253 research outputs found
Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.
Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.This work was funded by an MRC programme grant [G0800034] to SJB. LAS was the recipient of a BBSRC PhD studentship. ES and TK were funded by the DFG [Sachbeihilfe KL 1028/5-Â1].This is the author accepted manuscript. The final version is available from Rockefeller University Press via http://dx.doi.org/10.1083/jcb.20141100
Experiences of dysphagia after stroke: an interview study of stroke survivors and their informal caregivers
(1) Background: Swallowing difficulties (dysphagia) after stroke are not uncommon and is a consistent risk factor for stroke-associated pneumonia. This interview study explores the perspectives of stroke survivors, who had their swallowing assessed in the first few days of admission to hospital, and their informal caregivers. (2) Methods: A participatory approach was used involving people affected by stroke in the interpretation and analysis of the interview data. Data was thematically analysed and six themes were identified. (3) Results: These themes included how past-future experiences may influence a person’s emotional response to events; understanding what is happening and adjustment; the impact of dysphagia; attitudes to care; communication to patients and procedural issues. (4) Conclusion: The findings highlight the importance of effective public health messages to improve people’s responsiveness to the signs of stroke, standardisation of assessment and management procedures, effective communication to patients about the consequences of dysphagia, and the impact of dysphagia on the person who had the stroke and their informal caregiver
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A three-dimensional ex vivo tri-culture model mimics cell-cell interactions between acute myeloid leukemia and the vascular niche
Ex vivo studies of human disease, such as acute myeloid leukemia, are generally limited to the analysis of two-dimensional cultures which often misinterpret the effectiveness of chemotherapeutics and other treatments. Here we show that matrix metalloproteinase-sensitive hydrogels prepared from poly(ethylene glycol) and heparin functionalized with adhesion ligands and pro-angiogenic factors can be instrumental to produce robust three-dimensional culture models, allowing for the analysis of acute myeloid leukemia development and response to treatment. We evaluated the growth of four leukemia cell lines, KG1a, MOLM13, MV4-11 and OCI-AML3, as well as samples from patients with acute myeloid leukemia. Furthermore, endothelial cells and mesenchymal stromal cells were co-seeded to mimic the vascular niche for acute myeloid leukemia cells. Greater drug resistance to daunorubicin and cytarabine was demonstrated in three-dimensional cultures and in vascular co-cultures when compared with two-dimensional suspension cultures, opening the way for drug combination studies. Application of the C-X-C chemokine receptor type 4 (CXCR4) inhibitor, AMD3100, induced mobilization of the acute myeloid leukemia cells from the vascular networks. These findings indicate that the three-dimensional tri-culture model provides a specialized platform for the investigation of cell-cell interactions, addressing a key challenge of current testing models. This ex vivo system allows for personalized analysis of the responses of patients’ cells, providing new insights into the development of acute myeloid leukemia and therapies for this disease
Modeling Galactic Conformity with the Color-Halo Age Relation in the Illustris Simulation
Comparisons between observational surveys and galaxy formation models find
that the mass of dark matter haloes can largely explain galaxies' stellar mass.
However, it remains uncertain whether additional environmental variables,
generally referred to as assembly bias, are necessary to explain other galaxy
properties. We use the Illustris Simulation to investigate the role of assembly
bias in producing galactic conformity by considering 18,000 galaxies with
> . We find a significant signal of
galactic conformity: out to distances of about 10 Mpc, the mean red fraction of
galaxies around redder galaxies is higher than around bluer galaxies at fixed
stellar mass. Dark matter haloes exhibit an analogous conformity signal, in
which the fraction of haloes formed at earlier times (old haloes) is higher
around old haloes than around younger ones at fixed halo mass. A plausible
interpretation of galactic conformity can be given as a combination of the halo
conformity signal with the galaxy color-halo age relation: at fixed stellar
mass, particularly toward the low-mass end, Illustris' galaxy colors correlate
with halo age, with the reddest galaxies (often satellites) being
preferentially found in the oldest haloes. In fact, we can explain the galactic
conformity effect with a simple semi-empirical model, by assigning stellar mass
based on halo mass (abundance matching) and by assigning galaxy color based on
halo age (age matching). We investigate other interpretations for the galactic
conformity, particularly its dependence on the isolation criterion and on the
central-satellite information. Regarding comparison to observations, we
conclude that the adopted selection/isolation criteria, projection effects, and
stacking techniques can have a significant impact on the measured amplitude of
the conformity signal.Comment: 15 pages, 8 figures; accepted for publication in MNRAS (minor
revisions to match accepted version
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3D Quantification of Vascular-Like Structures in z Stack Confocal Images
Optical slice microscopy is commonly used to characterize the morphometric features of 3D cellular cultures, such as in vitro vascularization. However, the quantitative analysis of those structures is often performed on a single 2D maximum intensity projection image, limiting the accuracy of data obtained from 3D cultures. Here, we present a protocol for the quantitative analysis of z stack images, utilizing Fiji, Amira, and WinFiber3D. This protocol facilitates the in-depth examination of vascular-like structures within 3D cell culture models
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Techniques for RNA extraction from cells cultured in starPEG-heparin hydrogels
Three-dimensional (3D) cell culture models that provide a biologically relevant microenvironment are imperative to investigate cell–cell and cell–matrix interactions in vitro. Semi-synthetic star-shaped poly(ethylene glycol) (starPEG)–heparin hydrogels are widely used for 3D cell culture due to their highly tuneable biochemical and biomechanical properties. Changes in gene expression levels are commonly used as a measure of cellular responses. However, the isolation of high-quality RNA presents a challenge as contamination of the RNA with hydrogel residue, such as polymer or glycosaminoglycan fragments, can impact template quality and quantity, limiting effective gene expression analyses. Here, we compare two protocols for the extraction of high-quality RNA from starPEG–heparin hydrogels and assess three subsequent purification techniques. Removal of hydrogel residue by centrifugation was found to be essential for obtaining high-quality RNA in both isolation methods. However, purification of the RNA did not result in further improvements in RNA quality. Furthermore, we show the suitability of the extracted RNA for cDNA synthesis of three endogenous control genes confirmed via quantitative polymerase chain reaction (qPCR). The methods and techniques shown can be tailored for other hydrogel models based on natural or semi-synthetic materials to provide robust templates for all gene expression analyses
Combining exercise with cognitive training and vitamin D
Changes in functional brain connectivity (FBC) may indicate how lifestyle modifications can prevent the progression to dementia; FBC identifies areas that are spatially separate but temporally synchronized in their activation and is altered in those with mild cognitive impairment (MCI), a prodromal state between healthy cognitive aging and dementia. Participants with MCI were randomly assigned to one of five study arms. Three times per week for 20-weeks, participants performed 30-min of (control) cognitive training, followed by 60-min of (control) physical exercise. Additionally, a vitamin
Proof of concept of a personalized genetic risk tool to promote smoking cessation:High acceptability and reduced cigarette smoking
Relatively little is known about the possible effects of personalized genetic risk information on smoking, the leading preventable cause of morbidity and mortality. We examined the acceptability and potential behavior change associated with a personalized genetically-informed risk tool (RiskProfile) among current smokers. Current smokers (n=108) were enrolled in a pre-post study with three visits. At Visit 1, participants completed a baseline assessment and genetic testing via 23andMe. Participants’ raw genetic data (CHRNA5 variants) and smoking heaviness were used to create a tailored RiskProfile tool that communicated personalized risks of smoking-related diseases and evidence-based recommendations to promote cessation. Participants received their personalized RiskProfile intervention at Visit 2, approximately 6 weeks later. Visit 3 involved a telephone-based follow-up assessment 30 days after intervention. Of enrolled participants, 83% were retained across the three visits. Immediately following intervention, acceptability of RiskProfile was high (M=4.4; SD=0.6 on scale of 1 to 5); at 30-day follow-up, 89% of participants demonstrated accurate recall of key intervention messages. In the full analysis set of this single-arm trial, cigarettes smoked per day decreased from intervention to 30-day follow-up [11.3 vs. 9.8, difference=1.5, 95% CI (0.6—2.4), p=.001]. A personalized genetically-informed risk tool was found to be highly acceptable and associated with a reduction in smoking, although the absence of a control group must be addressed in future research. This study demonstrates proof of concept for translating key basic science findings into a genetically-informed risk tool that was used to promote progress toward smoking cessation
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