12,496 research outputs found
The formation and function of ER-endosome membrane contact sites
No full textRecent advances in membrane contact site (MCS) biology have revealed key roles for MCSs in inter-organellar exchange, the importance of which is becoming increasingly apparent. Roles for MCSs in many essential physiological processes including lipid transfer, calcium exchange, receptor tyrosine kinase signalling, lipid droplet formation, autophagosome formation, organelle dynamics and neurite outgrowth have been reported. The ER forms an extensive and dynamic network of MCSs with a diverse range of functionally distinct organelles. MCSs between the ER and endocytic pathway are particularly abundant, suggesting important physiological roles. Here, our current knowledge of the formation and function of ER contact sites with endocytic organelles from studies in mammalian systems is reviewed. Their relatively poorly defined molecular composition and recently identified functions are discussed. In addition, likely, but yet to be established, roles for these contacts in lipid transfer and calcium signalling are considered. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim Levine and Anant K. Menon
Gedragsinzichten bieden meer beleidskansen dan er nu worden benut
No full textGedragsinzichten zijn onontbeerlijk om te komen tot effectief beleid, de mens is immers geen homo economicus. Dat geldt echter niet alleen voor uitvoeringsvraagstukken, maar ook voor het ontwerpen van beleid. Hier ligt er nog een groot onbenut potentieel.Policy Analysi
Embedding research (ER) led by nurses, midwives and allied health professionals (NMAHPs): the NMAHP-ER model.
No full textPrevious embedded researcher models have focused predominantly on an individual being a temporary team member and embedded for a project-limited short-term placement. To develop an innovative research capacity building model to address the challenges of developing, embedding and sustaining, research led by Nurses, Midwives, and Allied Health Professionals (NMAHPs) in complex clinical environments. This healthcare and academic research partnership model offers an opportunity to support the 'how' of enabling NMAHP research capacity building from within the researchers' clinical area of expertise. Collaboration between three healthcare and academic organisations and the iterative process of cocreation, development and refinement took place over 6 months during 2021. The collaboration relied on virtual meetings, emails, telephone calls and document review. A codesigned NMAHP embedded research (ER) model is ready for trialling with the individual being an existing clinician working collaboratively within the healthcare setting and with academia to develop the skills to become the ER. This model supports NMAHP-led research activity in clinical organisations in a visible and manageable way. As a shared, long-term vision, the model will contribute to research capacity and capability of the wider healthcare workforce. It will lead, facilitate and support research in and across clinical organisations in collaboration with higher education institutions. [Abstract copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Sequencing human-gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites
No full textThe gibbon genome exhibits extensive karyotypic diversity with an increased rate of chromosomal rearrangements during evolution. In an effort to understand the mechanistic origin and implications of these rearrangement events, we sequenced 24 synteny breakpoint regions in the white-cheeked gibbon (Nomascus leucogenys, NLE) in the form of high-quality BAC insert sequences (4.2 Mbp). While there is a significant deficit of breakpoints in genes, we identified seven human gene structures involved in signaling pathways (DEPDC4, GNG10), phospholipid metabolism (ENPP5, PLSCR2), beta-oxidation (ECH1), cellular structure and transport (HEATR4), and transcription (ZNF461), that have been disrupted in the NLE gibbon lineage. Notably, only three of these genes show the expected evolutionary signatures of pseudogenization. Sequence analysis of the breakpoints suggested both nonclassical nonhomologous end-joining (NHEJ) and replication-based mechanisms of rearrangement. A substantial number (11/24) of human-NLE gibbon breakpoints showed new insertions of gibbon-specific repeats and mosaic structures formed from disparate sequences including segmental duplications, LINE, SINE, and LTR elements. Analysis of these sites provides a model for a replication-dependent repair mechanism for double-strand breaks (DSBs) at rearrangement sites and insights into the structure and formation of primate segmental duplications at sites of genomic rearrangements during evolution
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No full textN.B.: When citing this work, cite the original article. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Radiation Protection Dosimetry following peer review. The definitive publisher-authenticated version
Molecular refinement of gibbon genome rearrangements
No full textThe gibbon karyotype is known to be extensively rearranged when compared to the human and to the ancestral primate karyotype. By combining a bioinformatics (paired-end sequence analysis) approach and a molecular cytogenetics approach, we have refined the synteny block arrangement of the white-cheeked gibbon (Nomascus leucogenys, NLE) with respect to the human genome. We provide the first detailed clone framework map of the gibbon genome and refine the location of 86 evolutionary breakpoints to <1 Mb resolution. An additional 12 breakpoints, mapping primarily to centromeric and telomeric regions, were mapped to approximately 5 Mb resolution. Our combined FISH and BES analysis indicates that we have effectively subcloned 49 of these breakpoints within NLE gibbon BAC clones, mapped to a median resolution of 79.7 kb. Interestingly, many of the intervals associated with translocations were gene-rich, including some genes associated with normal skeletal development. Comparisons of NLE breakpoints with those of other gibbon species reveal variability in the position, suggesting that chromosomal rearrangement has been a longstanding property of this particular ape lineage. Our data emphasize the synergistic effect of combining computational genomics and cytogenetics and provide a framework for ultimate sequence and assembly of the gibbon genome
Next-Generation Sequencing: Application in Liver Cancer—Past, Present and Future?
No full textHepatocellular Carcinoma (HCC) is the third most deadly malignancy worldwide characterized by phenotypic and molecular heterogeneity. In the past two decades, advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. More recently, improvements of sophisticated next-generation sequencing (NGS) technologies have enabled complete and cost-efficient analyses of cancer genomes at a single nucleotide resolution and advanced into valuable tools in translational medicine. Although the use of NGS in human liver cancer is still in its infancy, great promise rests in the systematic integration of different molecular analyses obtained by these methodologies, i.e., genomics, transcriptomics and epigenomics. This strategy is likely to be helpful in identifying relevant and recurrent pathophysiological hallmarks thereby elucidating our limited understanding of liver cancer. Beside tumor heterogeneity, progress in translational oncology is challenged by the amount of biological information and considerable “noise” in the data obtained from different NGS platforms. Nevertheless, the following review aims to provide an overview of the current status of next-generation approaches in liver cancer, and outline the prospects of these technologies in diagnosis, patient classification, and prediction of outcome. Further, the potential of NGS to identify novel applications for concept clinical trials and to accelerate the development of new cancer therapies will be summarized
Valt er geld te verdienen aan het voorspellen van Voetbaluitslagen?
No full textIn dit verslag is onderzocht of er geld te verdienen valt aan het spelen van online voetbaltoto. Er zijn twee modellen onderzocht; één op basis van onderlinge resultaten en de ander op basis van achtergrondvariabelen. Vervolgens zijn deze getest op fictieve en historische data en met elkaar vergeleken. Als conclusie is er gevonden dat er zeker een kans bestaat dat de modellen winstgevend kunnen zijn, maar dat er te weinig data is om dit met zekerheid te zeggen.StatisticsApplied mathematicsElectrical Engineering, Mathematics and Computer Scienc
The secretion inhibitor Exo2 perturbs trafficking of Shiga toxin between endosomes and the trans-Golgi network
No full textThe small-molecule inhibitor Exo2 {4-hydroxy-3-methoxy-(5,6,7,8-tetrahydrol[1]benzothieno[2,3-d]pyrimidin-4-yl)hydraz-one benzaldehyde} has been reported to disrupt the Golgi apparatus completely and to stimulate Golgi–ER (endoplasmic reticulum) fusion in mammalian cells, akin to the well-characterized fungal toxin BFA (brefeldin A). It has also been reported that Exo2 does not affect the integrity of the TGN (trans-Golgi network), or the direct retrograde trafficking of the glycolipid-binding cholera toxin from the TGN to the ER lumen. We have examined the effects of BFA and Exo2, and found that both compounds are indistinguishable in their inhibition of anterograde transport and that both reagents significantly disrupt the morphology of the TGN in HeLa and in BS-C-1 cells. However, Exo2, unlike BFA, does not induce tubulation and merging of the TGN and endosomal compartments. Furthermore, and in contrast with its effects on cholera toxin, Exo2 significantly perturbs the delivery of Shiga toxin to the ER. Together, these results suggest that the likely target(s) of Exo2 operate at the level of the TGN, the Golgi and a subset of early endosomes, and thus Exo2 provides a more selective tool than BFA for examining membrane trafficking in mammalian cells
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