Structural and functional basis for p38-MK2 activated Rsk signalling in Toll-Like receptor-stimulated dendritic cells

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation

Studies on the interaction between the estrogen and vitamin D endocrine system

Estrogen deficiency and vitamin D deficiency play key roles in the pathogenesis of postmenopausal osteoporosis. Aim of the studies in this thesis is to extend our knowledge on the interaction between E2 and 1,25-(0H)2D3 and thereby to provide more insight into the significance of E, for 1,25-(0H)2D3 mediated processes in calcium and bone metabolism. Furthermore the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR genotypes in relation to BMD and fracture risk are studied. The first part of the thesis focuses on the effect of E2 on 1,25-(0H)2D3 mediated processes. In chapters 2 and 3 the effect of E, deficiency and E2 repletion on 1,25-(0H),D, synthesis and 1,25-(0H)2D3 mediated intestinal calcium absorption in a rat model for postmenopausal osteoporosis is described. An important bone anabolic factor is IGF-1. Both 1,25-(0H)2D3 as well as Ez have been shown to regulate IGF-I expression in vitro. Chapter 4 describes the effect of E, deficiency and E2 repletion on IGF-I levels in bone in vivo in relation to bone metabolism. The effect of E2 on bone mineralization is discussed in Chapter 5. The second part of the thesis considers the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR gene polymorphisms in relation to BMD and fracture risk. Chapter 6 describes a pilot study addressed to whether differences in rates of bone turnover between women with either extremely low or extremely high BMD can be ascribed to genetic variations of the VDR. Furthermore, the biochemical response to short-term substitution of 1,25-(0H)2D3 in both BMD groups was related to VDR gene polymorphisms. In chapter 7 functional consequences of VDR gene polymorphisms in vitro are studied. Chapter 8 discusses the association between ERa gene polymorphism and fracture risk in postmenopausal women. Moreover, the interaction between ERa gene and VDR gene polymorphisms on fracture risk is described. In chapter 9 the results are discussed and suggestions for future research are made. Finally, the main findings are summarized in Chapter 10

Regulation of the Redox Environment

All organisms maintain a strict redox environment, crucial for cell physiology, by preserving the pro-oxidant compounds generated during cell metabolism and from antioxidant system elements. In pathophysiological conditions, the redox environment is altered, causing oxidative stress, cell damage, and eventually cell death. In this chapter, we review the elements involved in the redox environment, including the oxidant, antioxidant, and glutathione systems. In addition, we summarize the physicochemical bases of the redox environment and the biological functions of the glutathione cycle. Finally, we propose a redox environment regulation model that considers some regulated variables that are actively involved in maintaining the redox environment: reactive oxygen species, reactive nitrogen species, and the redox couple GSH2/GSSG

Long-term release of carbon dioxide from Arctic tundra ecosystems in Alaska

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecosystems 20 (2017): 960–974, doi:10.1007/s10021-016-0085-9.Releases of the greenhouse gases carbon dioxide (CO2) and methane (CH4) from thawing permafrost are expected to be among the largest feedbacks to climate from arctic ecosystems. However, the current net carbon (C) balance of terrestrial arctic ecosystems is unknown. Recent studies suggest that these ecosystems are sources, sinks, or approximately in balance at present. This uncertainty arises because there are few long-term continuous measurements of arctic tundra CO2 fluxes over the full annual cycle. Here, we describe a pattern of CO2 loss based on the longest continuous record of direct measurements of CO2 fluxes in the Alaskan Arctic, from two representative tundra ecosystems, wet sedge and heath tundra. We also report on a shorter time series of continuous measurements from a third ecosystem, tussock tundra. The amount of CO2 loss from both heath and wet sedge ecosystems was related to the timing of freeze-up of the soil active layer in the fall. Wet sedge tundra lost the most CO2 during the anomalously warm autumn periods of September – December 2013 - 2015, with CH4 emissions contributing little to the overall C budget. Losses of C translated to approximately 4.1% and 1.4% of the total soil C stocks in active layer of the wet sedge and heath tundra, respectively, from 2008 – 2015. Increases in air temperature and soil temperatures at all depths may trigger a new trajectory of CO2 release, which will be a significant feedback to further warming if it is representative of larger areas of the Arctic.This work was funded by the National Science Foundation Division of Polar Programs Arctic Observatory Network grant numbers 856864, 1304271, 0632264, and 1107892. This study was also partially funded by the NSF Alaska Experimental Program to Stimulate Competitive Research award number OIA-1208927.2017-11-2

Toxicological and therapeutic evaluation of the algae Macrocystis pyrifera (Phaeophyceae) in rodents

Macrocystis pyrifera is a giant brown seaweed with high nutritional content, used as a dietary supplement in some farm animals. It contains fucoidan which has a pharmacological effect on lipids and glucose metabolism. Some brown seaweeds can bioaccumulate toxic elements in their cell wall, representing a problem if toxicity tests that guarantee the safety of their consumption are not done. M. pyrifera, does not present toxicological studies that guarantee its safety. This work aimed to perform the acute and subchronic toxicological evaluation of M. pyrifera in rodents as well as to determine its possible therapeutic effect. Fronds of M. pyrifera were collected in Baja California Sur, Mexico, for drying and obtaining algae flour. The acute toxicity test LD50 was performed in C57BL / 6 male mice (25 ± 3 g) for 7 days, finding an LD50 greater than 10 g kg-1. Subchronic toxicity was determined for 121 days in adult male Sprague Dawley rats (98 ± 2 g), during which the experimental animals showed no signs of toxicity, or changes in the hematological, biochemical and histopathological parameters of the organs. The reactive oxygen species, lipid peroxidation or glutathione ratio were not different from the control group. A therapeutic effect on the regulation of body weight and a hypolipidemic effect (triacylglycerides: 82.27 ± 5.55 mg dl-1, cholesterol: 98.61 ± 6.48 mg dl-1) were found. It is concluded that, under the conditions in which this study was developed, the consumption of M. pyrifera as a functional ingredient is safe

Changing Professional Identity in the Transition from Practitioner to Lecturer in Higher Education: an Interpretive Phenomenological Analysis

This research explores the experiences of five professional practitioners from disciplines including teaching, youth work, sport and health who had become lecturers in Higher Education. Their experiences are considered using Interpretative Phenomenological Analysis and tentative conclusions are reached on the meaning of such experiences for the individuals. The work extends previous studies (Shreeve 2010, 2011; Gourlay 2011a, 2011b; Boyd & Harris 2010) to consider the relationship between knowledge and influence and how institutional preference for knowledge gained from research impacts on the validity of knowledge derived from professional experience. The research finds shared feelings associated with inauthenticity and loss arising from concerns that the contribution of the professional in Higher Education is undervalued. The research challenges the assumption that professional practitioners adopt the professional identity of a lecturer in Higher Education instead finding that they create their own professional identities in the liminal space between the professional and academic domains, but points to difficulties associated with constructed nature of such professional identities within the institutional structure of a Higher Education institution

Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside—a Comprehensive Review

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions

Nanoscale oxygen defect gradients in UO2+x surfaces.

Oxygen defects govern the behavior of a range of materials spanning catalysis, quantum computing, and nuclear energy. Understanding and controlling these defects is particularly important for the safe use, storage, and disposal of actinide oxides in the nuclear fuel cycle, since their oxidation state influences fuel lifetimes, stability, and the contamination of groundwater. However, poorly understood nanoscale fluctuations in these systems can lead to significant deviations from bulk oxidation behavior. Here we describe the use of aberration-corrected scanning transmission electron microscopy and electron energy loss spectroscopy to resolve changes in the local oxygen defect environment in [Formula: see text] surfaces. We observe large image contrast and spectral changes that reflect the presence of sizable gradients in interstitial oxygen content at the nanoscale, which we quantify through first-principles calculations and image simulations. These findings reveal an unprecedented level of excess oxygen incorporated in a complex near-surface spatial distribution, offering additional insight into defect formation pathways and kinetics during [Formula: see text] surface oxidation