Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic αβ chains associated with invariant CD3‐γδε components and ζ chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of αβ TCR complexes on their surfaces expressed by mature CD4+ and CD8+ T cells. (...) Recent evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCRα chain, which has a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCRα proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of αβ TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCRα instability during T cell development. (shrink)

Tumor‐infiltrating lymphocyte (TIL) therapy is a promising approach for treating refractory or advanced solid cancers by using autologous TILs harvested from cancer tissues. Despite the heterogeneity of cancer, TIL therapy can potentially produce a positive therapeutic response, including complete remission.After decades of research on lymphocyte functions, culture/expansion methods, therapeutic protocols, and multiple clinical trials, TIL therapy has finally reached a stage where it can be formally approved for clinical use.TIL therapy is expected to hold a unique position among anti‐cancer (...) therapeutic options as a standard intervention. To successfully introduce TIL therapy into clinical settings, there is a need to expand therapeutic indications and set up the best protocols for cancer tissue sampling and manufacturing, and related clinical trials. Moreover, studies on next‐generation TIL therapy have already begun, and post‐approval real‐world data will promote and support further research. (shrink)

We have rapidly gained insights into the presence and function of T lymphocytes in non‐lymphoid tissues, the tissue‐resident memory T (TRM) cells. The central pillar of adaptive immunity has been expanded from classic central memory T cells giving rise to progeny upon reinfection and effector memory cells circulating through the blood and patrolling the tissues to include TRM cells that reside and migrate inside solid organs and tissues. Their development and maintenance have been studied in detail, providing exciting clues (...) on how their unique properties used to fight infections may benefit therapies against solid tumors. We provide an overview of CD8 TRM cells and the properties that make them of interest for vaccination and cancer therapies. (shrink)

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the (...) epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. (shrink)

Experiments with cell lines have unveiled the implication of the Rho/Rac family of GTPases in cytoskeletal organization, mitogenesis, and cell migration. However, there have not been adequate animal models to investigate the role of these proteins in more physiological settings. This scenario has changed recently in the case of the T‐cell lineage after the generation of animal models for Rho/Rac family members, their regulators, and effectors. These studies have revealed the implication of these GTPases on multiple regulatory layers of T‐cells, (...) including the coordination of cytoskeletal change, activation of kinase cascades, stimulation of calcium fluxes, and the induction of gene expression. These pathways affect the transition of different T‐cell maturation stages, the positive/negative selection of thymocytes, T‐cell responses to antigens, and the homeostasis of peripheral T‐lymphocytes. Moreover, these animals have revealed interesting cross‐talks between Rho/Rac pathways and other signal transduction routes that participate in lymphocyte responses. BioEssays 24:602–612, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, a series of mechanisms are proposed, supported by evidence from different fields, by which CD38 overexpression can facilitate CD4 T cell depletion in HIV infection. According to this model, increased catalytic activity of CD38 may reduce CD4 T cells’ cytoplasmic nicotin‐amide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This will reduce mitochondrial function. Simultaneously, CD38's (...) catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca2+ concentrations, further altering mitochondrial integrity. These mechanisms will decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets. (shrink)

Much was accomplished in the last decade in understanding how the adaptive immune system evolved to combat pathogens. Essential features of antigen presentation and T lymphocyte recognition were decipherd, setting the stage for further studies that elucidated basic elements of lymphocyte differentiation (including positive and negative selection during lymphocyte ontogeny) and the major interactions that occur among cells in secondary lymphoid organs in an ongoing immune response. The major challenges of today are found in the burgeoning fields of programmed (...) cells death, enzymology of recombination and somatic mutation, development of memory, and the recognition of pathogens by unconventional lymphocytes. (shrink)

The T lymphocyte receptor for antigen, which operates in conjunction with gene products of the major histocompatibility complex (MHC), is a molecular complex comprised of five polypeptide chains. Both the 49 kDa alpha and 43 kDa beta chains are immunoglobulin‐like and thus contain variable domains responsible for ligand binding. In contrast, the 20–25 kDa T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other and held (...) in noncovalent association with the T3 chains. T3‐Ti receptor crosslinking leads to conformational modification of a second T lineage specific molecule, termed the 50 kDa T11 structure which in turn leads to protein kinase C activation, elevation in intracytoplasmic free calcium and Na+/H+ antiport stimulation. (shrink)

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T‐cell development and mature T‐cell effector function, a multichain receptor (the pre‐T‐cell antigen receptor or the T‐cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC‐γ1 activation, Ca2+ influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT including (...) expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. BioEssays 26:61–67, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

My purpose in what follows is not so much to defend the basic principle of utilitarianism as to indicate the form of it which seems most promising as a basic moral and political position. I shall take the principle of utility as offering a criterion for two different sorts of evaluation: first, the merits of acts of government, social policies, and social institutions, and secondly, the ultimate moral evaluation of the actions of individuals. I do not take it as implying (...) that the individual should live his life on the basis of constant evaluations of this sort. For there are different levels of decision making each with its appropriate criteria. For example, we each inevitably make many of our decisions from the point of view of our own personal self-fulfilment and this cannot regularly take a directly utilitarian form, nor should the utilitarian want it to do so. His claim is at most that we should sometimes review our life from the point of view of a kind of impersonal moral truth of a universalistic utilitarian character. (shrink)

This chapter examines the philosophy of T. H. Green, the initial leading figure among the absolute idealists who dominated British philosophy in the late 19th century. Green sought to establish that the existence and nature of human beings, especially of the human mind, was not susceptible of a purely empirical or scientific explanation. He claimed that the only possible explanation involved reference to the existence of an Eternal Consciousness, which was gradually realizing itself in the temporal world, more especially in (...) the life of human beings. Further issues in his philosophy are examined, such as that things count as real only if they are in unchanging relations to each other, the difference between negative and positive freedom, the nature of moral choice, the superiority of a virtue ethic to a utilitarian one. (shrink)

The current position on the deceased’s consent and the family’s consent to organ and tissue donation from the dead is a double veto—each has the power to withhold and override the other’s desire to donate. This paper raises, and to some extent answers, questions about the coherence of the double veto. It can be coherently defended in two ways: if it has the best effects and if the deceased has only negative rights of veto. Whether the double veto has better (...) effects than other policies requires empirical investigation, which is not undertaken here. As for rights, the paper shows that it is entirely possible that individuals have a negative right of veto but no positive right to compel acceptance of their offers. Thus if intensivists and transplant teams turn down the deceased’s offer, they do not thereby violate the deceased’s right. This leaves it open whether non-rights based reasons—such as avoiding bad publicity or distress —require intensivists and transplant teams to turn down or accept the deceased’s offer. This, however, is beyond the scope of this paper. The current position may or may not be wrong, but it is at least coherent. (shrink)

The differentiation of T lymphocytes, the cells that are responsible for cell‐mediated immunity, takes place within the thymus, but details of the developmental pathway have long been obscure. Although distinct subpopulations of thymocytes had been characterized, they acted like separate developmental streams rather than sequential differentiation stages. Recently, a minor subgroup of thymocytes representing an earlier blast population has been identified, offering the hope that the key developmental events will be discerned by focus on this new population of precursor (...) cells. (shrink)

We began with three propositions: that people have a right not to be treated as mere means to the ends of others, that a woman who voluntarily becomes pregnant nevertheless has the right to an abortion, and that a woman who voluntarily gives birth does not have a right to abandon her child until she finds a substitute caretaker. These propositions initially seemed inconsistent, for the prohibition on treating others as mere means appeared to rule out the possibility of (...) class='Hi'>positive rights, thus making it impossible to countenance the right to abort or the right not to be abandoned . But we have seen that the prohibition on treating people as mere means to the ends of others is best understood as ruling out basic positive rights while permitting derivative ones. Since a willing mother is responsible for bringing her child into the world in the first place, she cannot abandon it without violating its negative right not to be killed, and so such a child has a derivative positive right not to be abandoned. A pregnant woman, on the other hand, has a negative right not to have her body invaded, and from this negative right derives a positive right to abort her fetus, so long as doing so is not disproportionate to the seriousness of the threat . Therefore, far from being in conflict, propositions , , and have been shown to be in harmony with one another, the latter two being plausibly grounded in the first. Insofar as we have reason to accept , then, we have reason to accept and . Moreover, we have seen that a proper understanding of allows us to embed and in a larger moral perspective in which the limits of compulsory altruism are firmly drawn: enforceable rights to the use or assistance of others may be allowed into the moral domain only if they are “sponsored” by some negative right. Every putative positive right must find such a sponsor, or perish. (shrink)

The differentiation of T Lymphocytes within the thymus is an important biological phenomenon during wich these cell acquire their functions to further control the immune system. Numerous experiments under various conditions have been devised to understand the different mechanisms involved in this complex process. Nevertheless, interpretation of these experiments lead to still contradictory debatable hypotheses. Modelisation of this process through classical simulation methods cannot be envisaged because they are not adapted to modifications of the model structure, which is the (...) point of interest. For these reasons, we proposed a new approach of automatic search for model. The program consists of four independent connected modules : The generator produces model, based on the rationale of formal grammars. Protocol and experimental data are stored in a set of experiments. The simulator using a protocol and a model provides simulated results. Finally, the supervisor by comparing simulated results and experimental data, adapts the model parameters to increase their fit and either chooses a new experiment to explore, or modifies the model structure. Change of the model structure is performed among still unexplored models according to their promise level, which is iteratively evaluated relatively to previously explored models through a proposed model distance. The generator is written in Prolog and the other modules in C++. The architecture of the program allows us to modify or complete a module without changing anything in the other modules. As a consequence, the proposed modeling approach conceived to study T lymphocyte differentiation within the thymus remains independent of this biological phenomenon and can be applied to other biological problems. (shrink)

Objective: To determine if the medical record might overestimate the quality of care through false, and potentially unethical, documentation by physicians.Design: Prospective trial comparing two methods for measuring the quality of care for four common outpatient conditions: structured reports by standardised patients who presented unannounced to the physicians’ clinics, and abstraction of the medical records generated during these visits.Setting: The general medicine clinics of two veterans affairs medical centres.Participants: Twenty randomly selected physicians from among eligible second and third year internal (...) medicine residents and attending physicians.Main measurements: Explicit criteria were used to score the medical records of physicians and the reports of SPs generated during 160 visits . Individual scoring items were categorised into four domains of clinical performance: history, physical examination, treatment, and diagnosis. To determine the false positive rate, physician entries were classified as false positive , false negative, true positive, and true negative.Results: False positives were identified in the medical record for 6.4% of measured items. The false positive rate was higher for physical examination and diagnosis than for history and treatment . For individual physician subjects, the false positive rate ranged from 0.098 to 0.397.Conclusions: These data indicate that the medical record falsely overestimates the quality of important dimensions of care such as the physical examination. Though it is doubtful that most subjects in our study participated in regular, intentional falsification, we cannot exclude the possibility that false positives were in some instances intentional, and therefore fraudulent, misrepresentations. Further research is needed to explore the questions raised but incompletely answered by this research. (shrink)

Binding of antigen or lectin to the surface of a T lymphocyte initiates a complex sequence of events which result in both T cell proliferation and the acquisition of immunologic functions. This complex sequence of events is most likely programmed and precisely timed by a series of contingent gene activations in which one member of this series activates the next. The two most obvious examples of these stages are the set of genes activated when antigen interacts with the antigen receptor (...) and the set of genes activated when IL‐2 interacts with its receptor. However, it is likely that several other parallel pathways of gene activation are necessary to bring about T‐cell division. An example would be the antigen‐induced activation of the c‐myc gene, which in turn is likely to be involved in regulating an additional group of genes not directly controlled by either IL‐2 or antigen. A fundamental understanding of T‐lymphocyte activation necessitates identification of the factors involved in initiating each of these contingent levels of gene activation. (shrink)

How do we think about animals? How do we decide what they deserve and how we ought to treat them? Subhuman takes an interdisciplinary approach to these questions, drawing from research in philosophy, neuroscience, psychology, law, history, sociology, economics, and anthropology. Subhuman argues that our attitudes to nonhuman animals, both positive and negative, largely arise from our need to compare ourselves to them.

Abstract I argue that the two primary motivations in the literature for positing seemings as sui generis mental states are insufficient to motivate this view. Because of this, epistemological views which attempt to put seemings to work don’t go far enough. It would be better to do the same work by appealing to what makes seeming talk true rather than simply appealing to seeming talk. Content Type Journal Article Pages 1-12 DOI 10.1007/s11406-012-9363-8 Authors T. Ryan Byerly, Department of Philosophy, Baylor (...) University, Waco, TX, USA Journal Philosophia Online ISSN 1574-9274 Print ISSN 0048-3893. (shrink)

The general proposition of the positive youth development approach is that developmental assets such as psychosocial competence can promote healthy adolescent development and reduce problem behavior. Despite that many Western studies have shown that PYD attributes are negatively related to adolescent delinquency, not all empirical findings support the negative associations. Although different dimensions of PYD attributes may bear differential relationships with delinquency, this possibility has not been properly examined so far. In addition, related studies in mainland China do not (...) exist. Finally, the possible mediating role of life satisfaction in linking PYD attributes to delinquency has rarely been studied. To address the research gaps and understand how PYD attributes are associated with adolescent delinquency and the underlying mediating effect of life satisfaction, matched longitudinal data were collected from 2,648 mainland Chinese secondary school students at two waves which were separated by one year. On each occasion, participants completed a questionnaire containing validated measures of PYD attributes, life satisfaction, and delinquency. Congruent with the general theoretical prediction of the PYD approach, different PYD attributes were inversely related to concurrent and future adolescent delinquency in separate regression analyses. In addition, the negative predictions were mediated by life satisfaction. When all PYD attributes were included in a single path analysis model, three findings were observed. First, two PYD dimensions, including self-identity and general PYD attributes, showed robust negative predictions on delinquency via life satisfaction. Second, prosocial attributes displayed a weak and unstable negative predictive effect. Third, cognitive-behavioral competence showed an unexpected positive predictive effect on delinquency directly or via its negative effects on life satisfaction. The present findings add value to the existing literature by revealing the predictive role of PYD attributes on life satisfaction and delinquency among mainland Chinese adolescents. The findings also reinforce the importance of investigating individual dimensions of PYD attributes simultaneously in the research field. The present study suggests that it is promising to cultivate PYD attributes as a strategy to reduce delinquency among adolescents in mainland China. (shrink)

The COVID-19 pandemic has negatively impacted the psychosocial functioning of children and families. It is important to consider adversity in relation to processes of positive adaptation. To date, there are no empirically validated multi-item scales measuring COVID-related positive adaptation within families. The aim of the current study was to develop and validate a new measure: the Family Positive Adaptation during COVID-19 Scale. The sample included 372 female and 158 male caregivers of children ages 5–18 years old from (...) the United Kingdom, the United States, Canada, and Australia, who completed measures in May 2020. Participants responded to a 14-item survey indexing a range of perceived coping and adaptation behaviors at the beginning of the pandemic. An exploratory factor analysis yielded an optimal one-factor solution comprised of seven items related to family cohesion, flexibility, routines, and meaning-making. Multigroup confirmatory factor analysis demonstrated measurement invariance across female and male caregivers, demonstrating that the factor structure, loadings, and thresholds did not vary by caregiver sex. There was evidence for concurrent validity with significant bivariate correlations between the Family PACS scores and measures of caregiver positive coping, parenting practices, couple satisfaction, and family functioning, but not negatively-valenced constructs. Findings inform our conceptualization of how families have adapted to adverse pandemic-related conditions. Further, we provide preliminary support for the Family PACS as a practical tool for evaluating positive family adaptation during this global crisis, with implications for future widespread crises. (shrink)

In contrast to mainstream theories focusing on adolescent developmental deficits, the positive youth development (PYD) approach highlights adolescent developmental plasticity and potentials. There are rich empirical research and review studies showing that PYD attributes promote adolescent well-being. However, the existing literature shows several limitations. First, while there are many Western studies, Chinese studies are sparse, particularly studies in mainland China. Second, most PYD studies are cross-sectional studies with data collected at one single time point. Third, researchers in different Chinese (...) contexts seldom employed validated Chinese scales assessing different domains of PYD attributes. Fourth, few studies have examined the relationships between PYD attributes (measures of eudaimonic well-being) and life satisfaction (measure of hedonic well-being) and hopelessness (measure of negative well-being) in a single study. Finally, the role of life satisfaction or hopelessness as a mediator of the relationship between PYD attributes and psychological well-being is unclear. To explore the importance of PYD attributes to Chinese adolescent psychological well-being, we conducted a longitudinal study with two waves of data collected from junior high school students in mainland China ( N = 2,648). At both times, validated measures of PYD attributes, life satisfaction, and hopelessness were employed. Results showed that PYD attributes concurrently and longitudinally predicted life satisfaction and hopelessness with small effect sizes. Cross-lagged panel analyses showed that while Wave 2 life satisfaction did not serve as a mediator of the relationship between Wave 1 PYD attributes and Wave 2 hopelessness, Wave 2 hopelessness served as a mediator of the link from Wave 1 PYD attributes to Wave 2 life satisfaction. In view of the paucity of research findings in this area, the present findings clarify the association between PYD attributes and hedonic well-being (indexed by life satisfaction) and negative psychological well-being (indexed by hopelessness) in Chinese adolescents. (shrink)

Why does one theory "succeed" while another, possibly clearer interpretation, fails? By exploring two observationally equivalent yet conceptually incompatible views of quantum mechanics, James T. Cushing shows how historical contingency can be crucial to determining a theory's construction and its position among competing views. Since the late 1920s, the theory formulated by Niels Bohr and his colleagues at Copenhagen has been the dominant interpretation of quantum mechanics. Yet an alternative interpretation, rooted in the work of Louis de Broglie in the (...) early 1920s and reformulated and extended by David Bohm in the 1950s, equally well explains the observational data. Through a detailed historical and sociological study of the physicists who developed different theories of quantum mechanics, the debates within and between opposing camps, and the receptions given to each theory, Cushing shows that despite the preeminence of the Copenhagen view, the Bohm interpretation cannot be ignored. Cushing contends that the Copenhagen interpretation became widely accepted not because it is a better explanation of subatomic phenomena than is Bohm's, but because it happened to appear first. Focusing on the philosophical, social, and cultural forces that shaped one of the most important developments in modern physics, this provocative book examines the role that timing can play in the establishment of theory and explanation. (shrink)

This paper examines a model of income and quality of life that controls the love of money, job satisfaction, gender, and marital status and treats employment status (full-time versus part-time), income level, and gender as moderators. For the whole sample, income was not significantly related to quality of life when this path was examined alone. When all variables were controlled, income was negatively related to quality of life. When (1) the love of money was negatively correlated to job satisfaction and (...) (2) job satisfaction was positively related to both income and quality of life, income was negatively related to quality of life for full-time, high-income, and male employees. When these two conditions failed to exist, income was not related to quality of life for part-time, median- or low-income, and female employees. This model provides new insights regarding the impact of the love of money and job satisfaction on the income–quality of life relationship. (shrink)

Green agrees with Kant on the abstract character of moral law as categorical imperatives and that intentional dispositions are central to a moral justification of punishment. The central problem with Kant's account is that we are unable to know these dispositions beyond a reasonable estimate. Green offers a practical alternative, positing moral law as an ideal to be achieved, but not immediately enforceable through positive law. Moral and positive law are bridged by Green's theory of the common good (...) through the dialectic of morality. Thus, Green appears to offer an alternative that remains committed to Kantian morality whilst taking proper stock of our cognitive limitations. Unfortunately, Green fails to unravel fully Kant's dichotomy of moral and positive law that mirrors Green's solution, although Green offers a number of improvements, such as the importance of the community in establishing rights and linking the severity of punishment to the extent that a criminal act threatens the continued maintenance of a system of rights. (shrink)

Nucleosome positioning refers to sequence‐specific locations for histones interacting with the nucleic acid. Examples of occurrence of this phenomenon, its possible mechanisms and its significance are presented.

The question as to why some hosts can eradicate their tumors while others succumb to tumor‐progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti‐tumor immunity by affecting the frequency and/or variety of tumor‐reactive CD8 and/or CD4 tumor‐infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, (...) “a hole in the TCR repertoire” might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti‐tumor immune responses in different hosts. Besides tumor‐intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals’ immune systems will allow to better harness immune system to design new personalized cancer immunotherapy. (shrink)

In ethics, it is commonly supposed that we have both positive duties and negative duties, things we ought to do and things we ought not to do. Given the many parallels between ethics and epistemology, we might suppose that the same is true in epistemology, and that we have both positive epistemic duties and negative epistemic duties. I argue that this is false; that is, that we have negative epistemic duties, but no positive ones. There are things (...) that we ought not to believe, but there is nothing that we ought to believe, on purely epistemic grounds. I also consider why the parallels between ethics and epistemology break down at this particular point, suggesting that it is due to what I call the infinite justificational ‘fecundity’ of perceptual and propositional evidence. (shrink)

This paper provides a provisional examination of Rod Watson ''s work and contributions to EM/CA/MCA, in part through a critique of misrepresentations of his arguments in secondary accounts of his work. The form of these misrepresentations includes adumbration and traducement of his arguments. Focusing on the reflexivity of category and sequence and turn-generated categories, we suggest that his analytic position within ethnomethodological fields is unique and remarkable, yet largely unacknowledged. We argue that a re-examination of the body of Watson ''s (...) work makes relevant explicit and appropriate acknowledgement of his contributions through his unconventional approach and his extension of prior works in novel and stimulating directions. (shrink)

Dieser Artikel enthält eine kritische Diskussion der von Peter Stemmer in seinem Buch "Normativität. Eine ontologische Untersuchung" vorgelegten Analyse von Normativität. Zentraler Kritikpunkt ist der Umstand, dass der für Stemmers Analyse zentrale Begriff des Wollens unanalysiert bleibt, sich dieses jedoch, so das hier vorgestellte Argument, entweder in einer Weise analysieren lassen wird, die, als Tendenz gedeutet, weniger zu leisten vermag als Stemmer für seine Analyse benötigt, oder, als intentionaler Zustand gedeutet, selbst bereits Normativität voraussetzt und somit für Stemmers reduktive Analyse (...) von Normativität nicht geeignet ist. Gegen Ende des Aufsatzes wird eine pragmatistische Fundierung von Normativität angedeutet und verschiedene Ressourcen aufgezeigt, deren sich Stemmer bedienen könnte, um seine Position gegen die vorgebrachten Einwände zu verteidigen. (shrink)

It was shown recently that epimorphisms need not be surjective in a variety K of Heyting algebras, but only one counter-example was exhibited in the literature until now. Here, a continuum of such examples is identified, viz. the variety generated by the Rieger-Nishimura lattice, and all of its (locally finite) subvarieties that contain the original counter-example K . It is known that, whenever a variety of Heyting algebras has finite depth, then it has surjective epimorphisms. In contrast, we show that (...) for every integer $n \geq 2$ , the variety of all Heyting algebras of width at most n has a non-surjective epimorphism. Within the so-called Kuznetsov-Gerčiu variety (i.e., the variety generated by finite linear sums of one-generated Heyting algebras), we describe exactly the subvarieties that have surjective epimorphisms. This yields new positive examples, and an alternative proof of epimorphism surjectivity for all varieties of Gödel algebras. The results settle natural questions about Beth-style definability for a range of intermediate logics. (shrink)

Chalmers (2018) considers a wide range of possible responses to the meta-problem of consciousness. Among them is the ignorance hypothesis -- the view that there only appears to be a hard problem because of our inadequate conception of the physical. Although Chalmers quickly dismisses this view, I argue that it has much greater promise than he recognizes. The plausibility of the ignorance hypothesis depends on how exactly one frames the 'problem intuitions' that a solution to the meta-problem must explain. I (...) argue that problem intuitions are hybrid intuitions that encompass one's intuitive take on the phenomenal and one's intuitive take on the physical. The ignorance hypothesis undermines the second half of these hybrid intuitions. I show how the ignorance hypothesis is preferable to the alternatives and attempt to explain why there is such widespread resistance to this promising position. (shrink)