Triptolide (TPL) Inhibits Global Transcription by Inducing Proteasome-Dependent Degradation of RNA Polymerase II (Pol II)

Triptolide (TPL), a key biologically active component of the Chinese medicinal herb Tripterygium wilfordii Hook. f., has potent anti-inflammation and anti-cancer activities. Its anti-proliferative and pro-apoptotic effects have been reported to be related to the inhibition of Nuclear Factor κB (NF-κB) and Nuclear Factor of Activated T-cells (NFAT) mediated transcription and suppression of HSP70 expression. The direct targets and precise mechanisms that are responsible for the gene expression inhibition, however, remain unknown. Here, we report that TPL inhibits global gene transcription by inducing proteasome-dependent degradation of the largest subunit of RNA polymerase II (Rpb1) in cancer cells. In the presence of proteosome inhibitor MG132, TPL treatment causes hyperphosphorylation of Rpb1 by activation of upstream protein kinases such as Positive Transcription Elongation Factor b (P-TEFb) in a time and dose dependent manner. Also, we observe that short time incubation of TPL with cancer cells induces DNA damage. In conclusion, we propose a new mechanism of how TPL works in killing cancer. TPL inhibits global transcription in cancer cells by induction of phosphorylation and subsequent proteasome-dependent degradation of Rpb1 resulting in global gene transcription, which may explain the high potency of TPL in killing cancer

Beak and feather disease virus in wild and captive parrots: an analysis of geographic and taxonomic distribution and methodological trends

Psittacine beak and feather disease (PBFD) has emerged in recent years as a major threat to wild parrot populations and is an increasing concern to aviculturists and managers of captive populations. Pathological and serological tests for screening for the presence of beak and feather disease virus (BFDV) are a critical component of efforts to manage the disease and of epidemiological studies. Since the disease was first reported in the mid-1970s, screening for BFDV has been conducted in numerous wild and captive populations. However, at present, there is no current and readily accessible synthesis of screening efforts and their results. Here, we consolidate information collected from 83 PBFD- and BFDV-based publications on the primary screening methods being used and identify important knowledge gaps regarding potential global disease hotspots. We present trends in research intensity in this field and critically discuss advances in screening techniques and their applications to both aviculture and to the management of threatened wild populations. Finally, we provide an overview of estimates of BFDV prevalence in captive and wild flocks alongside a complete list of all psittacine species in which the virus has been confirmed. Our evaluation highlights the need for standardised diagnostic tests and more emphasis on studies of wild populations, particularly in view of the intrinsic connection between global trade in companion birds and the spread of novel BFDV strains into wild populations. Increased emphasis should be placed on the screening of captive and wild parrot populations within their countries of origin across the Americas, Africa and Asia

A prognostic index for operable, node-negative breast cancer

Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited, Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival ('good outcome') or distant relapse within 6 years of diagnosis ('poor outcome'). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated. This index was then validated by testing its predictive power on a second, independent set of cases. A combination of histological grade plus immunochemical staining for BCL-2, p27 and Cyclin D 1, generated a useful prognostic index for tamoxifen-treated patients but not for those treated by surgery alone, The value of the index was confirmed in a second set of tamoxifen-treated, early stage breast cancers. Over-all, it correctly predicted good and poor outcome in 79 and 74% of cases, respectively (odds ratio 11.0). Other markers assessed added little to prediction of outcome. In the case of molecular assays, sensitivity and reliability were compromised by the age of the tissue specimens and the variability of fixation protocols. In selecting patients for adjuvant systemic chemotherapy, the proposed index improves considerably on current international guidelines and matches the performance reported for 'gene-expression signature' analysis. (C) 2004 Cancer Research UK.</p

Introduction: new research in monetary history - A map

This handbook aims to provide a comprehensive (though obviously not exhaustive) picture of state-of-the-art international scholarship on the history of money and currency. The chapters of this handbook cover a wide selection of research topics. They span chronologically from antiquity to nowadays and are geographically stretched from Latin America to Asia, although most of them focus on Western Europe and the USA, as a large part of the existing research does. The authors of these chapters constitute, we hope, a balanced sample of various generations of scholars who contributed to what Barry Eichengreen defined as "the new monetary and financial history" &#8211; an approach that combines the analysis of monetary aggregates and policies with the structure and dynamics of the banking sector and financial markets. We have structured this handbook in ten broad thematic parts: the historical origins of money; money, coinage, and the state; trade, money markets, and international currencies; money and metals; monetary experiments; Asian monetary systems; exchange rate regimes; monetary integration; central banking and monetary policy; and aggregate price shocks. In this introduction, we offer for each part some historical context, a few key insights from the literature, and a brief analytical summary of each chapter. Our aim is to draw a map that hopefully will help readers to organize their journey through this very wide and diverse research area

Impact of educational interventions on adolescent attitudes and knowledge regarding vaccination: A pilot study

© 2018 Carolan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Current immunisation levels in England currently fall slightly below the threshold recommended by the World Health Organization, and the three-year trend for vaccination uptake is downwards. Attitudes towards vaccination can affect future decisions on whether or not to vaccinate, and this can have significant public health implications. Interventions can impact future vaccination decisions, and these interventions can take several forms. Relatively little work has been reported on the use of vaccination interventions in young people, who form the next generation of individuals likely to make vaccination decisions. Method We investigated the impact of two different types of educational intervention on attitudes towards vaccination in young people in England. A cohort of young people (n = 63) was recruited via a local school. This group was divided into three sub-groups; one (n = 21) received a presentation-based intervent ion, one (n = 26) received an interactive simulation-based intervention, and the third (n = 16) received no intervention. Participants supplied information on (1) their attitudes towards vaccination, and (2) their information needs and views on personal choice concerning vaccination, at three time points: immediately before and after the intervention, and after six months. Results Neither intervention had a significant effect on participants’ attitudes towards vaccination. However, the group receiving the presentation-based intervention saw a sustained uplift in confidence about information needs, which was not observed in the simulation-based intervention group. Discussion Our findings with young people are consistent with previous work on vaccination interventions aimed at adults, which have shown limited effectiveness, and which can actually reduce intention to vaccinate. Our findings on the most effective mode of delivery for the intervention should inform future discussion in the growing “games for health” domain, which proposes the use of interactive digital resources in healthcare education

Lytic activity by temperate phages of Pseudomonas aeruginosa in long-term cystic fibrosis chronic lung infections

Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of cystic fibrosis (CF) patients. The transmissible Liverpool epidemic strain (LES) harbours multiple inducible prophages (LESϕ2; LESϕ3; LESϕ4; LESϕ5; and LESϕ6), some of which are known to confer a competitive advantage in an in vivo rat model of chronic lung infection. We used quantitative PCR (Q-PCR) to measure the density and dynamics of all five LES phages in the sputa of 10 LES-infected CF patients over a period of 2 years. In all patients, the densities of free-LES phages were positively correlated with the densities of P. aeruginosa, and total free-phage densities consistently exceeded bacterial host densities 10–100-fold. Further, we observed a negative correlation between the phage-to-bacterium ratio and bacterial density, suggesting a role for lysis by temperate phages in regulation of the bacterial population densities. In 9/10 patients, LESϕ2 and LESϕ4 were the most abundant free phages, which reflects the differential in vitro induction properties of the phages. These data indicate that temperate phages of P. aeruginosa retain lytic activity after prolonged periods of chronic infection in the CF lung, and suggest that temperate phage lysis may contribute to regulation of P. aeruginosa density in vivo

Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model

Background: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. Methodology/Principal Findings: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. Conclusions/Significance: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications fo