Assessing the Efficacy of Nano- and Micro-Sized Magnetic Particles as Contrast Agents for MRI Cell Tracking

Iron-oxide based contrast agents play an important role in magnetic resonance imaging (MRI) of labelled cells in vivo. Currently, a wide range of such contrast agents is available with sizes varying from several nanometers up to a few micrometers and consisting of single or multiple magnetic cores. Here, we evaluate the effectiveness of these different particles for labelling and imaging stem cells, using a mouse mesenchymal stem cell line to investigate intracellular uptake, retention and processing of nano- and microsized contrast agents. The effect of intracellular confinement on transverse relaxivity was measured by MRI at 7 T and in compliance with the principles of the ‘3Rs’, the suitability of the contrast agents for MR-based cell tracking in vivo was tested using a chick embryo model. We show that for all particles tested, relaxivity was markedly reduced following cellular internalisation, indicating that contrast agent relaxivity in colloidal suspension does not accurately predict performance in MR-based cell tracking studies. Using a bimodal imaging approach comprising fluorescence and MRI, we demonstrate that labelled MSC remain viable following in vivo transplantation and can be tracked effectively using MRI. Importantly, our data suggest that larger particles might confer advantages for longer-term imaging

Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems

HIF (hypoxia inducible factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There is increasing evidence that cell signaling pathways encode temporal information, and thus cell fate may be determined by the dynamics of protein levels. We have developed a mathematical model to describe the transient dynamics of the HIF-1α protein measured in single cells subjected to hypoxic shock. The essential characteristics of these data are modeled with a system of differential equations describing the feedback inhibition between HIF-1α and prolyl hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD sensor responsible for controlling the HIF-1α transient response, and make here testable predictions regarding HIF-1α dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIF-1α in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIF-1α and transcriptional targets of HIF-1α display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behaviour of HIF-1α results in differential dynamics in transcriptional targets

Conceptualising and Enacting Pathways to Transformative Climate Justice: Examples from the Philippines

Scholarship on climate change adaptation is increasingly moving from incremental responses to climate injustice towards transformative approaches that deliberately change systems to achieve just and equitable outcomes. A transformative understanding of climate justice is relatively new and evidence of how this could be achieved is in its infancy. In this paper, we conceptualise transformative climate justice as comprised of three subcomponents: (1) inclusive justice (seeking to ensure that no one, especially the most vulnerable, is left behind), (2) epistemological justice (drawing upon diverse knowledges and worldviews), and (3) restorative justice (healing and restoration of communities and the environment). We then present examples of how different local communities in the Philippines are experimenting with climate adaptation strategies that embody these three components of transformative climate justice. Through case studies of communities in Itbayat (Batanes), Tambaliza (Iloilo), and Barangay Assumption (Koronadal), we demonstrate how their adaptive strategies contribute to community and ecological resilience. We find that transformative climate justice arises from mundane and everyday struggles, takes place at the “middle place” between top-down and bottom-up initiatives, and requires a deliberate redistribution of power to counter decision-making processes that reproduce injustices

Comparison of the shear bond strength of 3D printed temporary bridges materials, on different types of resin cements and surface treatment

Thus, purpose of this study was to compare the shear bond strength of the resin cement and the resin modified glass ionomer cement on 3D printed temporary material for crowns and bridges in combination with different surface treatment modalities. Test specimens VarseoSmile Temp material (Bego, Bremen, Germany) (n=64) in the form of rectangular blocks (n=32) and cylindrical test specimens (n=32) were printed using the Varseo S 3D printer (Bego, Bremen, Germany). The specimens were divided into 4 groups, with 8 specimens of each kind. Two groups (n=16 pairs) were blasted with Perlablast® Micro [PM] 50µm (Bego, Bremen, Germany) and two groups (n=16 pairs) were blasted with alumina [AL] 50µm. The cylindric specimen were cemented on the rectangular block with a load of 20N using a Zwick/Roell machine (Ulm, Germany), to ensure a comparable cementing process. One group (n=8) of each pre-treatment was cemented with Fuji Cem 2 [Fuji+AL & Fuji+PM] and one of each with Variolink® Esthetic [Vario+AL & Vario+PM]. The Fuji Cem 2 was chemically cured while dual curing Variolink® Esthetic was additionally light cured using LED (Bluephase II, Ivoclar Vivadent, Ellwagen, Germany; light intensity, >1,000 mW/cm2, high power modus). The shear strength was performed with Zwick/Roell universal test machine (speed, 0.8 mm/min), fracture and statistical analysis was performed (T-test, p<0.05). T-test showed a significant difference Fuji Cem 2 (Fuji+AL & Fuji&PM) and Variolink® Esthetic (Vario+AL &Vario+PM) (p=0.000). Fuji+AL & Fuji+PM showed a significant difference for surface pre-treatment (p=0.002). Vario+AL & Vario+PM no significance (p=0.872) for pre-treatment method was detectable. Variolink® Esthetic showed a higher bond strength compared to Fuji Cem 2 and an increasing bond strength for Fuji Cem 2 with alumina pre-treatment. There was no significant difference for Vario+AL and Vario+PM

Improving Patient Experience by Providing Consistent Education Regarding Medication Side Effects

https://digitalcommons.psjhealth.org/stvincent-bootcamp/1033/thumbnail.jp

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.Peer reviewedFinal Accepted Versio