13,137 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
Watts-level super-compact narrow-linewidth Tm-doped silica all-fiber laser near 1707 nm with fiber Bragg gratings
No full text
Watts-level ultra-short wavelength operation of a Tm-doped all fiber laser was developed by using a 1550 nm Er-doped fiber laser pump source and a pair of fiber Bragg gratings (FBGs). The laser yielded 1.28 W of continuous-wave output at 1707.01 nm with a narrow linewidth of similar to 44 pm by means of a 20 cm Tm-doped fiber. The dependencies of the slope efficiencies and pump threshold of the Tm-doped fiber laser versus the length of active fiber and reflectivity of the output mirror (FBG) were investigated in detail, in which the maximum average slope efficiency was 36.1%. There is no doubt that this all fiber laser will be a perfect pump source for mid-IR laser output.</p
Silencing disease genes in the laboratory and the clinic
No full textSynthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology
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.
Precipitation characteristics along a semiarid mountain front in the North American monsoon region: implications for hydrologic modeling and ecosystem distribution
No full textEeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways
No full textBackground: The small molecule Eeyarestatin I (ESI) inhibits the endoplasmic reticulum (ER)-cytosol dislocation and
subsequent degradation of ERAD (ER associated protein degradation) substrates. Toxins such as ricin and Shiga/Shiga-like
toxins (SLTx) are endocytosed and trafficked to the ER. Their catalytic subunits are thought to utilise ERAD-like mechanisms
to dislocate from the ER into the cytosol, where a proportion uncouples from the ERAD process, recovers a catalytic
conformation and destroys their cellular targets. We therefore investigated ESI as a potential inhibitor of toxin dislocation.
Methodology and Principal Findings: Using cytotoxicity measurements, we found no role for ESI as an inhibitor of toxin
dislocation from the ER, but instead found that for SLTx, ESI treatment of cells was protective by reducing the rate of toxin
delivery to the ER. Microscopy of the trafficking of labelled SLTx and its B chain (lacking the toxic A chain) showed a delay in
its accumulation at a peri-nuclear location, confirmed to be the Golgi by examination of SLTx B chain metabolically labelled
in the trans-Golgi cisternae. The drug also reduced the rate of endosomal trafficking of diphtheria toxin, which enters the
cytosol from acidified endosomes, and delayed the Golgi-specific glycan modifications and eventual plasma membrane
appearance of tsO45 VSV-G protein, a classical marker for anterograde trafficking.
Conclusions and Significance: ESI acts on one or more components that function during vesicular transport, whilst at least
one retrograde trafficking pathway, that of ricin, remains unperturbed
Recommended from our members
RING1B is a Key Regulator of the Estrogen Response Pathway in ER+ Breast Cancer
No full textPolycomb repressive complexes 1 and 2 (PRC1 and PRC2) are essential regulators of stem cell pluripotency, lineage commitment, and development. Increasing amount of evidence suggests that PRC1 and PRC2 are strongly implicated in cancer, where subunits of both complexes behave in non-canonical ways to promote the expression of cancer-driving genes. Previous studies in our lab has shown that RING1B, the E3-ligase subunit of PRC1, colocalizes with ERα at active regions of the genome such as enhancers and superenhancers to regulate the oncogenic transcriptional program driving the growth of ER+ breast cancer cells. Nevertheless, the molecular mechanisms underlying the functional interaction between RING1B and ERα is not clear. Further, how RING1B is recruited to enhancers, superenhancers, and promoters of active-transcribed genes is completely unknown. We first discovered that RING1B is dynamically recruited to the chromatin within 8 to 12bps of ERα binding sites upon E2 stimulation. Furthermore, RING1B and ERα are mutually dependent on each other for recruitment to the chromatin, and RING1B is also dependent on chromatin-associated RNA for binding to RING1B-ERα co-target sites. Upon acute estrogen stimulation, RING1B is recruited to ERα target genes to directly participate in their transcription via mechanisms such as orchestrating enhancer-promoting looping and promoting E2-induced enhancer and superenhancer establishment. Thus, RING1B depletion severely attenuates the expression of RING1B-ERα co-target genes, decreases E2-induced R-loop formation, and abrogates E2-induced proliferation and clonogenic abilities of ER+ breast cancer cells. Although RING1B orchestrate E2-induced genome-wide chromatin accessibility changes, we found that changes in chromatin accessibility are not necessarily correlated with 3D chromatin architectural changes and transcriptional activation. Overall, our data suggest that the Polycomb protein RING1B is a key regulator of the E2-induced transcriptional activities in ER+ breast cancer.</p
Corresponding author:
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
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
- …
