are spatially tuned and can be independently compromised by early abnormal visual experience

Early monocular defocus disrupts the normal development of receptive-field structure in V2 neurons of macaque monkeys

Experiencing different quality images in the two eyes soon after birth can cause amblyopia, a developmental vision disorder. Amblyopic humans show the reduced capacity for judging the relative position of a visual target in reference to nearby stimulus elements (position uncertainty) and often experience visual image distortion. Although abnormal pooling of local stimulus information by neurons beyond striate cortex (V1) is often suggested as a neural basis of these deficits, extrastriate neurons in the amblyopic brain have rarely been studied using microelectrode recording methods. The receptive field (RF) of neurons in visual area V2 in normal monkeys is made up of multiple subfields that are thought to reflect V1 inputs and are capable of encoding the spatial relationship between local stimulus features. We created primate models of anisometropic amblyopia and analyzed the RF subfield maps for multiple nearby V2 neurons of anesthetized monkeys by using dynamic two-dimensional noise stimuli and reverse correlation methods. Unlike in normal monkeys, the subfield maps of V2 neurons in amblyopic monkeys were severely disorganized: subfield maps showed higher heterogeneity within each neuron as well as across nearby neurons. Amblyopic V2 neurons exhibited robust binocular suppression and the strength of the suppression was positively correlated with the degree of hereogeneity and the severity of amblyopia in individual monkeys. Our results suggest that the disorganized subfield maps and robust binocular suppression of amblyopic V2 neurons are likely to adversely affect the higher stages of cortical processing resulting in position uncertainty and image distortion

Separating underwater ambient noise from flow noise recorded on stereo acoustic tags attached to marine mammals

A.M.v.B.B. and P.B. were funded by The Netherlands Ministry of Defence. Fieldwork efforts and support for P.M. and F.S. was provided by the US Office of Naval Research [award numbers N00014-08-1-0984 and N00014-10-1-0355]. P.W. received a PhD studentship with matched funding from The Netherlands Ministry of Defence (administered by The Netherlands Organisation for Applied Scientific Research, TNO) and UK Natural Environment Research Council [NE/J500276/1].Sound-recording acoustic tags attached to marine animals are commonly used in behavioural studies. Measuring ambient noise is of interest to efforts to understand responses of marine mammals to anthropogenic underwater sound, or to assess their communication space. Noise of water flowing around the tag reflects the speed of the animal, but hinders ambient noise measurement. Here, we describe a correlation-based method for stereo acoustic tags to separate the relative contributions of flow and ambient noise. The uncorrelated part of the noise measured in digital acoustic recording tag (DTAG) recordings related well to swim speed of a humpback whale (Megaptera novaeangliae), thus providing a robust measure of flow noise over a wide frequency bandwidth. By removing measurements affected by flow noise, consistent ambient noise estimates were made for two killer whales (Orcinus orca) with DTAGs attached simultaneously. The method is applicable to any multi-channel acoustic tag, enabling application to a wide range of marine species.Publisher PDFPeer reviewe

All That Glitters Is Not Gold: Towards Process Discovery Techniques with Guarantees

The aim of a process discovery algorithm is to construct from event data a process model that describes the underlying, real-world process well. Intuitively, the better the quality of the event data, the better the quality of the model that is discovered. However, existing process discovery algorithms do not guarantee this relationship. We demonstrate this by using a range of quality measures for both event data and discovered process models. This paper is a call to the community of IS engineers to complement their process discovery algorithms with properties that relate qualities of their inputs to those of their outputs. To this end, we distinguish four incremental stages for the development of such algorithms, along with concrete guidelines for the formulation of relevant properties and experimental validation. We will also use these stages to reflect on the state of the art, which shows the need to move forward in our thinking about algorithmic process discovery.Comment: 13 pages, 4 figures. Submitted to the International Conference on Advanced Information Systems Engineering, 202