Hobbes's Moral Factualism: Reason, Facts, and Intentions

This thesis answers the question: what is Hobbes’s moral theory? Two dominant interpretations have answered this question on previous attempts. First, the orthodox account, which argues that Hobbes’s subjective theory of the good makes for a subjective moral theory; second, the dissent interpretation, which argues that Hobbes’s objective moral theory is underpinned by an objective theory of the good. In both cases, authors believe that one’s moral theory is necessarily linked to one’s theory of the good. I disagree and argue in defence of a Hobbesian subjective theory of the good and an objective moral theory. Hobbes thought morality depends on objective facts instead of objective values, which makes for a moral factualist reading. The moral laws are the laws of nature, which aim for nature’s preservation. The orthodox argue that those laws of nature apply only to those who desire their preservation. I argue that the laws of nature indeed depend on desires, however, they are categorically obligatory still. Morality namely depends on the universal ability to desire and the fact that all people do desire some thing. One does not need to value one’s preservation in itself; rather, because all desire some thing, one’s preservation becomes an analytical necessity: one ought to stay alive to enjoy whatever it is one values. As such, the objects of one’s desires remain subjective, as do one’s judgments of those objects; yet, given all desire, all will need to survive. The laws of nature apply to all

TRAF6 prevents autoimmunity by homeostatic suppression of MALT1 paracaspase activity

Balance of immune signaling in T lymphocytes is critical for a functional adaptive immune response. Upon antigen engagement of a T cell receptor (TCR), assembly of the CARD11-BCL10-MALT1 (CBM) complex drives downstream canonical NF-κB signaling pathway activation, which promotes T cell survival, differentiation, and proliferation. Within the CBM complex, MALT1 acts as both a scaffold to induce NF-κB activation and a protease that facilitates optimal T cell responses. Upon antigenic stimulation, MALT1 recruits the E3 ubiquitin ligase TRAF6 to the CBM complex, but the physiological role of this interaction has remained elusive. Therefore, novel murine models lacking interaction between MALT1 and TRAF6 were generated by CRISPR-Cas9 gene editing. Strikingly, abrogation of TRAF6 binding to MALT1 disrupts immune homeostasis and causes fatal, early-onset autoimmune inflammation. While NF-κB activity is completely dependent on TRAF6 expression, as well as MALT1-TRAF6 interaction, constitutive MALT1 cleavage activity was shown to be the direct effect of abolished binding to TRAF6. Secondary genome editing and inactivation of MALT1 protease function in mice completely rescues the fatal phenotype triggered by the disrupted MALT1-TRAF6 interaction, revealing that aberrant MALT1 protease activity is responsible for the autoinflammation caused by defective TRAF6 regulation. Further, autoimmunity in T cell specific TRAF6 knockout mice was ameliorated by therapeutic treatment with a potent MALT1 inhibitor. Thus, TRAF6 acts as both a positive regulator of CBM-dependent NF-κB signaling upon antigen engagement and as a negative regulator of MALT1 protease activity in resting T cells. Indeed, TRAF6 functions as a brake on MALT1 protease activity in resting T cells, essential for the maintenance of peripheral tolerance. By unraveling the complex dual role of TRAF6 in T cells, these data provide a rationale for the use of MALT1 inhibitors for new therapeutic approaches in the treatment of autoimmune disease.Das Gleichgewicht von Immunsignalwegen in T-Lymphozyten ist entscheidend für eine funktionelle adaptive Immunität. Durch die Antigenbindung an einen T-Zell Rezeptor (TZR) wird der CARD11-BCL10-MALT1 (CBM) Komplex gebildet, welcher den kanonischen NF-κB Signalweg aktiviert und damit Überleben, Differenzierung und Proliferation von T-Zellen vermittelt. Als Teil des CBM Komplexes fungiert MALT1 sowohl als Gerüstprotein zur Induktion von NF-κB als auch als Protease, welche eine optimale Immunantwort gewährleistet. Antigenstimulation führt dazu, dass MALT1 die E3-Ubiquitin Ligase TRAF6 an den CBM Komplex rekrutiert, aber die genaue physiologische Relevanz dieser Interaktion ist unklar. Aus diesem Grund wurden neuartige Mausmodelle mit fehlender MALT1-TRAF6 Interaktion mit Hilfe von CRISPR-Cas9 Genom Editierung generiert. Die Zerstörung der MALT1-TRAF6 Interaktion führt zu einer Störung der Immunhomöostase und einer früh einsetzenden und tödlich verlaufenden Autoimmunität bei Mäusen. Während die NF-κB Aktivierung vollständig von TRAF6 und der Rekrutierung von TRAF6 an MALT1 abhängt, führt der Verlust von TRAF6 gleichzeitig zu einer konstitutiven Spaltung von MALT1 Substraten. Sekundäre Genomeditierung und Inaktivierung der MALT1 Proteaseaktivität in Mäusen hebt den tödlichen Phänotyp verursacht durch den Verlust der MALT1-TRAF6 Interaktion vollständig auf, was somit beweist, dass die konstitutive MALT1 Proteaseaktivität verantwortlich für die Autoentzündungen nach fehlender TRAF6 Interaktion ist. Weiterhin mildert sich die Autoimmunität in Mäusen mit spezifischer Ablation von TRAF6 in T Zellen durch gezielte therapeutische Behandlung mit einem potenten MALT1 Inhibitor. Somit ist TRAF6 ein positiver Regulator der CBM Komplex-abhängigen Signalübertragung nach Antigenstimulation in aktivierten T Zellen und gleichzeitig ein negativer Regulator der MALT1 Protease Aktivität in ruhenden T-Zellen. Durch die Unterbindung der Enzymaktivität von MALT1 in ruhenden T-Zellen trägt TRAF6 somit entscheidend zur Aufrechterhaltung einer peripheren Immuntoleranz bei. Diese Daten verdeutlichen die komplexe duale Rolle von TRAF6 und bieten eine Grundlage für die Benutzung von MALT1 Inhibitoren in neuen Therapieansätzen zur Behandlung von Autoimmunerkrankungen

Colloidal Self-Assembly of Novel Materials Displaying Structural Colour

Self-assembly of colloids is a powerful technique for the synthesis of novel materials. While top-down manufacturing methods can also produce structures patterned on the mesoscale, they are frequently limited in resolution, slow to employ or restricted to two-dimensional systems; in contrast, self-assembly theoretically offers full control over the three-dimensional microstructure of a material and can be tuned by varying initial conditions and external forces. Self-assembly is particularly attractive because of its prevalence in the natural world; most naturally occurring nanostructures with interesting properties are produced through self-assembly processes that can then be mimicked in synthetic systems. One such class of materials exhibits structural colour, where light is differentially scattered or reflected based not on absorption but on the physical arrangement of the material on the nanoscale. Structurally produced colours tend to be brighter and more vivid than pigment-based ones and do not fade over time. As such they have numerous potential applications not only as a source of colouration but also in next-generation non-backlit displays and optoelectronic systems. This thesis discusses the synthesis, functionalisation and self-assembly of colloids into novel functional materials, particularly those that mimic naturally occurring structural colour based on disordered and ordered systems. The functionalisation of colloids with DNA introduces a specific, tuneable and thermally reversible attractive potential between particles, making it an excellent system to explore self-assembly. DNA-coated polystyrene particles were used to investigate gel formation through a spinodal decomposition mechanism and how the resulting gel structure reproducibly depends upon suspension properties. Subsequently, the tendency of such gels to produce structural colour was investigated using both polystyrene and silica DNA-coated colloidal systems, in comparison with similar natural materials. Finally, soft solution-phase photonic crystals were assembled using highly charged colloids of a low refractive index. This system was found to exhibit isotropic structural colour tuneable throughout the visible range, coupled with high transparency.This work was supported by the EPSRC Cambridge NanoDTC, EP/L015978/

An analysis of the work sampling technique of work measurement in the clerical field

Thesis (M.B.A.)--Boston Universit