The future of mining in the Adria region: current status, SWOT and Gap analysis of the mineral sector

The Adria region which includes the countries of: Albania, Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia, and corresponds to the Dinarides, northwesternmost Hellenides, and the Vardar zone, has a long history of mining. Here, the main strengths and challenges of the mineral sector of the Adria region were assessed using the following methodology: (1) presentation of the current status of mineral exploration and exploitation, (2) SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis on parameters including geological potential, economic environment, legal and regulatory framework, innovation and technology framework, environmental protection and land use planning, governmental and social potential, human resources and educational potential, (3) Gap analysis, and (4) integration of the results obtained in the development of a roadmap for the actions required to promote investments in the mineral sector in the Adria region. The main strengths of the regional mineral sector include the significant mineral potential due to a favourable geological setting, significant reserves, a long mining tradition, and active exploration areas, as well as a significant number of active and abundant mines and the availability of secondary raw materials. Nevertheless, there are many challenges that the mineral sector faces, such as difficulties in ensuring social acceptance, a lack of new exploration campaigns in many areas, estimation of resources or reserves that do not follow international codes and standards, regulations related to environmental issues in the mineral sector of Adria countries that do not comply with European legislation, and the limited availability of qualified technical, scientific and managerial personnel involved in the whole mineral cycle. Therefore, actions and measures such as awareness campaigns to highlight the significance of Raw Materials in the sustainable development of the region, further exploration, reserves calculation in alignment with internationally recognized codes, harmonization with spatial plans, and reforms to attract investors and capacity building programs should be taken for further development of the Adria region’s mineral sector in a sustainable manner

Genetic Risk Score for Coronary Disease Identifies Predispositions to Cardiovascular and Noncardiovascular Diseases.

BACKGROUND: The taxonomy of cardiovascular (CV) diseases is divided into a broad spectrum of clinical entities. Many such diseases coincide in specific patient groups and suggest shared predisposition. OBJECTIVES: This study focused on coronary artery disease (CAD) and investigated the genetic relationship to CV and non-CV diseases with reported CAD comorbidity. METHODS: This study examined 425,196 UK Biobank participants to determine a genetic risk score (GRS) based on 300 CAD associated variants (CAD-GRS). This score was associated with 22 traits, including risk factors, diseases secondary to CAD, as well as comorbid and non-CV conditions. Sensitivity analyses were performed in individuals free from CAD or stable angina diagnosis. RESULTS: Hypercholesterolemia (odds ratio [OR]: 1.27; 95% CI: 1.26 to 1.29) and hypertension (OR: 1.11; 95% CI: 1.10 to 1.12) were strongly associated with the CAD-GRS, which indicated that the score contained variants predisposing to these conditions. However, the CAD-GRS was also significant in patients with CAD who were free of CAD risk factors (OR: 1.37; 95% CI: 1.30 to 1.44). The study observed significant associations between the CAD-GRS and peripheral arterial disease (OR: 1.28; 95% CI: 1.23 to 1.32), abdominal aortic aneurysms (OR: 1.28; 95% CI: 1.20 to 1.37), and stroke (OR: 1.08; 95% CI: 1.05 to 1.10), which remained significant in sensitivity analyses that suggested shared genetic predisposition. The score was also associated with heart failure (OR: 1.25; 95% CI: 1.22 to 1.29), atrial fibrillation (OR: 1.08; 95% CI: 1.05 to 1.10), and premature death (OR: 1.04; 95% CI: 1.02 to 1.06). These associations were abolished in sensitivity analyses that indicated that they were secondary to prevalent CAD. Finally, an inverse association was observed between the score and migraine headaches (OR: 0.94; 95% CI: 0.93 to 0.96). CONCLUSIONS: A wide spectrum of CV conditions, including premature death, might develop consecutively or in parallel with CAD for the same genetic roots. In conditions like heart failure, the study found evidence that the CAD-GRS could be used to stratify patients with no or limited genetic overlap with CAD risk. Increased genetic predisposition to CAD was inversely associated with migraine headaches.National Institute of Health Research (NIHR) Barts Biomedical Research Centre - NIHR (IS-BRC-1215-20022)Fondation Leducq (CADgenomics, 12CVD02)Sonderforschungsbereich CRC 1123 (B2)German Federal Ministry of Education and Research (BMBF) (ERA-CVD: grant JTC2017_21-040

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD. 2022, The Author(s).T. Kessler is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02). T.J. was supported by a Medical Research Council DTP studentship (MR/S502443/1). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health and Care Research (NIHR) Senior Investigator. J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence. O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). P.S.d.V. was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946. The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes, 01KL1802), within the scheme of target validation (BlockCAD, 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net, 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02), the Sonderforschungsbereich SFB TRR 267 (B05), and EXC2167 (PMI). This work was supported by the British Heart Foundation (BHF) under grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School. This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (203141/Z/16/Z to M.F. and H.W.) and the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. C.P.N. and T.R.W. received funding from the British Heart Foundation (SP/16/4/32697). C.J.W. is funded by NIH grant R35-HL135824. B.N.W. is supported by the National Science Foundation Graduate Research Program (DGE, 1256260). This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application 9922). O.M. was funded by the Swedish Heart and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ‘Malmö population-based cohorts’ (STYR 2019/2046). T.R.W. is funded by the British Heart Foundation. I.K., S. Koyama, and K. Ito are funded by the Japan Agency for Medical Research and Development, AMED, under grants JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209 and JP20ek0109487. The Biobank Japan is supported by AMED under grant JP20km0605001. J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: New Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02. A.V.K. has been funded by grant 1K08HG010155 from the National Human Genome Research Institute. K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542) and the NIH (1K08HL153937). A.S.B. has been supported by funding from the National Health and Medical Research Council (NHMRC) of Australia (APP2002375). D.S.A. has received support from a training grant from the NIH (T32HL007604). N.P.B., M.C.C., J.F. and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554). EPIC-CVD was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The coordinating center was supported by core funding from the UK Medical Research Council (G0800270; MR/L003120/1), British Heart Foundation (SP/09/002, RG/13/13/30194, RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute.Scopu

Χαρτογράφηση της διακυτταρικής επικοινωνίας μέσω εξωσωμάτων στο Πολλαπλούν Μυέλωμα

Αναγνωρίζοντας πως τα εξωσώματα διαδραματίζουν καίριο ρόλο στη διακυτταρική επικοινωνία, τόσο στην υγεία, όσο και στην ασθένεια, η συμμετοχή τους έχει επιβεβαιωθεί σε μια σειρά από βιολογικές διαδικασίες στο πολλαπλούν μυέλωμα, όπως η οστεόλυση, η αγγειογένεση, η ανοσοκαταστολή και η ανθεκτικότητα στη θεραπεία. H παρούσα εργασία αποσκοπεί στη χαρτογράφηση της διακυτταρικής επικοινωνίας μέσω εξωσωμάτων στο πολλαπλούν μυέλωμα και ως εκ τούτου, την απόδειξη της ορθότητας της ιδέας ως προς α. την ανάδειξη των εξωσωμάτων ως μεταφραστικοί βιοδείκτες, β. τη διαστρωμάτωση ασθενών, βάσει μεταβότυπου και γ. την αποσαφήνιση μηχανισμών της παραπρωτεϊναιμίας. Για το σκοπό αυτό, πραγματοποιήθηκαν εργαστηριακές και υπολογιστικές προσεγγίσεις, αναφορικά με την απομόνωση, ταυτοποίηση και ανάλυση (ποιοτική/ποσοτική) των εξωσωμάτων από το πλάσμα του μυελού των οστών, καθώς και το πλάσμα περιφερικού αίματος ασθενών με πολλαπλούν μυέλωμα και υψηλή, ενδιάμεση και χαμηλή διήθηση του μυελού των οστών. Αντίστοιχα, διερευνήθηκαν εμπύρηνα κύτταρα από τον μυελό των οστών και το περιφερικό αίμα των ίδιων ασθενών. Συνοπτικά, η μη-στοχευμένη και στοχευμένη μεταβολομική ανάλυση με χρήση υγρής χρωματογραφίας φασματομετρίας μάζας, συνδυάστηκε με μικροσκοπία φθορισμού και ανάλυση εικόνας με νευρωνικά δίκτυα. 3D κυτταρικές καλλιέργειες συνετέλεσαν στον έλεγχο ποιότητας. Τα ευρήματα της εργασίας συνηγορούν πως ο απορρέον μεταβότυπος του περιφερικού αίματος, σε σχέση με εκείνον του μυελού των οστών είναι έντονα ετερογενής (ακόμη κι αν γίνεται λόγος για παρόμοια μοριακά μονοπάτια, τα κλάσματα των μεταβολιτών διαφοροποιούνται). Στον αντίποδα, ο μεταβότυπος των εξωσωμάτων είναι ενδεικτικός του κυτταρικού μεταβολισμού που τα αφορά. Tα εξωσώματα και οι απορρέοντες μεταβότυποι, καθώς αποτελούν συνισταμένη του γονιδιακού προφίλ και των περιβαλλοντικών επιδράσεων, δύναται να υπερκεράσουν τους περιορισμούς του γονιδιώματος και του πρωτεόματος, συμπληρώνοντας τα γνωσιακά κενά.Exosomes play a key role in intercellular communication in health and disease status; their contribution in multiple myeloma has been reported in a series of biological processes, including osteolysis, angiogenesis, immune suppression, and drug resistance. Herein, we aim to map intercellular communication in multiple myeloma via exosomes and hence, to provide a proof of concept for a. exosomes serving as translational biomarkers, b. metabotypes toward patient stratification, and c. shedding light on the molecular mechanisms of paraproteinaemia. For this, wet- and dry-lab approaches took place for the isolation, identification, qualification, and quantification of exosomes derived from bone marrow plasma and peripheral blood plasma of multiple myeloma patients with high, moderate and low bone marrow infiltration. Similarly, bone marrow nucleated cells and peripheral blood nucleated cells were explored (same patient cohort). In brief, un-targeted and targeted metabolomic analysis by liquid chromatography mass spectrometry were coupled to fluorescence microscopy and image analysis via neural networks. 3D cell cultures empowered quality control. Our findings suggest that the peripheral blood plasma metabotype is highly heterogeneous when compared to the one of bone marrow plasma (even if similar molecular pathways are highlighted, classes of metabolites differ). On the contrary, exosomal metabotypes are in agreement with cell metabotypes. Exosomes and the metabotypes revealed, as they are considered as the net result of genome-environment interplay, may go beyond genome/proteome limitations, bridging knowledge gaps

Mineral Raw Materials’ Resource Efficiency in Selected ESEE Countries: Strengths and Challenges

The mineral raw materials’ resource efficiency is currently recognized in Europe as the way for the future development of the European mining economies. With this aim, a West Balkan Mineral Register was created in the EIT Raw Materials RESEERVE Project, including Primary and Secondary Raw Materials of six Eastern and South-Eastern Europe (ESEE) countries, i.e., Albania, Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia. Within the Project, a Strengths, Weaknesses, Opportunities, and Threats (SWOT) and Gap Analysis was also performed for the development of the raw material sector in the region. This paper summarizes the main strengths to be exploited, i.e., the significant geological potential, the presence of critical raw materials (e.g., Sb, Co, REEs) in primary and secondary raw materials, and the challenges to address, i.e., compliance of resources/reserves classification with international standards, integration of state’s mineral policy with spatial planning strategies, improvement of the business environment, capacity building of the raw materials workforce and enhancement of the public acceptance of the sector, in order to achieve the sustainable development of the mineral resources of the six ESEE countries. These opportunities comply with the objectives of the EU Raw Materials Initiative and are expected to contribute in the further enhancement of those economies in transition for the upcoming years