The Agrobacterium VirE3 effector protein: a potential plant transcriptional activator

During the infection of plants, Agrobacterium tumefaciens introduces several Virulence proteins including VirE2, VirF, VirD5 and VirE3 into plant cells in addition to the T-DNA. Here, we report that double mutation of virF and virE3 leads to strongly diminished tumor formation on tobacco, tomato and sunflower. The VirE3 protein is translated from a polycistronic mRNA containing the virE1, virE2 and virE3 genes, in Agrobacterium. The VirE3 protein has nuclear localization sequences, which suggests that it is transported into the plant cell nucleus upon translocation. Indeed we show here that VirE3 interacts in vitro with importin-α and that a VirE3–GFP fusion protein is localized in the nucleus. VirE3 also interacts with two other proteins, viz. pCsn5, a component of the COP9 signalosome and pBrp, a plant specific general transcription factor belonging to the TFIIB family. We found that VirE3 is able to induce transcription in yeast when bound to DNA through the GAL4-BD. Our data indicate that the translocated effector protein VirE3 is transported into the nucleus and there it may interact with the transcription factor pBrp to induce the expression of genes needed for tumor development

Loudly sing cuckoo : More-than-human seasonalities in Britain

This research was funded by a grant from the Arts and Humanities Research Council, grant number AH/E009573/1.Peer reviewedPostprin

Quantifying the Relationship between Capability and Health in Older People: Can't Map, Won't Map

BACKGROUND: Intuitively, health and capability are distinct but linked concepts. This study aimed to quantify the link between a measure of health status (EQ-5D-3L) and capability (ICECAP-O) using regression-based methods. METHODS: EQ-5D-3L and ICECAP-O data were collected from a sample of older people ( n = 584), aged over 65 years, requiring a hospital visit and/or care home resident, and recruited to one of 3 studies forming the Medical Crisis in Older People (MCOP) program in England. The link of EQ-5D-3L with 1) ICECAP-O tariff scores were estimated using ordinary least squares (OLS) or censored least absolute deviation (CLAD) regression models; and 2) ICECAP-O domain scores was estimated using multinomial logistic (MNL) regression. Mean absolute error (MAE), root mean squared error (RMSE), absolute difference (AD) between mean observed and estimated values, and the R(2) statistic were used to judge model performance. RESULTS: In this sample of older people ( n = 584), higher scores on the EQ-5D-3L were shown to be linked with higher ICECAP-O scores when using linear regression. An OLS-regression model was identified to be the best performing model with the lowest error statistics (AD = 0.0000; MAE = 0.1208; MSE = 0.1626) and highest goodness of fit ( R(2) = 0.3532); model performance was poor when predicting the lower ICECAP-O tariff scores. The three domains of the EQ-5D-3L showing a statistically significant quantifiable link with the ICECAP-O tariff score were self-care, usual activities, and anxiety/depression. CONCLUSION: A quantifiable, but weak, link between health (EQ-5D-3L) and capability (ICECAP-O) was identified. The findings from this study add further support that the ICECAP-O is providing complimentary information to the EQ-5D-3L. Mapping between the 2 measures is not advisable and the measures should not be used as direct substitutes to capture the impact of interventions in economic evaluations

Immunomodulation Through Low-Dose Radiation for Severe COVID-19:Lessons From the Past and New Developments

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT

A translocation motif in relaxase TrwC specifically affects recruitment by its conjugative type IV secretion system

Type IV secretion system (T4SS) substrates are recruited through a translocation signal that is poorly defined for conjugative relaxases. The relaxase TrwC of plasmid R388 is translocated by its cognate conjugative T4SS, and it can also be translocated by the VirB/D4 T4SS of Bartonella henselae, causing DNA transfer to human cells. In this work, we constructed a series of TrwC variants and assayed them for DNA transfer to bacteria and human cells to compare recruitment requirements by both T4SSs. Comparison with other reported relaxase translocation signals allowed us to determine two putative translocation sequence (TS) motifs, TS1 and TS2. Mutations affecting TS1 drastically affected conjugation frequencies, while mutations affecting either motif had only a mild effect on DNA transfer rates through the VirB/D4 T4SS of B. henselae. These results indicate that a single substrate can be recruited by two different T4SSs through different signals. The C terminus affected DNA transfer rates through both T4SSs tested, but no specific sequence requirement was detected. The addition of a Bartonella intracellular delivery (BID) domain, the translocation signal for the Bartonella VirB/D4 T4SS, increased DNA transfer up to 4% of infected human cells, providing an excellent tool for DNA delivery to specific cell types. We show that the R388 coupling protein TrwB is also required for this high-efficiency TrwC-BID translocation. Other elements apart from the coupling protein may also be involved in substrate recognition by T4SSs

Recent advances in the structural and molecular biology of type IV secretion systems

Bacteria use type IV secretion (T4S) systems to deliver DNA and protein substrates to a diverse range of prokaryotic and eukaryotic target cells. T4S systems have great impact on human health, as they are a major source of antibiotic resistance spread among bacteria and are central to infection processes of many pathogens. Therefore, deciphering the structure and underlying translocation mechanism of T4S systems is crucial to facilitate development of new drugs. The last five years have witnessed considerable progress in unraveling the structure of T4S system subassemblies, notably that of the T4S system core complex, a large 1 MegaDalton (MDa) structure embedded in the double membrane of Gram-negative bacteria and made of 3 of the 12 T4S system components. However, the recent determination of the structure of ∼3 MDa assembly of 8 of these components has revolutionized our views of T4S system architecture and opened up new avenues of research, which are discussed in this review

Rhythms of walking : history and presence in a city street

Peer reviewedPostprin

Link to publication Citation for published version (APA)

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial van Kuijk, A.W.R.; Vergunst, C.E.; Gerlag, D.; Bresnihan, B.; Gomez-Reino, J.J.; Regine, R.; Verschueren, P.C.; van der Leij, C.; Maas, M.; Kraan, M.C.; Tak, P.P. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website

Taking a hike: Exploring leisure walkers embodied experiences

This paper uses walk along interviewing to investigate embodied experiences of walking on the South Downs Way, a long distance trail in southern England. Using a qualitative methodology - encompassing 93 walk-along interviews and auto-ethnographic reflections of two walker/researchers - it explores how walkers conceptualise their own walking experiences and captures this information while they are walking. It contributes to and extends the emerging body of literature which explores people’s experience, specifically aiming to develop a deeper understanding of leisure walking experiences in the dynamic space of the walk. It examines a range of bodily sensations and emotional states associated with the leisure walking experience in the context of temporal and environmental aspects, identifying those feelings that are innate and those which are mediated by external conditions. Current experiences intertwine with memories of other places and times in a process where connections are made between mind, body, the immediate physical environment, self and others, and disconnections from everyday life and the wider environment. These connections and disconnections create a sense of perspective, achievement and well-being

Altered perivascular fibroblast activity precedes ALS disease onset

Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology