NEPTUNE (Nuclear process-driven Enhancement of Proton Therapy UNravEled)

Protontherapy is an important radiation modality that has been used to treat cancer for over 60 years. In the last 10 years, clinical proton therapy has been rapidly growing with more than 80 facilities worldwide [1]. The interest in proton therapy stems from the physical properties of protons allowing for a much improved dose shaping around the target and greater healthy tissue sparing. One shortcoming of protontherapy is its inability to treat radioresistant cancers, being protons radiobiologically almost as effective as photons. Heavier particles, such as 12C ions, can overcome radioresistance but they present radiobiological and economic issues that hamper their widespread adoption. Therefore, many strategies have been designed to increase the biological effectiveness of proton beams. Examples are chemical radiosensitizing agents or, more recently, metallic nanoparticles. The goal of this project is to investigate the use of nuclear reactions triggered by protons generating short-range high- LET alpha particles inside the tumours, thereby allowing a highly localized DNA-damaging action. Specifically, we intend to consolidate and explain the promising results recently published in [2], where a significant enhancement of biological effectiveness was achieved by the p-11B reaction. Clinically relevant binary approaches were first proposed with Boron Neutron Capture Therapy (BNCT), which exploits thermal neutron capture in 10B, suitably accumulated into tumour before irradiation. The radiosensitising effects due to the presence of 10B will be compared to those elicited by p-11B, using the same carrier and relating the observed effects with intracellular 11B and 10B distribution as well as modelled particle action and measured dose deposition at the micro/nanometer scale. Moreover, the p-19F reaction, which also generates secondary particles potentially leading to local enhancement of proton effectiveness, will be investigated. The in-vivo imaging of 11B and 19F carriers will be studied, in particular by optimizing 19F-based magnetic resonance

Branched Poly(ethylene imine)s as Anti‐algal and Anti‐cyanobacterial Agents with Selective Flocculation Behavior to Cyanobacteria over Algae

Poly(ethylene imine)s (PEIs) have been widely studied for biomedical applications, including antimicrobial agents against potential human pathogens. The interactions of branched PEIs (B‐PEIs) with environmentally relevant microorganisms whose uncontrolled growth in natural or engineered environments causes health, economic, and technical issues in many sectors of water management are studied. B‐PEIs are shown to be potent antimicrobials effective in controlling the growth of environmentally relevant algae and cyanobacteria with dual‐functionality and selectivity. Not only did they effectively inhibit growth of both algae and cyanobacteria, mostly without causing cell death (static activity), but they also selectively flocculated cyanobacteria over algae. Thus, unmodified B‐PEIs provide a cost‐effective and chemically facile framework for the further development of effective and selective antimicrobial agents useful for control of growth and separation of algae and cyanobacteria in natural or engineered environments.Poly(ethylene imine)s (B‐PEIs) are shown as effective antimicrobial agents against environmentally relevant microorganisms (algae CR – Chlamydomonas reinhardtii, cyanobacterium SE – Synechococcus elongatus). B‐PEIs have dual‐functionalities and can 1) inhibit growth of both algae and cyanobacteria and 2) selectively flocculate cyanobacteria over algae. These molecules provide a cost‐effective and chemically facile framework for the further development of selective anti‐algal and anti‐cyanobacterial agents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146449/1/mabi201800187_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146449/2/mabi201800187.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146449/3/mabi201800187-sup-0001-SupMat.pd

The Last Trees Standing: Climate modulates tree survival factors during a prolonged bark beetle outbreak in Europe

Plant traits are an expression of strategic tradeoffs in plant performance that determine variation in allocation of finite resources to alternate physiological functions. Climate factors interact with plant traits to mediate tree survival. This study investigated survival dynamics in Norway spruce (Picea abies) in relation to tree-level morphological traits during a prolonged multi-year outbreak of the bark beetle, Ips typographus, in Central Europe. We acquired datasets describing the trait attributes of individual spruce using remote sensing and field surveys. We used nonlinear regression in a hypothesis-driven framework to quantify survival probability as a function of tree size, crown morphology, intraspecific competition and a growing season water balance. Extant spruce trees that persisted through the outbreak were spatially clustered, suggesting that survival was a nonrandom process. Larger diameter trees were more susceptible to bark beetles, reflecting either life history tradeoffs or a dynamic interaction between defense capacity and insect aggregation behavior. Competition had a strong negative effect on survival, presumably through resource limitation. Trees with more extensive crowns were buffered against bark beetles, ostensibly by a more robust photosynthetic capability and greater carbon reserves. The outbreak spanned a warming trend and conditions of anomalous aridity. Sustained water limitation during this period amplified the consequences of other factors, rendering even smaller trees vulnerable to colonization by insects. Our results are in agreement with prior research indicating that climate change has the potential to intensify bark beetle activity. However, forest outcomes will depend on complex cross-scale interactions between global climate trends and tree-level trait factors, as well as feedback effects associated with landscape patterns of stand structural diversity

Tumor promoting properties of a cigarette smoke prevalent polycyclic aromatic hydrocarbon as indicated by the inhibition of gap junctional intercellular communication via phosphatidylcholine-specific phospholipase C

Inhibition of gap junctional intercellular communication (GJIC) and the activation of intracellular mitogenic pathways are common hallmarks of epithelial derived cancer cells. We previously determined that the 1-methyl and not the 2-methyl isomer of anthracene, which are prominent cigarette smoke components, activated extracellular receptor kinase, and inhibited GJIC in WB-F344 rat liver epithelial cells. Using these same cells, we show that an immediate upstream response to 1-methylanthracene was a rapid ( LT 1 min) release of arachidonic acid. Inhibition of phosphatidylcholine-specific phospholipase C prevented the inhibition of GJIC by 1-methylanthracene. In contrast, inhibition of phosphatidylinositol specific phospholipase C, phospholipase A(2), diacylglycerol lipase, phospholipase D, protein kinase C, and tyrosine protein kinases had no effect on 1-methylanthracene-induced inhibition of GJIC. Inhibition of protein kinase A also prevented inhibition of GJIC by 1-methylanthracene. Direct measurement of phosphatidylcholine-specific phospholipase C and sphingomyelinase indicated that only phosphatidylcholine-specific phospholipase C was activated in response to 1-methylanthracene, while 2-methylanthracene had no effect. 1-methylanthracene also activated p38-mitogen activated protein kinase; however, like extracellular kinase, its activation was not involved in 1-methylanthracene-induced regulation of GJIC, and this activation was independent of phosphatidylcholine-specific phospholipase C. Although mitogen activated protein kinases were activated, Western blot analyzes indicated no change in connexin43 phosphorylation status. Our results indicate that phosphatidylcholine-specific phospholipase C is an important enzyme in the induction of a tumorigenic phenotype, namely the inhibition of GJIC; whereas mitogen activated protein kinases triggered in response to 1-methylanthracene, were not involved in the deregulation of GJIC

ELIXIR and Toxicology: a community in development [version 2; peer review: 2 approved]

Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology, and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities