Herpesvirus Telomerase RNA (vTR) with a Mutated Template Sequence Abrogates Herpesvirus-Induced Lymphomagenesis

Telomerase reverse transcriptase (TERT) and telomerase RNA (TR) represent the enzymatically active components of telomerase. In the complex, TR provides the template for the addition of telomeric repeats to telomeres, a protective structure at the end of linear chromosomes. Human TR with a mutation in the template region has been previously shown to inhibit proliferation of cancer cells in vitro. In this report, we examined the effects of a mutation in the template of a virus encoded TR (vTR) on herpesvirus-induced tumorigenesis in vivo. For this purpose, we used the oncogenic avian herpesvirus Marek's disease virus (MDV) as a natural virus-host model for lymphomagenesis. We generated recombinant MDV in which the vTR template sequence was mutated from AATCCCAATC to ATATATATAT (vAU5) by two-step Red-mediated mutagenesis. Recombinant viruses harboring the template mutation replicated with kinetics comparable to parental and revertant viruses in vitro. However, mutation of the vTR template sequence completely abrogated virus-induced tumor formation in vivo, although the virus was able to undergo low-level lytic replication. To confirm that the absence of tumors was dependent on the presence of mutant vTR in the telomerase complex, a second mutation was introduced in vAU5 that targeted the P6.1 stem loop, a conserved region essential for vTR-TERT interaction. Absence of vTR-AU5 from the telomerase complex restored virus-induced lymphoma formation. To test if the attenuated vAU5 could be used as an effective vaccine against MDV, we performed vaccination-challenge studies and determined that vaccination with vAU5 completely protected chickens from lethal challenge with highly virulent MDV. Taken together, our results demonstrate 1) that mutation of the vTR template sequence can completely abrogate virus-induced tumorigenesis, likely by the inhibition of cancer cell proliferation, and 2) that this strategy could be used to generate novel vaccine candidates against virus-induced lymphoma

Identification of Cellular Infiltrates during Early Stages of Brain Inflammation with Magnetic Resonance Microscopy

A comprehensive view of brain inflammation during the pathogenesis of autoimmune encephalomyelitis can be achieved with the aid of high resolution non-invasive imaging techniques such as microscopic magnetic resonance imaging (μMRI). In this study we demonstrate the benefits of cryogenically-cooled RF coils to produce μMRI in vivo, with sufficient detail to reveal brain pathology in the experimental autoimmune encephalomyelitis (EAE) model. We could visualize inflammatory infiltrates in detail within various regions of the brain, already at an early phase of EAE. Importantly, this pathology could be seen clearly even without the use of contrast agents, and showed excellent correspondence with conventional histology. The cryogenically-cooled coil enabled the acquisition of high resolution images within short scan times: an important practical consideration in conducting animal experiments. The detail of the cellular infiltrates visualized by in vivo μMRI allows the opportunity to follow neuroinflammatory processes even during the early stages of disease progression. Thus μMRI will not only complement conventional histological examination but will also enable longitudinal studies on the kinetics and dynamics of immune cell infiltration

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model.

OBJECTIVE: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing rational therapeutic approaches for treatment of progressive MS. It has been suggested that myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG35-55 )-induced EAE in nonobese diabetic (NOD) mice resembles secondary progressive MS. The objective was to determine whether the published data merits such claims. METHODS: Induction and monitoring of EAE in NOD mice and literature review. RESULTS: It is evident that the NOD mouse model lacks validity as a progressive MS model as the individual course seems to be an asynchronous, relapsing-remitting neurodegenerative disease, characterized by increasingly poor recovery from relapse. The seemingly progressive course seen in group means of clinical score is an artifact of data handling and interpretation. INTERPRETATION: Although MOG35-55 -induced EAE in NOD mice may provide some clues about approaches to block neurodegeneration associated with the inflammatory penumbra as lesions form, it should not be used to justify trials in people with nonactive, progressive MS. This adds further support to the view that drug studies in animals should universally adopt transparent raw data deposition as part of the publication process, such that claims can adequately be interrogated. This transparency is important if animal-based science is to remain a credible part of translational research in MS.Stichting MS ResearchWellcome TrustMedical Research CouncilNational Multiple Sclerosis Society. Grant Number: RG4132A5/

Vegan diets : practical advice for athletes and exercisers.

With the growth of social media as a platform to share information, veganism is becoming more visible, and could be becoming more accepted in sports and in the health and fitness industry. However, to date, there appears to be a lack of literature that discusses how to manage vegan diets for athletic purposes. This article attempted to review literature in order to provide recommendations for how to construct a vegan diet for athletes and exercisers. While little data could be found in the sports nutrition literature specifically, it was revealed elsewhere that veganism creates challenges that need to be accounted for when designing a nutritious diet. This included the sufficiency of energy and protein; the adequacy of vitamin B12, iron, zinc, calcium, iodine and vitamin D; and the lack of the long-chain n-3 fatty acids EPA and DHA in most plant-based sources. However, via the strategic management of food and appropriate supplementation, it is the contention of this article that a nutritive vegan diet can be designed to achieve the dietary needs of most athletes satisfactorily. Further, it was suggested here that creatine and β-alanine supplementation might be of particular use to vegan athletes, owing to vegetarian diets promoting lower muscle creatine and lower muscle carnosine levels in consumers. Empirical research is needed to examine the effects of vegan diets in athletic populations however, especially if this movement grows in popularity, to ensure that the health and performance of athletic vegans is optimised in accordance with developments in sports nutrition knowledge

The accessibility and acceptability of self-management support interventions for men with long term conditions: a systematic review and meta-synthesis of qualitative studies

Background: Self-management support interventions can improve health outcomes, but their impact is limited by the numbers of people able or willing to access them. Men’s attendance at existing self-management support services appears suboptimal despite their increased risk of developing many of the most serious long term conditions. The aim of this review was to determine whether current self-management support interventions are acceptable and accessible to men with long term conditions, and explore what may act as facilitators and barriers to access of interventions and support activities. Methods: A systematic search for qualitative research was undertaken on CINAHL, EMBASE, MEDLINE, PsycINFO and Social Science Citation Index, in July 2013. Reference lists of relevant articles were also examined. Studies that used a qualitative design to explore men’s experiences of, or perceptions towards, self-management support for one or more long term condition were included. Studies which focused on experiences of living with a long term condition without consideration of self-management support were excluded. Thirty-eight studies met the inclusion criteria. A meta-ethnography approach was employed to synthesise the findings. Results: Four constructs associated with men’s experience of, and perceptions towards, self management support were identified: 1) need for purpose; 2) trusted environments; 3) value of peers; and 4) becoming an expert. The synthesis showed that men may feel less comfortable participating in self-management support if it is viewed as incongruous with valued aspects of their identity, particularly when activities are perceived to challenge masculine ideals associated with independence, stoicism, and control. Men may find self-management support more attractive when it is perceived as action-oriented, having a clear purpose, and offering personally meaningful information and practical strategies that can be integrated into daily life. Conclusions: Self-management support is most likely to be successful in engaging men when it is congruent with key aspects of their masculine identity. In order to overcome barriers to access and fully engage with interventions, some men may need self-management support interventions to be delivered in an environment that offers a sense of shared understanding, connectedness, and normality, and involves and/or is facilitated by men with a shared illness experience

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype

New horizons for future research - Critical issues to consider for maximizing research excellence and impact.

We live in an era in which the pace of research and the obligation to integrate new discoveries into a field's conceptual framework are rapidly increasing. At the same time, uncertainties about resources, funding, positions and promotions, the politics of science, publishing (the drive to publish in so-called high-impact journals) and many other concerns are mounting. To consider many of these phenomena in depth, a meeting was recently convened to discuss issues critical to conducting research with an emphasis on the neurobiology of metabolism and related areas. Attendees included a mix of senior and junior investigators from the United States, Latin America, and Western Europe, representing several relevant disciplines. Participants were initially assigned to small groups to consider specific questions in depth, and the results of those deliberations were then presented and discussed over several plenary sessions. Although there was spirited discussion with sometimes differing opinions on some issues, in general there was good consensus among individuals and the various groups. While the discussions were wide-ranging, we have condensed the topics into three (albeit often overlapping) major areas: 1) General research issues applicable to multiple areas of translational research; for instance, animal models, sex and gender differences, examples of emerging technologies, as well as the issue of data reproducibility and related topics. 2) Funding issues, such as how to secure industry funding without compromising research direction or academic integrity, and the training of students and fellows, with a focus on how to optimally prepare trainees for the diverse potential career paths available. 3) Finally, specific research topics of interest were discussed, including whether peptides or other signaling compounds, or specific brain areas, have “thematic functions” or the challenges associated with investigating the function of G-protein-coupled receptors (GPCR) in the brain

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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