Use of Learning Media by Undergraduate Medical Students in Pharmacology: A Prospective Cohort Study

The ubiquity of the internet and computer-based technologies has an increasing impact on higher education and the way students access information for learning. Moreover, there is a paucity of information about the quantitative and qualitative use of learning media by the current student generation. In this study we systematically analyzed the use of digital and non-digital learning resources by undergraduate medical students. Daily online surveys and semi-structured interviews were conducted with a cohort of 338 third year medical students enrolled in a general pharmacology course. Our data demonstrate a predominant use of digital over non-digital learning resources (69 +/- 7% vs. 31 +/- 7%;p 300 pages) (10.6 +/- 3.3%),internet search (7.9 +/- 1.6%) and e-learning cases (7.6 +/- 3.0%). When comparing learning media use of teaching vs. pre-exam self-study periods, textbooks were used significantly less during self-study (-55%;p < 0.01), while exam questions (+334%;p < 0.01) and e-learning cases (+176%;p < 0.01) were utilized more. Taken together, our study revealed a high prevalence and acceptance of digital learning resources by undergraduate medical students, in particular mobile applications

E-government adoption: A cultural comparison

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer Science + Business Media, LLC 2008.E-government diffusion is an international phenomenon. This study compares e-government adoption in the U.K. to adoption in the U.S. In particular, this study seeks to determine if the same factors are salient in both countries. Several studies have explored citizen acceptance of e-government services in the U.S. However, few studies have explored this phenomenon in the U.K. To identify the similarities and differences between the U.K. and the U.S. a survey is conducted in the U.K. and the findings are compared to the literature that investigates diffusion in the U.S. This study proposes a model of e-government adoption in the U.K. based on salient factors in the U.S. A survey is administered to 260 citizens in London to assess the importance of relative advantage, trust and the digital divide on intention to use e-government. The results of binary logistic regression indicate that there are cultural differences in e-government adoption in the U.K. and the U.S. The results indicate that of the prevailing adoption constructs, relative advantage and trust are pertinent in both the U.S. and the U.K., while ICT adoption barriers such as access and skill may vary by culture. Implications for research and practice are discussed

Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.(VLID)471264

Urothelial Plaque Formation in Post-Golgi Compartments

Urothelial plaques are specialized membrane domains in urothelial superficial (umbrella) cells, composed of highly ordered uroplakin particles. We investigated membrane compartments involved in the formation of urothelial plaques in mouse umbrella cells. The Golgi apparatus did not contain uroplakins organized into plaques. In the post-Golgi region, three distinct membrane compartments containing uroplakins were characterized: i) Small rounded vesicles, located close to the Golgi apparatus, were labelled weakly with anti-uroplakin antibodies and they possessed no plaques; we termed them “uroplakin-positive transporting vesicles” (UPTVs). ii) Spherical-to-flattened vesicles, termed “immature fusiform vesicles” (iFVs), were uroplakin-positive in their central regions and contained small urothelial plaques. iii) Flattened “mature fusiform vesicles” (mFVs) contained large plaques, which were densely labelled with anti-uroplakin antibodies. Endoytotic marker horseradish peroxidase was not found in these post-Golgi compartments. We propose a detailed model of de novo urothelial plaque formation in post-Golgi compartments: UPTVs carrying individual 16-nm particles detach from the Golgi apparatus and subsequently fuse into iFV. Concentration of 16-nm particles into plaques and removal of uroplakin-negative membranes takes place in iFVs. With additional fusions and buddings, iFVs mature into mFVs, each carrying two urothelial plaques toward the apical surface of the umbrella cell

CUL-2^LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis

Replisome disassembly is the final step of DNA replication in eukaryotes, involving the ubiquitylation and CDC48-dependent dissolution of the CMG helicase (CDC45-MCM-GINS). Using Caenorhabditis elegans early embryos and Xenopus laevis egg extracts, we show that the E3 ligase CUL-2(LRR-1) associates with the replisome and drives ubiquitylation and disassembly of CMG, together with the CDC-48 cofactors UFD-1 and NPL-4. Removal of CMG from chromatin in frog egg extracts requires CUL2 neddylation, and our data identify chromatin recruitment of CUL2(LRR1) as a key regulated step during DNA replication termination. Interestingly, however, CMG persists on chromatin until prophase in worms that lack CUL-2(LRR-1), but is then removed by a mitotic pathway that requires the CDC-48 cofactor UBXN-3, orthologous to the human tumour suppressor FAF1. Partial inactivation of lrr-1 and ubxn-3 leads to synthetic lethality, suggesting future approaches by which a deeper understanding of CMG disassembly in metazoa could be exploited therapeutically

NEDDylation is essential for Kaposi's sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which are aggressive malignancies associated with immunocompromised patients. For many non-viral malignancies, therapeutically targeting the ubiquitin proteasome system (UPS) has been successful. Likewise, laboratory studies have demonstrated that inhibition of the UPS might provide a promising avenue for the treatment of KSHV-associated diseases. The largest class of E3 ubiquitin ligases are the cullin-RING ligases (CRLs) that are activated by an additional ubiquitin-like protein, NEDD8. We show that pharmacological inhibition of NEDDylation (using the small molecule inhibitor MLN4924) is cytotoxic to PEL cells by inhibiting NF-κB. We also show that CRL4B is a novel regulator of latency as its inhibition reactivated lytic gene expression. Furthermore, we uncovered a requirement for NEDDylation during the reactivation of the KSHV lytic cycle. Intriguingly, inhibition prevented viral DNA replication but not lytic cycle-associated gene expression, highlighting a novel mechanism that uncouples these two features of KSHV biology. Mechanistically, we show that MLN4924 treatment precluded the recruitment of the viral pre-replication complex to the origin of lytic DNA replication (OriLyt). These new findings have revealed novel mechanisms that regulate KSHV latency and reactivation. Moreover, they demonstrate that inhibition of NEDDylation represents a novel approach for the treatment of KSHV-associated malignancies

Use of learning media by undergraduate medical students in pharmacology: a prospective cohort study.

The ubiquity of the internet and computer-based technologies has an increasing impact on higher education and the way students access information for learning. Moreover, there is a paucity of information about the quantitative and qualitative use of learning media by the current student generation. In this study we systematically analyzed the use of digital and non-digital learning resources by undergraduate medical students. Daily online surveys and semi-structured interviews were conducted with a cohort of 338 third year medical students enrolled in a general pharmacology course. Our data demonstrate a predominant use of digital over non-digital learning resources (69 ± 7% vs. 31 ± 7%; p < 0.01) by students. Most used media for learning were lecture slides (26.8 ± 3.0%), apps (22.0 ± 3.7%) and personal notes (15.5 ± 2.7%), followed by textbooks (> 300 pages) (10.6 ± 3.3%), internet search (7.9 ± 1.6%) and e-learning cases (7.6 ± 3.0%). When comparing learning media use of teaching vs. pre-exam self-study periods, textbooks were used significantly less during self-study (-55%; p < 0.01), while exam questions (+334%; p < 0.01) and e-learning cases (+176%; p < 0.01) were utilized more. Taken together, our study revealed a high prevalence and acceptance of digital learning resources by undergraduate medical students, in particular mobile applications

Experimental setting and timeline.

<p>A mixed-methods design of quantitative (online surveys) and qualitative (semi-structured interviews) studies was employed during an undergraduate pharmacology course at Technische Universität München, Germany. The course consisted of a 28-day teaching period with daily lectures and twice-weekly seminars, followed by a 10-day self-study period and a final written exam.</p

YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells

Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high cells proliferate, EWS-FLI1low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment