A Versatile Model of Microfluidic Perifusion System for the Evaluation of C-Peptide Secretion Profiles: Comparison Between Human Pancreatic Islets and HLSC-Derived Islet-Like Structures

A robust and easy-to-use tool for the ex vivo dynamic evaluation of pancreatic islet (PI) function is essential for further development of novel cell-based therapeutic approaches to treating diabetes. Here, we developed four different glucose perifusion protocols (GPPs) in a microfluidic perifusion system (MPS), based entirely on commercially available components. After validation, the GPPs were used to evaluate C-peptide secretion profiles of PIs derived from different donors (healthy, obese, and type 2 diabetic) and from human liver stem-cell-derived islet-like structures (HLSC-ILS). Using this device, we demonstrated that PIs derived from healthy donors displayed a physiological C-peptide secretion profile as characterized by the response to (a) different glucose concentrations, (b) consecutive pulses of high-glucose concentrations, (c) a glucose threshold ranging from 5–8 mM, and (d) a constant high-glucose perifusion in a biphasic manner. Moreover, we were able to detect a dysregulated secretion profile in PIs derived from both obese and type 2 diabetes mellitus (T2DM) donors. Finally, we also evaluated the kinetic secretion profiles of HLSC-ILS, demonstrating that, nonetheless, with a lower amplitude of secretion compared to PI derived from healthy donors, they were already glucose-responsive on day seven post-differentiation. In conclusion, we have provided evidence that our MPS is a versatile device and may represent a valuable tool to study insulin-producing cells in vitro

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

The dust content of the Crab Nebula

We have modelled the near-infrared to radio images of the Crab Nebula with a Bayesian SED model to simultaneously fit its synchrotron, interstellar (IS), and supernova dust emission. We infer an IS dust extinction map with an average AV = 1.08 ± 0.38 mag, consistent with a small contribution (22 per cent) to the Crab’s overall infrared emission. The Crab’s supernova dust mass is estimated to be between 0.032 and 0.049 M (for amorphous carbon grains) with an average dust temperature Tdust = 41 ± 3 K, corresponding to a dust condensation efficiency of 8–12 per cent. This revised dust mass is up to an order of magnitude lower than some previous estimates, which can be attributed to our different IS dust corrections, lower SPIRE flux densities, and higher dust temperatures than were used in previous studies. The dust within the Crab is predominantly found in dense filaments south of the pulsar, with an average V-band dust extinction of AV = 0.20–0.39 mag, consistent with recent optical dust extinction studies. The modelled synchrotron power-law spectrum is consistent with a radio spectral index αradio = 0.297 ± 0.009 and an infrared spectral index αIR = 0.429 ± 0.021. We have identified a millimetre excess emission in the Crab’s central regions, and argue that it most likely results from two distinct populations of synchrotron emitting particles. We conclude that the Crab’s efficient dust condensation (8–12 per cent) provides further evidence for a scenario where supernovae can provide substantial contributions to the IS dust budgets in galaxies

Chemical Evolution of CoCrMo Wear Particles: An in Situ Characterization Study

The unexpected high failure rates of CoCrMo hip implants are associated with the release of a large number of inflammatory wear particles. CoCrMo is nominally a stable material; however, previous chemical speciation studies on CoCrMo wear particles obtained from periprosthetic tissue revealed only trace amounts of Co remaining despite Co being the major component of the alloy. The unexpected high levels of Co dissolution in vivo raised significant clinical concerns particularly related to the Cr speciation in the dissolution process. At high electrochemical potentials, the alloy's Cr-rich passive film breaks down (transpassive polarization), facilitating alloy dissolution. The potential release of the carcinogenic Cr(VI) species in vivo has been a subject of debate. While the large-scale Co dissolution observed on in vivo produced particles could indicate a highly oxidizing in vivo environment, Cr(VI) species were not previously detected in periprosthetic tissue samples (except in the specific case of post-mortem tissue of diabetic patients). However, Cr(VI) is likely to be an unstable (transient) species in biological environments, and studies on periprosthetic tissue do not provide information about intermediate reaction products or the exposure history of the wear particles. Here, an in situ spectromicroscopy approach was developed, utilizing the high chemical resolution of synchrotron radiation, to study CoCrMo reactivity as a function of time and oxidizing conditions. The results reveal limited Co dissolution from CoCrMo particles, which increases dramatically at a critical electrochemical potential. Furthermore, in situ XAS detected only Cr(III) dissolution, even at potentials where Cr(VI) is known to be produced, suggesting that Cr(VI) species are extremely transient in simulated biological environments where the oxidation zone is small

Galilean quantum gravity with cosmological constant and the extended q-Heisenberg algebra

We define a theory of Galilean gravity in 2+1 dimensions with cosmological constant as a Chern-Simons gauge theory of the doubly-extended Newton-Hooke group, extending our previous study of classical and quantum gravity in 2+1 dimensions in the Galilean limit. We exhibit an r-matrix which is compatible with our Chern-Simons action (in a sense to be defined) and show that the associated bi-algebra structure of the Newton-Hooke Lie algebra is that of the classical double of the extended Heisenberg algebra. We deduce that, in the quantisation of the theory according to the combinatorial quantisation programme, much of the quantum theory is determined by the quantum double of the extended q-deformed Heisenberg algebra.Comment: 22 page

Recent advances on information transmission and storage assisted by noise

The interplay between nonlinear dynamic systems and noise has proved to be of great relevance in several application areas. In this presentation, we focus on the areas of information transmission and storage. We review some recent results on information transmission through nonlinear channels assisted by noise. We also present recent proposals of memory devices in which noise plays an essential role. Finally, we discuss new results on the influence of noise in memristors.Comment: To be published in "Theory and Applications of Nonlinear Dynamics: Model and Design of Complex Systems", Proceedings of ICAND 2012 (Springer, 2014

Stimulation of Na⁺/H⁺ Exchanger Isoform 1 Promotes Microglial Migration

Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling. © 2013 Shi et al

Symptoms and syndromes associated with SARS-CoV-2 infection and severity in pregnant women from two community cohorts

We tested whether pregnant and non-pregnant women differ in COVID-19 symptom profile and severity, and we extended previous investigations on hospitalized pregnant women to those who did not require hospitalization. Two female community-based cohorts (18-44 years) provided longitudinal (smartphone application, N = 1,170,315, n = 79 pregnant tested positive) and cross-sectional (web-based survey, N = 1,344,966, n = 134 pregnant tested positive) data, prospectively collected through self-participatory citizen surveillance in UK, Sweden and USA. Pregnant and non-pregnant were compared for frequencies of events, including SARS-CoV-2 testing, symptoms and hospitalization rates. Multivariable regression was used to investigate symptoms severity and comorbidity effects. Pregnant and non-pregnant women positive for SARS-CoV-2 infection were not different in syndromic severity, except for gastrointestinal symptoms. Pregnant were more likely to have received testing, despite reporting fewer symptoms. Pre-existing lung disease was most closely associated with syndromic severity in pregnant hospitalized. Heart and kidney diseases and diabetes increased risk. The most frequent symptoms among non-hospitalized women were anosmia [63% pregnant, 92% non-pregnant] and headache [72%, 62%]. Cardiopulmonary symptoms, including persistent cough [80%] and chest pain [73%], were more frequent among pregnant who were hospitalized. Consistent with observations in non-pregnant populations, lung disease and diabetes were associated with increased risk of more severe SARS-CoV-2 infection during pregnancy

Effectiveness, cost-effectiveness and cost-benefit of a single annual professional intervention for the prevention of childhood dental caries in a remote rural Indigenous community

Background The aim of the study is to reduce the high prevalence of tooth decay in children in a remote, rural Indigenous community in Australia, by application of a single annual dental preventive intervention. The study seeks to (1) assess the effectiveness of an annual oral health preventive intervention in slowing the incidence of dental caries in children in this community, (2) identify the mediating role of known risk factors for dental caries and (3) assess the cost-effectiveness and cost-benefit of the intervention. Methods/design The intervention is novel in that most dental preventive interventions require regular re-application, which is not possible in resource constrained communities. While tooth decay is preventable, self-care and healthy habits are lacking in these communities, placing more emphasis on health services to deliver an effective dental preventive intervention. Importantly, the study will assess cost-benefit and cost-effectiveness for broader implementation across similar communities in Australia and internationally. Discussion There is an urgent need to reduce the burden of dental decay in these communities, by implementing effective, cost-effective, feasible and sustainable dental prevention programs. Expected outcomes of this study include improved oral and general health of children within the community; an understanding of the costs associated with the intervention provided, and its comparison with the costs of allowing new lesions to develop, with associated treatment costs. Findings should be generalisable to similar communities around the world. The research is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12615000693527; date of registration: 3rd July 2015