Arsenic Exposure and Type 2 Diabetes: MicroRNAs as Mechanistic Links?

PURPOSE OF REVIEW: The goal of this review is to delineate the following: (1) the primary means of inorganic arsenic (iAs) exposure for human populations, (2) the adverse public health outcomes associated with chronic iAs exposure, (3) the pathophysiological connection between arsenic and type 2 diabetes (T2D), and (4) the incipient evidence for microRNAs as candidate mechanistic links between iAs exposure and T2D. RECENT FINDINGS: Exposure to iAs in animal models has been associated with the dysfunction of several different cell types and tissues, including liver and pancreatic islets. Many microRNAs that have been identified as responsive to iAs exposure under in vitro and/or in vivo conditions have also been shown in independent studies to regulate processes that underlie T2D etiology, such as glucose-stimulated insulin secretion from pancreatic beta cells. Defects in insulin secretion could be, in part, associated with aberrant microRNA expression and activity. Additional in vivo studies need to be performed with standardized concentrations and durations of arsenic exposure in order to evaluate rigorously microRNAs as molecular drivers of iAs-associated diabetes

DEFINING THE MOLECULAR EFFECTS OF ARSENIC EXPOSURE IN CIRCULATION AND IN PANCREATIC BETA CELLS

Type 2 diabetes (T2D) is a complex metabolic disorder characterized by hyperglycemia. Exposures to environmental toxicants are less studied in the context of T2D, but these toxicants, alone or in conjunction with other environmental and lifestyle factors, may play a contributing role to the development of T2D. Numerous population studies have found an association between exposure to inorganic arsenic (iAs) in drinking water and an increased incidence or prevalence of T2D. These studies also indicate that metabolism of iAs into monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites, which facilitates clearance of iAs from the body, influences individual susceptibility to adverse effects of iAs exposure. Population studies of iAs exposure point to defects in insulin secretion as being the primary cause of metabolic dysfunction, and the impairment of insulin secretion has been validated in lab studies. While the exact mechanism by which iAs affects pancreatic beta cells and insulin secretion is unknown, microRNAs (miRNAs) have emerged as potential drivers. MiRNAs are environmentally responsive, short non-coding RNAs that are important components of gene regulatory networks involved in T2D. While miRNA expression changes have been observed in the presence of some metals including arsenic, and have specifically been shown to play a role in metabolism and glucose homeostasis, the role of miRNAs in the pancreas in the context of environmental metal exposures remains highly understudied. To address this gap in knowledge, I utilized a cohort exposed to iAs through drinking water, as well as an in vitro cell line to identify miRNAs that link iAs exposure to diabetes. I identified a novel association between a methylated metabolite of iAs and 6 circulating plasma miRNAs, several of which have known links to diabetes. I also found that the inhibition of insulin secretion from beta cells exposed to iAs was concurrent to the upregulation of miR-146, an important regulator of several genes involved in the pathogenesis of T2D. Lastly, I examined the enhancer profile of pancreatic beta cells exposed to iAs or MAs and found that both exposures were associated with decreased activity of transcriptional regulatory elements enriched in binding sites for important transcription factors critical in maintaining pancreatic beta cell identity and function, including Pdx1. The results from this body of work contribute to the field of toxicology and environmental health by addressing major knowledge gaps in gene regulation and noncoding RNAs, and warrant further study and validation in the context of metabolic diseases such as T2D.Doctor of Philosoph

On the interaction of mesoscopic quantum systems with gravity

We review the different aspects of the interaction of mesoscopic quantum systems with gravitational fields. We first discuss briefly the foundations of general relativity and quantum mechanics. Then, we consider the non-relativistic expansions of the Klein-Gordon and Dirac equations in the post-Newtonian approximation. After a short overview of classical gravitational waves, we discuss two proposed interaction mechanisms: (i) the use of quantum fluids as generator and/or detector of gravitational waves in the laboratory, and (ii) the inclusion of gravitomagnetic fields in the study of the properties of rotating superconductors. The foundations of the proposed experiments are explained and evaluated.Comment: 27 pages, study for ESA: typos corrected, references and clarifications added. To appear in Annalen der Physi

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases

Risk communication films: Process, product and potential for improving preparedness and behaviour change

The medium of film is well established for education and communication about hazardous phenomena as it provides engaging ways to directly view hazards and their impacts. Empirical analysis can help to understand films' effectiveness in informing populations at risk and catalysing action to reduce risk. Using volcanic eruptions as a focus, an evidence-based methodology was devised to create, use, and track the outcomes of digital film tools designed to raise hazard and risk awareness, and develop preparedness efforts. Experiences from two contrasting eruptions were documented, with the secondary purpose of fostering social and cultural memories of eruptions, developed in response to demand from at-risk communities during field-based research. The films were created as a partnership with local volcano monitoring scientists and at-risk populations who, consequently, became the leading focus of the films, thus offering a substantial contrast to other types of hazard communication. The films were analysed by sharing them with at-risk communities and evaluating the immediate influence on learning and affect. Results indicated that the use of local content and actors to share experiences and teach valuable lessons were inspirational. Recognizable faces and spaces helped to convey disaster risk reduction messages. They also motivated audiences to consider ownership of risk and potential actions to reduce risk and strengthen resilience. This study demonstrated the effectiveness of co-production in the design and execution of intervention strategies for volcanic risk reduction. Co-production of films with local agencies resulted in products that were contextually appropriate, meaningful for audiences, and useful risk communication tools

Search for gravitational waves associated with the InterPlanetary Network short gamma ray bursts

We outline the scientific motivation behind a search for gravitational waves associated with short gamma ray bursts detected by the InterPlanetary Network (IPN) during LIGO's fifth science run and Virgo's first science run. The IPN localisation of short gamma ray bursts is limited to extended error boxes of different shapes and sizes and a search on these error boxes poses a series of challenges for data analysis. We will discuss these challenges and outline the methods to optimise the search over these error boxes.Comment: Methods paper; Proceedings for Eduardo Amaldi 9 Conference on Gravitational Waves, July 2011, Cardiff, U

Swift follow-up observations of candidate gravitational-wave transient events

We present the first multi-wavelength follow-up observations of two candidate gravitational-wave (GW) transient events recorded by LIGO and Virgo in their 2009-2010 science run. The events were selected with low latency by the network of GW detectors and their candidate sky locations were observed by the Swift observatory. Image transient detection was used to analyze the collected electromagnetic data, which were found to be consistent with background. Off-line analysis of the GW data alone has also established that the selected GW events show no evidence of an astrophysical origin; one of them is consistent with background and the other one was a test, part of a "blind injection challenge". With this work we demonstrate the feasibility of rapid follow-ups of GW transients and establish the sensitivity improvement joint electromagnetic and GW observations could bring. This is a first step toward an electromagnetic follow-up program in the regime of routine detections with the advanced GW instruments expected within this decade. In that regime multi-wavelength observations will play a significant role in completing the astrophysical identification of GW sources. We present the methods and results from this first combined analysis and discuss its implications in terms of sensitivity for the present and future instruments.Comment: Submitted for publication 2012 May 25, accepted 2012 October 25, published 2012 November 21, in ApJS, 203, 28 ( http://stacks.iop.org/0067-0049/203/28 ); 14 pages, 3 figures, 6 tables; LIGO-P1100038; Science summary at http://www.ligo.org/science/Publication-S6LVSwift/index.php ; Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p110003

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000

Metabolic Phenotype of Wild-Type and As3mt-Knockout C57BL/6J Mice Exposed to Inorganic Arsenic: The Role of Dietary Fat and Folate Intake

BACKGROUND: Inorganic arsenic (iAs) is a diabetogen. Interindividual differences in iAs metabolism have been linked to susceptibility to diabetes in iAs-exposed populations. Dietary folate intake has been shown to influence iAs metabolism, but to our knowledge its role in iAs-associated diabetes has not been studied. OBJECTIVE: The goal of this study was to assess how folate intake, combined with low-fat (LFD) and high-fat diets (HFD), affects the metabolism and diabetogenic effects of iAs in wild-type (WT) mice and in As3mt-knockout (KO) mice that have limited capacity for iAs detoxification. METHODS: Male and female WT and KO mice were exposed to 0 or [Formula: see text] iAs in drinking water. Mice were fed the LFD containing [Formula: see text] or [Formula: see text] folate for 24 weeks, followed by the HFD with the same folate levels for 13 weeks. Metabolic phenotype and iAs metabolism were examined before and after switching to the HFD. RESULTS: iAs exposure had little effect on the phenotype of mice fed LFD regardless of folate intake. High folate intake stimulated iAs metabolism, but only in WT females. KO mice accumulated more fat than WT mice and were insulin resistant, with males more insulin resistant than females despite similar %fat mass. Feeding the HFD increased adiposity and insulin resistance in all mice. However, iAs-exposed male and female WT mice with low folate intake were more insulin resistant than unexposed controls. High folate intake alleviated insulin resistance in both sexes, but stimulated iAs metabolism only in female mice. CONCLUSIONS: Exposure to [Formula: see text] iAs in drinking water resulted in insulin resistance in WT mice only when combined with a HFD and low folate intake. The protective effect of high folate intake may be independent of iAs metabolism, at least in male mice. KO mice were more prone to developing insulin resistance, possibly due to the accumulation of iAs in tissues. https://doi.org/10.1289/EHP3951

First Low-Latency LIGO+Virgo Search for Binary Inspirals and their Electromagnetic Counterparts

Aims. The detection and measurement of gravitational-waves from coalescing neutron-star binary systems is an important science goal for ground-based gravitational-wave detectors. In addition to emitting gravitational-waves at frequencies that span the most sensitive bands of the LIGO and Virgo detectors, these sources are also amongst the most likely to produce an electromagnetic counterpart to the gravitational-wave emission. A joint detection of the gravitational-wave and electromagnetic signals would provide a powerful new probe for astronomy. Methods. During the period between September 19 and October 20, 2010, the first low-latency search for gravitational-waves from binary inspirals in LIGO and Virgo data was conducted. The resulting triggers were sent to electromagnetic observatories for followup. We describe the generation and processing of the low-latency gravitational-wave triggers. The results of the electromagnetic image analysis will be described elsewhere. Results. Over the course of the science run, three gravitational-wave triggers passed all of the low-latency selection cuts. Of these, one was followed up by several of our observational partners. Analysis of the gravitational-wave data leads to an estimated false alarm rate of once every 6.4 days, falling far short of the requirement for a detection based solely on gravitational-wave data.Comment: 13 pages, 13 figures. For a repository of data used in the publication, go to: http://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=P1100065 Also see the announcement for this paper on ligo.org at: http://www.ligo.org/science/Publication-S6CBCLowLatency