The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.

Hybrid QM(CASPT2//CASSCF/6-31G*)/MM(Amber) computations have been used to map the photoisomerization path of the retinal chromophore in Rhodopsin and explore the reasons behind the photoactivity efficiency and spectral control in the visual pigments. It is shown that while the electrostatic environment plays a central role in properly tuning the optical properties of the chromophore, it is also critical in biasing the ultrafast photochemical event: it controls the slope of the photoisomerization channel as well as the accessibility of the S(1)/S(0) crossing space triggering the ultrafast decay. The roles of the E113 counterion, the E181 residue, and the other amino acids of the protein pocket are explicitly analyzed: it appears that counterion quenching by the protein environment plays a key role in setting up the chromophore's optical properties and its photochemical efficiency. A unified scenario is presented that discloses the relationship between spectroscopic and mechanistic properties in rhodopsins and allows us to draw a solid mechanism for spectral tuning in color vision pigments: a tunable counterion shielding appears as the elective mechanism for L<-->M spectral modulation, while a retinal conformational control must dictate S absorption. Finally, it is suggested that this model may contribute to shed new light into mutations-related vision deficiencies that opens innovative perspectives for experimental biomolecular investigations in this field.

Energies and structures of different arrangements of the stacked adenine homodimer have been computed at the ab initio CASPT2 level of theory in isolation and in an aqueous environment. Adenine dimers are shown to form excimer singlet states with different degrees of stacking and interaction. A model for a 2-fold decay dynamics of adenine oligomers can be supported in which, after initial excitation in the middle UV range, unstacked or slightly stacked pairs of nucleobases will relax by an ultrafast internal conversion to the ground state, localizing the excitation in the monomer and through the corresponding conical intersection with the ground state. On the other hand, long-lifetime intrastrand stacked excimer singlet states will be formed in different conformations, including neutral and charge transfer dimers, which originate the red-shifted emission observed in the oligonucleotide chains and that will evolve toward the same monomer decay channel after surmounting an energy barrier. By computing the transient absorption spectra for the different structures considered and their relative stability in vacuo and in water, it is concluded that in the adenine homodimers the maximum-overlap face-to-face orientations are the most stable excimer conformations observed in experiment.

Based on CASPT2 results, the present contribution establishes for the first time that cytosine photodimer formation (C< >C) is mediated along the triplet and singlet manifold by a singlet-triplet crossing, (T1/S0)X, and by a conical intersection, (S1/S0)CI, respectively. The former can be accessed in a barrierless way from a great variety of photochemical avenues and exhibits a covalent single bond between the ethene C6-C6' carbon atoms of each monomer. The efficiency of the stepwise triplet mechanism, however, would be modulated by the effectiveness of the intersystem crossing mechanism. The results provide the grounds for the understanding of the potential photogenotoxicity of endogenous and exogenous compounds via triplet-triplet sensitization, with a lower bound for cytosine oligonucleotides predicted to be 2.70 eV, and give support to the traditional view of the primary role of triplet excited states in the photochemistry of DNA, a well-known source of photoproducts in solution under triplet photosensitization conditions. The function played by singlet excimers (excited dimers) to explain both the red-shifted fluorescence and photoreaction is highlighted. A rationale on the pronounced wavelength dependence of the observed fluorescence is offered. Geometrical arrangements at the time of light irradiation close to, but energetically above, (S1/S0)CI are suggested as reactive orientations that become prone to produce C< >C directly, with no energy barrier. Because of the outstanding intrinsic ability of cytosine to form stable relaxed excimers, the system located near the bound relaxed excimer has to accumulate enough vibrational energy to surmount a small barrier of 0.2 eV to reach (S1/S0)CI, making the overall process to proceed at a slower relative rate as compared to other compounds such as thymine, which is not susceptible of forming so stable excimers.

Highlights Low levels of physical activity are a risk factor associated with Alzheimer's disease. Older adults who exercise are more likely to maintain cognition. Exercise modulates amyloid β turnover, inflammation, synthesis, and release of neurotrophins, and cerebral blood flow.

Circulating oxidative damage biomarkers, such as MDA and protein carbonylation, are related to frailty and not to age or sex. These parameters may be considered as potential biomarkers of frailty in the context of a multidisciplinary health-promoting approach for older adults.

Alterations in muscle play an important role in common diseases and conditions. Reactive oxygen species (ROS) are generated during hindlimb unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of this study was to determine the mechanism by which XO activation causes unloading-induced muscle atrophy in rats, and its possible prevention by allopurinol, a well-known inhibitor of this enzyme. For this purpose we studied one of the main redox sensitive signalling cascades involved in skeletal muscle atrophy i.e. p38 MAPKinase, and the expression of two well known muscle specific E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFbx; also known as atrogin-1) and Muscle RING (Really Interesting New Gene) Finger-1 (MuRF-1). We found that hindlimb unloading induced a significant increase in XO activity and in the protein expression of the antioxidant enzymes CuZnSOD and Catalase in skeletal muscle. The most relevant new fact reported in this paper is that inhibition of XO with allopurinol, a drug widely used in clinical practice, prevents soleus muscle atrophy by ∼20% after hindlimb unloading. This was associated with the inhibition of the p38 MAPK-MAFbx pathway. Our data suggest that XO was involved in the loss of muscle mass via the activation of the p38MAPK-MAFbx pathway in unloaded muscle atrophy. Thus, allopurinol may have clinical benefits to combat skeletal muscle atrophy in bedridden, astronauts, sarcopenic, and cachexic patients.

By using the multiconfigurational second-order perturbation method CASPT2, including corrections for the basis set superposition error, the lowest-singlet excited state of the face-to-face pi-stacked cytosine homodimer is revealed to be bound by about half an eV, being the source of an emissive feature consistent with the observed redshifted fluorescence.