De Novo synthesis of VP16 coordinates the exit from HSV latency in vivo

The mechanism controlling the exit from herpes simplex virus latency (HSV) is of central importance to recurrent disease and transmission of infection, yet interactions between host and viral functions that govern this process remain unclear. The cascade of HSV gene transcription is initiated by the multifunctional virion protein VP16, which is expressed late in the viral replication cycle. Currently, it is widely accepted that VP16 transactivating function is not involved in the exit from latency. Utilizing the mouse ocular model of HSV pathogenesis together with genetically engineered viral mutants and assays to quantify latency and the exit from latency at the single neuron level, we show that in vivo (i) the VP16 promoter confers distinct regulation critical for viral replication in the trigeminal ganglion (TG) during the acute phase of infection and (ii) the transactivation function of VP16 (VP16TF) is uniquely required for the exit from latency. TG neurons latently infected with the VP16TF mutant in 1814 do not express detectable viral proteins following stress, whereas viruses with mutations in the other major viral transcription regulators ICP0 and ICP4 do exit the latent state. Analysis of a VP16 promoter/reporter mutant in the background of in 1814 demonstrates that the VP16 promoter is activated in latently infected neurons following stress in the absence of other viral proteins. These findings support the novel hypothesis that de novo expression of VP16 regulates entry into the lytic program in neurons at all phases of the viral life cycle. HSV reactivation from latency conforms to a model in which stochastic derepression of the VP16 promoter and expression of VP16 initiates entry into the lytic cycl

Brownville\u27s Ice Man: Jakob Larson

A pamphlet providing information about Jakob Jake Larson\u27s ice business in Brownville, Maine, in the early 1900s. Written by local historian Bill Sawtell, circa 2000

An exploration of practitioner-researcher collaboration on randomized controlled trials of complex interventions

Background. The past two decades have seen great interest in the development and evaluation of complex social interventions. The randomised controlled trial (RCT) is the normative research design for these evaluations and academic-practitioner collaboration in the conduct of studies is increasingly common to maximise rigour and relevance. However, gaps remain in what is known about how collaboration can be most effective in the co-production of knowledge. Practical examples of academic-practitioner collaboration can address these knowledge gaps. Aim: To demonstrate the development of academic-practitioner collaboration in the conduct of RCTs of complex health and education interventions through practical examples spanning two decades. Methods: Insider research drew on: four of my publications; experience of working on RCTs; and wider experience, gained over 20 years, working as a health visitor. Findings and conclusions: A general trend, in studies, across time is shown of: more relevant practitioners actively involved; in increasingly varied and influential study roles; with greater capacity to contribute to the research process. Improved management of the boundary between intervention and evaluation is also demonstrated. These trends have increased the potential for a more equal and effective blend of academic and practitioner knowledge and as such the co-production of more useful research. Key practitioner voices have been missing from decision-making processes in RCTs, however, which is likely to have had a negative impact on the utility of the findings. Creative approaches to collaboration, utilising skills in interpersonal relations, awareness of context and spanning of boundaries can bring these harder to reach voices into the research process. These are skills central to health visiting practice. Although health visitors are relatively new to RCTs they are well positioned to be part of the process of conducting the rigorous and relevant RCTs that are important in the development of services, including health visiting

Non-Citizen Commemoration in Fifth and Fourth Century BC Attica

The present thesis is an iconographic study of funerary monuments that memorialise, votive reliefs that include and decree reliefs that honour non-citizens resident in Attica or involved with Athens in the course of the fifth and fourth centuries BC. Non-citizens here include metics (free resident foreigners), slaves, and foreigners. Collected together in this thesis are 173 funerary monuments, 34 epigraphic attestations of non-citizens dedicating, 65 votive reliefs that include non-citizens, and 60 decree reliefs. While non-citizens were marginalised legally and politically, they contributed to Athenian society and Athens’ position in the wider Greek world and their presence in the commemorative landscape was part of their contribution. This thesis employs and expands the ‘free spaces’ paradigm adapted by Kostas Vlassopoulos (2007), which envisions certain spaces in Athens as facilitating shared experiences between citizens and non-citizens that created shared identities. It argues that the cemeteries and sanctuaries of Attica were, when it came to commemoration, ‘free spaces’ traversed by both citizens and non-citizens, and that a shared iconography was created and used by citizens and non-citizens alike that both reflected their shared experiences and identities and contributed to those shared experiences and identities

Death with Dignity

This paper examines the issue of euthanasia, or physician assisted suicide, which has become increasingly prominent in the media and subject to public debate in recent years, both in the United States and the United Kingdom. This can largely be attributed to the publicity surrounding high-profile cases in which people suffering from terminal illnesses have ended their lives through voluntary euthanasia, and the increase in “suicide tourism” to Switzerland from the United Kingdom and other countries. The paper analyzes common arguments against euthanasia such as religious objections and concerns about a “slippery slope” leading to involuntary euthanasia. It reviews individual cases of voluntary euthanasia and relevant studies, and examines the opposing arguments in favor of the legalization of euthanasia