39 research outputs found
The Use of Monoclonal Antibody Directed Chimeric Antigen Receptors to Guide T Cell and Treg Homing for GvHD Control and Tissue Tolerance in Murine Models
No full textHow the OH reactivity affects the ozone production efficiency: case studies in Beijing and Heshan, China
No full textTotal OH reactivity measurements were conducted on the Peking
University campus (Beijing) in August 2013 and in Heshan (Guangdong province)
from October to November 2014. The daily median OH reactivity was 20 ± 11 s−1 in Beijing and 31 ± 20 s−1 in Heshan, respectively.
The data in Beijing showed a distinct diurnal pattern with the maxima over
27 s−1 in the early morning and minima below 16 s−1 in the afternoon. The
diurnal pattern in Heshan was not as evident as in Beijing. Missing
reactivity, defined as the difference between measured and calculated OH
reactivity, was observed at both sites, with 21 % missing reactivity in Beijing and
32 % missing reactivity in Heshan. Unmeasured primary species, such as
branched alkenes, could contribute to missing reactivity in Beijing,
especially during morning rush hours. An observation-based model with the RACM2
(Regional Atmospheric Chemical Mechanism version 2) was used to understand
the daytime missing reactivity in Beijing by adding unmeasured oxygenated
volatile organic compounds and simulated intermediates of the degradation
from primary volatile organic compounds (VOCs). However, the model could not find a convincing
explanation for the missing reactivity in Heshan, where the ambient air was found to be
more aged, and the missing reactivity was presumably attributed to oxidized
species, such as unmeasured aldehydes, acids and dicarbonyls. The ozone
production efficiency was 21 % higher in Beijing and 30 % higher in
Heshan when the model was constrained by the measured reactivity, compared to
the calculations with measured and modeled species included, indicating the
importance of quantifying the OH reactivity for better understanding ozone
chemistry
The presence of 5-HT in myenteric varicosities is not due to uptake of 5-HT released from the mucosa during dissection: use of a novel method for quantifying 5-HT immunoreactivity in myenteric ganglia
No full textAuthor version made available according to Publisher copyright policy. This is the accepted version of the following article:
Keating, D. J., Peiris, H., Kyloh, M., Brookes, S. J. H. and Spencer, N. J. (2013), The presence of 5-HT in myenteric varicosities is not due to uptake of 5-HT released from the mucosa during dissection: use of a novel method for quantifying 5-HT immunoreactivity in myenteric ganglia. Neurogastroenterology & Motility, 25: 849–853,
which has been published in final form at
http://dx.doi.org/10.1111/nmo.12189.
In addition, authors may also transmit, print and share copies with colleagues, provided that there is no systematic distribution of the submitted version, e.g. posting on a listserve, network or automated delivery
RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells
No full textCopyright © 2014 Heshan Peiris et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer’s disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 . Similar to neurons, cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS
Huntingtin-associated protein 1 regulates exocytosis, vesicle docking, readily releasable pool size and fusion pore stability in mouse chromaffin cells
No full textArticle first published online: 17 FEB 2014Huntingtin-associated protein 1 (HAP1) was initially established as a neuronal binding partner of huntingtin, mutations in which underlie Huntington's disease. Subcellular localization and protein interaction data indicate that HAP1 may be important in vesicle trafficking and cell signalling. In this study, we establish that HAP1 is important in several steps of exocytosis in adrenal chromaffin cells. Using carbon-fibre amperometry, we measured single vesicle exocytosis in chromaffin cells obtained from HAP1(-/-) and HAP1(+/+) littermate mice. Numbers of Ca(2+)-dependent and Ca(2+)-independent full fusion events in HAP1(-/-) cells are significantly decreased compared with those in HAP1(+/+) cells. We observed no change in the frequency of 'kiss-and-run' fusion events or in Ca(2+) entry. Whereas release per full fusion event is unchanged in HAP1(-/-) cells, early fusion pore duration is prolonged, as indicated by the increased duration of pre-spike foot signals. Kiss-and-run events have a shorter duration, indicating opposing roles for HAP1 in the stabilization of the fusion pore during full fusion and transient fusion, respectively. We use electron microscopy to demonstrate a reduction in the number of vesicles docked at the plasma membrane of HAP1(-/-) cells, where membrane capacitance measurements reveal the readily releasable pool of vesicles to be reduced in size. Our study therefore illustrates that HAP1 regulates exocytosis by influencing the morphological docking of vesicles at the plasma membrane, the ability of vesicles to be released rapidly upon stimulation, and the early stages of fusion pore formation.Kimberly D. Mackenzie, Michael D. Duffield, Heshan Peiris, Lucy Phillips, Mark P. Zanin, Ee Hiok Teo, Xin-Fu Zhou and Damien J. Keatin
Local sphingosine kinase 1 activity improves islet transplantation
No full textPancreatic islet transplantation is a promising clinical treatment for type 1 diabetes, but success is limited by extensive β-cell death in the immediate posttransplant period and impaired islet function in the longer term. Following transplantation, appropriate vascular remodeling is crucial to ensure the survival and function of engrafted islets. The sphingosine kinase (SK) pathway is an important regulator of vascular beds, but its role in the survival and function of transplanted islets is unknown. We observed that donor islets from mice deficient in SK1 (Sphk1 knockout) contain a reduced number of resident intraislet vascular endothelial cells. Furthermore, we demonstrate that the main product of SK1, sphingosine-1-phosphate, controls the migration of intraislet endothelial cells in vitro. We reveal in vivo that Sphk1 knockout islets have an impaired ability to cure diabetes compared with wild-type controls. Thus, SK1-deficient islets not only contain fewer resident vascular cells that participate in revascularization, but likely also a reduced ability to recruit new vessels into the transplanted islet. Together, our data suggest that SK1 is important for islet revascularization following transplantation and represents a novel clinical target for improving transplant outcomes.Darling Rojas-Canales, Daniella Penko, Kay K. Myo Min, Kate A. Parham, Heshan Peiris, Rainer V. Haberberger, Stuart M. Pitson, Chris Drogemuller, Damien J. Keating, Shane T. Grey, Patrick T. Coates, Claudine S. Bonder and Claire F. Jessu
Endothelial progenitor cells enhance islet engraftment, influence beta-cell function and modulate islet connexin 36 expression
No full textThe success of pancreatic islet transplantation is limited by delayed engraftment and suboptimal function in the longer term. Endothelial progenitor cells (EPCs) represent a potential cellular therapy that may improve the engraftment of transplanted pancreatic islets. In addition, EPCs may directly affect the function of pancreatic β-cells. The objective of this study was to examine the ability of EPCs to enhance pancreatic islet transplantation in a murine syngeneic marginal mass transplant model and to examine the mechanisms through which this occurs. We found that cotransplanted EPCs improved the cure rate and initial glycemic control of transplanted islets. Gene expression data indicate that EPCs, or their soluble products, modulate the expression of the β-cell surface molecule connexin 36 and affect glucose-stimulated insulin release in vitro. In conclusion, EPCs are a promising candidate for improving outcomes in islet transplantation, and their mechanisms of action warrant further study.Daniella Penko, Darling Rojas-Canales, Daisy Mohanasundaram, Heshan S. Peiris, Wai Y. Sun, Christopher J. Drogemuller, Damien J. Keating, P. Toby H. Coates, Claudine S. Bonder, and Claire F. Jessu
Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis
No full textIncreasing non-shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 (RCAN1), a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non-shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle. UCP1 generates heat at the expense of reducing ATP production, whereas SLN increases ATP consumption to generate heat. Gene expression profiles demonstrate a high correlation between Rcan1 expression and metabolic syndrome. On an evolutionary timescale, in the context of limited food resources, systemic suppression of prolonged NST by RCAN1 might have been beneficial; however, in the face of caloric abundance, RCAN1-mediated suppression of these adaptive avenues of energy expenditure may now contribute to the growing epidemic of obesity.David Rotter, Heshan Peiris, D Bennett Grinsfelder, Alyce M Martin, Jana Burchfield ... Claire F Jessup ... et al
The β-cell/EC axis: how do islet cells talk to each other?
No full textAuthor version made available in accordance with the publisher's policy.Within the pancreatic islet, the beta cell represents the ultimate biosensor. Its central function is
to accurately sense glucose levels in the blood, and consequently release appropriate amounts of
insulin. As the only cell type capable of insulin production, the beta cell must balance this crucial
workload with self-preservation and, when required, regeneration. Evidence suggests that the
beta cell has an important ally in intra-islet endothelial cells. As well as providing a conduit for
delivery of the primary input stimulus (glucose) and dissemination of its most important effector
(insulin), intra-islet blood vessels deliver oxygen to these dense clusters of metabolically active
cells. Furthermore, it appears that endothelial cells directly impact insulin gene expression,
secretion and beta cell survival.
This review discusses the molecules and pathways involved in the crosstalk between beta cells
and intra-islet endothelial cells. The evidence supporting the intra-islet endothelial cell as an
important partner for beta cell function is examined to highlight the relevance of this axis in the
context of type 1 and type 2 diabetes. Recent work which has established the potential of
endothelial cells or their progenitors to enhance the reestablishment of glycaemic control
following pancreatic islet transplantation in animal models is discussed
