Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy·s −1 ). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy·s −1 ) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.ultra-high dose-rate irradiation | cognitive dysfunction | neuronal morphology | neuroinflammation | reactive oxygen species R adiation therapy (RT) remains an essential part of cancer treatment, and, today, the benefit of RT would increase dramatically if normal tissues surrounding the tumor could tolerate higher doses of radiation (1-3). In the last decade, major advances in high-precision treatment delivery and multimodal imaging have improved tolerance to RT (4), but the selective protection of normal tissue remains a significant clinical challenge and the radiation-induced toxicities still adversely impact the patient's quality of life. This latter fact largely remains an unmet medical need, and points to the urgency of developing improved RT modalities for combating those cancers refractory to treatment.This issue is especially critical for those afflicted with brain tumors, including glioblastoma multiforme (GBM), for which standard treatment consists of surgical resection followed by RT and concomitant chemotherapy (temozolomide). Typical radiotherapeutic protocols for GBM induce neurocognitive complications, including impairments in learning and memory, attention, and executive function and a variety of mood disorders (5-8). A breadth of past work from our laboratories has linked adverse neurocognitive outcomes following cranial irradiation to a range of neuropathologies, including reductions in dendritic complexity and spine density (9-12), reductions in microvascular density (13-15), reduced myelination and synapse density, and increased neuroinflammation (16,17). These changes are persistent and problematic in the conventionally irradiated brain and have prompted efforts to more fully develop a truly innovative approach to RT, where we have concept...

The ligand 2,6-bis( 1 '-ethyl-5'-methylbenzimidazol-2'-yl)pyridine ( L5) reacts with lanthanide perchlorate in acetonitrile to give the mononuclear triple-helical complexes [Ln( L5),I3+ (Ln = Eu, Gd or Tb). The crystal structure of [Eu( L5),] [ClO4],*4MeCN has been determined, which shows three unco-ordinated perchlorate anions and an [Eu( L5),I3+ cation where the three tridentate ligands are wrapped around a pseudo-C, axis. The co-ordination sphere around Eu"' may be best described as a slightly distorted trigonal-tricapped prism where the six benzimidazole nitrogen atoms occupy the vertices of the prism and the three pyridine nitrogen atoms occupy the capping positions. A detailed geometrical analysis showed that the ethyl groups in L5 produce a slide of the strands which is responsible for the distortion of the triple-helical structure as exemplified by the low symmetry for the Eu"' site in the luminescence spectra of [ Eu( L5),I3+. Proton N M R spectra in acetonitrile indicate that the triple-helical structure is maintained for [Ln(Li),I3+ {Ln = Eu or Tb; L = 2,6-bis(l '-R-benzimidazol-2'-yl)pyridine [R = Me L'. Et Lz. Pr L3 or CH,C,H,(OMe),-3,5 L4] or L5} on the N M R time-scale, but the stability of the complexes together with the structural arrangement of the ligands depend on the size of the substituents bound to the benzimidazole nitrogen atoms. Photophysical studies of [ Eu( Li),I3+ show that these steric effects affect the quantum yield in solution and that methyl groups bound to the 5 positions of the benzimidazole rings in L5 shift the n d n * transitions centred on the ligand, but do not strongly modify the emission properties of [Eu( L5),I3+. Extended Huckel calculations give a qualitative insight into the factor controlling the n -n* transitions of the ligands and complexes.The development of stable luminescent lanthanide complexes is a subject of increasing interest mainly due to their potential uses as fluorescent sensors in natural,' medical,2 analytical and bioinorganic sciences, and probes based on Eu"' and Tb"' are of special interest because of the particularly suitable spectroscopic properties of these ions. To obtain strongly luminescent complexes, the lanthanide metal ion should be bound to chromophoric ligands which are able (i) to absorb energy and then transfer it efficiently to the cation and (ii) to protect the lanthanide ion from external interactions which usually quench the luminescen~e.~,~ Macrocyclic, macrobicyclic ' or podand-type ligands containing heterocyclic aromatic donor groups have been extensively used for this purpose, but it has been shown recently that much simpler linear oligo-multidentate ligands, such as L' or L8, selfassemble with Ln"' to produce stable mono-" and di-nuclear " triple-stranded helicates which possess well defined and protected metallic sites. In these molecular light-conversion devices the Ln"' ions are co-ordinated by nine nitrogen atoms in a pseudo-tricapped trigonal-prismatic arrangement leading to a pseudo-D, symmetry for the cations [Eu(L1),...

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Migration of radionuclides in soils and their transfer to edible plants are usually estimated using volume-averaged bulk concentrations. However, radionuclides might not be homogeneously distributed in soils due to heterogeneous water flow and solute transport. One important cause of heterogeneous transport is preferential flow. The aim of this study was to investigate the spatial distribution of radionuclides in the soil in relation to preferential flow paths and to assess the possible consequences for their transfer from soil to plants. We identified the preferential flow paths in a forest soil by staining them with a blue dye, and we compared radionuclide activity in samples from the stained preferential flow paths with those from the unstained soil matrix. The activities of the atmospherically deposited radionuclides 137 Cs, 210 Pb, 239,240 Pu, 238 Pu, and 241 Am were enriched in the preferential flow paths by a factor of up to 3.5. Despite their different depositional histories, the distribution of the radionuclides between preferential flow paths and matrix was similar. Our findings indicate increased transport of radionuclides through the preferential flow paths, representing a possible risk of groundwater contamination. Furthermore, enrichment of radionuclides in the preferential flow paths might influence the uptake by plants. The heterogeneous radionuclide distribution in the soil and the more intense rooting in the preferential flow paths can be incorporated into soil-to-plant transfer models. Taking the correlated radionuclide and root distribution between the two flow regions into account provides a more physical and biological basis for the calculation of plant activities with transfer models than using the homogeneously mixed bulk soil activities as input parameters.