The regulation of cellular microRNAs during KSHV lytic replication

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human tumour virus and the causative agent of Kaposi’s sarcoma (KS), as well as multiple lymphoproliferative diseases. As is characteristic of all herpesviruses, KSHV can undergo both latent and lytic replication cycles. During latent infection, viral gene expression is limited, enabling persistence of the viral genome. Whereas lytic replication is characterised by the abundant transcription of viral genes, and the production and release of infectious virions. Interestingly, both of these cycles are important for KSHV pathogenesis. Viruses have developed numerous mechanisms to manipulate host mRNA expression. Indeed, the dysregulation of cellular miRNAs has emerged as a common mechanism utilised by viruses to influence the host cell transcriptome during infection. In chapter 3, the differential expression of cellular miRNAs was investigated following KSHV lytic reactivation. Notably miR-142-3p and miR-25-p were found to be downregulated. Importantly, overexpression of these miRNAs had a significant impact on KSHV lytic replication, culminating in a substantial reduction in the production of infectious virions. In Chapter 4, GPRC5A was identified as a direct target of miR-142-3p, with the KSHV�mediated downregulation of miR-142-3p thought to contribute to the upregulation of GPRC5A expression during KSHV lytic replication. Subsequent analysis implicated GPRC5A in the regulation of actin dynamics as well as a potential involvement in lipid raft stability. Both of which may enhance viral egress and dissemination. Finally, in Chapter 5 investigations were undertaken to determine the potential mechanisms involved in the regulation of miR-142-3p expression. Results highlighted ORF50 and ADAR editing as potential factors involved in the downregulation of miR-142-3p following KSHV lytic reactivation. To summarise, this study identifies a number of previously unidentified host cell interactions during KSHV lytic replication, which could prove valuable targets for the development of novel therapeutic approaches

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Metropolitan Contractor Improvement Partnership 2013-2018 Strategic Plan

25 pagesThis report, the Metropolitan Contractor Improvement Partnership 2013-2018 Strategic Plan, identifies the key issues facing the organization, and suggests goals, strategies, and actions to address those issues.Economic Development Administration University Cente

Bunyavirus requirement for endosomal K+ reveals new roles of cellular ion channels during infection

In order to multiply and cause disease a virus must transport its genome from outside the cell into the cytosol, most commonly achieved through the endocytic network. Endosomes transport virus particles to specific cellular destinations and viruses exploit the changing environment of maturing endocytic vesicles as triggers to mediate genome release. Previously we demonstrated that several bunyaviruses, which comprise the largest family of negative sense RNA viruses, require the activity of cellular potassium (K+) channels to cause productive infection. Specifically, we demonstrated a surprising role for K+ channels during virus endosomal trafficking. In this study, we have used the prototype bunyavirus, Bunyamwera virus (BUNV), as a tool to understand why K+ channels are required for progression of these viruses through the endocytic network. We report three major findings: First, the production of a dual fluorescently labelled bunyavirus to visualize virus trafficking in live cells. Second, we show that BUNV traffics through endosomes containing high [K+] and that these K+ ions influence the infectivity of virions. Third, we show that K+ channel inhibition can alter the distribution of K+ across the endosomal system and arrest virus trafficking in endosomes. These data suggest high endosomal [K+] is a critical cue that is required for virus infection, and is controlled by cellular K+ channels resident within the endosome network. This highlights cellular K+ channels as druggable targets to impede virus entry, infection and disease

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss

Prisoners’ Families’ Research: Developments, Debates and Directions

After many years of relative obscurity, research on prisoners’ families has gained significant momentum. It has expanded from case-oriented descriptive analyses of family experiences to longitudinal studies of child and family development and even macro analyses of the effects on communities in societies of mass incarceration. Now the field engages multi-disciplinary and international interest although it arguably still remains on the periphery of mainstream criminological, psychological and sociological research agendas. This chapter discusses developments in prisoners’ families’ research and its positioning in academia and practice. It does not aim to provide an all-encompassing review of the literature rather it will offer some reflections on how and why the field has developed as it has and on its future directions. The chapter is divided into three parts. The first discusses reasons for the historically small body of research on prisoners’ families and for the growth in research interest over the past two decades. The second analyses patterns and shifts in the focus of research studies and considers how the field has been shaped by intersecting disciplinary interests of psychology, sociology, criminology and socio-legal studies. The final part reflects on substantive and ethical issues that are likely to shape the direction of prisoners’ families’ research in the future

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep

AbstractThe circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep