The Keap1/Nrf2 Signaling Pathway in the Thyroid-2020 Update.

The thyroid gland has a special relationship with oxidative stress. On the one hand, like all other tissues, it must defend itself against reactive oxygen species (ROS). On the other hand, unlike most other tissues, it must also produce reactive oxygen species in order to synthesize its hormones that contribute to the homeostasis of other tissues. The thyroid must therefore also rely on antioxidant defense systems to maintain its own homeostasis in the face of continuous self-exposure to ROS. One of the main endogenous antioxidant systems is the pathway centered on the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1). Over the last few years, multiple links have emerged between the Keap1/Nrf2 pathway and thyroid physiology, as well as various thyroid pathologies, including autoimmunity, goiter, hypothyroidism, hyperthyroidism, and cancer. In the present mini-review, we summarize recent studies shedding new light into the roles of Keap1/Nrf2 signaling in the thyroid

Thyroid Disorders in Patients Treated with Dimethyl Fumarate for Multiple Sclerosis: A Retrospective Observational Study.

Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto's thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators. In a retrospective observational study, we investigated the prevalence and incidence of thyroid disorders (TD) among 163 patients with MS treated with DMF. Only 7/163 patients (4.3%) were diagnosed with functional TD; most (5/163, 3.0%) were diagnosed before DMF treatment. Functional TD were diagnosed under or after DMF in only 2 patients (1.2%). Under DMF, one patient developed transient mild hypothyroidism with negative thyroid autoantibodies. After DMF discontinuation, another patient developed hyperthyroidism due to Graves' disease. No patient developed thyroid structural disease under or after DMF. The very low incidence of functional TD indicates an overall very good thyroid tolerance of DMF, arguing against screening for TD in MS patients considered for or treated with DMF, and supporting the further study of Nrf2 activators for the prevention and treatment of TD

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer.

The Keap1/Nrf2 pathway is a key mediator of general redox and tissue-specific homeostasis. It also exerts a dual role in cancer, by preventing cell transformation of normal cells but promoting aggressiveness, and drug resistance of malignant ones. Although Nrf2 is well-studied in other tissues, its roles in the thyroid gland are only recently emerging. This review focuses on the involvement of Keap1/Nrf2 signaling in thyroid physiology, and pathophysiology in general, and particularly in thyroid cancer. Studies in mice and cultured follicular cells have shown that, under physiological conditions, Nrf2 coordinates antioxidant defenses, directly increases thyroglobulin production and inhibits its iodination. Increased Nrf2 pathway activation has been reported in two independent families with multinodular goiters due to germline loss-of-function mutations in KEAP1. Nrf2 pathway activation has also been documented in papillary thyroid carcinoma (PTC), due to somatic mutations, or epigenetic modifications in KEAP1, or other pathway components. In PTC, such Nrf2-activating KEAP1 mutations have been associated with tumor aggressiveness. Furthermore, polymorphisms in the prototypical Nrf2 target genes NQO1 and NQO2 have been associated with extra-thyroidal extension and metastasis. More recently, mutations in the Nrf2 pathway have also been found in Hürthle-cell (oncocytic) thyroid carcinoma. Finally, in in vitro, and in vivo models of poorly-differentiated, and undifferentiated (anaplastic) thyroid carcinoma, Nrf2 activation has been associated with resistance to experimental molecularly-targeted therapy. Thus, Keap1/Nrf2 signaling is involved in both benign and malignant thyroid conditions, where it might serve as a prognostic marker or therapeutic target

Rare and common genetic variations in the Keap1/Nrf2 antioxidant response pathway impact thyroglobulin gene expression and circulating levels, respectively.

Nuclear factor, erythroid 2-like 2 (Nrf2) is a transcription factor that has been gaining attention in the field of pharmacology and especially in the chemoprevention of diseases such as cancer, metabolic and neurodegenerative diseases, etc. This is because natural compounds such as sulforaphane, which is found in broccoli sprout extracts, can activate Nrf2. The repertoire of the roles of Nrf2 is ever increasing; besides its traditional antioxidant and cytoprotective effects, Nrf2 can have other functions as a transcription factor. We have recently shown that Nrf2 directly regulates the expression of thyroglobulin (Tg), which is the most abundant thyroidal protein and the precursor of thyroid hormones. Two functional binding sites for Nrf2 (antioxidant response elements, AREs) were identified in the regulatory region of the TG gene. Interestingly, we then observed that one of these AREs harbors a rare single-nucleotide polymorphism (SNP). Also recently, we performed the first genome-wide association study (GWAS) for common SNPs that impact the circulating levels of Tg. Based on these investigations, we were triggered (i) to investigate whether common SNPs in the Nrf2 pathway correlate with circulating Tg levels; and (ii) to examine whether the rare SNP in one of the TG regulatory AREs may affect gene expression. To address the first question, we analyzed GWAS data from a general population and its two subpopulations, one with thyroid disease and/or abnormal thyroid function tests and the other without, in which circulating Tg levels had been measured. Statistically significant associations with Tg levels were observed in the genes encoding Nrf2 and Keap1, including, notably, a known functional SNP in the promoter of the gene encoding Nrf2. Regarding the rare SNP (rs778940395) in the proximal ARE of the TG enhancer, luciferase reporter gene expression studies in PCCL3 rat thyroid follicular cells showed that this SNP abrogated the basal and sulforaphane- or TSH-induced luciferase activity, behaving as a complete loss-of-function mutation. Thus, both rare and common genetic variation in the Keap1/Nrf2 pathway can impact TG expression and Tg circulating levels, respectively

What lies beneath : detecting sub-canopy changes in savanna woodlands using a three-dimensional classification method

QUESTION : Increasing population pressure, socio-economic development and associated natural resource use in savannas are resulting in large-scale land cover changes, which can be mapped using remote sensing. Is a three-dimensional (3D) woody vegetation structural classification applied to LiDAR (Light Detection and Ranging) data better than a 2D analysis to investigate change in fine-scale woody vegetation structure over 2 yrs in a protected area (PA) and a communal rangeland (CR)? LOCATION : Bushbuckridge Municipality and Sabi Sand Wildtuin, NE South Africa. METHODS : Airborne LiDAR data were collected over 3 300 ha in April 2008 and 2010. Individual tree canopies were identified using object-based image analysis and classified into four height classes: 1–3, 3–6, 6–10 and >10 m. Four structural metrics were calculated for 0.25-ha grid cells: canopy cover, number of canopy layers present, cohesion and number of height classes present. The relationship between top-of-canopy cover and sub-canopy cover was investigated using regression. Gains, losses and persistence (GLP) of cover at each height class and the four structural metrics were calculated. GLP of clusters of each structural metric (calculated using LISA – Local Indicators of Spatial Association – statistics) were used to assess the changes in clusters of eachmetric over time. RESULTS : Top-of-canopy cover was not a good predictor of sub-canopy cover. The number of canopy layers present and cohesion showed gains and losseswith persistence in canopy cover over time, necessitating the use of a 3D classification to detect fine-scale changes, especially in structurally heterogeneous savannas. Trees >3 min height showed recruitment and gains up to 2.2 times higher in the CR where they are likely to be protected for cultural reasons, but losses of up to 3.2-foldmore in the PA, possibly due to treefall caused by elephant and/or fire. CONCLUSION : Land use has affected sub-canopy structure in the adjacent sites, with the low intensity use CR showing higher structural diversity. A 3D classification approach was successful in detecting fine-scale, short-term changes between land uses, and can thus be used as amonitoring tool for savannawoody vegetation structure. Remove selectedThe Carnegie Airborne Observatory is made possible by the Avatar Alliance Foundation, Margaret A. Cargill Foundation, John D. and Catherine T. MacArthur Foundation, Grantham Foundation for the Protection of the Environment, W.M. Keck Foundation, Gordon and Betty Moore Foundation, Mary Anne Nyburg Baker and G. Leonard Baker Jr. and William R. Hearst III. Application of the CAO data in South Africa is made possible by the Andrew Mellon Foundation and the endowment of the Carnegie Institution for Science.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1654-109X2016-07-31hb201

Unsustainable fuelwood extraction from South African savannas

Wood and charcoal supply the majority of sub-Saharan Africa’s rural energy needs. The long-term supply of fuelwood is in jeopardy given high consumption rates. Using airborne light detection and ranging (LiDAR), we mapped and investigated savanna aboveground biomass across contrasting land uses, ranging from densely populated communal areas to highly protected areas in the Lowveld savannas of South Africa. We combined the LiDAR observations with socio-economic data, biomass production rates and fuelwood consumption rates in a supply–demand model to predict future fuelwood availability. LiDAR-based biomass maps revealed disturbance gradients around settlements up to 1.5 km, corresponding to the maximum distance walked to collect fuelwood. At current levels of fuelwood consumption (67% of households use fuelwood exclusively, with a 2% annual reduction), we calculate that biomass in the study area will be exhausted within thirteen years. We also show that it will require a 15% annual reduction in consumption for eight years to a level of 20% of households using fuelwood before the reduction in biomass appears to stabilize to sustainable levels. The severity of dwindling fuelwood reserves in African savannas underscores the importance of providing affordable energy for rural economic development.The CSIR researchers were funded by the CSIR Strategic Research Panel and the Department of Science and Technology’s Earth Observation Unit. SUCSES study (Sustainability in Communal Socio-Ecological Systems) which provided data on fuelwood use in Justicia was funded by the South African National Research Foundation. The airborne campaign and analysis was funded by the Andrew Mellon Foundation.http://iopscience.iop.org/1748-9326am201

Morphometrics and genetics highlight the complex history of Eastern Mediterranean spiny mice

© 2020 The Linnean Society of London, Biological Journal of the Linnean Society. Spiny mice of the Acomys cahirinus group display a complex geographical structure in the Eastern Mediterranean area, as shown by previous genetic and chromosomal studies. To better elucidate the evolutionary relationships between insular populations from Crete and Cyprus and continental populations from North Africa and Cilicia in Turkey, genetic and morphometric variations were investigated, based on mitochondrial D-loop sequences, and the size and shape of the first upper molar. The Cypriot and the Cilician populations show idiosyncratic divergence in molar size and shape, while Cretan populations present a geographical structure with at least three differentiated subpopulations, as shown by congruent distributions of haplogroups, Robertsonian fusions and morphometric variation. A complex history of multiple introductions is probably responsible for this structure, and insular isolation coupled with habitat shift should have further promoted a pronounced and rapid morphological evolution in molar size and shape on Crete and Cyprus

Biomass increases go under cover : woody vegetation dynamics in South African rangelands

Woody biomass dynamics are an expression of ecosystem function, yet biomass estimates do not provide information on the spatial distribution of woody vegetation within the vertical vegetation subcanopy. We demonstrate the ability of airborne light detection and ranging (LiDAR) to measure aboveground biomass and subcanopy structure, as an explanatory tool to unravel vegetation dynamics in structurally heterogeneous landscapes. We sampled three communal rangelands in Bushbuckridge, South Africa, utilised by rural communities for fuelwood harvesting. Woody biomass estimates ranged between 9 Mg ha-1 on gabbro geology sites to 27 Mg ha-1 on granitic geology sites. Despite predictions of woodland depletion due to unsustainable fuelwood extraction in previous studies, biomass in all the communal rangelands increased between 2008 and 2012. Annual biomass productivity estimates (10–14% p.a.) were higher than previous estimates of 4% and likely a significant contributor to the previous underestimations of modelled biomass supply. We show that biomass increases are attributable to growth of vegetation <5 m in height, and that, in the high wood extraction rangeland, 79% of the changes in the vertical vegetation subcanopy are gains in the 1-3m height class. The higher the wood extraction pressure on the rangelands, the greater the biomass increases in the low height classes within the subcanopy, likely a strong resprouting response to intensive harvesting. Yet, fuelwood shortages are still occurring, as evidenced by the losses in the tall tree height class in the high extraction rangeland. Loss of large trees and gain in subcanopy shrubs could result in a structurally simple landscape with reduced functional capacity. This research demonstrates that intensive harvesting can, paradoxically, increase biomass and this has implications for the sustainability of ecosystem service provision. The structural implications of biomass increases in communal rangelands could be misinterpreted as woodland recovery in the absence of three-dimensional, subcanopy information.S1 Dataset. Biomass model data. Data include 2012 LiDAR-derived average height and canopy cover extraction metrics, as well as field-work based allometry. Each line item is per 25 m x 25 m grid cell. Metadata are included in the dataset.S2 Dataset. Biomass and subcanopy data. Data include 2008 and 2012 biomass estimates derived from biomass models as well as % subcanopy returns for voxel data for the height class categories: 1-3m, 3-5m, 5-10m and >10m. Each line item is per 25 m x 25 m grid cell. Data are organized per land extraction category into separate worksheets. Metadata are included in the dataset.S3 Dataset. Biomass changes (Mg ha-1) in relation to relative height and canopy cover change. Data include biomass change estimates (2008–2012), percentage height and canopy cover changes for each 25 m x 25 m grid cell. Each height class (relative to height in 2008) are shown on separate worksheets. Metadata are included in the dataset.S1 Fig. Site-specific biomass model residuals. The residual spread demonstrates heteroskedasticity with increasing biomass fitted values for rangelands with a) high, b) intermediate and c) low extraction pressure.S2 Fig. Biomass changes (%) relative to height-specific change in subcanopy returns (%). Height categories are: 1–3 m, 3–5 m, 5–10 m and >10 m.The Carnegie Airborne Observatory (CAO) is made possible by the Avatar Alliance Foundation, Margaret A. Cargill Foundation, John D. and Catherine T. MacArthur Foundation, Grantham Foundation for the Protection of the Environment, W. M. Keck Foundation, Gordon and Betty Moore Foundation, Mary Anne Nyburg Baker and G. Leonard Baker, Jr., and William R. Hearst III. Application of the CAO data in South Africa is made possible through the Andrew Mellon Foundation and the endowment of the Carnegie Institution for Science, the Council for Scientific and Industrial Research (CSIR), and the South African Department of Science and Technology (grant agreement DST/ CON 0119/2010, Earth Observation Application Development in Support of SAEOS). CSIR coauthors are supported by the European Union’s Seventh Framework Programme (FP7/2007-2013, grant agreement n°282621, AGRICAB). PJM acknowledges funding from the National Research Foundation (NRF: SFH1207203615). Additionally, PJM and ETFW acknowledge the DST-NRF Centre of Excellence in Tree Health Biotechnology (CTHB) and, PJM and BFNE, the Applied Centre for Climate and Earth Systems Science (ACCESS). BFNE acknowledges financial support from Exxaro.http://www.plosone.orgam201

Interaction of Genetic Variations in NFE2L2 and SELENOS Modulates the Risk of Hashimoto's Thyroiditis.

Background: Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by NFE2L2, is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in NFE2L2 on the risk of developing HT. Methods: In a case-control candidate gene association study, functional SNPs in the NFE2L2 promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene SELENOS, encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. SELENOS and NFE2L2 SNPs were genotyped using TaqMan &lt;sup&gt;®&lt;/sup&gt; assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. Results: When all three NFE2L2 SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43, p = 0.072). Among subjects harboring only major NFE2L2 alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the SELENOS minor allele. Conversely, in subjects heterozygous or homozygous for the SELENOS risk allele, the presence of an NFE2L2 minor allele significantly increased HT risk by 2.8-fold (p = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. Conclusions: The NFE2L2 promoter genotype interacts with the SELENOS promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways

Magnetic fields in cosmic particle acceleration sources

We review here some magnetic phenomena in astrophysical particle accelerators associated with collisionless shocks in supernova remnants, radio galaxies and clusters of galaxies. A specific feature is that the accelerated particles can play an important role in magnetic field evolution in the objects. We discuss a number of CR-driven, magnetic field amplification processes that are likely to operate when diffusive shock acceleration (DSA) becomes efficient and nonlinear. The turbulent magnetic fields produced by these processes determine the maximum energies of accelerated particles and result in specific features in the observed photon radiation of the sources. Equally important, magnetic field amplification by the CR currents and pressure anisotropies may affect the shocked gas temperatures and compression, both in the shock precursor and in the downstream flow, if the shock is an efficient CR accelerator. Strong fluctuations of the magnetic field on scales above the radiation formation length in the shock vicinity result in intermittent structures observable in synchrotron emission images. Resonant and non-resonant CR streaming instabilities in the shock precursor can generate mesoscale magnetic fields with scale-sizes comparable to supernova remnants and even superbubbles. This opens the possibility that magnetic fields in the earliest galaxies were produced by the first generation Population III supernova remnants and by clustered supernovae in star forming regions.Comment: 30 pages, Space Science Review