Cross-talk between Mirk/Dyrk1B kinase and Sonic hedgehog (Shh)/Gli pathway affects physiology and pathology. Here, we reveal a novel role for Dyrk1B in regulating ventral progenitor and neuron ...subtypes in the embryonic chick spinal cord (SC) via the Shh pathway. Using
in ovo gain-and-loss-of-function
approaches at E2, we report that Dyrk1B affects the proliferation and differentiation of neuronal progenitors at E4 and impacts on apoptosis specifically in the motor neuron (MN) domain. Especially, Dyrk1B overexpression decreases the numbers of ventral progenitors, MNs, and V2a interneurons, while the pharmacological inhibition of endogenous Dyrk1B kinase activity by AZ191 administration increases the numbers of ventral progenitors and MNs. Mechanistically, Dyrk1B overexpression suppresses Shh, Gli2 and Gli3 mRNA levels, while conversely, Shh, Gli2 and Gli3 transcription is increased in the presence of Dyrk1B inhibitor AZ191 or Smoothened agonist SAG. Most importantly,
in phenotype rescue
experiments, SAG restores the Dyrk1B-mediated dysregulation of ventral progenitors. Further at E6, Dyrk1B affects selectively the medial lateral motor neuron column (LMCm), consistent with the expression of Shh in this region. Collectively, these observations reveal a novel regulatory function of Dyrk1B kinase in suppressing the Shh/Gli pathway and thus affecting ventral subtypes in the developing spinal cord. These data render Dyrk1B a possible therapeutic target for motor neuron diseases.
Abstract Antibodies against Glutamic-acid-decarboxylase (GAD65) are seen in various CNS excitability disorders including stiff-person syndrome, cerebellar ataxia, encephalitis and epilepsy. To ...explore pathogenicity, we examined whether distinct epitope specificities or other co-existing antibodies may account for each disorder. The epitope recognized by all 27 tested patients, irrespective of clinical phenotype, corresponded to the catalytic core of GAD. No autoantibodies against known GABAergic antigens were found. In a screen for novel specificities using live hippocampal neurons, three epilepsy patients, but no other, were positive. We conclude that no GAD-specific epitope defines any neurological syndrome but other antibody specificities may account for certain phenotypes.
Large-scale land cover classification from satellite imagery is still a challenge due to the big volume of data to be processed, to persistent cloud-cover in cloud-prone areas as well as seasonal ...artefacts that affect spatial homogeneity. Sentinel-2 times series from Copernicus Earth Observation program offer a great potential for fine scale land cover mapping thanks to high spatial and temporal resolutions, with a decametric resolution and five-day repeat time. However, the selection of best available scenes, their download together with the requirements in terms of storage and computing resources pose restrictions for large-scale land cover mapping. The dataset presented in this paper corresponds to global cloud-free pixel based composite created from the Sentinel-2 data archive (Level L1C) available in Google Earth Engine for the period January 2017- December 2018. The methodology used for generating the image composite is described and the metadata associated with the 10 m resolution dataset is presented. The data with a total volume of 15 TB is stored on the Big Data platform of the Joint Research Centre. It can be downloaded per UTM grid zone, loaded into GIS clients and displayed easily thanks to pre-computed overviews.
This paper presents a hierarchical conflation process applied to open datasets for the creation of a seamless pan-European map of building footprints in vector format, named Digital Building Stock ...Model – DBSM. The objective is the sequential addition of input components (which currently include OpenStreetMap, Microsoft GlobalML Building Footprints, European Settlement Map), taking into account their limitations, and aiming at the highest level of completeness possible, for planning and evaluating energy transition scenarios at the EU level. The results indicate how DBSM compares robustly against cadastral data from Estonia, used as reference area. The comparison of DBSM with GHS-BUILT-S, a 10 metres resolution grid with worldwide coverage that encodes the built-up surface in each pixel as derived from Sentinel-2 imagery for the year 2018, reveals a relative overestimation of the latter, factored by 0.68 at the EU scale for a sound match.
Neurogenesis during embryonic and adult life is tightly regulated by a network of transcriptional, growth and hormonal factors. Emerging evidence indicates that activation of the stress response, via ...the associated glucocorticoid increase, reduces neurogenesis and contributes to the development of adult diseases.As corticotrophin-releasing hormone (CRH) or factor is the major mediator of adaptive response to stressors, we sought to investigate its involvement in this process. Accordingly, we found that CRH could reverse the damaging effects of glucocorticoid on neural stem/progenitor cells (NS/PCs), while its genetic deficiency results in compromised proliferation and enhanced apoptosis during neurogenesis. Analyses in fetal and adult mouse brain revealed significant expression of CRH receptors in proliferating neuronal progenitors. Furthermore, by using primary cultures of NS/PCs, we characterized the molecular mechanisms and identified CRH receptor-1 as the receptor mediating the neuroprotective effects of CRH. Finally, we demonstrate the expression of CRH receptors in human fetal brain from early gestational age, in areas of active neuronal proliferation. These observations raise the intriguing possibility for CRH-mediated pharmacological applications in diseases characterized by altered neuronal homeostasis, including depression, dementia, neurodegenerative diseases, brain traumas and obesity.
Neuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system with less than 40% long-term survival in children diagnosed with high-risk disease. These ...clinical observations underscore the need for novel insights in the mechanisms of malignant transformation and progression. Accordingly, it was recently reported that Prox1, a homeobox transcription regulator, is expressed in higher levels in human neuroblastoma with favorable prognosis. Consistently, we have recently shown that Prox1 exerts a strong antiproliferative effect on neural precursor cells during embryonic development. Thus, Prox1 is a candidate gene with a critical role in suppressing malignant neuroblastoma transformation. Here, we provide evidence that Prox1 strongly suppresses the proliferation of mouse and human neuroblastoma cell lines and blocks the growth of neuroblastoma tumors in SCID mice. Conversely, short hairpin RNA (shRNA) -mediated knockdown of basal Prox1 expression significantly induces proliferation, genomic instability and the ability of neuroblastoma cells to form tumors. Mechanistically, analysis of an inducible Prox1-overexpressing Neuro2A cell line indicates that Prox1 is sufficient to suppress CyclinD1, CyclinA and CyclinB1, consistent with a role in cell cycle arrest. Surprisingly, Prox1 strongly induces CyclinE1 expression in the same system despite its action on blocking cell cycle progression, which could account for the context dependent oncogenic function of Prox1. Most importantly, Prox1 was sufficient to decrease Cdc25A and induce p27-Kip1, but not p21-Cip1 or p53. By alleviating the Prox1 action in Cdc25A and p27-Kip1 expression, we were able to rescue its effect on cell cycle arrest. Together these data suggest that Prox1 negatively regulates neuroblastoma carcinogenesis through suppression of Cdc25A and induction of p27-Kip1 to counteract CyclinE1 overexpression and block cell cycle progression. Furthermore, these observations render Prox1 a candidate target for the treatment of neuroblastoma tumors.
Geo-information on settlements from Earth Observation offers a base for objective and scalable monitoring of the evolution of cities and settlements, including their location, extent and other ...attributes. In this work, we deploy the best available global knowledge on the presence of human settlements and built-up structures derived from Earth Observation to advance the understanding of the human presence on Earth. We start from a concept of Generalised Settlement Area to identify the Earth surface within which any built-up structure is present. We further characterise the resulted map by using an agreement map among the state of the art of remote sensing products mapping built-up areas or other strictly related semantic abstractions as urban areas or artificial surfaces. The agreement map is formed by a grid of 1 km
2
, where each cell is classified according to the number of EO-derived products reporting any positive occurrence of the abstractions related to the presence of built-up structures. The paper describes the characteristics of the Generalised Settlement Area, the differences in the agreement map across geographic regions of the world, and outlines the implications for potential users of the EO-derived products used in this study.
This letter introduces the new European Settlement Map (ESM) production workflow, presents some indicatory results, and discusses the validation process. Unlike the previous ESM versions, the ...built-up (BU) extraction is realized through supervised learning (not only by means of image filtering and processing techniques) based on textural and morphological features. Input data are the Copernicus very-high-resolution image collection for the reference year 2015 coming from a variety of sensors. The workflow is fully automated, and it does not include any postprocessing. For the first time, a new layer containing nonresidential buildings was derived by using only remote sensing imagery and training data. The produced BU map is delivered at 2-m-pixel resolution (level-1 layer), while the residential/nonresidential layer (level 2) is delivered at 10-m spatial resolution. More than 46 000 scenes were processed, and around 6 million km 2 of the European territory was mapped. The workflow was executed on the JRC Big Data platform. The validation showed a balanced accuracy of 0.81 and 0.91 for level 1 and 2 layers, respectively, and 0.71 for only the nonresidential layer.
The objective of this work was to develop, use and present a detailed questionnaire for the evaluation of health management in dairy small ruminants; it includes 442 questions organised in seven ...sections: general, infrastructure, animals, production characteristics, health management, nutrition, human resources. Consistency of replies was evaluated in 27 farmers, interviewed twice. Inconsistent replies were given by all farmers to 30 different questions (Cronbach’s coefficient alpha: 0.987). Then, interviews were performed in 444 farms around Greece. Mean duration of an interview was 63.6 min. Clarifications were requested by 273 farmers to 22 different questions (maximum per farmer: 8). The experience of the investigator, the primary language of farmers and asking clarifications by the farmers affected the duration of the interview. The questionnaire can be used for research work in the field, to record details in the farms under study. In accord with the needs of a particular study, it can be modified, by adding more specific questions or omitting others deemed of less importance. Moreover, it can also be used for routine monitoring purposes, as a useful means to record and maintain details of farms during clinical work. To the best of our knowledge, the questionnaire is the most extensive and detailed one available internationally for dairy small ruminants.
The objectives of this review paper are to present udder defences, including teat of the udder, mammary epithelial cells, leucocytes, immunoglobulins, complement system and chemical antibacterial ...agents, to describe cooperation and interactions between them and to elaborate on potentials regarding their significance in mammary immunisation strategies. The teat of the udder provides initial protection to the mammary gland. The mammary epithelial cells synthesise antibacterial proteins and the leucocytes produce various inflammation mediators (cytokines or chemokines), phagocytose bacteria and recognise antigenic structures. In the mammary gland, four immunoglobulins (IgG1, IgG2, IgM and IgA) have important roles against bacterial pathogens. The complement system is a collection of proteins, participating in the inflammatory process through various pathways. Other components contributing to humoral mammary defence include lactoferrin, lysozyme and the lactoperoxidase/myeloperoxidase systems, as well as oligosaccharides, gangliosides, reactive oxygen species, acute phase proteins (e.g., haptoglobin and serum amyloid A), ribonucleases and a wide range of antimicrobial peptides. Management practices, genetic variations and nutrition can influence mammary defences and should be taken into account in the formulation of prevention strategies against ovine mastitis.
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