How to increase future mineral supply from EU sources

Europe’s insufficient mineral production and increasing industrial demands are reflected in high dependency on imported raw materials. Although exploration and exploitation of Europe’s mineral raw materials are essential activities, the land available for extraction is constantly diminishing. To improve the sustained mineral supply from European deposits, access to mineral deposits needs to be ensured and they need to be protected from potential sterilisation. Mineral deposits need to be properly evaluated, taking into account the geological setting and the viability of exploitation in accordance with other land-user and environmental requirements. Their incorporation into spatial plans will be of key importance. In the near future, each Member State needs to identify and protect the access to its selected significant mineral deposits within its national legislation framework. This paper presents a list of mineral deposits in Slovenia that should be protected and discusses criteria for their selection

AP4 suppresses DNA damage, chromosomal instability and senescence via inducing MDC1/Mediator of DNA damage Checkpoint 1 and repressing MIR22HG/miR-22-3p

Background AP4 (TFAP4) encodes a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor and is a direct target gene of the oncogenic transcription factor c-MYC. Here, we set out to determine the relevance of AP4 in human colorectal cancer (CRC) cells. Methods A CRISPR/Cas9 approach was employed to generate AP4 -deficient CRC cell lines with inducible expression of c-MYC. Colony formation, β-gal staining, immunofluorescence, comet and homologous recombination (HR) assays and RNA-Seq analysis were used to determine the effects of AP4 inactivation. qPCR and qChIP analyses was performed to validate differentially expressed AP4 targets. Expression data from CRC cohorts was subjected to bioinformatics analyses. Immunohistochemistry was used to evaluate AP4 targets in vivo. Ap4 -deficient APC min/+ mice were analyzed to determine conservation. Immunofluorescence, chromosome and micronuclei enumeration, MTT and colony formation assays were used to determine the effects of AP4 inactivation and target gene regulation on chromosomal instability (CIN) and drug sensitivity. Results Inactivation of AP4 in CRC cell lines resulted in increased spontaneous and c-MYC-induced DNA damage, chromosomal instability (CIN) and cellular senescence. AP4 -deficient cells displayed increased expression of the long non-coding RNA MIR22HG, which encodes miR-22-3p and was directly repressed by AP4. Furthermore, Mediator of DNA damage Checkpoint 1 ( MDC1 ), a central component of the DNA damage response and a known target of miR-22-3p, displayed decreased expression in AP4 -deficient cells. Accordingly, MDC1 was directly induced by AP4 and indirectly by AP4-mediated repression of miR-22-3p. Adenomas and organoids from Ap4 -deficient APC min/+ mice displayed conservation of these regulations. Inhibition of miR-22-3p or ectopic MDC1 expression reversed the increased senescence, DNA damage, CIN and defective HR observed in AP4 -deficient CRC cells. AP4 -deficiency also sensitized CRC cells to 5-FU treatment, whereas ectopic AP4 conferred resistance to 5-FU in a miR-22-3p and MDC1-dependent manner. Conclusions In summary, AP4, miR-22-3p and MDC1 form a conserved and coherent, regulatory feed-forward loop to promote DNA repair, which suppresses DNA damage, senescence and CIN, and contributes to 5-FU resistance. These findings explain how elevated AP4 expression contributes to development and chemo-resistance of colorectal cancer after c-MYC activation

Pan-cancer EMT-signature identifies RBM47 down-regulation during colorectal cancer progression

Epithelial-mesenchymal transition (EMT) plays an important role in tumor invasion and metastasis. A comprehensive, bioinformatics analysis of CCLE and TCGA datasets of seven tumor types allowed us to identify a novel pan-cancer EMT-associated gene expression signature consisting of 16 epithelial and 4 mesenchymal state-associated mRNAs. Among the identified epithelial cell state-associated factors, down-regulation of the RBM47 (RNA binding motif protein 47) mRNA displayed the most significant association with metastasis and poor survival in multiple cohorts of colorectal cancer (CRC) patients. Moreover, decreased RBM47 protein expression was associated with metastasis in a cohort of primary CRCs. RBM47 was directly suppressed during EMT induced by IL6-activated STAT3 or ectopic SNAIL and SLUG expression via conserved binding motifs of these factors within the RBM47 promoter. Moreover, RNAi-mediated down-regulation of RBM47 in CRC lines resulted in increased cell migration, invasion and metastases formation. As demonstrated by the example of RBM47, the EMT-associated signature characterized here allows to identify biomarkers for predicting clinical outcome of CRC and presumably other cancer entities. In addition, our functional analysis of RBM47 shows that the down-regulation of RBM47 during CRC progression may promote EMT and metastasis

The primary and secondary mineral resources of Montenegro and their mapping into the European data model

Primary and secondary mineral resources are of strategic importance to the EU economy. Montenegro, as a country candidate for membership in the EU, is required to follow (and later to implement) European policies, strategies as well as initiatives, including those related to mineral resources and the mining sector. The importance of providing access to mineral raw materials in the future is recognized by the EU, as well as meeting the needs of European industry, maintaining employment and ensuring further development. Considering the overall economic situation in Montenegro, it is important to encourge the mining sector and other industries based on the use of mineral resources in making a greater contribution to the development and sustainability of society as a whole and also increase the share of national GDP. The potential for discovery and utilization of primary and secondary mineral resources in Montenegro is demonstrated. The most important metallic mineral resources are bauxite, lead and zinc, while conventional energy resources include coal (oil and gas potential has yet to be proven). In addition, there are abundant non-metallic mineral raw materials - industrial minerals and construction materials. Secondary mineral resources, especially aluminous red mud (bauxite residue), are also significant and have been the subject of research in recent years. Tailings from flotation processes at operating and abandoned lead and zinc mines might also be of interest for metal recovery. Bottom and flay ash from thermal power plants, slag from steel production, as well as marlstone and limestone from the hanging wall of coal deposits may also have potential. Waste rocks could be used particularly for secondary aggregate production. A database was developed and the most important deposits of primary and secondary mineral resources in Montenegro were mapped during the RESEERVE project. Mineral data were harmonised so as to be INSPIRE compliant. In addition, some novel geochemical exploration results of secondary mineral resources are presented

Availability of mental health service providers and suicide rates in Slovenia: a nationwide ecological study

Aim To investigate the influence of socioeconomic factors, mental health service availability, and prevalence of mental disorders on regional differences in the suicide rate in Slovenia. Methods The effects of different socioeconomic factors, mental health service availability, and mental disorders factors on suicide rates from 2000-2009 were analyzed using a general linear mixed model (GLMM). Pearson correlations were used to explore the direction and magnitude of associations. Results Among socioeconomic factors, unemployment rate ranked as the most powerful predictor of suicide and an increase of one unit in the unemployment rate increased regional suicide rate by 2.21 (β = 2.21, 95% confidence intervals [CI] = 1.87-2.54, P < 0.001). On the other hand, higher marriage/divorce ratio was negatively related to the suicide rate and an increase of one unit in marriage/divorce ratio reduced regional suicide rate by 1.16 (β = -1.16, 95% CI = -2.20 to -0.13, P < 0.031). The most influential mental health service availability parameter was higher psychiatrist availability (4 psychiatrists and more working at outpatient clinics per 100 000 inhabitants), which was negatively correlated with the suicide rate and reduced regional suicide rate by 2.95 (β = -2.95, 95% CI = -4.60 to -1.31, P = 0.002). Another negatively correlated factor was the antidepressant/ anxiolytic ratio higher than 0.5, which reduced the regional suicide rate by 2.32 (β = -2.32, 95% CI = -3.75 to -0.89, P = 0.003). Among mental health disorders, only the prevalence of alcohol use disorders was significantly related to the regional suicide rates and an increase of one unit in the prevalence of alcohol use disorders per 1000 inhabitants increased the regional suicide rate by 0.02 (β = 0.02, 95% CI = 0.01- 0.03, P = 0.008). Conclusions Besides unemployment, which was a very strong predictor of suicide rates, unequal availability of mental health services and quality of depressive disorder treatment may contribute to variations in suicide rates in different regions

The f_LT Response Function of D(e,e'p)n at Q^2=0.33(GeV/c)^2

The interference response function f_LT (R_LT) of the D(e,e'p)n reaction has been determined at squared four-momentum transfer Q^2 = 0.33 (GeV/c)^2 and for missing momenta up to p_miss= 0.29 (GeV/c). The results have been compared to calculations that reproduce f_LT quite well but overestimate the cross sections by 10 - 20% for missing momenta between 0.1 (GeV/c) and 0.2 (GeV/c) .Comment: 12 Pages, 10 figure

A measurement of the axial form factor of the nucleon by the p(e,e'pi+)n reaction at W=1125 MeV

The reaction p(e,e'pi+)n was measured at the Mainz Microtron MAMI at an invariant mass of W=1125 MeV and four-momentum transfers of Q^2=0.117, 0.195 and 0.273 (GeV/c)^2. For each value of Q^2, a Rosenbluth separation of the transverse and longitudinal cross sections was performed. An effective Lagrangian model was used to extract the `axial mass' from experimental data. We find a value of M_A=(1.077+-0.039) GeV which is (0.051+-0.044) GeV larger than the axial mass known from neutrino scattering experiments. This is consistent with recent calculations in chiral perturbation theory.Comment: 14 pages, 5 figures, uses elsart.cl

ERBB4 Promoter Polymorphism Is Associated with Poor Distant Disease-Free Survival in High-Risk Early Breast Cancer

Peer reviewe

ORAMA project deliverable 1.2. Final analysis and recommendations for the improvement of statistical data collection methods in Europe for primary raw materials

This report brings together the outputs of Task 1.1 and 1.2 of Work Package 1 of the ORAMA project. Task 1.1 aims to produce an inventory of how minerals data are collected within Europe, via a survey of data providers, and Task 1.2 aims to review previous work from past projects, working groups and professional organisations in this subject area. Together this has built a comprehensive understanding of how minerals data are collected in Europe, what data gaps exist, what the issues are with regard to creating harmonised European datasets for minerals information and what good practice examples exist that lessons can be learnt from. The results of the survey show that countries that have a clear legal and regulatory procedure for collecting data often have the most robust systems in place. These countries often also have a strong motivation for collecting such data, such as receiving a significant income from mineral royalties as a result of state ownership of minerals, although resource management or land use planning also provide motivation for the collection of data. The results of the survey also showed there is a large variety in the way data is collected within Europe. This variety is not necessarily an issue with regard harmonisation as long as data providers ensure that they adhere to common data standards and classification systems, such as INSPIRE or UNFC when providing data for aggregation at a European level. The review of previous projects showed the breadth of work that had gone into the improvement of statistical datasets over the last few years. Especially from projects such as Minventory and Minerals4EU, which provide a clear roadmap for harmonising European minerals datasets, or the work of the EGS MREG (EuroGeoSurveys Mineral Resources Expert Group) towards the harmonisation of resource and reserve codes within Europe. A common theme of many of these recommendations is the need for common standards to be adhered to and that in some instances these specifications may need to be adapted to accommodate statistical data for mineral resources which are aggregated at a national scale

Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells

Experimental and clinical data support a growth inhibitory role for HER4 in breast cancer. Clinically HER4 expression is extinguished during breast tumorigenesis supporting a tumor suppressor function for HER4, however, a molecular mechanism to explain the selective loss of HER4 expression has remained elusive. Epigenetic mechanisms, for example, aberrant gene promoter hypermethylation, have been shown to ablate tumor suppressor gene expression in breast carcinomas. We identified a CpG island within the HER4 promoter and show by pyrosequencing of bisulfite-treated DNA an inverse correlation between HER4 expression and the extent of promoter methylation. Treatment of the HER4-negative BT20 cell line with the DNA demethylating agent 5-aza-2′-deoxycytidine (DAC)-enhanced HER4 expression, confirming a role for DNA methylation in suppressed HER4 expression. DAC treatment to reactive HER4 expression in combination with the HER4 ligand heregulin-β1 (HRG) resulted in apoptosis of BT20 cells providing a novel therapeutic strategy for triple-negative tumors. The BT20 cells were rescued from apoptosis when preincubated with HER4 small interfering RNA, thereby confirming a role for HER4 in DAC/HRG-induced apoptosis. We verified HER4 promoter methylation in primary breast carcinomas and detected a significant increase in HER4 promoter methylation in HER4-negative breast tumors (P<0.001). Furthermore, increased levels of HER4 promoter methylation were significantly associated with worse patient prognosis (P=0.0234). Taken together, our data support a tumor suppressor function for HER4, which is epigenetically suppressed in breast tumors through promoter hypermethylation