Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.AIMS/HYPOTHESIS: Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction. METHODS: The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals. RESULTS: Beta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA. CONCLUSIONS/INTERPRETATION: Changes in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.Swiss National Science FoundationFondation Francophone pour la Recherche sur le DiabèteWellcome Trust Senior Investigator AwardMRC Programme GrantRoyal Society Wolfson Research Merit AwardWellcome Trust project gran

Field theoretic description of the abelian and non-abelian Josephson effect

We formulate the Josephson effect in a field theoretic language which affords a straightforward generalization to the non-abelian case. Our formalism interprets Josephson tunneling as the excitation of pseudo-Goldstone bosons. We demonstrate the formalism through the consideration of a single junction separating two regions with a purely non-abelian order parameter and a sandwich of three regions where the central region is in a distinct phase. Applications to various non-abelian symmetry breaking systems in particle and condensed matter physics are given.Comment: 10 pages no figure

Roles of Noncoding RNAs in Islet Biology.

The discovery that most mammalian genome sequences are transcribed to ribonucleic acids (RNA) has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs (ncRNAs), including micro-RNAs (miRNAs), PIWI-associated RNAs, small nucleolar RNAs, tRNA-derived fragments, long non-coding RNAs, and circular RNAs. While the involvement of miRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of ncRNAs are also participating in different aspects of islet physiology. The aim of this article will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the past 15 years on the role of ncRNAs in the control of α- and β-cell development and function and to highlight the recent discoveries in the field. We not only describe the role of ncRNAs in the control of insulin and glucagon secretion but also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their ncRNAs inside small extracellular vesicles, allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell-to-cell communication between β-cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed. © 2020 American Physiological Society. Compr Physiol 10:893-932, 2020

Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal β cells.

tRNA-derived fragments (tRFs) are an emerging class of small non-coding RNAs with distinct cellular functions. Here, we studied the contribution of tRFs to the regulation of postnatal β cell maturation, a critical process that may lead to diabetes susceptibility in adulthood. We identified three tRFs abundant in neonatal rat islets originating from 5' halves (tiRNA-5s) of histidine and glutamate tRNAs. Their inhibition in these islets reduced β cell proliferation and insulin secretion. Mitochondrial respiration was also perturbed, fitting with the mitochondrial enrichment of nuclear-encoded tiRNA-5 <sup>HisGTG</sup> and tiRNA-5 <sup>GluCTC</sup> . Notably, tiRNA-5 inhibition reduced Mpc1, a mitochondrial pyruvate carrier whose knock down largely phenocopied tiRNA-5 inhibition. tiRNA-5 <sup>HisGTG</sup> interactome revealed binding to Musashi-1, which was essential for the mitochondrial enrichment of tiRNA-5 <sup>HisGTG</sup> . Finally, tiRNA-5s were dysregulated in the islets of diabetic and diabetes-prone animals. Altogether, tiRNA-5s represent a class of regulators of β cell maturation, and their deregulation in neonatal islets may lead to diabetes susceptibility in adulthood

Flow-weighted values of runoff tracers (δ18O, DOC, Ba, alkalinity) from the six largest Arctic rivers

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 35 (2008): L18606, doi:10.1029/2008GL035007.We present new flow-weighted data for δ 18OH2O, dissolved organic carbon (DOC), dissolved barium and total alkalinity from the six largest Arctic rivers: the Ob', Yenisey, Lena, Kolyma, Yukon and Mackenzie. These data, which can be used to trace runoff, are based upon coordinated collections between 2003 and 2006 that were temporally distributed to capture linked seasonal dynamics of river flow and tracer values. Individual samples indicate significant variation in the contributions each river makes to the Arctic Ocean. Use of these new flow-weighted estimates should reduce uncertainties in the analysis of freshwater transport and fate in the upper Arctic Ocean, including the links to North Atlantic thermohaline circulation, as well as regional water mass analysis. Additional improvements should also be possible for assessing the mineralization rate of the globally significant flux of terrigenous DOC contributed to the Arctic Ocean by these major rivers.Supported by the U.S. National Science Foundation (OPP-0229302), the U.S. Geological Survey and the Water Resources Division of Canada’s Department of Indian Affairs and Northern Development

Circular RNAs as novel regulators of β-cell functions in normal and disease conditions.

There is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of β-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of β-cells functions. We used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, β-cell proliferation, and apoptosis. We identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced β-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key β-cell genes, such as Slc2a2, Akt1, and Mtpn. Our findings point to circular RNAs as novel regulators of β-cell activities and suggest an involvement of this novel class of non-coding RNAs in β-cell dysfunction under diabetic conditions

A socially inspired energy feedback technology: challenges in a developing scenario

Raising awareness of the environmental impact of energy generation and consumption has been a recent concern of contemporary society worldwide. Underlying the awareness of energy consumption is an intricate network of perception and social interaction that can be mediated by technology. In this paper we argue that issues regarding energy, environment and technology are very much situated and involve tensions of sociocultural nature. This exploratory investigation addresses the subject by introducing the design of a Socially-inspired Energy Eco-Feedback Technology (SEET), which is composed of an interactive system to trigger and mediate collective savings and a tangible device as a public feedback. Results of an evaluation situated in the context of a school in a socially disadvantaged area in Brazil are discussed, shedding light on the sociocultural aspects related to the subject. The role of the SEET to motivate energy awareness collectively among the social group is assessed, as well as the design characteristics that contributed to that. Outcomes bring to light social aspects and dynamics that would hardly have been predicted, evidencing critical factors related to a socially inspired design approach in the energy awareness domain

The rapid response of the Canada Basin to climate forcing : from bellwether to alarm bells

Author Posting. © Oceanography Society, 2011. This article is posted here by permission of Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 24 no. 3 (2011): 146–159, doi:10.5670/oceanog.2011.66.Sea ice extent in the Arctic Ocean diminished significantly during the first decade of the 2000s, most particularly in the Canada Basin where the loss of both multiyear and first-year ice was greater than in the other three subbasins. Using data collected during basin-wide surveys conducted from 2003–2010 together with data collected during the 1990s and 2000s at one station in the southern Canada Basin, we investigate the response of the Canada Basin water column to this significant decrease in ice cover. Changes were evident from the surface down to the Atlantic layer: some changes were the result of Beaufort Gyre forcing on regional processes, others were the result of Arctic Ocean atmospheric forcing on a hemispheric scale and large-scale advection. These changes have troubling consequences for the ecosystem.We acknowledge support from Fisheries and Oceans Canada, the US National Science Foundation Office of Polar Programs (grant OPP-0424864), and the Canadian International Polar Year office

Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study.

Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred

Closed-loop acoustic stimulation during sedation with dexmedetomidine (CLASS-D): Protocol for a within-subject, crossover, controlled, interventional trial with healthy volunteers

Introduction: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine. Methods: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volunteers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation. Results: The primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep. Discussion: This investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation