OBJECTIVE(S): To determine whether variation in cell associated (CA) unspliced (US) HIV RNA in HIV-infected individuals on antiretroviral therapy (ART) has a circadian basis. METHODS: Prospective ...observational study of HIV-infected individuals on ART. Blood was collected on three occasions and CA-US HIV RNA and mRNA of the Circadian-locomotor-output-cycles-kaput (CLOCK)-associated genes quantified by real time PCR. CLOCK-associated proteins were over expressed in a cell line stably transfected with an HIV long terminal repeat (LTR) luciferase reporter. RESULTS: Using a mixed effects model, there was a significant increase in log-CA-US RNA at the third visit compared to the first visit (effect size of 0.619 with standard error (SE) of 0.098, p<0.001) and an independent effect of time of blood draw (effect size 0.051, (SE 0.025), p=0.040). The CLOCK-associated gene, Brain-and-muscle-ARNT-like-1 (BMAL-1) had a significant relationship with log CA-US HIV RNA (effect size 8.508 (SE 3.777), p = 0.028) and also with time (p=0.045). Over expression of BMAL-1 and CLOCK in a cell line stably transfected with an HIV-LTR luciferase reporter resulted in an increase in luciferase expression and this was reduced following mutation of the second E-box in the HIV-LTR. CONCLUSIONS: The basal level of HIV transcription on ART can vary significantly and is modulated by the circadian regulator BMAL-1, amongst other factors.
British Empire in India was born not through the absent-minded actions of a misguided trading company, but rather through the long-standing institutionally aggressive policy of the East India Company ...and the efforts of the various other forms of power, including the British and Mughal states, to assert authority over it. Moving away from an historiography created in the late eighteenth century that has divided the Company's history into an earlier trading period and a later imperial era, this dissertation argues for continuities in the story of the Company's political involvement in South Asia. As its authority matured towards the end of the seventeenth century, this “commercial” Company honed distinctly political strategies—ideological, legal, martial, and diplomatic—to compete against, negotiate with, and influence various states and individuals in Europe and Asia. By focusing on the institutions through which the Company governed and ideologies by which those institutions were legitimated and challenged, this dissertation reevaluates the history and historiography of early Anglo-Indian contact within its oft-overlooked political and global context while highlighting the broader themes of the ways in which state, commercial, and imperial power were constructed in the early modern period.