Sustained NF-κB Activation and Inhibition in β-Cells Have Minimal Effects on Function and Islet Transplant Outcomes

The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation. Transgenic mice expressing a dominant active IKKβ (constitutively active) or a non-degradable form of IκBα (constitutive inhibition) under control of the rat insulin promoter were generated. Islets from these mice were transplanted into streptozotocin diabetic mice in suboptimal numbers. Further, the effects of salicylate (an inhibitor of NF-κB) treatment of normal islets prior to transplantation, and the effects of salicylate administration to mice prior to and after islet implantation were evaluated. Transplantation outcomes were not affected using islets expressing a non-degradable form of IκBα when compared to wild type controls. However, the transplantation outcomes using islets isolated from mice expressing a constitutively active mutant of NF-κB were marginally worse, although no aberrations of islet function in vitro could be detected. Salicylate treatment of normal islets or mice had no effect on transplantation outcome. The current study draws attention to the complexities of NF-κB in pancreatic beta cells by suggesting that they can adapt with normal or near normal function to both chronic activation and inhibition of this important transcription factor

Overview : Integrative and Comprehensive Understanding on Polar Environments (iCUPE) - concept and initial results

The role of polar regions is increasing in terms of megatrends such as globalization, new transport routes, demography, and the use of natural resources with consequent effects on regional and transported pollutant concentrations. We set up the ERA-PLANET Strand 4 project "iCUPE - integrative and Comprehensive Understanding on Polar Environments" to provide novel insights and observational data on global grand challenges with an Arctic focus. We utilize an integrated approach combining in situ observations, satellite remote sensing Earth observations (EOs), and multi-scale modeling to synthesize data from comprehensive long-term measurements, intensive campaigns, and satellites to deliver data products, metrics, and indicators to stakeholders concerning the environmental status, availability, and extraction of natural resources in the polar areas. The iCUPE work consists of thematic state-of-the-art research and the provision of novel data in atmospheric pollution, local sources and transboundary transport, the characterization of arctic surfaces and their changes, an assessment of the concentrations and impacts of heavy metals and persistent organic pollutants and their cycling, the quantification of emissions from natural resource extraction, and the validation and optimization of satellite Earth observation (EO) data streams. In this paper we introduce the iCUPE project and summarize initial results arising out of the integration of comprehensive in situ observations, satellite remote sensing, and multi-scale modeling in the Arctic context.Peer reviewe

Overview: Integrative and Comprehensive Understanding on Polar Environments (iCUPE) – concept and initial results

The role of polar regions is increasing in terms of megatrends such as globalization, new transport routes, demography, and the use of natural resources with consequent effects on regional and transported pollutant concentrations. We set up the ERA-PLANET Strand 4 project “iCUPE – integrative and Comprehensive Understanding on Polar Environments” to provide novel insights and observational data on global grand challenges with an Arctic focus. We utilize an integrated approach combining in situ observations, satellite remote sensing Earth observations (EOs), and multi-scale modeling to synthesize data from comprehensive long-term measurements, intensive campaigns, and satellites to deliver data products, metrics, and indicators to stakeholders concerning the environmental status, availability, and extraction of natural resources in the polar areas. The iCUPE work consists of thematic state-of-the-art research and the provision of novel data in atmospheric pollution, local sources and transboundary transport, the characterization of arctic surfaces and their changes, an assessment of the concentrations and impacts of heavy metals and persistent organic pollutants and their cycling, the quantification of emissions from natural resource extraction, and the validation and optimization of satellite Earth observation (EO) data streams. In this paper we introduce the iCUPE project and summarize initial results arising out of the integration of comprehensive in situ observations, satellite remote sensing, and multi-scale modeling in the Arctic context

New insights into the control of pancreatic islet cell function

Diabetes is a disease, characterized by the failure of the body to make or use insulin, resulting in improper glucose homeostasis. Insulin, a hormone that regulates glucose uptake, metabolism and storage in various cells of the body, is produced by pancreatic beta cells, located in the islets of Langerhans. Diabetes can be characterized as one of two types, type 1, also known as autoimmune or insulin-dependent diabetes, and type 2, also known as adult onset, or insulin resistance. Type 1, or insulin-dependent diabetes mellitus (IDDM) is characterized by the selective destruction of insulin-secreting pancreatic beta cells. Proinflammatory cytokines, such as interleukin (IL)-1 beta and interferon (IFN)-gamma, are believed to participate in the death of beta cells during the development of autoimmune diabetes. In the first part of this application, the activation of endoplasmic reticulum stress by salicylates will be examined as a mechanism by which to attenuate cytokine signaling, and consequently, cytokine-mediated beta-cell damage. Type 2 diabetes is characterized by the inability of the body to either produce enough, or respond to the hormone insulin, also known as insulin resistance. Many factors, such as blood glucose levels, hormones and autonomic innervations can all modulate islet secretory function. In the second part of this application, the regulation of pancreatic function by a novel peptide hormone, neuronostatin, which shares the same precursor hormone as somatostatin, will be examined. In addition, the signaling cascades activated by, and potential receptors for, neuronostatin will be examined using basic biochemical and molecular biology techniques

Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNβ in mouse pancreatic β-cells.

Autoimmune destruction of insulin producing pancreatic β-cells is the hallmark of type I diabetes. One of the key molecules implicated in the disease onset is the immunoproteasome, a protease with multiple proteolytic sites that collaborates with the constitutive 19S and the inducible 11S (PA28) activators to produce immunogenic peptides for presentation by MHC class I molecules. Despite its importance, little is known about the function and regulation of the immunoproteasome in pancreatic β-cells. Of special interest to immunoproteasome activation in β-cells are the effects of IFNβ, a type I IFN secreted by virus-infected cells and implicated in type I diabetes onset, compared to IFNγ, the classic immunoproteasome inducer secreted by cells of the immune system. By qPCR analysis, we show that mouse insulinoma MIN6 cells and mouse islets accumulate the immune proteolytic β1(i), β2(i) and β5(i), and 11S mRNAs upon exposure to IFNβ or IFNγ. Higher concentrations of IFNβ than IFNγ are needed for similar expression, but in each case the expression is transient, with maximal mRNA accumulation in 12 hours, and depends primarily on Interferon Regulatory Factor 1. IFNs do not alter expression of regular proteasome genes, and in the time frame of IFNβ-mediated response, the immune and regular proteolytic subunits co-exist in the 20S particles. In cell extracts with ATP, these particles have normal peptidase activities and degrade polyubiquitinated proteins with rates typical of the regular proteasome, implicating normal regulation by the 19S activator. However, ATP depletion rapidly stimulates the catalytic rates in a manner consistent with levels of the 11S activator. These findings suggest that stochastic combination of regular and immune proteolytic subunits may increase the probability with which unique immunogenic peptides are produced in pancreatic β-cells exposed to IFNβ, but primarily in cells with reduced ATP levels that stimulate the 11S participation in immunoproteasome function

Creating Public History Master Programs: International Guidelines

Universities create new public history Master’s programs every year. Public history university programs first emerged in the United States (the first public history program was launched at the University of California, Santa Barbara, in 1976). Public history Master’s programs are now established throughout the world (See the IFPH’s map of public history programs) and the number of programs keeps growing. At the same time, creating a new program can be overwhelming and challenging. Indeed, while Public History belongs to the overall historical discipline, it bears some crucial specificity regarding its practices and training. In 2015, the National Council on Public History in the United States published useful best practices for “Establishing and Developing a Public History Program.” However, the field has rapidly changed in the past few years and numerous programs are emerging outside the United States. Although public history programs were successfully integrated into university systems in the United States, the same practices do not necessarily translate to other countries and contexts. In response to International Federation for Public History (IFPH) members and partnering universities’ needs for a set of teaching and training guidelines to be adapted to a range of international contexts, a Curriculum and Training committee was launched in 2021. Composed of IFPH members from a variety of national contexts and public history backgrounds, the Committee was tasked with leading practitioner discussions and drafting a new set of model practices to reference when creating Master’s level public history programs. More than 40 participants from all over the world took part in our online discussions. What started as a basic forum for ideas and questions evolved into more structured collaborative writing sessions. With the range and variations of national circumstances, university requirements, departmental objectives, and available resources, there can be no one-size-fits-all set of guidelines. Rather, this reference intends to offer ideas and suggestions, which may be applied, adapted, and modified according to national, local, and university contexts. Having said that, we strongly believe that these steps can help colleagues (faculty and administrators) around the globe launch discussions on the need and demand for a Master’s in Public History program at their institution. We are aware that each process and institution is unique. As such, this document presents different components for the creation of a public history program, identifies stages and processes, and proposes general guidelines with the aim of offering guidance in the creation, implementation, and evaluation of Master’s programs in public history