64 research outputs found
Human B-cell development at the single-cell level
No full textB cells play an integral part of our immune system. In adults they develop in the bone marrow in a regulated process in which the specificity of their B-cell antigen receptor (BCR), a membrane bound antibody, is established. This is generated by somatic recombination of immunoglobulin (Ig) gene segments that encode the antigen binding region of Ig heavy and light chains. Most studies of B-cell development have been carried out in mouse models, while those in humans have mainly been performed at the population level. This thesis aimed to delineate early B-cell development in human bone marrow and investigate how the BCR repertoire is shaped, at the single-cell level. To this end, we analysed human bone marrow early B-lineage cells using flow cytometry and 5’ single-cell RNA- and VDJ sequencing.
In Paper I, we investigated the influence of BCR and T-cell antigen receptor genes on unsupervised clustering and downstream analyses in 5’ single-cell RNA sequencing data from B and T cells. In Paper II, we aimed to delineate the stages of B-cell development in the adult human bone marrow at the single-cell level and investigate how the BCR repertoire is shaped throughout development. In Paper III, we analysed the expression of Ig light chain transcripts during B-cell development, to infer recombination status of the kappa and lambda light chain loci.
In conclusion, we have developed a protocol to analyse 5’ single-cell RNA sequencing data which generates biologically relevant clusters of B and T cells. By using flow cytometry and the protocol developed in Paper I to analyse 5’ single-cell RNA and VDJ sequencing data, we can put forward a novel model of human B-cell development, which includes shaping of the BCR repertoire from the earliest pro-B cells to mature naïve B cells. For instance, we show a step-wise selection of the BCR repertoire, mainly exerted on the H-CDR3 region. Moreover, our data indicate that recombination of Ig lambda light chain is independent of that of kappa, a model that challenges the current dogma
Scientific Models and Metalinguistic Negotiation
No full textThe aim of this paper is to explore the possibility that, at least, some metaphysical debates are ‘metalinguistic negotiations’ (to employ a recent term coined by David Plunkett and Timothy Sundell). I will take the dispute between the dominant approaches of realism and the anti-realism ones (especially Fictionalism) about the ontological status of scientific models as a case-study. I will argue that such a debate may be better understood as a disagreement, at bottom normatively, motivated, insofar as a normative and non-factual question may be involved in it: how the relevant piece of language ought to be used. Even though I will generally assess the prospects for a broadly deflationist approach, I shall outline a sense in which the dispute can be recast as ‘minimally substantive’. ; El objetivo de este artículo es explorar la posibilidad de que al menos algunas disputas ontológicas puedan ser mejor entendidas como lo que David Plunkett y Timothy Sundell han llamado ‘negociaciones metalingüísticas’. Utilizaré como caso de estudio el debate sobre el estatus ontológico de los modelos científicos entre los enfoques dominantes del realismo y del antirrealismo (especialmente, el ficcionalismo). Argumentaré que este debate puede verse mejor como un debate motivado normativamente, en tanto que una pregunta normativa y no-fáctica aparece implicada, a saber: ¿cómo deben usarse los elementos del lenguaje relevantes? Aunque evaluaré de forma general las perspectivas de un enfoque ampliamente deflacionista, perfilaré un sentido en el que dicha disputa puede verse como ‘mínimamente sustantiva’
Human B-cell development at the single-cell level
No full textB cells play an integral part of our immune system. In adults they develop in the bone marrow in a regulated process in which the specificity of their B-cell antigen receptor (BCR), a membrane bound antibody, is established. This is generated by somatic recombination of immunoglobulin (Ig) gene segments that encode the antigen binding region of Ig heavy and light chains. Most studies of B-cell development have been carried out in mouse models, while those in humans have mainly been performed at the population level. This thesis aimed to delineate early B-cell development in human bone marrow and investigate how the BCR repertoire is shaped, at the single-cell level. To this end, we analysed human bone marrow early B-lineage cells using flow cytometry and 5’ single-cell RNA- and VDJ sequencing. In Paper I, we investigated the influence of BCR and T-cell antigen receptor genes on unsupervised clustering and downstream analyses in 5’ single-cell RNA sequencing data from B and T cells. In Paper II, we aimed to delineate the stages of B-cell development in the adult human bone marrow at the single-cell level and investigate how the BCR repertoire is shaped throughout development. In Paper III, we analysed the expression of Ig light chain transcripts during B-cell development, to infer recombination status of the kappa and lambda light chain loci. In conclusion, we have developed a protocol to analyse 5’ single-cell RNA sequencing data which generates biologically relevant clusters of B and T cells. By using flow cytometry and the protocol developed in Paper I to analyse 5’ single-cell RNA and VDJ sequencing data, we can put forward a novel model of human B-cell development, which includes shaping of the BCR repertoire from the earliest pro-B cells to mature naïve B cells. For instance, we show a step-wise selection of the BCR repertoire, mainly exerted on the H-CDR3 region. Moreover, our data indicate that recombination of Ig lambda light chain is independent of that of kappa, a model that challenges the current dogma
Disagreement and the Semantics of Normative and Evaluative Terms
No full textIn constructing semantic theories of normative and evaluative terms, philosophers have commonly deployed a certain type of disagreement -based argument. The premise of the argument observes the possibility of genuine disagreement between users of a certain normative or evaluative term, while the conclusion of the argument is that, however differently those speakers employ the term, they must mean the same thing by it. After all, if they did not, then they would not really disagree. We argue that in many of the cases in which this argument is deployed, the conclusion not only fails to follow from the premises, but is very likely false. Disagreements between speakers who do not mean the same things by their words are common, genuine, and not easily distinguished from ordinary disagreements over the truth of literally expressed content. We make this case by developing the notion of a metalinguistic negotiation, an exchange in which speakers tacitly negotiate the proper deployment of some linguistic expression in a context. Metalinguistic negotiations express disagreements over information that is conveyed pragmatically and about what concepts should be deployed in the context at hand. We argue that neither of these features poses any obstacle to metalinguistic negotiations serving to express genuine, substantive disagreements that can be well worth engaging in. Contrary to what has been widely assumed in the literature, many normative and evaluative disputes�among ordinary speakers and even among philosophers themselves�may be of exactly this type, a conclusion with important consequences for both the subject matter and the methodology of metanormative theory
Conflict and Content.
No full textSpeakers differ from one another in philosophically problematic ways. Two speakers can vary not simply with respect to what they believe, but also in the ways they speak, the concepts they employ, and the standards they bring to bear. The fact of imperfect convergence gives rise to a wide range of philosophical puzzles, largely via a single generalization: If two speakers disagree with each other, then at least one of them says something false. The generalization is plausible, but mistaken. Counterexamples are common, diverse, and thoroughly entrenched in ordinary talk, scientific discourse, and philosophical inquiry. I focus on a particular family of counterexamples, disagreements about the proper application of linguistic items, or what I call metalinguistic disagreements.
Coming to grips with the widespread existence of metalinguistic disagreement requires a nuanced account of the ways in which information can be transmitted via an utterance, and it suggests a substantial rethinking of conventional philosophical wisdom about the nature of meaning. I begin with a philosophical case study in metalinguistic disagreement—disagreements about aesthetics. I go on to explore the more general linguistic properties of metalinguistic disagreements, focusing on their striking failure to license so-called metalinguistic negation. I conclude with a consideration of semantic methodology, arguing that, despite widely held assumptions to the contrary, metalinguistic disagreements can be adjudicated with reference to objective, non-linguistic features of the world. It is possible therefore to roundly reject a pernicious relativism about scientific discourse while simultaneously allowing for widespread, interpersonal variation in meaning.PhDPhilosophyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64626/1/tsundell_1.pd
Scientific Models and Metalinguistic Negotiation
No full textThe aim of this paper is to explore the possibility that, at least, some metaphysical debates are ‘metalinguistic negotiations’ (to employ a recent term coined by David Plunkett and Timothy Sundell). I will take the dispute between the dominant approaches of realism and the anti-realism ones (especially Fictionalism) about the ontological status of scientific models as a case-study. I will argue that such a debate may be better understood as a disagreement, at bottom normatively, motivated, insofar as a normative and non-factual question may be involved in it: how the relevant piece of language ought to be used. Even though I will generally assess the prospects for a broadly deflationist approach, I shall outline a sense in which the dispute can be recast as ‘minimally substantive’
Facial Expression Recognition in low vs high psychopathic tendencies
No full textAs a part of the Personality and Psychophysiological Study at Örebro University, Sweden, I have been allowed to take part of the data gathered on individuals with high psychopathic personality traits (using the Youth Psychopathic Traits Inventory; Andershed et al., 2002) and the Facial Expression Recognition Task (Calder et al., 1996). The data has not been shared to the author yet, and the direction of the hypotheses remains unknown. Previous literature has been mixed
An Examination of Federal Reserve Behavior: An Applied Reaction Function Approach
No full textFederal Reserve behavior and interest rates are crucial determinants of the general well-being of the agricultural sector. This report investigates the factors that have influenced Federal Reserve policy and ultimately the level of interest rates. The author develops a partial adjustment model for the Federal funds rate and documents improved forecasting performance in comparison to competing models on an in-sample and out-of-sample basis. The author attributes the improved forecasting performance to the inclusion of international variables, a domestic banking default risk proxy, and slope dummy variables that capture shifts over time in the Federal Reserve's reaction to the unemployment rate and deviations in M1 from target
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