Rapid Atlantification along the Fram Strait at the beginning of the 20th century.

The recent expansion of Atlantic waters into the Arctic Ocean represents undisputable evidence of the rapid changes occurring in this region. Understanding the past variability of this “Atlantification” is thus crucial in providing a longer perspective on the modern Arctic changes. Here, we reconstruct the history of Atlantification along the eastern Fram Strait during the past 800 years using precisely dated paleoceanographic records based on organic biomarkers and benthic foraminiferal data. Our results show rapid changes in water mass properties that commenced in the early 20th century—several decades before the documented Atlantification by instrumental records. Comparison with regional records suggests a poleward expansion of subtropical waters since the end of the Little Ice Age in response to a rapid hydrographic reorganization in the North Atlantic. Understanding of this mechanism will require further investigations using climate model simulations

NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL

European Atlas of Natural Radiation

Natural ionizing radiation is considered as the largest contributor to the collective effective dose received by the world population. The human population is continuously exposed to ionizing radiation from several natural sources that can be classified into two broad categories: high-energy cosmic rays incident on the Earth’s atmosphere and releasing secondary radiation (cosmic contribution); and radioactive nuclides generated during the formation of the Earth and still present in the Earth’s crust (terrestrial contribution). Terrestrial radioactivity is mostly produced by the uranium and thorium radioactive families together with potassium. In most circumstances, radon, a noble gas produced in the radioactive decay of uranium, is the most important contributor to the total dose. This Atlas aims to present the current state of knowledge of natural radioactivity, by giving general background information, and describing its various sources. This reference material is complemented by a collection of maps of Europe displaying the levels of natural radioactivity caused by different sources. It is a compilation of contributions and reviews received from more than 80 experts in their field: they come from universities, research centres, national and European authorities and international organizations. This Atlas provides reference material and makes harmonized datasets available to the scientific community and national competent authorities. In parallel, this Atlas may serve as a tool for the public to: • familiarize itself with natural radioactivity; • be informed about the levels of natural radioactivity caused by different sources; • have a more balanced view of the annual dose received by the world population, to which natural radioactivity is the largest contributor; • and make direct comparisons between doses from natural sources of ionizing radiation and those from man-made (artificial) ones, hence to better understand the latter.JRC.G.10-Knowledge for Nuclear Security and Safet

European Atlas of Natural Radiation

Natural ionizing radiation is considered as the largest contributor to the collective effective dose received by the world population. The human population is continuously exposed to ionizing radiation from several natural sources that can be classified into two broad categories: high-energy cosmic rays incident on the Earth’s atmosphere and releasing secondary radiation (cosmic contribution); and radioactive nuclides generated during the formation of the Earth and still present in the Earth’s crust (terrestrial contribution). Terrestrial radioactivity is mostly produced by the uranium and thorium radioactive families together with potassium. In most circumstances, radon, a noble gas produced in the radioactive decay of uranium, is the most important contributor to the total dose.This Atlas aims to present the current state of knowledge of natural radioactivity, by giving general background information, and describing its various sources. This reference material is complemented by a collection of maps of Europe displaying the levels of natural radioactivity caused by different sources. It is a compilation of contributions and reviews received from more than 80 experts in their field: they come from universities, research centres, national and European authorities and international organizations.This Atlas provides reference material and makes harmonized datasets available to the scientific community and national competent authorities. In parallel, this Atlas may serve as a tool for the public to: • familiarize itself with natural radioactivity;• be informed about the levels of natural radioactivity caused by different sources;• have a more balanced view of the annual dose received by the world population, to which natural radioactivity is the largest contributor;• and make direct comparisons between doses from natural sources of ionizing radiation and those from man-made (artificial) ones, hence to better understand the latter.Additional information at: https://remon.jrc.ec.europa.eu/About/Atlas-of-Natural-Radiatio

Goal 16, Promuovere societ\ue0 pacifiche e inclusive per uno sviluppo sostenibile

Rapporto Lombardia \ue8 un prodotto editoriale realizzato a partire dal 2017 da PoliS-Lombardia ed \ue8 rivolto, in primo luogo, ai policy maker di Regione Lombardia e, pi\uf9 in generale, ai decisori dei settori politici, economici e sociali della Lombardia. Rapporto Lombardia, in particolare, si propone per essere uno strumento di analisi di contesto a supporto delle loro scelte. Per attuare le misure necessarie a raggiungere gli obiettivi di sostenibilit\ue0 economica, sociale e ambientale, l\u2019Agenda ONU 2030 riconosce un ruolo fondamentale alle qualit\ue0 delle istituzioni e alla capacit\ue0 delle stesse di mettere nelle condizioni i cittadini di esercitare i diritti soggettivi civili e politici quali la sicurezza, l\u2019accesso alle informazioni, la libert\ue0 di espressione, la partecipazione ai processi democratici. Molti dei Target del Goal 16 (Promuovere societ\ue0 pacifiche e inclusive per uno sviluppo sostenibile, garantire a tutti l\u2019accesso alla giustizia, e creare istituzioni efficaci, responsabili e inclusive a tutti i livelli) intercettano temi di stretta attualit\ue0 per Regione Lombardia quali, per esempio, il contrasto e la prevenzione ai fenomeni della corruzione che minano la fiducia dei cittadini nelle istituzioni democratiche e la lotta alle infiltrazioni della criminalit\ue0 organizzata nell\u2019economia e nelle societ\ue0 che minacciano il funzionamento di interi settori produttivi e sono in grado di condizionare le scelte degli amministratori locali e in ultima istanza l\u2019efficacia delle politiche pubbliche. Il capitolo 16, in particolare, si sofferma su alcuni fondamentali temi: Target 16.1 - Ridurre significativamente in ogni dove tutte le forme di violenza e i tassi di mortalit\ue0 connessi con un affondo specifico sulla criminalit\ue0 degli stranieri che rappresenta un fenomeno sempre pi\uf9 diffuso anche nel territorio regionale e in qualche modo alimenta la ridotta percezione di sicurezza dei cittadini lombardi; Target 16.2 - Eliminare l\u2019abuso, lo sfruttamento, il traffico e tutte le forme di violenza e tortura contro i bambini viene dato spazio alle esperienze virtuose presenti in regione di assistenza di minori vittime di abuso, un fenomeno che \ue8 ancora poco conosciuto;Target 16.4 - Ridurre in maniera significativa il finanziamento illecito e il traffico di armi, potenziare il recupero e la restituzione dei beni rubati e combattere tutte le forme di crimine organizzato; Target 16.5 - Ridurre sensibilmente la corruzione e gli abusi di potere in tutte le loro forme in considerazione degli allarmi ripetutamente lanciati sulla permeabilit\ue0 della pubblica amministrazione locale e regionale alla corruzione, i cui confini e la cui dimensione sfuggono ancora a una chiara definizione vista anche la difficolt\ue0 a catturare il fenomeno; Target 16.6 - Sviluppare istituzioni efficaci, responsabili e trasparenti a tutti i livelli. Il Goal 16 ha natura trasversale alle tre aree in cui si articola l\u2019Agenda ONU (sociale, economica, ambientale) in quanto riconosce la centralit\ue0 delle qualit\ue0 delle istituzioni e l\u2019importanza del riconoscimento di alcuni diritti politici

DataSheet_2_NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential.xlsx

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL.</p

DataSheet_1_NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential.pdf

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL.</p

Chapter 5: Radon

Natural ionising radiation is considered the largest contributor to the collective effective dose received by the world’s population. Man is continuously exposed to ionising radiation from several sources that can be grouped into two categories: first, high-energy cosmic rays incident on the Earth’s atmosphere and releasing secondary radiation (cosmic contribution); and, second, radioactive nuclides generated when the Earth was formed and still present in its crust (terrestrial contribution). Terrestrial radioactivity is mostly produced by the uranium (U) and thorium (Th) radioactive families together with potassium (40K), a long-lived radioactive isotope of the elemental potassium. In most cases, radon (222Rn), a noble gas produced by radioactive decay of the 238U progeny, is the major contributor to the total dose. This European Atlas of Natural Radiation has been conceived and developed as a tool for the public to become familiar with natural radioactivity; be informed about the levels of such radioactivity caused by different sources; and have a more balanced view of the annual dose received by the world’s population, to which natural radioactivity is the largest contributor. At the same time, it provides reference material and generates harmonised data, both for the scientific community and national competent authorities. Intended as an encyclopaedia of natural radioactivity, the Atlas describes the different sources of such radioactivity, cosmic and terrestrial, and represents the state-of-the art of this topic. In parallel, it contains a collection of maps of Europe showing the levels of natural sources of radiation. This work unfolds as a sequence of chapters: the rationale behind; some necessary background information; terrestrial radionuclides; radon; radionuclides in water and river sediments; radionuclides in food; cosmic radiation and cosmogenic radionuclides. The final chapter delivers the overall goal of the Atlas: a population-weighted average of the annual effective dose due to natural sources of radon, estimated for each European country as well as for all of them together, giving, therefore, an overall European estimate. As a complement, this introductory chapter offers an overview of the legal basis and requirements on protecting the public from exposure to natural radiation sources. In Europe, radiation has a long tradition. Based on the Euratom Treaty, the European Atomic Energy Community early established a set of legislation for protecting the public against dangers arising from artificial ('man-made') ionising radiation, but this scope has since been extended to include natural radiation. Indeed, the recently modernised and consolidated Basic Safety Standards Directive from 2013 contains detailed provisions on the protection from all natural radiation sources, including radon, cosmic rays, natural radionuclides in building material, and naturally occurring radioactive material