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"Hogan, Patrick"
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What literature teaches us about emotion
\"Literature provides us with otherwise unavailable insights into the ways emotions are produced, experienced and enacted in human social life. It is particularly valuable because it deepens our comprehension of the mutual relations between emotional response and ethical judgment. These are the central claims of Hogan's study, which carefully examines a range of highly esteemed literary works in the context of current neurobiological, psychological, sociological and other empirical research. In this work, he explains the value of literary study for a cognitive science of emotion and outlines the emotional organization of the human mind. He explores the emotions of romantic love, grief, mirth, guilt, shame, jealousy, attachment, compassion and pity - in each case drawing on one work by Shakespeare and one or more works by writers from different historical periods or different cultural backgrounds, such as the eleventh-century Chinese poet Li Ch'ing-Chao and the contemporary Nigerian playwright Wole Soyinka\"-- Provided by publisher.
Book
BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells
The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos–Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8
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T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF–IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
Chronic antigen stimulation leads to CD8
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T cell exhaustion, which is mediated by persistent activation of the transcription factor NFAT in the absence of AP-1. Seo, González-Avalos and colleagues show that overexpressed BATF cooperates with IRF4 to counteract NFAT-induced exhaustion and promote better tumor control by CAR T cells in mouse models.
Journal Article
The road not taken en route to T cell exhaustion
The first detailed investigation of CD8
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tumor-infiltrating T cell differentiation in the hours after cells enter a tumor has yielded an unexpected twist. Naive T cells veer away from effector fate and enter the path towards exhaustion much earlier than expected.
Journal Article
A Mechanism for Value-Sensitive Decision-Making
We present a dynamical systems analysis of a decision-making mechanism inspired by collective choice in house-hunting honeybee swarms, revealing the crucial role of cross-inhibitory 'stop-signalling' in improving the decision-making capabilities. We show that strength of cross-inhibition is a decision-parameter influencing how decisions depend both on the difference in value and on the mean value of the alternatives; this is in contrast to many previous mechanistic models of decision-making, which are typically sensitive to decision accuracy rather than the value of the option chosen. The strength of cross-inhibition determines when deadlock over similarly valued alternatives is maintained or broken, as a function of the mean value; thus, changes in cross-inhibition strength allow adaptive time-dependent decision-making strategies. Cross-inhibition also tunes the minimum difference between alternatives required for reliable discrimination, in a manner similar to Weber's law of just-noticeable difference. Finally, cross-inhibition tunes the speed-accuracy trade-off realised when differences in the values of the alternatives are sufficiently large to matter. We propose that the model, and the significant role of the values of the alternatives, may describe other decision-making systems, including intracellular regulatory circuits, and simple neural circuits, and may provide guidance in the design of decision-making algorithms for artificial systems, particularly those functioning without centralised control.
Journal Article
Imagining Kashmir : emplotment and colonialism
\"During the partition of the Indian subcontinent in 1947, Kashmir Valley--an intricate mix of regional, ethnic, linguistic, religious, and caste communities--became a hotly disputed territory. With portions of the region divided among India, Pakistan, and the People's Republic of China, major territorial disputes, particularly between India and Pakistan, have persisted over historical and cultural claims to the land. 'Imagining Kashmir' negotiates the cinematic and literary imaginations of the Kashmir region's conflicts and diverse citizenship, analyzing a wide range of narratives from writers and directors such as Salman Rushdie, Bharat Wakhlu, Mani Rutman, and Mirza Waheed in conjunction with research in psychology, cognitive science, and social neuroscience. Hogan provides a historical and cultural analysis of Kashmir that advances the existing theoretical knowledge of narrative, colonialism, and their corresponding ideologies in relation to the the cognitive and affective operations of identity. Hogan considers how narrative organizes people's understanding of, and emotions about, real political situations, and the ways in which such situations in turn influence cultural narratives, re-forming and potentially deforming them\"--Provided by publisher.
BOOK
TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8⁺ T cell exhaustion
T cells expressing chimeric antigen receptors (CAR T cells) have shown impressive therapeutic efficacy against leukemias and lymphomas. However, they have not been as effective against solid tumors because they become hyporesponsive (“exhausted” or “dysfunctional”) within the tumor microenvironment, with decreased cytokine production and increased expression of several inhibitory surface receptors. Here we define a transcriptional network that mediates CD8⁺ T cell exhaustion. We show that the high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN). Using a previously established CAR T cell model, we show that TOX and TOX2 are highly induced in CD8⁺ CAR⁺ PD-1high TIM3high (“exhausted”) tumor-infiltrating lymphocytes (CAR TILs), and CAR TILs deficient in both TOX and TOX2 (Tox DKO) are more effective than wild-type (WT), TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice. Like NR4A-deficient CAR TILs, Tox DKO CAR TILs show increased cytokine expression, decreased expression of inhibitory receptors, and increased accessibility of regions enriched for motifs that bind activation- associated nuclear factor κB (NFκB) and basic region-leucine zipper (bZIP) transcription factors. These data indicate that Tox and Nr4a transcription factors are critical for the transcriptional program of CD8⁺ T cell exhaustion downstream of NFAT. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that disruption of TOX and NR4A expression or activity could be promising strategies for cancer immunotherapy.
Journal Article
Defining ‘T cell exhaustion’
‘T cell exhaustion’ is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection. Their responses highlight the dichotomy between terminally differentiated exhausted T cells that are TCF1– and the self-renewing TCF1+ population from which they derive. These TCF1+ cells are considered by some to have stem cell-like properties akin to memory T cell populations, but the developmental relationships are unclear at present. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of exhaustion, but key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations.
Journal Article